Use of indole, 6- and 7-azaindole derivatives as inhibitors of ferroptosis-regulated cell death

Abstract

The present invention relates to compounds of the following general formula (I) as agents for inhibiting ferroptosis: [Formula 1] TIFF2024506530000104.tif25140 or a pharma- ceutically acceptable salt and / or solvate thereof.

Description

[Technical field]

[0001] The present invention relates to compounds for use as agents for inhibiting ferroptosis, more particularly to compounds for preventing and / or treating disorders associated with ferroptosis. [Background technology]

[0002] Ferroptosis is a new type of non-apoptotic regulated cell death that was first described in 2012 and is usually associated with high intracellular levels of free iron and lipid peroxidation. This death pathway is directly linked to the ability of cells to control their own internal oxidative stress, particularly through the activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). Failure of glutathione-dependent antioxidant defenses leads to the oxidative death of cells, particularly Fe, via the Fenton reaction. 2+ This is due to lipid peroxidation by oxidants, which causes the accumulation of lipid-based reactive oxygen species (ROS), thereby leading to membrane damage and cell death.

[0003] Recent studies have shown that ferroptosis is involved in the pathophysiology of numerous human diseases [Li et al., Cell Death Dis., 2020, 11(88); Tang et al., Cell Research, 2021, 31:107-125; Sun et al., Biomed. Pharmacother., 2020, 127, 110108], affecting the heart, brain, eyes, liver, skin, kidneys, lungs, intestines, or the whole body. Ferroptosis involves three major metabolisms, including thiols, lipids, and iron, which lead to the occurrence of iron-dependent lipid peroxidation and ultimately cell death.

[0004] The hallmarks of ferroptosis have been used as key elements to define ferroptosis-related disease biomarkers. Ferroptosis is an iron-dependent, controlled tissue necrosis mainly driven by uncontrolled lipid peroxidation and subsequent membrane damage. Alterations in physiological levels of the following components have been reported as associated with ferroptosis: iron, reactive oxygen species (ROS) (including lipid ROS such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), as well as oxidized phosphatidylethanolamine (oxPE) species followed by oxidized phosphatidylserine (oxPS) and oxidized phosphatidylinositol (oxPI) [Wiernicki et al., Cell Death Dis., 2020, 11(922)]), as well as related peroxide detoxifying molecules (including the thiol-containing compound glutathione GSH, or coenzyme Q10, also known as ubiquinone), and long-chain fatty acid-CoA ligase 4 (ACSL4) [Chen X. et al., Front. in Cell and Dev. Biol., 2021, 9(637162)]. These key biochemical ferroptosis biomarkers can be measured and quantified by assays in body fluids (blood, plasma, serum, urine, cerebrospinal fluid) or highlighted by immunohistochemical labeling on biopsies of injured tissue.

[0005] Depending on both the pathology and the injured organ, some of the ferroptosis-related biomarkers may change in amount and / or activity (increase> or decrease<) relative to normal physiological thresholds. Here, only reference values ​​are given for serum. (1) Iron metabolism (measured by serum iron and ferritin levels) exceeds physiological thresholds (serum iron >180 μg / dL in males and >160 μg / dL in females [Pagana et al., Mosby's Diagnostic and Laboratory Test Reference-Elsevier eBook on Vital Source, 14th Edition, Elsevier, 2019, ISBN: 9780323609678] and ferritin >300 ng / mL in males and >200 ng / mL in females [Wang et al., Biochim Biophy. Acta, 2010, 1800(8):760-769]). (2) Glutathione redox status (by measuring reduced glutathione (GSH) and oxidized glutathione (GSSG) in plasma and glutathione peroxidase activity (GPx) using ELISA) (GSH < 717 μmol / L, GSSG > 5.32 μmol / L, GSH / GSSG ratio < 156, GPx < 20 UI / gHb in men and < 26 UI / gHb in women) [Haleng J. et al., Rev. Med. Liege, 2007]). (3) oxidative stress (by measuring plasma levels of total Q10 and reduced, active Q10 (Q10H2)) (Q10 < 3.44 μmol / L and Q10H2 < 3.04 μmol / L in men and Q10 < 1.88 μmol / L and Q10H2 < 1.64 μmol / L in women [Kaikkonen et al., Scand J Clin Lab Invest, 1999, 59:457-466]). (4) lipid peroxidation (measured by detection of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) adducts) exceeds physiological thresholds (4-HNE >10 μmol / L [Chen and Niki, IUBMB Life, 2008, 58(372-373)] and MDA >3 μmol / L using the thiobarbituric acid method [Banjare et al., J. Sci. Soc., 2017; 44(137-9)]).

[0006] It is noted here that upregulation of ACSL4 enzyme levels in injured organ tissues was also previously reported as a putative biomarker of ferroptosis (ACSL4 expression can be monitored by transcriptomic and proteomic approaches).

[0007] Pathologies associated with ferroptosis that affect the heart include, among others [Li et al., Free Radic. Biol. Med., 2020, 160, 303-318; Qin et al., Biomed. Pharmacother., 2021, 141, 111872], myocardial ischemia-reperfusion injury, particularly after arterial ligation, and cardiomyopathies, particularly doxorubicin-induced cardiomyopathy [Li et al., 2020].

[0008] Pathologies related to ferroptosis that affect the brain include stroke, especially ischemic stroke [Li et al., 2020] or hemorrhagic stroke [Li et al., JCI Insight, 2017, 2(7): e90777], traumatic brain injury [Xie et al., CNS Neurosci Ther., 2019, 25: 465-475], contusion spinal cord injury [Zhang et al., Neural Regen. Res., 2019, 14(3): 532], as well as neurodegenerative disorders, specifically chronic neurodegenerative disorders, more specifically Alzheimer's disease [Li et al., 2020], Huntington's disease [Mi et al., Neuromolecular Med., 2019, 21, 110-119], Parkinson's disease [Do Van et al., Neurobiol Dis.,2016,94:169-78], amyotrophic lateral sclerosis (Charcot disease) [Li et al.,2020], Friedreich's ataxia [Cotticelli et al.,J Pharmacol Exp Ther.,2019,369(1):47-54], periventricular leukomalacia [Skouta et al.,J.Am.Chem.Soc.,2014,136,4551-4556], and dementia, which may be associated with one or several of the aforementioned conditions.

[0009] Pathologies associated with ferroptosis that affect the eye include retinal disorders, particularly Stargardt disease, and age-related macular degeneration (AMD), specifically dry AMD [Sun et al., Invest Ophth Vis Sci., 2018, 59(9), 2482; Chen et al., J. Biol. Chem., 2021, 296, 100187].

[0010] Ferroptosis-related pathologies that affect the liver include chronic liver disease and acute liver failure. Notable chronic liver diseases include nonalcoholic steatohepatitis (NASH) [Qi et al., Am J Pathol., 2020, 190(1)], chronic infections such as hepatitis B and C [Cappelletti et al., Int J Mol Sci., 2020, 21(14)], and alcoholic liver disease [Zhou et al., Hepatol Commun., 2019, 3(5)]. Acute liver failure can be due in particular to drug-induced liver injury (DILI), such as acetaminophen (APAP)-induced liver injury [Yamada et al., Cell Death Dis., 2020, 11(2)], or to ischemia-reperfusion injury induced by septic or hemorrhagic shock [Friedmann Angeli et al., Nat Cell Biol., 2014, 16(12):1180-91].

[0011] Pathologies associated with ferroptosis that affect the skin include cutaneous inflammatory diseases, such as psoriasis [Li et al., Cell Death Dis., 2020, 11(88)], and toxic epidermal necrolysis (Lyell's syndrome) [Zhang et al., J Invest Dermatol., 2020, 140(7), S79].

[0012] Pathologies associated with ferroptosis that affect the kidney include acute kidney injury (AKI), e.g., crystal (oxalate)-induced AKI, folic acid (FA)-induced AKI [Martin-Sanchez et al., 2017], and cisplatin-induced AKI [Deng et al., J Clin Invest., 2019, 129(11); Mishima et al., J Am Soc Nephrol., 2020, 31(2); Hu et al., Cell Death Dis., 2020, 11(1)], renal ischemia-reperfusion injury [Li et al., 2020], and acute tubular necrosis [Friedmann Angeli et al., 2014].

[0013] Pathologies related to ferroptosis that affect the lung include chronic obstructive pulmonary disease (COPD) [Yoshida et al., Nat Commun., 2019, 10, 3145], bronchial asthma [Tao et al., Oxid Med Cell Longev., 2020], lung damage caused by bacterial infections, especially those caused by Pseudomonas aeruginosa [Dar et al., J Clin Invest., 2018, 128(10), 4639-4653] or Mycobacterium tuberculosis [Amaral et al., J Exp Med., 2019, 216(3):556-570], as well as pulmonary fibrosis, e.g. radiation-induced pulmonary fibrosis (RILF) [Li et al., J Inflamm., 2019, 16:11] and paraquat-induced lung injury [Rashidipour et al., J Inflamm., 2019, 16:11]. al., Toxicology, 2020, 433-434:152407].

[0014] Pathologies associated with ferroptosis that affect the intestine include necrotizing enterocolitis [Subramanian et al., Acta Physiologica Sinica, 2020, 72(3)] and inflammatory bowel diseases, such as Crohn's disease [Mayr et al., Nat Commun., 2020, 11(1)].

[0015] Pathological conditions related to ferroptosis that affect the whole body include hemochromatosis [Imoto et al., Transfus Apher Sci., 2018, 57(4), 524-531], hemolytic disorders [Youssef et al., 2019, Ferroptosis in Hemolytic Disorders. In: Tang D. (eds) Ferroptosis in Health and Disease. Springer, Cham.], cytokine storm during viral infections [Edeas et al., Int J Infect Dis., 2020, 97; Yang and Lai, Cell Death Discov., 2020, 6], radiation-induced necrosis [Wu et al., Front Oncol., 2020, 10], and rheumatoid arthritis [Xie et al. al.,Inflammation.,2020,doi:10.1007 / s10753-020-01338-2], type I diabetes [Bruni et al.,Cell Transplant.,2018,27(6)], obesity-related insulin resistance, epilepsy including mitochondrial disease-related epilepsy and intractable epilepsy [Kahn-Kirby et al.,PLoS One.,2019,14(3), as well as pathologies associated with stress-induced premature tissue aging, such as atherosclerosis [Bai et al.,Free Radic Biol Med.,2020,160], hypertension [Yang et al.,Clin Exp Hypertens.,2020,42(8)], and type II diabetes [Li et al.,Nutrients.,2020,12(10)]. Summary of the Invention

[0016] Therefore, inhibition of ferroptosis is a new and attractive therapeutic strategy for the above-mentioned diseases.

[0017] There is a need for new ferroptosis inhibitors with high potency, good stability and low toxicity.

[0018] The present inventors have discovered new inhibitors of ferroptosis-regulated cell death, which prove to be highly attractive for the prevention and / or treatment of ferroptosis-related disorders.

[0019] Thus, the present invention provides a compound of the following general formula (I) for use as an agent for inhibiting ferroptosis: [ka] or a pharma- ceutical acceptable salt and / or solvate thereof, In the above formula, [ka] teeth [ka] and (i) [ka] but [ka] when X is N, Y is N(R2) and Z is C(H); (ii) [ka] but [ka] When -X is N(R1), -Y is N or N + (O - ) and Z is C(R3), or Y is CH and Z is N, or Y and Z are CH; R1 and R2 are each independently a hydrogen atom, CN, NO2, OR7, SR8, NR9R10 , C(O)R 11 , CO2R 12 , O.C.(O)R 13 , N.R. 14 C(O)R 15 , C(O)NR 16 R 17 , S(O)R S , SO2R S ', (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl groups, wherein the aforementioned aryl or heterocyclyl groups are not selected from halogen atoms, CN, NO2, OR 18 , S.R. 19 , N.R. 20 R 21 , C(O)R 22 , CO2R 23 , O.C.(O)R 24 , N.R. 25 C(O)R 26 , C(O)NR 27 R 28 , (C1-C6) alkyl, and (C1-C6) haloalkyl; R3, R4, R 4b and R5 are each independently a hydrogen atom, a halogen atom, CN, OR 29 , S.R. 30 , N.R. 31 R 32 , C(O)R 33 , CO2R 34 , O.C.(O)R 35 , N.R. 36 C(O)R 37 , C(O)NR 38 R 39 , (C1-C6) alkyl, or (C1-C6) haloalkyl group, wherein the alkyl or haloalkyl group is selected from the group consisting of OR 40 , S.R. 41 and N.R. 42 R 43 or R3, R4, R 4band R5 each independently represent an aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl group, wherein the aryl or heterocyclyl group is selected from the group consisting of halogen atoms, CN, NO2, OR, 44 , S.R. 45 , N.R. 46 R 47 , C(O)R 48 , CO2R 49 , O.C.(O)R 50 , N.R. 51 C(O)R 52 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl; R6 represents a hydrogen atom, a (C1-C6)alkyl or aryl-(C1-C6)alkyl group or a (C1-C6)alkylcarbonyl group optionally substituted by one or more substituents selected from the group consisting of OH, SH, NH2, (C1-C6)alkoxy, (C1-C6)thioalkoxy, (C1-C6)alkylamino and di((C1-C6)alkyl)amino groups, ·R S and R S ' each independently represent a (C1-C6) alkyl, aryl, or aryl-(C1-C6) alkyl group; R7~R 10 , R 12 , R 14 , and R 16 ~R 17 represent, independently of each other, a hydrogen atom, a (C1-C6) alkyl, aryl, or aryl-(C1-C6) alkyl group, ·R 11 , R 13 , and R 15 represent, independently of each other, a hydrogen atom, a (C1-C6)alkyl, an aryl, an aryl-(C1-C6)alkyl, a (C1-C6)alkoxy, a (C1-C6)alkylamino, or a di((C1-C6)alkyl)amino group; ·R18 From R 28 represent, independently of each other, a hydrogen atom, a (C1-C6) alkyl, or an aryl group; ·R 29 From R 39 are each independently a hydrogen atom, a (C1-C6) alkyl, an aryl, or an aryl-(C1-C6) alkyl group, the aryl group being not limited to a halogen atom, CN, NO2, OR 55 , S.R. 56 , N.R. 57 R 58 , C(O)R 59 , CO2R 60 , O.C.(O)R 61 , N.R. 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6) alkyl, and (C1-C6) haloalkyl; ·R 40 From R 43 represent, independently of each other, a hydrogen atom or a (C1-C6) alkyl group, ·R 44 From R 54 represent, independently of each other, a hydrogen atom, a (C1-C6) alkyl, or an aryl group; ·R 55 From R 65 represent, independently of each other, a hydrogen atom, a (C1-C6) alkyl, or an aryl group.

[0020] For the purposes of the present invention, the term "pharmaceutical acceptable" is intended to mean what is useful in the preparation of pharmaceutical compositions for pharmaceutical use, and what is generally safe and non-toxic.

[0021] The term "pharmaceutical acceptable salts or solvates" is intended to mean, in the framework of the present invention, salts or solvates of compounds which are pharmaceutical acceptable as defined above and which possess the pharmacological activity of the corresponding compounds.

[0022] Pharmaceutically acceptable salts include the following: (1) Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and trifluoroacetic acid; and (2) Base addition salts, which are formed when an acid proton present in a compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or is coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0023] Acceptable solvates for therapeutic use of the compounds of the invention include conventional solvates, such as those formed during the final steps of the preparation of the compounds of the invention due to the presence of solvents.

[0024] The term "halogen" as used herein refers to an atom of fluorine, bromine, chlorine, or iodine.

[0025] The term "(C1-C6) alkyl" as used herein refers to a straight or branched saturated hydrocarbon chain containing from 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0026] The term "(C1-C6) haloalkyl" as used herein refers to a (C1-C6) alkyl group as defined above, in which some or all hydrogen atoms are replaced by halogen atoms as defined above. This means that the (C1-C6) alkyl group is replaced by at least one halogen atom. This group can be, for example, a trifluoromethyl group.

[0027] The term "aryl", as used herein, refers to an aromatic hydrocarbon group preferably containing from 6 to 10 carbon atoms and containing one or more, in particular one or two, fused rings, advantageously a phenyl group, such as a phenyl or naphthyl group.

[0028] The term "heterocycle", as used herein, refers to a saturated, unsaturated (i.e. not aromatic) or aromatic monocyclic or bicyclic group, including bicyclic fused, bridged or spiro rings, preferably fused rings, advantageously containing from 5 to 10, especially 5 or 6 atoms in each ring, in which the ring atoms include one or more, advantageously from 1 to 3 heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms.

[0029] More specifically, the saturated heterocyclic group is a 5- or 6-membered saturated monocyclic heterocyclic group, such as a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydrothiophenyl group, a thiazolidinyl group, an isothiazolidinyl group, an oxazolidinyl group, an isoxazolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a triazolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, or a thiomorpholinyl group.

[0030] The unsaturated heterocyclic group is more specifically an unsaturated monocyclic or bicyclic heterocyclic group, each ring being a 5- or 6-membered ring, such as a pyrrolinyl, dihydrofuranyl, dihydrothiophenyl, thiazolinyl, isothiazolinyl, oxazolinyl, isoxazolinyl, imidazolinyl, pyrazolinyl, triazolinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyridazinyl, tetrahydropyridazinyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydrotriazinyl, tetrahydrotriazinyl, indolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl, 1,3-benzodioxolyl, 1,3-benzoxathiolyl, benzoxazolinyl, benzothiazolinyl, benzimidazolinyl, chromanyl, or chromenyl group.

[0031] Aromatic heterocyclic groups, also called heteroaryl groups, are more specifically aromatic monocyclic or bicyclic heterocyclic groups in which each ring contains a 5- or 6-membered ring, such as a pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl (such as 1,3,5-triazinyl), indolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl group.

[0032] The term "aryl-(C1-C6) alkyl" as used herein refers to an aryl group as defined above that is bonded to a molecule via a (C1-C6) alkyl group as defined above. Specifically, the -(C1-C6) alkyl-aryl group is a benzyl group.

[0033] The term "heterocyclyl-(C1-C6)alkyl" as used herein refers to a heterocyclyl group as defined above bonded to a molecule via a (C1-C6)alkyl group as defined above. Specifically, a -(C1-C6)alkyl-heterocyclyl group is a 5- or 6-membered saturated monocyclic heterocyclic group as defined above bonded to a molecule via a (C1-C6)alkyl group as defined above.

[0034] The term "(C1-C6) alkylcarbonyl" as used herein refers to a (C1-C6) alkyl group as defined above attached to a molecule via a -C(=O)- group, including, but not limited to, acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, and the like.

[0035] The term "(C1-C6)alkoxy" as used herein refers to a (C1-C6)alkyl group as defined above attached to a molecule via an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, n-hexoxy, and the like.

[0036] The term "(C1-C6)thioalkoxy" as used herein refers to a (C1-C6)alkyl group as defined above attached to a molecule via a sulfur atom, including, but not limited to, thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, isothiobutoxy, sec-thiobutoxy, t-thiobutoxy, n-thiopentoxy, n-thiohexoxy, and the like.

[0037] The term "(C1-C6)alkylamino", as used herein, refers to the group -NHAlk with Alk representing a (C1-C6)alkyl group as defined above, including, but not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, t-butylamino, n-pentylamino, n-hexylamino, and the like.

[0038] The term "di(C1-C6)alkylamino", as used herein, refers to a -NAlk1Alk2 group with Alk1 and Alk2, independently of each other, representing a (C1-C6)alkyl group as defined above, such as, but not limited to, dimethylamino, diethylamino, ethylmethylamino, etc.

[0039] According to a specific embodiment of the invention, R1 is a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 , C(O)R 11 , CO2R 12 , O.C.(O)R 13 , N.R. 14 C(O)R 15 , C(O)NR 16 R 17 , S(O)R S , SO2R S ', (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl groups, wherein the aforementioned aryl or heterocyclyl groups (which may be part of an aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group) are selected from the group consisting of halogen atoms, CN, NO2, OR 18 , S.R. 19 , N.R. 20 R 21 , (C1-C6) alkyl, and (C1-C6) haloalkyl, especially halogen atoms, NO2, OR 18 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, specifically NO2 and OR 18and optionally substituted with one or more substituents, in particular one substituent, selected from the group consisting of 18 From R 21 represent, independently of each other, a hydrogen atom or a (C1-C6) alkyl group.

[0040] According to another specific embodiment of the invention, R1 is a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 C(O)R 11 , CO2R 12 , O.C.(O)R 13 , N.R. 14 C(O)R 15 , C(O)NR 16 R 17 , (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl group, wherein said aryl or heterocyclyl group may be optionally substituted by one or more substituents as defined above.

[0041] According to yet another specific embodiment of the present invention, R1 is a hydrogen atom, CN, OR7, C(O)R 11 , CO2R 12 , O.C.(O)R 13 , SO2R S ', (C1-C6) alkyl, heterocyclyl, or heterocyclyl-(C1-C6) alkyl group, wherein the heterocyclyl group (which may be part of a heterocyclyl-(C1-C6) alkyl group) is selected from the group consisting of halogen atoms, CN, NO2, OR 18 , S.R. 19 , N.R. 20 R 21 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, especially halogen atoms, NO2, OR 18 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, specifically NO2 and OR 18and preferably the above-mentioned heterocyclyl group is optionally substituted by NO2, in which R 18 From R 21 represent, independently of each other, a hydrogen atom or a (C1-C6) alkyl group.

[0042] According to yet another specific embodiment of the present invention, R1 is a hydrogen atom, CN, OR7, C(O)R 11 , CO2R 12 , O.C.(O)R 13 , heterocyclyl, or heterocyclyl-(C1-C6)alkyl groups, said heterocyclyl groups being optionally substituted by one or more substituents as defined above.

[0043] In the above embodiment, the (C1-C6) alkyl group can be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, but is preferably a (C1-C3) alkyl group.

[0044] In the above embodiment, the aryl group may be part of an aryl-(C1-C6)alkyl group, but is preferably a phenyl group.

[0045] In the above embodiments, the heterocyclyl group may be part of a heterocyclyl-(C1-C6)alkyl group, but is in particular a 5- or 6-membered saturated, unsaturated (i.e. not aromatic) or aromatic, in particular saturated or aromatic, monocyclic group, the ring atoms of which contain one or more, advantageously one to three heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms, such as, for example, morpholinyl, pyridinyl or piperazinyl, e.g., a morpholinyl or pyridinyl group.

[0046] In the above embodiment, R S and R S' each independently represent a (C1-C6)alkyl, aryl, or aryl-(C1-C6)alkyl group, in particular a (C1-C6)alkyl or aryl group, particularly an aryl group such as a phenyl group.

[0047] In the above embodiment, R7 to R 10 , R 12 , R 14 , and R 16 ~R 17 are each independently a hydrogen atom, a (C1-C6) alkyl, aryl, or aryl-(C1-C6) alkyl group, R 11 , R 13 , and R 15 represent, independently of one another, a hydrogen atom, a (C1-C6)alkyl, an aryl, an aryl-(C1-C6)alkyl, a (C1-C6)alkoxy, a (C1-C6)alkylamino, or a di((C1-C6)alkyl)amino group, in particular a hydrogen atom, a (C1-C6)alkyl, an aryl, a (C1-C6)alkylamino, or a di((C1-C6)alkyl)amino group, specifically a (C1-C3)alkyl, an aryl such as phenyl, a (C1-C3)alkylamino, or a di((C1-C3)alkyl)amino group.

[0048] Specifically, in the above embodiment, R7 to R 17 represent, independently of each other, a hydrogen atom, a (C1-C6)alkyl, aryl, or aryl-(C1-C6)alkyl group, in particular a hydrogen atom, a (C1-C6)alkyl, or aryl group, typically a hydrogen atom, a (C1-C3)alkyl or aryl group, where the aryl group may be part of an aryl-(C1-C6)alkyl group but is preferably a phenyl group.

[0049] According to a specific embodiment of the invention, R2 is a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 , C(O)R 11 , CO2R 12 , O.C.(O)R 13 , N.R. 14 C(O)R 15 , C(O)NR 16R 17 , S(O)R S , SO2R S ', (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl groups, wherein the aforementioned aryl or heterocyclyl groups (which may be part of an aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group) are selected from the group consisting of halogen atoms, CN, NO2, OR 18 , S.R. 19 , N.R. 20 R 21 , (C1-C6) alkyl, and (C1-C6) haloalkyl, especially halogen atoms, NO2, OR 18 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, specifically NO2 and OR 18 and optionally substituted with one or more substituents, in particular one substituent, selected from the group consisting of 18 From R 21 are each independently a hydrogen atom or a (C1-C6) alkyl group.

[0050] In the above embodiment, R S and R S ' each independently represent a (C1-C6)alkyl, aryl, or aryl-(C1-C6)alkyl group, in particular a (C1-C6)alkyl or aryl group, particularly an aryl group such as a phenyl group.

[0051] According to another specific embodiment of the invention, R2 is a hydrogen atom, CN, NO2, OR7, SR8, NR9R 10 C(O)R 11 , CO2R 12 , O.C.(O)R 13 , N.R. 14 C(O)R 15 , C(O)NR 16 R 17, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl group, wherein said aryl or heterocyclyl group may be optionally substituted by one or more substituents as defined above.

[0052] According to yet another specific embodiment of the invention, R2 is C(O)R 11 , CO2R 12 , C(O)NR 16 R 17 , (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl groups, wherein the aryl or heterocyclyl groups are each independently selected from the group consisting of a halogen atom, OR 18 , S.R. 19 , N.R. 20 R 21 , (C1-C6) alkyl, and (C1-C6) haloalkyl; R 18 From R 21 are each independently a hydrogen atom or a (C1-C6) alkyl group.

[0053] According to yet another specific embodiment of the present invention, R2 is COR 12 , C(O)NR 16 R 17 , (C1-C6) alkyl, aryl, or aryl-(C1-C6) alkyl groups, in particular COR 12 , C(O)NR 16 R 17 or an aryl-(C1-C6)alkyl group, the aryl group being selected from the group consisting of halogen atoms, OR 18 , S.R. 19 , and N.R. 20 R 21 , especially OR 18 and optionally substituted with one or more substituents, in particular one substituent, selected from the group consisting of 18 From R21 are each independently a hydrogen atom or a (C1-C6) alkyl group.

[0054] In the above embodiment, the (C1-C6) alkyl group can be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, but is preferably a (C1-C3) alkyl group.

[0055] In the above embodiment, the aryl group may be part of an aryl-(C1-C6)alkyl group, but is preferably a phenyl group.

[0056] In the above embodiments, the heterocyclyl group may be part of a heterocyclyl-(C1-C6)alkyl group, but is in particular a 5- or 6-membered saturated, unsaturated (i.e. not aromatic) or aromatic, in particular saturated, monocyclic group, the ring atoms of which contain one or more, advantageously one to three heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms, such as, for example, morpholinyl, pyridinyl or piperazinyl, in particular a piperazinyl group.

[0057] In the above embodiment, R7 to R 10 , R 12 , R 14 , and R 16 ~R 17 are each independently a hydrogen atom, a (C1-C6) alkyl, aryl, or aryl-(C1-C6) alkyl group, R 11 , R 13 , and R 15represent, independently of one another, a hydrogen atom, a (C1-C6)alkyl, an aryl, an aryl-(C1-C6)alkyl, a (C1-C6)alkoxy, a (C1-C6)alkylamino, or a di((C1-C6)alkyl)amino group, in particular a hydrogen atom, a (C1-C6)alkyl, an aryl, a (C1-C6)alkylamino, or a di((C1-C6)alkyl)amino group, specifically a (C1-C3)alkyl, an aryl such as phenyl, a (C1-C3)alkylamino, or a di((C1-C3)alkyl)amino group.

[0058] Specifically, in the above embodiment, R7 to R 17 represent, independently of each other, a hydrogen atom, a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl group, in particular a hydrogen atom, a (C1-C6)alkyl or aryl-(C1-C6)alkyl group, typically a hydrogen atom, a (C1-C3)alkyl or aryl group, where the aryl group may be part of an aryl-(C1-C6)alkyl group but is preferably a phenyl group.

[0059] According to another specific embodiment of the invention, R3 is a hydrogen atom, a halogen atom, CN, OR 29 , S.R. 30 , N.R. 31 R 32 , C(O)R 33 , CO2R 34 , O.C.(O)R 35 , N.R. 36 C(O)R 37 , C(O)NR 38 R 39 , aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl groups, wherein the aryl or heterocyclyl groups are selected from the group consisting of halogen atoms, OR 44 , S.R. 45 , N.R. 46 R 47 , (C1-C6) alkyl, and (C1-C6) haloalkyl; R 29 From R 39represent, independently of each other, a hydrogen atom, a (C1-C6)alkyl, aryl, or aryl-(C1-C6)alkyl group, in particular a hydrogen atom or a (C1-C6)alkyl group, typically a hydrogen atom or a (C1-C3)alkyl group.

[0060] According to another specific embodiment of the invention, R3 is a hydrogen atom, a halogen atom, CN, OR 29 , S.R. 30 , N.R. 31 R 32 , C(O)R 33 , CO2R 34 , O.C.(O)R 35 , N.R. 36 C(O)R 37 or C(O)NR 38 R 39 In the formula, R 29 From R 39 represent, independently of one another, a hydrogen atom, a (C1-C6)alkyl, aryl or aryl-(C1-C6)alkyl group, in particular a hydrogen atom or a (C1-C6)alkyl group.

[0061] According to yet another specific embodiment of the present invention, R3 is a hydrogen atom, a halogen atom, CN, OR 29 , S.R. 30 , N.R. 31 R 32 , O.C.(O)R 35 , N.R. 36 C(O)R 37 , heterocyclyl, or heterocyclyl-(C1-C6)alkyl groups, the heterocyclyl groups being selected from the group consisting of halogen atoms, OR 44 , S.R. 45 , N.R. 46 R 47 and (C1-C6) alkyl groups, and preferably R3 is a hydrogen atom, a halogen atom, CN, NR 31 R 32 , O.C.(O)R 35 , heterocyclyl, or heterocyclyl-(C1-C6)alkyl groups, the aforementioned heterocyclyl groups being represented by OR 44 , S.R.45 , and N.R. 46 R 47 , especially OR 44 wherein R 29 From R 37 represent, independently of each other, a hydrogen atom, a (C1-C6)alkyl, aryl, or aryl-(C1-C6)alkyl group, in particular a hydrogen atom or a (C1-C6)alkyl group, typically a hydrogen atom or a (C1-C3)alkyl group.

[0062] In the above embodiment, R 44 From R 47 represent, independently of one another, a hydrogen atom or a (C1-C6)alkyl group, in particular a hydrogen atom or a (C1-C3)alkyl group.

[0063] According to yet another specific embodiment of the present invention, R3 is selected from the group consisting of a hydrogen atom, a halogen atom, OR 29 , S.R. 30 , N.R. 31 R 32 , C(O)R 33 , CO2R 34 O.C.(O)R 35 , N.R. 36 C(O)R 37 or C(O)NR 38 R 39 , preferably a hydrogen atom, a halogen atom, OR 29 , S.R. 30 , N.R. 31 R 32 , O.C.(O)R 35 , or N.R. 36 C(O)R 37 More preferably, a hydrogen atom or OC(O)R 35 R 29 From R 37 represent, independently of each other, a hydrogen atom, a (C1-C6)alkyl, aryl, or aryl-(C1-C6)alkyl group, in particular a hydrogen atom or a (C1-C6)alkyl group, typically a hydrogen atom or a (C1-C3)alkyl group.

[0064] In the above embodiment, the aryl group may be part of an aryl-(C1-C6)alkyl group, but is preferably a phenyl group.

[0065] In the above embodiments, the heterocyclyl group may be part of a heterocyclyl-(C1-C6)alkyl group, but is in particular a 5- or 6-membered, saturated, unsaturated (i.e. not aromatic) or aromatic, in particular aromatic, monocyclic group, the ring atoms of which contain one or more, advantageously one to three heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms, such as, for example, a pyridinyl, pyrimidinyl, pyrazolyl, piperazinyl or piperidinyl group, for example a pyridinyl, pyrimidinyl or pyrazolyl group.

[0066] In the above embodiment, the (C1-C6) alkyl group can be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, but is preferably a (C1-C3) alkyl group.

[0067] According to a particular embodiment of the invention, R4 is a hydrogen atom, a halogen atom, CN, OR 29 , S.R. 30 , N.R. 31 R 32 , (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl groups, wherein the aforementioned aryl or heterocyclyl groups (which may be part of an aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group) are each independently selected from the group consisting of halogen atoms, CN, NO, OR, 44 , S.R. 45 , N.R. 46 R 47 , C(O)R 48 , CO2R 49 , O.C.(O)R 50 , N.R. 51 C(O)R 52 , C(O)NR 53 R 54, (C1-C6) alkyl, and (C1-C6) haloalkyl groups, especially halogen atoms, OR 44 , S.R. 45 , N.R. 46 R 47 , C(O)R 48 , CO2R 49 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, specifically C(O)R 48 , CO2R 49 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, preferably C(O)R 48 and (C1-C6) alkyl groups.

[0068] According to another specific embodiment of the invention, R4 is a hydrogen atom, a halogen atom, CN, OR 29 , S.R. 30 , N.R. 31 R 32 , (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl groups, wherein said aryl or heterocyclyl groups may be optionally substituted by one or more substituents as defined above.

[0069] According to yet another specific embodiment of the present invention, R4 is selected from the group consisting of a hydrogen atom, a halogen atom, OR 29 , S.R. 30 , N.R. 31 R 32 , aryl, or heterocyclyl group, the aforementioned aryl or heterocyclyl group being optionally substituted with a halogen atom, OR 44 , S.R. 45 , N.R. 46 R 47 , C(O)R 48 , CO2R 49 , C(O)NR 53 R 54, (C1-C6) alkyl, and (C1-C6) haloalkyl groups, specifically C(O)R 48 , CO2R 49 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, preferably C(O)R 48 and (C1-C6) alkyl groups.

[0070] According to yet another specific embodiment of the present invention, R4 is a hydrogen atom, a halogen atom, NR 31 R 32 , aryl, or heterocyclyl group, the aforementioned aryl or heterocyclyl group being C(O)R 48 , CO2R 49 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, preferably C(O)R 48 and (C1-C6) alkyl groups.

[0071] In the above embodiment, the aryl group may be part of an aryl-(C1-C6)alkyl group, but is preferably a phenyl group.

[0072] In the above embodiments, the heterocyclyl group may be part of a heterocyclyl-(C1-C6)alkyl group, but is in particular a 5- or 6-membered saturated, unsaturated (i.e. not aromatic) or aromatic, in particular saturated, monocyclic group, the ring atoms of which contain one or more, advantageously one to three, heteroatoms selected from O, S and N, preferably O and N, the remainder being carbon atoms, such as, for example, a piperazinyl, piperidinyl, pyridinyl, pyrimidinyl or pyrazolyl group, for example a piperazinyl or piperidinyl group.

[0073] In the above embodiment, R 29 From R 32 are each independently a hydrogen atom, a (C1-C6) alkyl, an aryl, or an aryl-(C1-C6) alkyl group, the aryl group being preferably a phenyl group, which may be part of an aryl-(C1-C6) alkyl group, and which is preferably a halogen atom, CN, NO, OR 55 , S.R. 56 , N.R. 57 R 58 , C(O)R 59 , CO2R 60 , O.C.(O)R 61 , N.R. 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl groups, preferably halogen atoms, OR 55 , S.R. 56 , N.R. 57 R 58 , C(O)R 59 , CO2R 60 , O.C.(O)R 61 , N.R. 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl groups, in particular C(O)R 59 , CO2R 60 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl groups, specifically C(O)R 59 and optionally substituted with one or more substituents, in particular one substituent, selected from the group consisting of 55 From R 65 represent, independently of one another, a hydrogen atom, a (C1-C6) alkyl or aryl group, in particular an aryl group, preferably a phenyl group.

[0074] In the above embodiment, R 44 From R 54represent, independently of one another, a hydrogen atom, a (C1-C6) alkyl or aryl group, in particular an aryl group, preferably a phenyl group.

[0075] In the above embodiment, the (C1-C6) alkyl group can be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, but is preferably a (C1-C3) alkyl group.

[0076] According to a specific embodiment of the present invention, R 4b is a hydrogen atom, a halogen atom, OR 29 , S.R. 30 , N.R. 31 R 32 , (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl groups, wherein the aforementioned aryl or heterocyclyl groups (which may be part of an aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group) are each independently selected from the group consisting of halogen atoms, CN, NO, OR, 44 , S.R. 45 , N.R. 46 R 47 , C(O)R 48 , CO2R 49 , O.C.(O)R 50 , N.R. 51 C(O)R 52 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, especially halogen atoms, OR 44 , S.R. 45 , N.R. 46 R 47 , C(O)R 48 , CO2R 49 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, specifically C(O)R 48 , CO2R 49 , C(O)NR 53 R 54, (C1-C6) alkyl, and (C1-C6) haloalkyl groups, preferably C(O)R 48 and (C1-C6) alkyl groups.

[0077] According to a specific embodiment of the present invention, R 4b is a hydrogen atom, a halogen atom, OR 29 , S.R. 30 , N.R. 31 R 32 , aryl, or heterocyclyl group, the aforementioned aryl or heterocyclyl group being optionally substituted with a halogen atom, OR 44 , S.R. 45 , N.R. 46 R 47 , C(O)R 48 , CO2R 49 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, specifically C(O)R 48 , CO2R 49 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, preferably C(O)R 48 and (C1-C6) alkyl groups.

[0078] According to yet another specific embodiment of the present invention, R 4b is a hydrogen atom, a halogen atom, or NR 31 R 32 , aryl, or heterocyclyl group, the aforementioned aryl or heterocyclyl group being C(O)R 48 , CO2R 49 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, preferably C(O)R 48and (C1-C6) alkyl groups.

[0079] According to yet another specific embodiment of the present invention, R 4b is a hydrogen atom, a halogen atom, OR 29 , or N.R. 31 R 32 , preferably a hydrogen atom, a halogen atom, or OR 29 and more preferably represents a hydrogen atom.

[0080] In the above embodiment, the aryl group may be part of an aryl-(C1-C6)alkyl group, but is preferably a phenyl group.

[0081] In the above embodiments, the heterocyclyl group may be part of a heterocyclyl-(C1-C6)alkyl group, but is in particular a 5- or 6-membered saturated, unsaturated (i.e. not aromatic) or aromatic, in particular saturated, monocyclic group, the ring atoms of which contain one or more, advantageously one to three heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms.

[0082] In the above embodiment, R 29 From R 32 are each independently a hydrogen atom, a (C1-C6) alkyl, an aryl, or an aryl-(C1-C6) alkyl group, the aryl group being preferably a phenyl group, which may be part of an aryl-(C1-C6) alkyl group, and which is preferably a halogen atom, CN, NO, OR 55 , S.R. 56 , N.R. 57 R 58 , C(O)R 59 , CO2R 60 , O.C.(O)R 61 , N.R. 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl groups, preferably halogen atoms, OR55 , S.R. 56 , N.R. 57 R 58 , C(O)R 59 , CO2R 60 , O.C.(O)R 61 , N.R. 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl groups, in particular C(O)R 59 , CO2R 60 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl groups, specifically C(O)R 59 and optionally substituted with one or more substituents, in particular one substituent, selected from the group consisting of 55 From R 65 represent, independently of each other, a hydrogen atom, a (C1-C6) alkyl or aryl group, in particular an aryl group, preferably a phenyl group. 29 From R 32 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group, in particular a hydrogen atom.

[0083] In the above embodiment, R 44 From R 54 represent, independently of one another, a hydrogen atom, a (C1-C6) alkyl or aryl group, in particular an aryl group, preferably a phenyl group.

[0084] In the above embodiment, the (C1-C6) alkyl group can be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, but is preferably a (C1-C3) alkyl group.

[0085] In one specific embodiment of the invention, R4 is as defined above and R 4b is a hydrogen atom, a halogen atom, OR 29 , or N.R. 31 R 32 In the formula, R 29 From R32 are each independently a hydrogen atom or a (C-C) alkyl group, in particular a hydrogen atom, preferably R 4b is a hydrogen atom, a halogen atom, or OR 29 and more preferably represents a hydrogen atom.

[0086] In a specific embodiment of the invention, R5 is a hydrogen atom, a halogen atom, CN, OR 29 , S.R. 30 , N.R. 31 R 32 , (C1-C6) alkyl, or (C1-C6) haloalkyl group, wherein the alkyl or haloalkyl group is selected from the group consisting of OR 40 , S.R. 41、 and N.R. 42 R 43 or R5 represents an aryl, heterocyclyl, aryl-(C1-C6)alkyl, or heterocyclyl-(C1-C6)alkyl group, wherein said aryl or heterocyclyl group (which may be part of an aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group) is selected from the group consisting of a halogen atom, CN, NO2, OR 44 , S.R. 45 , N.R. 46 R 47 , C(O)R 48 , CO2R 49 , O.C.(O)R 50 , N.R. 51 C(O)R 52 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, especially halogen atoms, OR 44 , S.R. 45 , N.R. 46 R 47 , C(O)R 48 , CO2R 49 , C(O)NR 53 R 54 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, specifically halogen atoms, OR 44 , S.R. 45, N.R. 46 R 47 , (C1-C6)alkyl, and (C1-C6)haloalkyl groups, in particular halogen atoms, (C1-C6)alkyl, and (C1-C6)haloalkyl groups, preferably (C1-C6)alkyl groups.

[0087] In the above embodiment, R 29 From R 32 are each independently a hydrogen atom, a (C1-C6) alkyl, an aryl, or an aryl-(C1-C6) alkyl group, the aryl group being preferably a phenyl group, which may be part of an aryl-(C1-C6) alkyl group, and which is preferably a halogen atom, CN, NO, OR 55 , S.R. 56 , N.R. 57 R 58 , C(O)R 59 , CO2R 60 , O.C.(O)R 61 , N.R. 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl groups, preferably halogen atoms, OR 55 , S.R. 56 , N.R. 57 R 58 , C(O)R 59 , CO2R 60 , O.C.(O)R 61 , N.R. 62 C(O)R 63 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl groups, in particular C(O)R 59 , CO2R 60 , C(O)NR 64 R 65 , (C1-C6) alkyl and (C1-C6) haloalkyl groups, specifically C(O)R 59 and optionally substituted with one or more substituents, in particular one substituent, selected from the group consisting of 55From R 65 represent, independently of each other, a hydrogen atom, a (C1-C6) alkyl or aryl group, in particular an aryl group, preferably a phenyl group. 29 From R 32 represent, independently of one another, a hydrogen atom or a (C1-C6) alkyl group.

[0088] In another specific embodiment of the invention, R5 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl, a (C1-C6) haloalkyl group, wherein said alkyl or haloalkyl group is selected from the group consisting of OR 40 , S.R. 41 and N.R. 42 R 43 or R5 represents an aryl-(C1-C6)alkyl or heterocyclyl-(C1-C6)alkyl group, said aryl or heterocyclyl group being optionally substituted by one or more substituents, in particular one substituent, selected from the group consisting of: 44 , S.R. 45 , N.R. 46 R 47 , (C1-C6) alkyl, and (C1-C6) haloalkyl groups, in particular halogen atoms, (C1-C6) alkyl, and (C1-C6) haloalkyl groups, preferably (C1-C6) alkyl groups.

[0089] In yet another specific embodiment of the invention, R5 represents a hydrogen atom, a halogen atom, a (C1-C6) alkyl, a (C1-C6) haloalkyl group, or a heterocyclyl-(C1-C6) alkyl group, said alkyl or haloalkyl group being selected from the group consisting of OR 40 and the aforementioned heterocyclyl may be optionally substituted by one or more (C1-C6)alkyl groups.

[0090] Preferably, R5 represents a hydrogen atom.

[0091] In the above embodiment, the aryl group may be part of an aryl-(C1-C6)alkyl group, but is preferably a phenyl group.

[0092] In the above embodiments, the heterocyclyl group may be part of a heterocyclyl-(C1-C6)alkyl group, but is in particular a 5- or 6-membered saturated, unsaturated (i.e. not aromatic) or aromatic, in particular saturated, monocyclic group, the ring atoms of which contain one or more, advantageously one to three heteroatoms selected from O, S and N, preferably O and N, and the remainder are carbon atoms, such a ring being, for example, a piperazinyl group.

[0093] In the above embodiment, R 40 From R 43 represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group, in particular a hydrogen atom.

[0094] In the above embodiment, R 44 From R 54 represent, independently of one another, a hydrogen atom, a (C1-C6) alkyl or aryl group, in particular an aryl group, preferably a phenyl group.

[0095] In the above embodiment, the (C1-C6) alkyl group can be part of an aryl-(C1-C6) alkyl group or a heterocyclyl-(C1-C6) alkyl group, but is preferably a (C1-C3) alkyl group.

[0096] In a specific embodiment of the invention, R6 represents a hydrogen atom, a (C1-C3) alkyl or aryl-(C1-C3) alkyl group, or a (C1-C6) alkylcarbonyl group optionally substituted by one or more substituents selected from the group consisting of OH, SH, NH2, (C1-C3) alkoxy, (C1-C3) thioalkoxy, and (C1-C3) alkylamino groups, preferably R6 represents a hydrogen atom, a methyl, ethyl, benzyl, or a (C1-C6) alkylcarbonyl group optionally substituted by one or more substituents selected from the group consisting of OH, NH2, and SH, and specifically R6 represents a hydrogen atom or an ethyl group, in particular an ethyl group.

[0097] In a first aspect of the present invention, [ka] teeth [ka] And, During the ceremony, X is N, Y is N(R2) and Z is C(H), and the compound for use according to the invention therefore has the following general formula (Ii): [ka] And, In the above formula, R2, R4, R 4b , R5, and R6 are as defined in any one of the above embodiments.

[0098] In particular, R6 represents a hydrogen atom or a (C1-C6)alkyl group, preferably a (C1-C3)alkyl group, in particular a methyl or ethyl group, and advantageously R6 represents an ethyl group.

[0099] In a second aspect of the present invention, [ka] teeth [ka] And, During the ceremony, X is N (R1), Y is N and Z is C (R3) and the compound for use according to the invention therefore has the following general formula (I.ii.a): [ka] And, During the ceremony, R1, R3, R4, R 4b , R5, and R6 are as defined in any one of the above embodiments.

[0100] In particular, R6 represents a hydrogen atom, an ethyl group or a (C1-C6) alkylcarbonyl group optionally substituted by one or more substituents selected from the group consisting of OH, NH2 and SH, and advantageously R6 represents a hydrogen atom or an ethyl group, in particular an ethyl group.

[0101] In a third aspect of the present invention, [ka] teeth [ka] And, During the ceremony, X is N(R1) and Y is N + (O - ) and Z is C(R3), and the compound for use according to the invention therefore has the following general formula (I.ii.b): [ka] And, During the ceremony, R1, R3, R4, R 4b , R5, and R6 are as defined in any one of the above embodiments.

[0102] In particular, R6 represents a hydrogen atom or a (C1-C6)alkyl group, preferably a (C1-C3)alkyl group, in particular a methyl or ethyl group, and advantageously R6 represents an ethyl group.

[0103] In a fourth aspect of the present invention, [ka] teeth [ka] And, During the ceremony, X is N(R1), Y is CH and Z is N, and the compound for use according to the invention therefore has the following general formula (I.ii.c): [ka] And, During the ceremony, R1, R4, R 4b , R5, and R6 are as defined in any one of the above embodiments.

[0104] In particular, R6 represents a hydrogen atom or a (C1-C6)alkyl group, preferably a (C1-C3)alkyl group, in particular a methyl or ethyl group, and advantageously R6 represents an ethyl group.

[0105] In a fifth aspect of the present invention, [ka] teeth [ka] And, During the ceremony, X is N(R1), Y and Z are CH, and the compound for use according to the invention therefore has the following general formula (I.ii.d): [ka] And, During the ceremony, R1, R4, R 4b , R5, and R6 are as defined in any one of the above embodiments.

[0106] In particular, R6 represents a hydrogen atom, a (C1-C6)alkyl group or an aryl-(C1-C6)alkyl group, preferably a hydrogen atom, a (C1-C3)alkyl group or an aryl-(C1-C3)alkyl group, in particular a hydrogen atom, a methyl, ethyl or benzyl group, advantageously R6 represents a hydrogen atom, an ethyl or benzyl group, typically a hydrogen atom or an ethyl group.

[0107] Compounds for use according to the invention may in particular be selected from the group consisting of compounds 1-44 depicted below, and pharma- ceutically acceptable salts and / or solvates thereof. [ka] TIFF2024506530000025.tif235165TIFF2024506530000026.tif244165TIFF2024506530000027.tif94165

[0108] Specifically, compounds for use according to the invention may be selected from the group consisting of compounds 1-28 and pharma- ceutically acceptable salts and / or solvates thereof.

[0109] In a specific embodiment, the compound for use according to the invention is selected from the group consisting of compounds 4-6, 8-18, 22, 28, 29, 32, 34-44, particularly 4-6, 8-18, 22, 28, 34-44, in particular 4-6, 8-18, 22, 28, and pharma- ceutically acceptable salts and / or solvates thereof.

[0110] The present invention is also directed to compounds of general formula (I) as defined above for the prevention and / or treatment of disorders associated with ferroptosis.

[0111] Disorders associated with ferroptosis include myocardial ischemia-reperfusion injury, particularly that which occurs after arterial ligation; cardiomyopathies, particularly doxorubicin-induced cardiomyopathy; stroke, particularly ischemic or hemorrhagic stroke; traumatic brain injury; contusion spinal cord injury; neurodegenerative disorders, particularly chronic neurodegenerative disorders, more specifically Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease), Friedreich's ataxia, and dementia; and retinal disorders, particularly Stargardt's disease. or age-related macular degeneration (AMD), specifically dry AMD; chronic liver disease, particularly nonalcoholic steatohepatitis (NASH), chronic infections such as hepatitis, and alcoholic liver disease; acute liver failure, particularly due to drug-induced liver injury (DILI), such as acetaminophen (APAP)-induced liver injury, or due to ischemia-reperfusion injury induced by septic or hemorrhagic shock; skin inflammatory diseases, such as psoriasis; toxic epidermal necrolysis (LI). L's syndrome); acute kidney injury (AKI), such as oxalate-induced, folic acid (FA)-induced, and cisplatin-induced AKI, renal ischemia-reperfusion injury, and acute tubular necrosis; chronic obstructive pulmonary disease (COPD); bronchial asthma; lung damage due to bacterial infections, especially those caused by Pseudomonas aeruginosa or Mycobacterium tuberculosis; pulmonary fibrosis, such as radiation-induced pulmonary fibrosis (RILF) and paraquat-induced Such conditions may include lung injury; necrotizing enterocolitis; inflammatory bowel disease, such as Crohn's disease; hemochromatosis; hemolytic disorders; cytokine storm during viral infections; radiation-induced necrosis; rheumatoid arthritis; type I diabetes; insulin resistance associated with obesity; epilepsy, such as mitochondrial disease-associated epilepsy and intractable epilepsy; and pathologies associated with stress-induced premature tissue aging, such as atherosclerosis, hypertension, and type II diabetes.

[0112] In a particular embodiment, the disorder associated with ferroptosis is a cardiomyopathy, in particular doxorubicin-induced cardiomyopathy; contusion spinal cord injury; neurodegenerative disorders, in particular chronic neurodegenerative disorders, more particularly Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease), Friedreich's ataxia, and dementia; retinal disorders, in particular Stargardt's disease or age-related macular degeneration (AMD), in particular dry AMD; acute liver failure, in particular due to drug-induced liver injury (DILI), such as acetaminophen (APAP)-induced liver injury, or due to ischemia-reperfusion injury induced by septic or hemorrhagic shock; skin inflammatory diseases, such as psoriasis; toxic epidermal necrolysis (Lyell's syndrome); acute kidney injury (AKI), such as oxalate-induced, folic acid (FA)-induced, and cisplatin-induced AKI; bronchial asthma; lung damage caused by bacterial infections, particularly those caused by Pseudomonas aeruginosa or Mycobacterium tuberculosis; pulmonary fibrosis, such as radiation-induced pulmonary fibrosis (RILF) and paraquat-induced lung injury; necrotizing enterocolitis; hemochromatosis; hemolytic disorders; cytokine storm during viral infections; radiation-induced necrosis; rheumatoid arthritis; type I diabetes; insulin resistance associated with obesity; epilepsy, such as mitochondrial disease-associated epilepsy and refractory epilepsy; and pathologies associated with stress-induced premature tissue aging, such as hypertension and type II diabetes.

[0113] Preferably, the disorder associated with ferroptosis is selected from the group consisting of myocardial ischemia-reperfusion injury, particularly occurring after arterial ligation; stroke, particularly ischemic stroke or hemorrhagic stroke; traumatic brain injury; neurodegenerative disorders, particularly chronic neurodegenerative disorders, more particularly Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis (Charcot's disease); retinal disorders, particularly Stargardt's disease or age-related macular degeneration (AMD), particularly atrophic AMD; chronic liver disease, particularly non-alcoholic steatohepatitis (NASH); acute liver failure, particularly due to drug-induced liver injury (DILI), such as acetaminophen (APAP)-induced liver injury, or due to ischemia-reperfusion injury induced by septic or hemorrhagic shock; and acute kidney injury (AKI), such as folic acid (FA)-induced AKI, cisplatin-induced AKI, renal ischemia-reperfusion injury, and acute tubular necrosis.

[0114] In particular, the disorder associated with ferroptosis is selected from the group consisting of neurodegenerative disorders, in particular chronic neurodegenerative disorders, more particularly Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis (Charcot's disease); retinal disorders, in particular Stargardt's disease or age-related macular degeneration (AMD), in particular dry AMD; acute liver failure, in particular due to drug-induced liver injury (DILI), such as acetaminophen (APAP)-induced liver injury, or due to ischemia-reperfusion injury induced by septic or hemorrhagic shock; and acute kidney injury (AKI), such as folic acid (FA)-induced AKI, and cisplatin-induced AKI.

[0115] The present invention also relates to a method for inhibiting ferroptosis, comprising administering an effective dose of a compound of formula (I) as defined above to a human in need thereof. In particular, the present invention relates to a method for preventing and / or treating disorders associated with ferroptosis as defined above, comprising administering an effective dose of a compound of formula (I) as defined above to a human in need thereof.

[0116] The present invention also relates to the use of the compound of formula (I) as defined above for the manufacture of a medicament for use in the inhibition of ferroptosis.In particular, the present invention also relates to the use of the compound of formula (I) as defined above for the manufacture of a medicament for use in the prevention and / or treatment of disorders related to ferroptosis as defined above.

[0117] The present invention also relates to the use of the compounds of formula (I) as defined above for preserving and / or protecting biological materials, such as cells, tissues, body fluids and organs in vitro, in particular for non-therapeutic uses.

[0118] In the context of the present invention, "in vitro" means outside the organism from which the biomaterial originates.

[0119] As used herein, the expression "preservation and / or protection of a biomaterial" refers to improving the viability of said biomaterial, thereby enabling its long-term preservation. As is apparent from the description herein, this improvement in viability is obtained by preventing ferroptosis-induced cell death in said biomaterial.

[0120] Therefore, the present invention also refers to the in vitro use of the compounds of formula (I) as defined above as agents for inhibiting ferroptosis-induced cell death in biological materials.

[0121] The present invention is also directed to a method of inhibiting ferroptosis-induced cell death in a biological material, the method comprising exposing said biological material to a compound of formula (I) as defined above.

[0122] In the above aspects of the invention, the biological material is preferably a cell or tissue sample.

[0123] The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above and at least one pharma- ceutical acceptable excipient for use as an agent for the inhibition of ferroptosis, in particular for use as an agent for the prevention and / or treatment of disorders associated with ferroptosis as defined above.

[0124] The term "pharmaceutical acceptable excipient" is intended to mean, in the framework of the present invention, a substance that is pharmaceutical acceptable as defined above and that is formulated together with the active ingredient of the pharmaceutical composition, which is included for the purpose of long-term stabilization, bulking up solid formulations containing small amounts of potent active ingredients, providing therapeutic improvements to the active ingredient in the final dosage form (e.g., enhanced drug absorption, reduced viscosity, or enhanced solubility, etc.), or improving the taste or appearance of the pharmaceutical composition. Suitable excipients can be easily and intelligently selected by those skilled in the art, especially taking into account the dosage form and the route of administration.

[0125] Pharmaceutical compositions for use according to the present invention may be formulated for oral, topical or injectable administration, said compositions being intended for mammals, including humans.

[0126] The pharmaceutical compositions may be administered orally in solid or liquid (solution or suspension) form.

[0127] The solid composition can be in the form of tablets, gelatin capsules, powders, granules, etc. When the solid composition is prepared in the form of tablets, the main active ingredient is mixed with pharmaceutical vehicles such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. The tablet may be coated with sucrose or other suitable materials, or may be treated to extend or delay the activity and continuously release a predetermined amount of active agent. In powders or granules, the active ingredient can be mixed or granulated with dispersing agents, wetting agents, or suspending agents, and with flavor improvers or sweeteners. In gelatin capsules, the active ingredient can be introduced into soft or hard gelatin capsules, for example in the form of powders or granules as described above, or in the form of liquid compositions as described below.

[0128] The liquid composition may contain the active ingredient in a solvent such as water, together with a sweetener, a flavor enhancer, or a suitable colorant. The liquid composition may also be obtained by suspending or dissolving the powder or granules as described above in a liquid such as water, juice, milk, etc. For example, it may be a syrup or elixir.

[0129] For topical administration, the pharmaceutical composition may be in any form capable of being applied to the skin or mucosal surface, such as a cream, gel, ointment, patch, etc.

[0130] For administration by injection, aqueous suspensions, isotonic saline solutions, or sterile injectable solutions containing pharmacologically compatible dispersing agents and / or wetting agents are used.

[0131] The compound of the present invention as an active ingredient may be used in a dose ranging between 0.01 mg and 2,000 mg per day, but may be given as a single dose once a day, or as multiple doses over the course of a day, for example as equal doses twice a day. The dose administered per day is advantageously between 5 mg and 500 mg, and even more advantageously between 10 mg and 200 mg. The compound of the present invention will typically be formulated into the above-mentioned pharmaceutical composition before being administered to a patient. The effective dose of the active ingredient can be determined by the skilled artisan by routine tests, including evaluation of the effect of administration of the active ingredient on the disorder that is intended to be prevented and / or treated by said administration. For example, such tests can be carried out by analyzing the effect, both quantitative and qualitative, of administration of different amounts of the active ingredient on a series of markers characteristic (biological and / or clinical) of said disorder, in particular from human biological samples. Moreover, as is well known to those of skill in the art, the appropriate dose and associated dosage regimen for treating a given disease in a given patient will depend on a number of other factors, such as the stage of the disease and the physical and medical condition of the patient.

[0132] The present invention also relates to a compound of formula (I) or a pharmaceutical composition as defined above for use as a therapeutic active ingredient in a combined or add-on treatment regimen in a human in need thereof, in particular for inhibiting ferroptosis, more particularly for preventing and / or treating disorders associated with ferroptosis.

[0133] In some embodiments, the compounds of formula (I) of the present invention are administered to a human in need thereof simultaneously, separately or sequentially with a secondary active ingredient.

[0134] The compounds of formula (I) and / or pharmaceutical compositions defined above may be provided in combination products, which contain additional products, in particular secondary active ingredients, in particular intended for simultaneous, separate or sequential administration.

[0135] This secondary active ingredient is typically suitable for preventing and / or treating a disorder.

[0136] The present invention also relates to a kit comprising the pharmaceutical composition defined above and a delivery device (device that allows administration of the aforementioned composition), which is particularly suitable for parenteral enteral administration or topical administration.Examples of delivery devices include, but are not limited to, autoinjectors, particularly multi-chamber syringes, transdermal patches, pre-filled syringes, or needleless syringes.

[0137] The present invention also provides [ka] The present invention relates to a compound selected from the group consisting of: TIFF2024506530000029.tif249165TIFF2024506530000030.tif100165, and pharma- ceutically acceptable salts and / or solvates thereof.

[0138] Specifically, the compounds according to the present invention are selected from the group consisting of compounds 4 to 6, 8 to 18, 22, 28, 34 to 44, in particular 4 to 6, 8 to 18, 22, 28, and pharma- ceutically acceptable salts and / or solvates thereof.

[0139] The present invention also relates to a compound selected from the group consisting of compounds 4-6, 8-18, 22, 28, 29, 32, 34-44, in particular 4-6, 8-18, 22, 28, 34-44, specifically 4-6, 8-18, 22, 28, and pharma- ceutically acceptable salts and / or solvates thereof, for use as a medicament. [Brief description of the drawings]

[0140] [Figure 1]FIG. 1 shows dose-dependent protection by compound 6 against ferroptosis induced by erastin (Era), glutamate (Glu), or RSL3 (a (1S,3R)-RAS-selective lethal agent) in the mouse hippocampal neuronal cell line HT22. [Figure 2A] FIG. 2A shows dose-dependent protection by compound 6 against erastin (Era)-induced ferroptosis in the human neuroblastoma cell line SH-SY5Y. [Figure 2B] FIG. 2B shows dose-dependent protection by compound 25 against ferroptosis induced by erastin (Era) or RSL3 (a (1S,3R)-RAS-selective lethal agent) in the human neuroblastoma cell line SH-SY5Y. [Diagram 3] FIG. 3 depicts the ischemia-reperfusion model used in Example II.2. [Figure 4] FIG. 4 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of Compound 1 after hypoxic cold storage (4° C., 24 h) and a reoxygenation step (37° C., 6 h). [Diagram 5] FIG. 5 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 27 after hypoxic cold storage (4° C., 24 h) and a reoxygenation step (37° C., 6 h). [Figure 6] FIG. 6 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 5 after hypoxic cold storage (4° C., 24 h) and a reoxygenation step (37° C., 6 h). [Figure 7] FIG. 7 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 26 after hypoxic cold storage (4° C., 24 h) and a reoxygenation step (37° C., 6 h). [Figure 8] FIG. 8 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 25 after hypoxic cold storage (4° C., 24 h) and a reoxygenation step (37° C., 6 h). [Figure 9] FIG. 9 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 14 after hypoxic cold storage (4° C., 24 h) and a reoxygenation step (37° C., 6 h). [Figure 10] FIG. 10 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 11 after hypoxic cold storage (4° C., 24 h) and a reoxygenation step (37° C., 6 h). [Figure 11] FIG. 11 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 6 after hypoxic cold storage (4° C., 24 hours) and a reoxygenation step (37° C., 6 hours). [Figure 12] FIG. 12 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 12 after hypoxic cold storage (4° C., 24 hours) and a reoxygenation step (37° C., 6 hours). [Figure 13] FIG. 13 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 15 after hypoxic cold storage (4° C., 24 h) and a reoxygenation step (37° C., 6 h). [Figure 14] FIG. 14 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 13 after hypoxic cold storage (4° C., 24 h) and a reoxygenation step (37° C., 6 h). [Figure 15] FIG. 15 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 22 after hypoxic cold storage (4° C., 24 h) and a reoxygenation step (37° C., 6 h). [Figure 16] FIG. 16 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 20 after hypoxic cold storage (4° C., 24 hours) and a reoxygenation step (37° C., 6 hours). [Figure 17]FIG. 17 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of Compound 24 after hypoxic cold storage (4° C., 24 hours) and a reoxygenation step (37° C., 4 hours (gray) and 6 hours (black)). [Figure 18] FIG. 18 depicts the viability of human renal glomerular endothelial cells (hRGEC) treated with increasing concentrations of compound 7 after hypoxic cold storage (4° C., 24 hours) and a reoxygenation step (37° C., 4 hours (gray) and 6 hours (black)). [Figure 19] FIG. 19 depicts the viability of rat kidney cells (NRK-52E) treated with 200 μM cisplatin for 24 hours followed by increasing concentrations of a compound of the invention. [Figure 20] FIG. 20 depicts the viability of rat kidney cells (NRK-52E) treated with 200 μM cisplatin for 24 hours followed by increasing concentrations of a compound of the invention. [Figure 21] FIG. 21 depicts the viability of rat kidney cells (NRK-52E) treated with 200 μM cisplatin for 24 hours followed by increasing concentrations of a compound of the invention. [Figure 22] FIG. 22 depicts the viability of rat kidney cells (NRK-52E) treated with 200 μM cisplatin for 24 hours followed by increasing concentrations of a compound of the invention. [Figure 23] FIG. 23 depicts the viability of rat kidney cells (NRK-52E) treated with 200 μM cisplatin for 24 hours followed by increasing concentrations of a compound of the invention. [Figure 24] FIG. 24 depicts the viability of rat kidney cells (NRK-52E) treated with 200 μM cisplatin for 24 hours followed by increasing concentrations of a compound of the invention. [Diagram 25] FIG. 25 depicts dose-dependent protection by compounds 7, 1, 8, 9, 27, 25, 22, and 24 against NaIO 3 -induced retinal cell death in human retinal pigment epithelial cells (ARPE-19 cell line). [Figure 26]FIG. 26 shows dose-dependent protection by compound 16 against erastin (Era)-induced ferroptosis in human neuroblastoma cell line SH-SY5Y. [Figure 27] FIG. 27 shows dose-dependent protection by compound 17 against erastin (Era)-induced ferroptosis in human neuroblastoma cell line SH-SY5Y. [Figure 28] FIG. 28 shows dose-dependent protection by compound 18 against erastin (Era)-induced ferroptosis in human neuroblastoma cell line SH-SY5Y. [Figure 29] FIG. 29 shows cell viability of RPE cells after treatment with Compound 1 (SBL-02) prior to induction of phototoxicity compared to crocetin (CRO), a positive control (CONT-A2E), and a negative control (CONT+A2E). [Diagram 30] Figure 30 shows photopic ERGs measured at an intensity of 30 cd.s / m2 in mice treated intravitreally (IVT) with Compound 1 (SBL2) or its vehicle. I: injected eye, NI: non-injected eye, NINI: untreated or non-injected mouse. n=4 for VEH mice, n=5 for SBL2 mice, n=5 for NINI mice. [Diagram 31] Figure 31 shows scotopic ERG A measured at 5 levels of increasing light intensity in mice receiving IVT Compound 1 (SBL2 I) or its vehicle (VEH I). Uninjected eyes of the same mice served as controls (SBL2 NI and VEH NI). Uninjected mice in the absence of light (NINI) served as positive controls. n=4 for VEH mice, n=5 for SBL2 mice, and n=5 for NINI mice. [Diagram 32] Figure 32 shows scotopic ERG B measured at 5 levels of increasing light intensity in mice receiving IVT Compound 1 (SBL2 I) or its vehicle (VEH I). Uninjected eyes of the same mice served as controls (SBL2 NI and VEH NI). Uninjected mice in the absence of light (NINI) served as positive controls. n=4 for VEH mice, n=5 for SBL2 mice, and n=5 for NINI mice. [Diagram 33] FIG. 33 shows quantification of retinal thickness (expressed as distance from the optic nerve) in mice with and without intravitreal treatment with Compound 1 (SBL2). [Diagram 34] Figure 34 shows scotopic ERG A measured at 5 levels of increasing light intensity in mice treated with compound 7 (SBL1), its placebo (VEH), and no injection and no illumination (NINI). n=3 mice per injection group, and n=5 for NINI. [Diagram 35] Figure 35 shows scotopic ERG B measured at 5 levels of increasing light intensity in mice treated with compound 7 (SBL1), its placebo (VEH), and no injection and no illumination (NINI). n=3 mice per injection group, and n=5 for NINI. [Diagram 36] FIG. 36 shows quantification of retinal thickness in mice with and without intraperitoneal treatment with compound 7 (SBL2). [Figure 37] FIG. 37 shows the effects of Compound 7 (SBL-01) and Compound 1 (SBL-02) on the viability of dopaminergic neurons (TH staining) after 6-OHDA injury. [Figure 38] FIG. 38 shows the effect of compound 14 (SBL-571) on the viability of dopaminergic neurons (TH staining) after 6-OHDA injury. [Figure 39] FIG. 39 shows the effects of compound 22 (SBL-962) and compound 3 (SBL-1495) on the viability of dopaminergic neurons (TH staining) after 6-OHDA injury. [Diagram 40] FIG. 40 shows plasma levels of creatinine in an anesthetized rat model of ischemic acute renal failure induced by transient bilateral renal artery occlusion in rats with and without treatment with compound 7 (sibiriline). [Diagram 41]FIG. 41 shows plasma levels of urea in an anesthetized rat model of ischemic acute renal failure induced by transient bilateral renal artery occlusion in rats with and without treatment with compound 7 (sibiriline). EXAMPLES

[0141] The following abbreviations are commonly used in the art and are used in the examples below. [Table 1]

[0142] I. Synthesis of compounds according to the invention To prepare some compounds according to the invention, the general procedures A and B detailed below are followed.

[0143] General Procedure A: Buchwald-Hartwig CN Coupling of 4-Chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine A vial containing Pd2dba3 (17 mg, 0.1 equiv, 0.018 mmol), XPhos (17 mg, 0.2 equiv, 0.036 mmol), tBuONa (45 mg, 3 equiv, 0.54 mmol) and the corresponding amine (1.3 equiv, 0.23 mmol) was charged with 4-chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.18 mmol). The vial was placed under argon and dry dioxane was added before stirring at 100° C. for 16 h. After cooling, the reaction was diluted with EtOAc, filtered over a pad of Celite® and concentrated. The crude product was purified by flash chromatography to give the desired compound.

[0144] General Procedure B: Direct Amination of 4-Chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine A 0.5 mL microwave vial containing the phenol (21 mg, 2 equiv., 0.22 mmol) and the corresponding amine (2 equiv., 0.22 mmol) was charged with 4-chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (30 mg, 0.11 mmol). The vial was placed under argon and heated at 150 °C (neat) in a Biotage Initiator Microwave Reactor for 30 min. After cooling, the reaction was diluted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The crude product was purified by flash chromatography to give the desired compound.

[0145] Both procedures rely on the use of 4-chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine as the starting material. Another important compound, namely 2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine, is used to prepare some compounds according to the invention.

[0146] Synthesis of 4-chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine: [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (compound 23) (1 g, 4.1 mmol) was dissolved in anhydrous DMF (10 mL) under argon and MsCl was added dropwise (487 μL, 6.15 mmol, 1.5 equiv). The reaction was heated at 80° C. and stirred for 6 h, then cooled in an ice bath to give a precipitate. Water (40 mL) was added and the yellow solid was filtered, washed with more water, and dried under vacuum (696 mg, 65%). 1H-NMR(300MHz,DMSO-d6):1.35(t,J=7.0Hz,3H),4.09(q,J=7.0Hz,2H),6.85(d,J=2.1Hz,1H),7.02( d,J=8.8Hz,2H),7.17(d,J=5.2Hz,1H),7.92(d,J=8.8Hz,2H),8.12(d,J=5.2Hz,1H),12.39(bs,1H).

[0147] - Synthesis of (4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine: [ka] LDA was freshly prepared by adding a solution of nBuLi in hexanes (54 mL, 2.5 M, 135 mmol) dropwise to a solution of diisopropylamine (19 mL, 135 mmol) in anhydrous THF (150 mL) at -5°C and stirring for 20 min. A solution of 3-picoline (7 g, 75 mmol, 1 equiv) in anhydrous THF (100 mL) was then added dropwise at 0°C and the orange mixture was stirred for 20 min before adding a solution of 4-ethoxybenzonitrile (11.1 g, 75 mmol, 1 equiv) in anhydrous THF (100 mL) dropwise. After 1 h at 0°C, an additional solution of LDA in THF (150 mL) was added dropwise (prepared from 135 mmol, 54 mL of nBuLi and 19 mL of diisopropylamine) and the reaction was allowed to warm slowly to room temperature for 1 h before heating to reflux in a water bath for 2 h. After cooling, the yellow solution was carefully quenched with saturated NH4Cl (100 mL) and water (250 mL) was added. The precipitate was filtered, washed with diethyl ether and water, and dried under vacuum to give a pale yellow solid (11 g, 61%). 1 H-NMR(300MHz,DMSO-d6):1.35(t,J=7.1Hz,3H),4.07(q,J=7.1Hz,2H),6.78(d,J=2.2H z,1H),7.00-7.05(m,3H),7.85-7.89(m,3H),8.15(dd,J=4.7,1.6Hz,1H),12.0(bs,1H).

[0148] Other starting materials in the syntheses detailed below are either commercially available or can be readily prepared according to methods known to those skilled in the art.

[0149] Compound 1: 4-(1H-indol-2-yl)phenol [ka] 4-(1H-indol-2-yl)phenol was obtained by Fischer indole synthesis using phenylhydrazine and 4-hydroxyacetophenone as starting materials as described in Eur. J. Med. Chem., 2014, 74, 477-490. The desired compound was obtained as a brown solid (68%). 1 H NMR(300MHz;DMSO-d6):11.30(brs,1H),9.62(br s,1H);7.69(d,2H,J=7.2Hz);7.45(d,1H,J=7.7Hz);7.34(d,1H,J=7.7Hz);7.06-6.93(m,2H);6.82(d,2H,J=7.2Hz);6.68(s,1H).

[0150] Compound 2: 2-(4-methoxyphenyl)-1H-indole [ka] 2-(4-Methoxyphenyl)-1H-indole was obtained by Fischer indole synthesis using phenylhydrazine and 4-methoxyacetophenone as starting materials as described in Bioorg. Med. Chem. Lett., 2013, 23, 2671-2674. The desired compound was obtained as a light brown solid (56%). 1 H NMR(300MHz,CDCl3):8.50(br s,1H),7.61-7.58(m,3H),7.39(d,J=7.2Hz,1H),7.17(dt,J=7.2Hz,1.3Hz,1H), 7.10(dt,J=7.2Hz,1.3Hz,1H),6.98(d,J=8.7Hz,2H),6.71(s,1H),3.87(s,3H).

[0151] Compound 3: 2-(4-methoxyphenyl)-1H-indol-1-ol [ka] 1-(4-Methoxyphenyl)-2-(2-nitrophenyl)ethan-1-one (500 mg, 1.84 mmol) was dissolved in EtOAc:EtOH (9:1, 10 mL), tin chloride (1.47 g, 4.2 equiv, 7.74 mmol) was added in one portion, and the mixture was stirred at rt for 48 h. Brine was added, and the aqueous phase was extracted with EtOAc (2×30 mL), washed multiple times with water, dried over MgSO4, and concentrated to a red oil. Purification was carried out by flash chromatography (pure EtOAc followed by a gradient of 80:20 to 50:50 EtOAc:MeOH). The resulting solid was suspended in water, sonicated, filtered, and washed extensively with water. Drying under vacuum gave a pale beige solid (313 mg, 71%). 1 H NMR(300MHz,DMSO-d6)11.11(s,1H),7.81(d,J=9.0Hz,2H),7.50(d,J=7.8Hz,1H),7.39(d ,J=7.8Hz,1H),7.18-7.11(m,1H),7.12-6.94(m,3H),6.52(d,J=0.8Hz,1H),3.81(s,3H).

[0152] Compound 4: 2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-c]pyridine [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-c]pyridin-1-ol (50 mg, 0.2 mmol) was suspended in a mixture of acetic acid and ethanol (1:2, 9 mL) and iron powder was added (220 mg, 20 equiv, 3.9 mmol). The suspension was heated to reflux for 1 h and cooled to rt. Saturated NaHCO3 was carefully added and the reaction mixture was extracted with EtOAc (3 x 20 mL), washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (100:0 to 90:10 CH2Cl2:MeOH) to give a pale yellow solid (31 mg, 63%). 1 H NMR(300MHz,Methanol-d4):8.71(s,1H),8.06(d,J=6.0Hz,1H),7.92-7.80(m,2H),7.75(d, J=6.0Hz,1H),7.13-7.03(m,2H),7.00(s,1H),4.11(q,J=7.0Hz,2H),1.42(t,J=7.0Hz,3H).

[0153] Compound 5: 2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-c]pyridin-1-ol - Synthesis of 4-(4-ethoxystyryl)-3-nitropyridine: [ka] 4-Methyl-3-nitropyridine (7 g, 51 mmol) and 4-ethoxybenzaldehyde (8 g, 1.05 equiv, 54 mmol) were placed in a 120 mL pressure tube and dissolved in EtOH (60 mL). A catalytic amount of piperidine was added and the reaction was stirred at 110 °C until the starting material was consumed (approximately 72-96 h). The mixture was cooled to rt, concentrated to a volume of approximately 25 mL, and placed in a freezer, resulting in the formation of yellow crystals. A solid was obtained by filtration and washing with a minimal amount of cold EtOH, and purified by recrystallization from a mixture of hexanes:EtOAc (9:1). The crystals were filtered off, washed with hexanes, and dried under vacuum to give a bright yellow solid (11.3 g, 82%). 1H NMR(300MHz,CDCl3)δ 9.14(s,1H),8.69(d,J=5.4Hz,1H),7.66(d,J=5.4Hz,1H),7.55-7.44(m,3H),7.31(d ,J=16.1Hz,1H),6.92(d,J=6.8Hz,2H),4.08(q,J=7.0Hz,2H),1.44(t,J=7.0Hz,3H).

[0154] - Synthesis of N-(4-(4-ethoxystyryl)pyridin-3-yl)hydroxylamine: [ka] 4-(4-Ethoxystyryl)-3-nitropyridine (11 g, 41 mmol) was dissolved in a mixture of THF:MeOH (1:1, 600 mL) and cooled to 0° C. Sodium acetate (55.8 g, 10 equiv, 410 mmol) was added followed by tin chloride (46.3 g, 5 equiv, 205 mmol) in one portion. The reaction was stirred for 5 h while warming to rt, producing a thick orange slurry. TLC analysis showed no starting material, so the mixture was poured into ice-cold saturated NaHCO3 (1.5 L). The suspension was extracted with EtOAc:iPrOH (8:2, 4×600 mL) and the organic extract was washed with saturated NaHCO3, brine and dried over MgSO4. The solvent was removed to give a pale yellow solid (8.9 g, 85%). 1 H NMR(300MHz,DMSO-d6)δ 8.64(s,1H),8.54(d,J=1.8Hz,1H),8.38(s,1H),8.00(d,J=5.0Hz,1H),7.58(d,J=8.8Hz,2H),7.44(d,J=5.0Hz,1H) ,7.27(d,J=16.2Hz,1H),7.15(d,J=16.2Hz,1H),6.96(d,J=8.8Hz,2H),4.06(q,J=7.0Hz,2H),1.34(t,J=7.0Hz,3H).

[0155] - Synthesis of 2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-c]pyridin-1-ol: [ka] N-(4-(4-ethoxystyryl)pyridin-3-yl)hydroxylamine (9 g, 35 mmol) was suspended in a mixture of MeCN:H2O:AcOH (10:2:1, 390 mL) and cooled to -5 to 0 °C. DDQ (7.94 g, 1 equiv, 35 mmol) was added portionwise and stirred for 30 min to give a dark red solution, after which TLC analysis showed no starting material remaining. The crude product was quenched by addition of 1N HCl (100 mL) and diluted with Et2O (300 mL). The organic phase was extracted with 1N HCl and the combined aqueous layers were washed with Et2O:PE (1:1) until no DDQ by-product was extracted (3 x 500 mL). The aqueous layer was then transferred to an Erlinmeyer flask and made basic with saturated NaHCO3 under vigorous stirring. The precipitate was filtered off, washed with water, EtOAc, and finally Et2O, then dried under vacuum to give a brown solid (7.11 g, 80%). 1 H NMR(300MHz,DMSO-d6)δ 11.79(s,1H),8.73(s,1H),8.10(d,J=5.4Hz,1H),7.88(d,J=8.8Hz,2H),7.46(dd,J=5.4,1.0Hz,1H),7 .06(d,J=8.8Hz,2H),6.59(s,1H),4.10(q,J=7.0Hz,2H),3.16(d,J=4.9Hz,1H),1.36(t,J=7.0Hz,4H).

[0156] Compound 6: 2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-c]pyridin-1-yl benzoate [ka] (2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-c]pyridin-1-ol (compound 5) (1.95 g, 7.7 mmol) was placed under argon and dissolved in anhydrous CHCl (50 mL). Anhydrous pyridine (1.81 g, 1.8 mL, 23 mmol) was added, the mixture was cooled to approximately −15° C., and benzoyl chloride (1.33 mL, 1.6 g, 12 mmol) was added dropwise. The mixture was stirred for 1 h, warming back to 0° C., at which point TLC analysis indicated full conversion. The reaction was cooled to 0° C. with saturated N Quenched with aHCO3, extracted with CH2Cl2 (2 x 50 mL), dried over MgSO4, and concentrated to a brown oil. The product was purified by flash chromatography (silica gel neutralized with Et3N, CH2Cl2:MeOH gradient) to give 1.2 g of impure product. Further purification was carried out by dissolving in minimal Et2O, adding PE, and sonicating with stirring until a precipitate formed. The suspension was filtered and dried under vacuum to give a brown solid (912 mg, 32%). 1 H NMR(300MHz,CDCl3)δ 8.67(s,1H),8.35(s,1H),8.12(d,J=7.2Hz,2H),7.73-7.65(m,1H),7.62(d,J=8.8Hz,2H),7.52( t,J=7.8Hz,3H),6.91(d,J=8.8Hz,2H),6.62(s,1H),4.02(q,J=7.0Hz,2H),1.39(t,J=7.0Hz,3H).

[0157] Compound 7: 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)phenol [ka] 2-(4-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (1.06 g, 47.2 mmol) was placed in a 250 mL 3-neck round bottom flask equipped with an argon inlet and thermometer, suspended in anhydrous CHCl (50 mL) and cooled to -78 °C. Boron tribromide (1 M in CHCl, 141.7 mmol, 3 equiv.) was added dropwise and the dark brown mixture was stirred for 6 h while slowly warming to rt. The reaction was carefully quenched with saturated NaHCO solution (20 mL) and cooled to 0 °C, after which 2 M NaOH was added until the precipitated solid was almost completely dissolved (50 mL). The solution was stirred for 10 min, then loaded into a separatory funnel and washed with dichloromethane. The aqueous phase was then neutralized by dropwise addition of 6 M HCl under stirring. Filtration gave a brown solid, which was washed with saturated NaHCO3 solution and water to give 828 mg of crude product after drying under hivac®. Purification was achieved by recrystallization in nPrOH by adding a small amount of hexane (3 mL) to nPrOH (8 mL) and then heating to reflux. The solution was cooled to rt and kept at -20°C overnight. Filtration gave a light brown solid (535 mg, 54%). 1 H-NMR(300MHz,CDCl3):6.70(d,J=2.0Hz,1H),6.85(d,J=8.7Hz,2H),7.02(dd,J=7.8,4.7Hz,1H),7.76( d,J=8.7Hz,2H),7.85(dd,J=7.8,1.3Hz,1H),8.14(dd,J=4.7,1.3Hz,1H),9.71(bs,1H),11.93(bs,1H).

[0158] Compound 8: 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)phenylglycinate - 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl(tert-butoxycarbonyl)glycinate: [ka] 4-(1H-Pyrrolo[2,3-b]pyridin-2-yl)phenol (compound 7) (180 mg, 0.87 mmol) was suspended in CHCl (6 mL) containing DMAP (138 mg, 1.3 equiv, 1.13 mmol) and Boc-Gly-OH (182 mg, 1.2 equiv, 1.04 mmol) and EDCI-HCl (210 mg, 1.3 equiv, 1.13 mmol) were added. The mixture was stirred at rt for 16 h, after which water and EtOAc (15 mL each) were added. The crude mixture was extracted (2×15 mL), washed with brine, dried over MgSO and concentrated to a solid. Purification was carried out by flash chromatography (PE:EtOAc 80:20 to 0:100) to give a white solid (120 mg, 37%). 1 H NMR(300MHz,DMSO-d6)δ 12.15(s,1H),8.22(dd,J=4.7,1.6Hz,1H),8.06-7.88(m,3H),7.44(t,J=5.3Hz,1H),7.23(d,J=8 .8Hz,2H),7.07(dd,J=7.8,4.7Hz,1H),6.92(d,J=2.1Hz,1H),4.00(d,J=6.0Hz,2H),1.42(s,9H).

[0159] - Synthesis of 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)phenylglycinate hydrochloride: [ka] 4-(1H-Pyrrolo[2,3-b]pyridin-2-yl)phenyl(tert-butoxycarbonyl)glycinate (110 mg, 0.29 mmol) was dissolved in anhydrous dioxane (5 mL) and dry HCl (4 M in dioxane, 2.9 mL, 40 equiv, 11.6 mmol) was added dropwise. The suspension was stirred at rt for 16 h and filtered. The resulting paste was washed with EtOAc, CHCl and dried under vacuum to give a white solid (100 mg, quant.) containing residual dioxane. 1H NMR(300MHz,DMSO-d6)12.77(s,1H),8.64(br s,3H),8.30(dd,J=5.0,1.5Hz,1H),8.18(d,J=7.9Hz,1H),8.08(d,J=8.8Hz,2H),7.33(d ,J=8.8Hz,2H),7.24(dd,J=7.9,5.0Hz,1H),7.07(d,J=1.8Hz,1H),4.13(d,J=5.6Hz,2H).

[0160] Compound 9: 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl L-cysteinate - 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl(tert-butoxycarbonyl)-L-cysteinate: [ka] 4-(1H-Pyrrolo[2,3-b]pyridin-2-yl)phenol (compound 7) (50 mg, 2 equiv., 0.24 mmol) was suspended in CHCl (5 mL) containing DMAP (35 mg, 2.4 equiv., 0.29 mmol) and (Boc-Cys-OH) (52 mg, 1 equiv., 0.12 mmol) and EDCI-HCl (59 mg, 2.4 equiv., 0.29 mmol) were added. The mixture was stirred at rt for 16 h, after which the solvent was concentrated and water (20 mL) was added. The resulting suspension was sonicated, filtered, and washed with water, EtOAc, CHCl, and MeOH. A pale beige solid (52 mg, 53%) was isolated as the disulfide by drying under vacuum. 1H NMR(400MHz,DMSO-d6)δ 12.15(s,2H),8.21(d,J=4.5Hz,2H),7.98(d,J=8.5Hz,4H),7.92(d,J=8.0Hz,2H),7.78-7.6 8(m,2H),7.22(d,J=8.5Hz,4H),7.06(dd,J=8.0,4.5Hz,2H),6.90(d,J=1.5Hz,2H),4.55(br s,2H),3.37(t,J=11.6Hz,2H,obscured by water peak),3.17(t,J=11.6Hz,2H),1.43(s,18H).

[0161] - Synthesis of 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl L-cysteinate dihydrochloride: [ka] 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl(tert-butoxycarbonyl)-L-cysteinate (60 mg, 0.07 mmol) was dissolved in anhydrous dioxane (5 mL) and dry HCl (4 M in dioxane, 720 μL, 40 equiv, 2.9 mmol) was added dropwise. The suspension was stirred at rt for 16 h and filtered. The resulting paste was washed with CHCl, EtOAc, acetone, MeOH and dried under vacuum to give a beige solid corresponding to compound 9 in its oxidized form (45 mg, 90%). 1 H NMR(300MHz,DMSO-d6)δ 12.53(s,2H),9.11(s,6H),8.27(dd,J=4.9,1.5Hz,2H),8.06(d,J=8.8Hz,6H),7.37(d ,J=8.8Hz,4H),7.17(dd,J=7.8,4.9Hz,2H),6.99(d,J=1.8Hz,2H),3.65-3.58(m,4H).

[0162] Compound 10: 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl 3-Hydroxy-2-(hydroxymethyl)-2-methylpropanoate [ka] 4-(1H-Pyrrolo[2,3-b]pyridin-2-yl)phenol (compound 7) (20 mg, 0.09 mmol) was suspended in CHCl (5 mL) containing DMAP (14 mg, 1.2 equiv, 0.11 mmol) and 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid (17 mg, 1 equiv, 0.09 mmol) and EDCI-HCl (22 mg, 1.2 equiv, 0.11 mmol) were added. After stirring the mixture at rt for 16 h, the solvent was concentrated and water (10 mL) and EtOAc (10 mL) were added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO and concentrated to give the protected bis-MPA ester as a white solid (40 mg) which was used without further purification. The crude product was dissolved in THF (5 mL) containing aqueous HCl (200 μL, excess) and stirred at rt for 1 h. The reaction was quenched with saturated NaHCO3, extracted with EtOAc (2×20 mL), and the organic phase was washed with brine, dried over MgSO4, and concentrated. Purification was carried out by flash chromatography (100:0 to 90:10 CH2Cl2:MeOH gradient) to give a white solid (15 mg, 48%). 1 H NMR(300MHz,DMSO-d6)δ 12.14(s,1H),8.21(dd,J=4.7,1.6Hz,1H),8.07-7.86(m,3H),7.18(d,J=8.7Hz,2H),7.07(dd,J=7.8,4.7Hz,1H),6. 92(d,J=2.1Hz,1H),4.95(t,J=5.5Hz,2H),3.70(dd,J=10.5,5.5Hz,2H),3.55(dd,J=10.5,5.5Hz,2H),1.23(s,3H).

[0163] Compound 11: (4-((2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)phenyl)(phenyl)methanone [ka] General procedure A was followed using 4-aminobenzophenone (37 mg, 46%). 1 H-NMR(300MHz,DMSO-d6):1.35(t,J=7.0Hz,3H),4.08(q,J=7.0Hz,2H),6.89(d,J=2.1Hz,1H),6.97(d,J=5.5Hz,1H),7.02(d,J =8.9Hz,2H),7.40(d,J=8.8Hz,2H),7.51-7.69(m,3H),7.71-7.82(m,6H),8.02(d,J=5.5Hz,1H),9.23(bs,1H),11.95(bs,1H).

[0164] Compound 12: N-benzyl-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-amine [ka] General procedure A was followed using benzylamine (32 mg, 51%). 1 H-NMR(300MHz,DMSO-d6):1.35(t,J=7.0Hz,3H),4.07(q,J=7.0Hz,2H),4.49(d,J=6.0Hz,2H),6.05(d,J=5.6Hz,1H), 6.90(d,J=1.9Hz,1H),6.99(d,J=8.9Hz,2H),7.19-7.25(m,2H),7.30-7.42(m,4H),7.65-7.78(m,3H),11.58(bs,1H).

[0165] Compound 13: 2-(4-ethoxyphenyl)-4-(piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridine [ka] General procedure B was followed using piperidine (11 mg, 31%). 1H-NMR(300MHz,DMSO-d6):1.34(t,J=7.0Hz,3H),1.60-1.72(m,6H),3.36-3.41(m,4H),4.07(q,J=7.0Hz,2H),6.39 (d,J=5.5Hz,1H),6.78(s,1H),6.98(d,J=8.8Hz,2H),7.84(d,J=8.8Hz,2H),7.90(d,J=5.5Hz,1H),11.77(bs,1H).

[0166] Compound 14: 2-(4-ethoxyphenyl)-N-phenyl-1H-pyrrolo[2,3-b]pyridin-4-amine [ka] General procedure A was followed using aniline (18 mg, 30%). 1 H-NMR(300MHz,MeOD-d4):1.43(t,J=7.0Hz,3H),4.10(q,J=7.0Hz,2H),6.75(d,J=5.9Hz,1H),6.82(s,1H),7 .00(d,J=8.8Hz,2H),7.13(t,J=6.8Hz,1H),7.32-7.45(m,4H),7.72(d,J=8.9Hz,2H),7.85(d,J=5.9Hz,1H).

[0167] Compound 15: 2-(4-ethoxyphenyl)-4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine [ka] General procedure B was followed using N-methylpiperazine (5 mg, 13%). 1 H-NMR(300MHz,MeOD-d4):1.41(t,J=6.9Hz,3H),2.41(s,3H),2.69-2.73(d,J=4.5Hz,4H),3.51-3.56(d,J=4.5Hz ,4H),4.08(q,J=6.9Hz,2H),6.50(s,1H),6.72(s,1H),6.98(d,J=8.7Hz,2H),7.73(d,J=8.7Hz,2H),7.92(s,1H).

[0168] Compound 16: 2-(4-ethoxyphenyl)-3-((4-methylpiperazin-1-yl)methyl)-1H-pyrrolo[2,3-b]pyridine [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.42 mmol) was added to a solution of N-methylpiperazine (235 μL, 5 equiv, 2.1 mmol) and formaldehyde (37% aqueous, 170 μL, 5 equiv, 2.1 mmol) in acetic acid (5 mL). The solution was heated to 70 °C and stirred for 18 h. The mixture was concentrated in vacuo and quenched with saturated NaHCO3. The residue was extracted with CHCl2 (3 × 30 mL), washed with brine, dried over MgSO4, and concentrated to give a yellow paste. Purification was carried out by flash chromatography (98:2 to 92:8 CH2Cl2:MeOH) to give a pale beige solid (85 mg, 58%). 1 H NMR(300MHz,CDCl3)11.39(s,1H),8.18(d,J=3.8Hz,1H),8.05(d,J=7.9Hz,1H),7.76(d,J=8.7Hz,2H),7.16-7.01(m,3H),4.14(q,J=7.0Hz,2H),3.81(br s,2H),2.79(br s,8H),2.52(s,3H),1.49(t,J=7.0Hz,3H).

[0169] Compound 17: 2-(4-ethoxyphenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.67 mmol) was suspended in CHCl (10 mL) at 0° C. and N-iodosuccinimide (415 mg, 1.1 equiv, 1.84 mmol) was added portionwise. The mixture was stirred for 2 h at rt and concentrated in vacuo. The residue was suspended in water (20 mL), filtered, washed with CHCl, EtO, water and dried in vacuo to give a brown solid (220 mg, 36%). 1 H NMR(300MHz,DMSO-d6)8.25(d,J=4.7Hz,1H),7.79(d,J=8.0Hz,2H),7.68(d,J =7.8Hz,1H),7.20-6.99(m,3H),4.12(q,J=7.0Hz,2H),1.37(t,J=7.0Hz,3H).

[0170] Compound 18: 1-(2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2-trifluoroethan-1-ol -1-(2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2-trifluoroethan-1-one: [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.67 mmol) was dissolved in anhydrous DMF (10 mL) and trifluoroacetic anhydride (700 μL, 3 equiv, 5.03 mmol) was added dropwise at rt and the mixture was heated at 70° C. for 48 h. TLC analysis indicated starting material remained so additional trifluoroacetic anhydride (3 equiv) was added with heating for 24 h. The reaction was cooled to rt, quenched by dropwise addition of water (10 mL) and concentrated in vacuo. The residue was suspended in water, extracted with EtOAc (3×20 mL), washed with brine, dried over MgSO4 and concentrated to give a brown solid. Purification was carried out by flash chromatography (90:10 to 60:40 EtOAc:PE) to give a light brown solid (480 mg, 86%). 1 H NMR(300MHz,CDCl3)10.85(br s,1H),8.79(d,J=8.1Hz,1H),8.28(d,J=5.3Hz,1H),7.66(d,J=8.7Hz,2H),7.57- 7.53(m,1H),7.03(d,J=8.7Hz,2H),4.13(q,J=7.0Hz,2H),1.46(t,J=7.0Hz,3H).

[0171] - 1-(2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2-trifluoroethan-1-ol: [ka] 1-(2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2-trifluoroethan-1-one (50 mg, 0.15 mmol) was suspended in methanol (5 mL), cooled to 0° C., and sodium borohydride (6 mg, 1 eq, 0.15 mmol) was added. The reaction was stirred for 3 h while warming to room temperature, quenched with water, and extracted with EtOAc (2×10 mL). The organic phase was washed with brine, dried over MgSO4, and concentrated to give a white solid (47 mg, 95%). 1 H NMR(300MHz,CDCl3)8.40(d,J=7.8Hz,3H),8.14-8.05(m,1H),7.50(d,J=8.7Hz,2H),7.23-7.16( m,1H),7.01(d,J=8.7Hz,2H),5.41(q,J=7.2Hz,1H),4.11(q,J=7.0Hz,2H),1.47(t,J=7.0Hz,3H).

[0172] Compound 19: 2-(4-ethoxyphenyl)-1-(5-nitropyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine - Synthesis of 2-chloro-3-((4-ethoxyphenyl)ethynyl)pyridine: [ka] 2-Chloro-3-iodopyridine (500 mg, 2.09 mmol) was placed under argon and dissolved in anhydrous THF (10 mL). Et3N (1.44 mL, 5 equiv, 10 mmol) and 1-ethoxy-4-ethynylbenzene (365 mg, 1.2 equiv, 2.5 mmol) were added, followed by CuI (10 mg, 0.025 equiv, 0.05 mmol) and PdCl2(PPh3)2 (37 mg, 0.025 equiv, 0.05 mmol). The dark brown mixture was stirred at rt for 3 h, after which water (20 mL) and CHCl2 (20 mL) were added. The aqueous layer was extracted with CHCl2 and the organic extract was washed with water and brine, dried over MgSO4, and concentrated. The crude product was purified by flash chromatography (PE:EtOAc 85:15) to give the desired compound (440 mg, 82%). 1 H-NMR(300MHz,CDCl3):1.43(t,J=7.0Hz,3H),4.06(q,J=7.0Hz,2H),6.87(d,J=8.8Hz,2H),7.22(dd ,J=7.7,4.8Hz,1H),7.49(d,J=8.8Hz,2H),7.82(dd,J=7.7,1.9Hz,1H),8.31(dd,J=4.8,1.9Hz,1H).

[0173] - Synthesis of 2-(4-ethoxyphenyl)-1-(5-nitropyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine: [ka] To a vial containing Pd2dba3 (18 mg, 0.1 equiv, 0.019 mmol), Xantphos (22 mg, 0.2 equiv, 0.036 mmol), Cs2CO3 (189 mg, 3 equiv, 0.58 mmol), and 2-amino-5-nitropyridine (34 mg, 1.3 equiv, 0.25 mmol) was charged 2-chloro-3-((4-ethoxyphenyl)ethynyl)pyridine (50 mg, 0.19 mmol). The vial was placed under argon and anhydrous dioxane was added before stirring at 100 °C for 16 h. After cooling, the reaction was diluted with EtOAc, filtered over a pad of Celite®, and concentrated. The crude product was purified by flash chromatography (90:10 EtOAc:PE) to give a yellow solid (17 mg, 24%). 1 H-NMR(300MHz,CDCl3):1.45(t,J=7.0Hz,3H),4.06(q,J=7.0Hz,2H),6.74(s,1H),6.81-6.90(m,2H),7.15 -7.28(m,3H),7.95-8.02(m,2H),8.34(d,J=4.1Hz,1H),8.63(dd,J=8.9,2.8Hz,1H),9.27(d,J=2.4Hz,1H).

[0174] Compound 20: 4-(2-(2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl)morpholine [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.21 mmol) was dissolved in anhydrous DMF (2 mL) under argon and treated with K2CO3 (145 mg, 5 equiv, 1.05 mmol) and stirred at rt for 15 min, followed by addition of 4-(2-chloroethyl)morpholine hydrochloride (58 mg, 1.5 equiv, 0.32 mmol). The mixture was stirred at 70° C. for 18 h, concentrated in vacuo, and the residue was purified by flash chromatography (98:2 CH2Cl2:MeOH) to give the N1 regioisomer as a yellow oil (19 mg, 26%). N1-substituted compounds 1H-NMR(300MHz,CDCl3):1.46(t,J=7.0Hz,3H),2.23-2.39(m,4H),2.63(t,J=6.9Hz,2H),3.46-3.62(m,4H),4.10(q,J=7.0Hz,2H),4.46(t,J=6.9 Hz,2H),6.41(s,1H),6.95-7.03(m,2H),7.06(dd,J=7.8,4.8Hz,1H),7.44-7.51(m,2H),7.87(dd,J=7.8,1.6Hz,1H),8.30(dd,J=4.8,1.6Hz,1H).

[0175] Compound 21: tert-Butyl 4-chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate [ka] 4-Chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.18 mmol) was suspended in anhydrous CHCl (5 mL) under argon and DMAP (5 mg) was added followed by EtN (28 μL, 1.1 equiv, 0.20 mmol) and BocO (43 mg, 1.1 equiv, 0.20 mmol) and the mixture was stirred at rt for 4 h before water was added. The organic layer was washed with brine, dried over MgSO, filtered and concentrated. The crude product was purified by flash chromatography (90:10 PE:EtOAc) to give a white solid (45 mg, 71%). 1 H-NMR(300MHz, CDCl3):1.32(s,9H),1.45(t,J=7.0Hz,3H),4.09(q,J=7.0Hz,2H),6.56(s,1H) ),6.96(d,J=8.8Hz,2H),7.21(d,J=5.3Hz,1H),7.36(d,J=8.8Hz,2H),8.36(d,J=5.3Hz,1H).

[0176] Compounds 22 and 38: 1-acetyl-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl acetate [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (compound 23) (100 mg, 0.39 mmol) was suspended in acetic anhydride (3 mL) and stirred at reflux for 16 h. The solution was cooled to rt and saturated NaHCO3 was added slowly to quench excess reagent. The mixture was extracted with EtOAc (2 x 20 mL), washed with brine, dried over MgSO4, and concentrated to an oil. Purification was carried out by flash chromatography (70:30 PE:EtOAc) to give a white solid (54 mg, 41%). 1 H NMR(300MHz,CDCl3)7.91(d,J=8.2Hz,1H),7.32(d,J=8.8Hz,2H),6.96-6.91(m,3H), 6.52(s,1H),4.07(q,J=7.0Hz,2H),2.99(s,3H),2.38(s,3H),1.44(t,J=7.0Hz,3H).

[0177] Continued elution (50:50 PE:EtOAc) afforded a second crop (compound 38, containing only O-acetate) as a pale yellow foam (23 mg, 20%). 1 H NMR(300MHz,CDCl3)δ 9.17(s,1H),7.93(dd,J=8.2,0.7Hz,1H),7.57(d,J=8.8Hz,2H),6.98(d,J=8.8Hz,2H),6.83(d, J=8.2Hz,1H),6.66(d,J=2.2Hz,1H),4.09(q,J=7.0Hz,2H),2.29(s,3H),1.45(t,J=7.0Hz,3H).

[0178] Compound 23: 2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (2 g, 8.4 mmol) was suspended in a mixture of EtOAc (10 mL) and hexanes (40 mL) under argon and cooled to 0° C. mCPBA (2.7 g, 12.6 mmol, 1.5 equiv) was added in one portion and the reaction was allowed to warm slowly to rt and stirred for 12 h. The solvent was removed in vacuo and the residue was suspended in saturated K2CO3 solution (50 mL), stirred vigorously for 30 min, filtered, washed with water and dried under vacuum to give a yellow solid (1.5 g, 70%). 1 H-NMR(300MHz,DMSO-d6):1.35(t,J=7.1Hz,3H),4.08(q,J=7.1Hz,2H),6.92(s,1H),6.99-7. 09(m,3H),7.56(d,J=7.1Hz,1H),7.96(d,J=8.8Hz,2H),8.08(d,J=6.3Hz,1H),12.7(bs,1H).

[0179] Compound 24: 2-(4-ethoxyphenyl)-N,N-diisopropyl-7H-pyrrolo[2,3-b]pyridine-7-carboxamide [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.21 mmol) was dissolved in dry DMF (2 mL) and NaH (60% dispersion, 25 mg, 3 equiv, 0.63 mmol) was added at rt. After 15 min, N,N-diisopropylcarbamoyl chloride (41 mg, 1.2 equiv, 0.25 mmol) was added in one portion and the mixture was stirred for 16 h. More electrophile was added (1.2 equiv) and the reaction was stirred for 16 h before being quenched with water and extracted with EtOAc (2×10 mL). The extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (90:10 to 80:20 PE:EtOAc) to give a yellow solid (8 mg, 5%). 1H-NMR(300MHz,CDCl3):1.08(d,J=6.6Hz,3H),1.29(d,J=6.6Hz,3H),1.43(t,J=7.0H z,3H),1.63(d,J=6.7Hz,3H),1.77(d,J=6.7Hz,3H),3.25-3.39(m,1H),3.66-3.78(m, 1H),4.08(q,J=7.0Hz,2H),6.81(dd,J=7.3,6.4Hz,1H),6.89(s,1H),6.93(d,J=8.9Hz ,2H),7.51(dd,J=6.4,1.1Hz,1H),7.93(dd,J=7.3,1.1Hz,1H),8.06(d,J=8.9Hz,2H).

[0180] Compound 25: Benzyl 2-(4-ethoxyphenyl)-7H-pyrrolo[2,3-b]pyridine-7-carboxylate [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.21 mmol) was dissolved in anhydrous DMF (2 mL) under argon and treated with powdered KOH (35 mg, 3 equiv, 0.63 mmol) and stirred at rt for 15 min, after which benzyl chloroformate (36 μL, 1.2 equiv, 0.25 mmol) was added. The mixture was stirred at rt for 18 h, concentrated in vacuo, and the residue was purified by flash chromatography (CHCl) to give a brown solid (13 mg, 17%). 1 H-NMR(300MHz,CDCl3):1.44(t,J=7.0Hz,3H),4.10(q,J=7.0Hz,2H),5.93(s,2H),6.74(dd,J=7.3,6.4Hz,1H ),6.92(s,1H),6.97(d,J=8.9Hz,2H),7.31-7.50(m,6H),7.92(dd,J=7.4,1.0Hz,1H),8.11(d,J=8.9Hz,2H).

[0181] Compound 26: 7-benzyl-2-(4-ethoxyphenyl)-7H-pyrrolo[2,3-b]pyridine [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.21 mmol) was dissolved in anhydrous DMF (2 mL) under argon and treated with powdered KOH (35 mg, 3 equiv, 0.63 mmol) and stirred at rt for 15 min, after which BnBr (30 μL, 1.2 equiv, 0.25 mmol) was added. The mixture was stirred at rt for 12 h, quenched with saturated NH4Cl, and extracted with CHCl2 (2×10 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (60:40 PE:EtOAc) to give the N7 regioisomer as a yellow solid (26 mg, 38%). 1 H-NMR(300MHz,CDCl3):1.45(t,J=7.0Hz,3H),4.10(q,J=7.0Hz,2H),5.92(s,2H),6.72(dd,J=7.4,6.3Hz ,1H),6.93(s,1H),6.95-7.03(m,2H),7.31-7.51(m,6H),7.91(dd,J=7.4,1.1Hz,1H),8.07-8.18(m,2H).

[0182] Compound 27: 2-(4-ethoxyphenyl)-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-b]pyridine [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.21 mmol) was dissolved in anhydrous DMF (2 mL) under argon, nBu4NI (8 mg, 0.1 equiv, 0.021 mmol) was added, and the reaction was treated with NaH (42 mg, 5 equiv, 1.05 mmol) and stirred at rt for 15 min before adding PMBCl (36 mg, 1.1 equiv, 0.23 mmol). The mixture was stirred at rt for 12 h, quenched with water, and extracted with EtOAc (2×10 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (60:40 PE:EtOAc) to give the N7 regioisomer as a yellow oil (16 mg, 20%). 1 H-NMR(300MHz,CDCl3):1.45(t,J=7.0Hz,3H),3.81(s,3H),4.10(q,J=7.0Hz,2H),5.85(s,2H),6.72(dd,J=7.4,6.3Hz,1H),6.83-6.90(m,2H) ),6.91(s,1H),6.97(d,J=8.9Hz,2H),7.39(dd,J=6.3,1.1Hz,1H),7.44(d,J=8.7Hz,2H),7.90(dd,J=7.4,1.1Hz,1H),8.11(d,J=8.9Hz,2H).

[0183] Compound 28: (4-(7-benzyl-2-(4-ethoxyphenyl)-7H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)(phenyl)methanone - (4-(2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)(phenyl)methanone: [ka] A vial containing Pd(OAc)2 (4 mg, 0.1 equiv, 0.018 mmol), SPhos (15 mg, 0.2 equiv, 0.036 mmol), K2CO3 (65 mg, 3 equiv, 0.54 mmol), and (4-benzoylphenyl)boronic acid (49 mg, 1.2 equiv, 0.22 mmol) was charged with 4-chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.18 mmol). The vial was placed under argon and a mixture of dioxane (1.8 mL) and water (0.2 mL) was added, followed by stirring at 100 °C for 16 h. After cooling, the reaction was diluted with EtOAc and water, extracted with EtOAc (3 x 10 mL), washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (70:30 PE:EtOAc) to give a yellow solid (50 mg, 65%). 1 H-NMR(300MHz,CDCl3):1.47(t,J=7.0Hz,1H)1.47(t,J=7.0Hz,3H),4.13(q,J=7.0Hz,2H),6.90(s,1H),7.05(d,J=8.8Hz,2H) ,7.23(d,J=5.1Hz,1H),7.54(t,J=7.4Hz,2H),7.62(d,J=5.0Hz,1H),7.86-8.01(m,8H),8.33(d,J=5.0Hz,1H),12.53(s,1H).

[0184] -Synthesis of compound 28: [ka] (4-(2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)(phenyl)methanone (30 mg, 0.07 mmol) was dissolved in dry DMF (1 mL) and NaH (60% dispersion, 12 mg, 3 equiv, 0.22 mmol) was added. After 15 min, benzyl bromide (10 μL, 1.2 equiv, 0.08 mmol) was added and the reaction was stirred at room temperature for 16 h. The mixture was quenched with water and extracted with EtOAc (2×10 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (60:40 PE:EtOAc) to give the N7 regioisomer as an orange oil (12 mg, 32%). 1 H NMR(300MHz,CDCl3)8.16(d,J=8.8Hz,2H),8.03-7.83(m,6H),7.66-7.47(m,6H),7.39-7.34(m, 3H),7.12(s,1H),7.03-6.92(m,3H),6.06(s,2H),4.10(q,J=7.0Hz,2H),1.44(t,J=7.0Hz,3H).

[0185] Compound 29: tert-Butyl 2-(4-hydroxyphenyl)-1H-indole-1-carboxylate [ka] 4-(1H-indol-2-yl)phenol (200 mg, 0.96 mmol, 1 equiv) was placed under argon in a 25 mL flask, suspended in CHCl (10 mL) and cooled to 0° C. DMAP (12 mg, 0.09 mmol, 0.1 equiv) was added followed by BocO (250 mg, 1.14 mmol, 1.2 equiv) and the mixture was stirred for 4 h warming to rt. Water was added and the mixture was extracted with EtOAc (2×20 mL), washed with water, dried over MgSO and concentrated. Purification by flash chromatography (90:10 PE:EtOAc) gave a brown solid (177 mg, 60%). 1H NMR(300MHz,CDCl3)δ 8.33(s,1H),7.72-7.62(m,3H),7.42(dd,J=8.0,1.0Hz,1H),7.33-7.11(m,4H),6.81(dd,J=2.2,0.9Hz,1H),1.61(s,9H).

[0186] Compound 30: 4-(5-bromo-1H-indol-2-yl)phenol [ka] 4-Bromophenylhydrazine hydrochloride (5 g, 22.4 mmol, 1 equiv) and 4-hydroxyacetophenone (3.2 g, 23.5 mmol, 1.05 equiv) were dissolved in EtOH (50 mL) and heated to reflux for 4 h. The mixture was concentrated in vacuo to give the intermediate hydrazone, which was suspended in MsOH (40 mL) under argon. The suspension was heated at 90° C. for 7 h, cooled to rt, and quenched by careful addition to saturated NaHCO3. The product was extracted with a mixture of EtOAC:iPrOH (8:2, 3×100 mL), washed with brine, dried over MgSO4, and concentrated to a black solid. The crude product was recrystallized in a mixture of toluene:EtOAc (95:5), cooled to −20° C., and filtered. This process was repeated with the concentrated mother liquor, and both crops were combined to give a grey solid (3.9 g, 60%). 1 H NMR(300MHz,DMSO-d6)δ 11.53(s,1H),9.68(s,1H),7.70-7.63(m,3H),7.30(d,J=8.5Hz,1H),7.14(dd,J=8.5,2.0Hz,1H),6.85(d,J=8.7Hz,2H),6.67(d,J=2.1Hz,1H).

[0187] Compound 31: 2-(4-(benzyloxy)phenyl)-1H-indole [ka] Indole (274 mg, 2.34 mmol, 1 equiv) and 4-benzyloxyphenylboronic acid (800 mg, 3.5 mmol, 1.5 equiv) were placed in a 25 mL flask and dissolved in acetic acid (10 mL). Pd(OAc)2 (52 mg, 0.23 mmol, 0.1 equiv) was added and the mixture was stirred vigorously at rt in air for 20 h. The reaction was quenched by careful addition to saturated NaHCO3 and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, and concentrated to a brown oil. Purification by flash chromatography (100:0 to 90:10 CH2Cl2:MeOH) gave a light brown solid (380 mg, 54%). 1 H NMR(300MHz,DMSO-d6):δ 11.40(s,1H),7.79(d,J=8.9Hz,2H),7.50-7.34(m,7H),7.11(d,J=8.9Hz,2H ),7.08-7.02(m,1H),7.00-6.94(m,1H),6.76(d,J=1.4Hz,1H),5.17(s,2H).

[0188] Compound 32: 2-(4-(benzyloxy)phenyl)-1H-indol-5-ol [ka] 5-Hydroxyindole (311 mg, 2.34 mmol, 1 equiv) and 4-benzyloxyphenylboronic acid (800 mg, 3.5 mmol, 1.5 equiv) were placed in a 25 mL flask and dissolved in acetic acid (10 mL). Pd(OAc)2 (52 mg, 0.23 mmol, 0.1 equiv) was added and the mixture was stirred vigorously in air at rt for 20 h. The reaction was quenched by careful addition to saturated NaHCO3 and extracted with a mixture of EtOAc:iPrOH (8:2). The organic extract was washed with brine, dried over MgSO4, and concentrated to a black solid. Purification by flash chromatography (100:0 to 80:20 CH2Cl2:EtOAc) gave a contaminated light brown solid. The mixture was triturated in CHCl2 (5 mL) and filtered to give an off-white solid (115 mg, 16%). 1 H NMR(300MHz,DMSO-d6)δ 11.07(d,J=2.2Hz,1H),8.61(s,1H),7.73(d,J=8.7Hz,2H),7.50-7.33(m,5H),7.15(d,J= 8.6Hz,1H),7.10(d,J=8.7Hz,2H),6.80(d,J=2.3Hz,1H),6.60-6.55(m,2H),5.15(s,2H).

[0189] Compound 33: 4-(1-methyl-1H-indol-2-yl)phenol [ka] N-Methylindole (190 μL, 1.52 mmol, 1 equiv) was placed in a 25 mL flask under argon with Pd(OAc)2 (17 mg, 0.08 mmol, 0.05 equiv), Ag2O (283 mg, 1.22 mmol, 0.8 equiv), 4-iodophenol (669 mg, 3.04 mmol, 2 equiv), and 2-nitrobenzoic acid (381 mg, 2.28 mmol, 1.5 equiv). Dry DMF (8 mL) was added and the reaction was stirred at rt for 16 h. The mixture was filtered over Celite® and washed with additional EtOAc and brine. The aqueous phase was extracted with EtOAc (2×30 mL) and the organic extract was washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (95:5 to 80:20 PE:EtOAc) afforded a beige waxy solid (139 mg, 36%). 1 H NMR(300MHz,CDCl3)δ 7.65-7.60(m,1H),7.38(d,J=8.6Hz,2H),7.26-7.20(m,1H),7.16-7.10(m,1H),6.93(d,J=8.6Hz,2H),6.50(d,J=0.8Hz,1H),3.72(s,3H).

[0190] Compound 34: 2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-c]pyridin-1-yl diethylcarbamate [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-c]pyridin-1-ol (125 mg, 0.5 mmol, 1 equiv) was suspended in dry CHCl (50 mL) under argon and cooled to 0 °C. DIPEA (130 μL, 0.75 mmol, 1.5 equiv) was added followed by N,N-diethylcarbamoyl chloride (75 μL, 0.6 mmol, 1.2 equiv) and the mixture was stirred for 16 h at room temperature. The reaction was quenched by addition of water, extracted with CHCl (2×20 mL), washed with water, dried over MgSO and concentrated. Purification by flash chromatography (80:20 to 50:50 EtOAc:CHCl) gave a red oil that solidified on standing (106 mg, 61%). 1 H NMR(300MHz,CDCl3)δ 8.58(s,1H),8.22(d,J=5.5Hz,1H),7.51(d,J=8.8Hz,2H),7.39(dd,J=5.5,1.0Hz,1H),6.90(d,J=8.8Hz,2H),6.44(d,J=0.8Hz,1H),4 .01(q,J=7.0Hz,2H),3.34(q,J=7.3Hz,2H),3.24(q,J=7.3Hz,2H),1.37(t,J=7.0Hz,3H),1.14(t,J=7.3Hz,3H),1.07(t,J=7.3Hz,3H).

[0191] Compound 35: 2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-6-carbonitrile [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (190 mg, 0.75 mmol, 1 equiv) was suspended in dry MeCN (5 mL) under argon in a 25 mL pressure tube. Dimethyl sulfate (105 mg, 0.83 mmol, 1.1 equiv) was added and the mixture was heated at 60° C. overnight. The next day, more dimethyl sulfate was added (1 equiv) and the mixture was heated for 16 h. After cooling to rt, KCN (147 mg, 2.25 mmol, 3 equiv) and saturated NH4Cl (5 mL) were added and the biphasic mixture was stirred vigorously at 50° C. for 48 h. The reaction was quenched with saturated NaHCO3, extracted with EtOAc (2×20 mL), washed with brine, dried over MgSO4 and concentrated. Purification was carried out by flash chromatography (100:0 to 90:10 CH2Cl2:EtOAc) to give a pale orange solid (62 mg, 32%). 1 H NMR(300MHz,DMSO-d6)δ 12.61(s,1H),8.09(d,J=8.1Hz 1H),7.94(d,J=8.7Hz,2H),7.60(d,J=8.1Hz,1H),7.07(d,J=8.7Hz,2H),7.00(s,1H),4.11(q,J=7.3Hz,2H),1.35(t,J=7.3Hz,2H).

[0192] Compound 36: 2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-6-amine - 3-((4-ethoxyphenyl)ethynyl)pyridine-2,6-diamine: [ka] 3-Iodopyridine-2,6-diamine (synthesized from 2,6-diaminopyridine according to WO2019149965) (2 g, 8.51 mmol, 1 equiv.) was placed under argon and dissolved in anhydrous THF (20 mL). Et3N (5.9 mL, 5 equiv., 42.5 mmol) and 1-ethoxy-4-ethynylbenzene (1.49 mL, 1.2 equiv., 10.2 mmol) were added, followed by CuI (40 mg, 0.025 equiv., 0.21 mmol) and PdCl2(PPh3)2 (150 mg, 0.025 equiv., 0.21 mmol). The dark brown mixture was stirred at rt for 16 h, after which water (20 mL) and CHCl2 (20 mL) were added. The aqueous layer was extracted with CH2Cl2, and the organic extract was washed with water and brine, dried over MgSO4, and concentrated. Purification by flash chromatography (CH2Cl2:EtOAc 90:10 to 0:100) afforded the desired compound as a brown solid (1.95 g, 90%). 1 H NMR(300MHz,DMSO-d6)δ 7.43(d,J=8.8Hz,2H),7.19(d,J=8.2Hz,1H),6.91(d,J=8.8Hz,2H),5.88(s,2H),5.83-5.61(m,3H),4.04(q,J=7.0Hz,2H),1.33(t,J=7.0Hz,3H).

[0193] -Synthesis of compound 36: [ka] 3-((4-ethoxyphenyl)ethynyl)pyridine-2,6-diamine (200 mg, 0.79 mmol, 1 equiv.) was dissolved in dry DMSO (8 mL), tBuOK (220 mg, 1.97 mmol, 2.5 equiv) was added in one portion and the brown mixture was heated at 65 °C for 16 h. The reaction was quenched with saturated NH4Cl and extracted with a mixture of EtOAc and iPrOH (8:2, 3 x 50 mL). The organic extract was dried over MgSO4 and concentrated to a black solid. Purification by flash chromatography (98:2 to 95:5 CH2Cl2:MeOH) afforded the impure product, which was further purified by suspension in Et2O / EtOAc and sonication. The resulting red solid was filtered off, washed with Et2O, and dried under vacuum (25 mg, 12%). 1 H NMR(300MHz,DMSO-d6)δ 11.23(s,1H),7.69(d,J=8.3Hz,2H),7.50(d,J=8.6Hz,1H),6.92(d,J=8.3Hz,2H),6.50( s,1H),6.25(d,J=8.3Hz,1H),5.61(s,2H),4.05(q,J=6.9Hz,4H),1.34(t,J=6.9Hz,5H).

[0194] Compound 37: 4-(6-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol - 6-chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine: [ka] 2-(4-Ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (4 g, 16 mmol, 1 equiv) was suspended in dry THF (60 mL) under argon and cooled to 0 °C. HMDS (2.6 g, 16 mmol, 1 equiv) was added in one portion followed by ethyl chloroformate (4.34 g, 40 mmol, 2.5 equiv) dropwise. The reaction was allowed to stir at rt for 16 h, recooled to 0 °C and more HMDS (0.5 equiv) and ethyl chloroformate (1.25 equiv) were added. After 16 h the mixture was quenched with saturated NaHCO3 and the THF was removed in vacuo. The resulting red oil was dissolved in MeOH (50 mL) and NaOH (2N, 50 mL) was added. After 5 h saturated NH4Cl was added and MeOH was removed in vacuo. The mixture was extracted with EtOAc (3×100 mL), washed with brine, dried over MgSO and concentrated to give a mixture of isomers. Purification by flash chromatography (90:10 EtOAc:CH2Cl2) afforded the 6-chloroazaindole isomer as a brown solid (1.4 g, 36%). 1 H NMR(300MHz,DMSO-d6)δ 12.28(s,1H),7.91(d,J=8.2Hz,1H),7.83(d,J=8.8Hz,2H),7.09(d,J=8.2Hz,1H),7.0 0(d,J=8.8Hz,2H),6.79(d,J=2.1Hz,1H),4.05(q,J=7.0Hz,2H),1.33(t,J=7.0Hz,3H).

[0195] -Synthesis of compound 37: [ka] 6-Chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.55 mmol, 1 equiv.) was suspended in anhydrous CHCl (10 mL) under argon and cooled to −78° C. Boron tribromide (1 M solution in CHCl, 1.65 mL, 1.65 mmol, 3 equiv.) was added dropwise and the dark brown mixture was stirred for 6 h while warming to rt. The reaction was carefully quenched with saturated NaHCO solution (10 mL) and cooled to 0° C. before adding 2 M NaOH (10 mL). The solution was stirred for 10 min before loading into a separatory funnel and washing with dichloromethane. The aqueous phase was then neutralized by dropwise addition of 6 M HCl under stirring. The solid was filtered off, washed with saturated NaHCO3, water and dried under vacuum to give a brown powder of sufficient purity (130 mg, quantitative). 1 H-NMR(300MHz,DMSO-d6):δ 12.18(s,1H),9.76(s,1H),7.92(d,J=8.1Hz,1H),7.73(d,J=8.7Hz,2H),7.08(d,J=8.1Hz,1H),6.86(d,J=8.7Hz,2H),6.76(d,J=1.7Hz,1H).

[0196] Compounds 39 and 40: 4-(6-(6-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenol and 5-(2-(4-hydroxyphenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)pyridin-2-ol - 2-(4-ethoxyphenyl)-6-(6-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine [ka] 6-Chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.20 mmol, 1 equiv) was placed in a 25 mL Schlenk flask under argon with K2CO3 (83 mg, 0.6 mmol, 3 equiv), SPhos (16 mg, 0.04 mmol, 0.2 equiv), Pd(OAc)2 (4.5 mg, 0.020 mmol, 0.1 equiv), and (6-methoxypyridin-3-yl)boronic acid (43 mg, 0.28 mmol, 1.4 equiv). Dioxane (4.5 mL) and water (0.5 mL) were added and the mixture was heated at 100° C. for 4 h. After cooling to rt, water was added and the mixture was extracted with EtOAc (2×10 mL), washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (100:0 to 70:30 CH2Cl2:EtOAc) gave a brown solid (44 mg, 63%). 1 H NMR(300MHz,DMSO-d6)δ 12.12(s,1H),8.88(d,J=2.5Hz,1H),8.39(dd,J=8.7,2.5Hz,1H),7.96(d,J=8.1Hz,1H),7.89(d,J=8.8Hz,2H),7.63(d,J=8.1 Hz,1H),7.02(d,J=8.8Hz,2H),6.94(d,J=8.7Hz,1H),6.82(s,1H),4.09(q,J=7.0Hz,2H),3.92(s,3H),1.35(t,J=7.0Hz,3H).

[0197] -Synthesis of compounds 39 and 40: [ka] 2-(4-Ethoxyphenyl)-6-(6-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (24 mg, 0.07 mmol, 1 equiv) was dissolved in dry CHCl (5 mL) under argon and cooled to 0° C. AlCl (55 mg, 0.28 mmol, 4 equiv) was added and the mixture was stirred at rt for 16 h. The next day, more AlCl (4 equiv) was added and the mixture was heated to reflux for 8 h and stirred at rt overnight. The reaction was quenched with saturated NaHCO, extracted with EtOAc (2×50 mL), washed with brine, dried under MgSO, and concentrated. Purification by flash chromatography afforded two products, the first of which was eluted with 98:2 CHCl:MeOH to give a yellow solid that was identified as the monoether 39 (8 mg, 36%). 1 H NMR(300MHz,Methanol-d4)δ 8.80(d,J=2.5Hz,1H),8.33(dd,J=8.7,2.5Hz,1H),7.89(d,J=8.2Hz,1H),7.68(d, J=8.7Hz,2H),7.48(d,J=8.2Hz,2H),6.90-6.86(m,3H),6.65(s,1H),3.96(s,3H).

[0198] Elution was continued with 95:5 CH2Cl2:MeOH to give an orange solid, identified as the fully dealkalized product 40 (7 mg, 33%). 1 H NMR(300MHz,DMSO-d6)δ 11.93(s,1H),11.84(s,2H),9.71(s,1H),8.23(dd,J=9.6,2.7Hz,1H),8.09(s,1H),7.88(d,J=8.2Hz,1H),7.7 6(d,J=8.6Hz,2H),7.47(d,J=8.2Hz,1H),6.85(d,J=8.7Hz,2H),6.71(d,J=2.1Hz,1H),6.47(d,J=9.6Hz,1H).

[0199] Compound 41: 2-(4-ethoxyphenyl)-6-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine [ka] 6-Chloro-2-(4-ethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.20 mmol, 1 equiv.) was placed in a 25 mL Schlenk flask under argon with K2CO3 (83 mg, 0.6 mmol, 3 equiv.), Dppf (22 mg, 0.04 mmol, 0.2 equiv.), Pd(OAc)2 (4.5 mg, 0.020 mmol, 0.1 equiv.), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (54 mg, 0.28 mmol, 1.4 equiv.). Dioxane (4.5 mL) and water (0.5 mL) were added and the mixture was heated at 100° C. for 4 h. After cooling to rt, water was added and the mixture was extracted with EtOAc (2×10 mL), washed with brine, dried over MgSO and concentrated. Purification by flash chromatography (100:0 to 92:8 CH2Cl2:MeOH) gave a brown solid (25 mg, 41%). 1 H NMR(300MHz,DMSO-d6)δ 12.97(s,1H),12.00(s,1H),8.26(s,1H),8.05(s,1H),7.88-7.83(m,3H),7.40(d,J=8.1Hz,1 H),7.01(d,J=8.9Hz,2H),6.75(d,J=2.1Hz,1H),4.09(q,J=7.0Hz,2H),1.36(t,J=7.0Hz,3H).

[0200] Compound 43: 2-(4-ethoxyphenyl)-N-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine - 4-chloro-2-(4-ethoxyphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine: [ka] 4-Chloro-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (synthesized from 4-chloro-1H-pyrrolo[2,3-b]pyridine according to WO2019058132) (1.5 g, 3.5 mmol, 1 equiv.) was placed in a 100 mL Schlenk flask under argon with 4-ethoxyphenylboronic acid (0.7 g, 4.2 mmol, 1.2 equiv.), Na2CO3 (1.1 g, 10.5 mmol, 3 equiv.) and Pd(PPh3)2Cl2 (0.12 g, 0.18 mmol, 0.05 equiv.). A mixture of dioxane (50 mL) and water (15 mL) was added and the reaction was heated to 70 °C for 4 h. After cooling to room temperature, water was added and the mixture was extracted with EtOAc (2×50 mL), washed with brine, dried over MgSO4 and concentrated. Purification by flash chromatography (90:10 to 70:30 PE:EtOAc) gave an orange foam (1.21 g, 84%). 1 H NMR(300MHz,CDCl3)δ 8.34(d,J=5.3Hz,1H),7.86-7.83(m,2H),7.53-7.36(m,5H),7.20(d,J=5.3Hz,1H) ,6.97(d,J=8.7Hz,2H),6.56(s,1H),4.12(q,J=7.0Hz,2H),1.47(t,J=7.0Hz,3H).

[0201] -Synthesis of compound 43: [ka] 4-Chloro-2-(4-ethoxyphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.24 mmol, 1 equiv) was placed in a 25 mL Schlenk flask under argon with Cs2CO3 (156 mg, 0.48 mmol, 2 equiv), XPhos (23 mg, 0.048 mmol, 0.2 equiv), and Pd2dba3 (22 mg, 0.024 mmol, 0.1 equiv). Dioxane (10 mL) was added followed by aniline (32 mg, 0.34 mmol, 1.4 equiv) and the mixture was heated at 100 °C for 4 h. After cooling to rt, water was added and the mixture was extracted with EtOAc (2 x 50 mL), washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (90:10 to 70:30 PE:EtOAc) gave a yellow oil (87 mg, 79%). 1 H NMR(300MHz,CDCl3)δ 8.20(d,J=5.6Hz,1H),7.88(d,J=7.8Hz,2H),7.58-7.33(m,7H),7.26-7.12(m,3H),6.97(d,J=7.8Hz,2H) ,6.85(d,J=5.6Hz,1H),6.37(d,J=0.8Hz,1H),6.15(s,1H),4.14(q,J=7.0Hz,2H),1.49(t,J=7.0Hz,3H).

[0202] Compound 44: 2-(4-ethoxyphenyl)-N-methyl-N-phenyl-1H-pyrrolo[2,3-b]pyridin-4-amine - 2-(4-ethoxyphenyl)-N-methyl-N-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine: [ka] 4-Chloro-2-(4-ethoxyphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.24 mmol, 1 equiv) was placed in a 25 mL Schlenk flask under argon with Cs2CO3 (156 mg, 0.48 mmol, 2 equiv), XPhos (23 mg, 0.048 mmol, 0.2 equiv), and Pd2dba3 (22 mg, 0.024 mmol, 0.1 equiv). Dioxane (10 mL) was added followed by N-methylaniline (36 mg, 0.34 mmol, 1.4 equiv) and the mixture was heated at 100° C. for 4 h. After cooling to rt, water was added and the mixture was extracted with EtOAc (2×50 mL), washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (90:10 to 70:30 PE:EtOAc) gave a yellow oil (67 mg, 55%).

[0203] -Synthesis of compound 44: [ka] 2-(4-Ethoxyphenyl)-N-methyl-N-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (66 mg, 0.14 mmol, 1 equiv.) was dissolved in a mixture of THF (5 mL) and MeOH (5 mL) under argon. NaOH (140 μL, 2 M, 2 equiv.) was added and the reaction was heated at 55° C. overnight. After cooling to rt, saturated NH4Cl (10 mL) was added and the product was extracted with EtOAc (3×10 mL), washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (80:20 to 0:100 CH2Cl2:EtOAc) gave a yellow solid (17 mg, 35%). 1H NMR(300MHz,DMSO-d6)δ 11.75(s,1H),7.99(d,J=5.5Hz,1H),7.50(d,J=8.8Hz,2H),7.42-7.37(m,2H),7.26-7.16(m,3H),6.93(d,J=8.8 Hz,2H),6.55(d,J=5.5Hz,1H),5.50(d,J=2.3Hz,1H),4.03(q,J=7.0Hz,2H),3.46(s,3H),1.32(t,J=7.0Hz,3H).

[0204] II. Biological activity of the compounds according to the invention The activity of the compounds against ferroptosis was investigated in vitro on cellular models of pathologies. Ferroptosis is involved in several pathologies or dysfunctions of the organism, in particular in acute kidney injury associated with ischemia-reperfusion or resulting from the administration of cisplatin during anticancer chemotherapy, specifically during the treatment of head and neck (ear, nose and throat), lung, endometrial or bladder cancer. Ferroptosis is also involved in the physiological pathology of neurodegenerative diseases such as Parkinson's disease, or in neurological disorders associated with excitotoxicity, such as trauma or stroke.

[0205] II.1. Neurotoxicity and Excitotoxicity Assays Model The excitotoxicity model used was mouse hippocampal neuronal HT22 cells treated with glutamate [Dixon et al., Cell, 2012, 149(5), 1060-1072]. Ferroptosis and oxidative stress are both associated with this glutamate-induced cell death [Chu et al., Neural Regen. Res., 2020, 15(3), 528-536]. Phenotypic screens were also performed with additional cell death inducers erastin and RSL3 (a (1S,3R)-Ras-selective lethal agent) in HT22 and SH-SY5Y (human neuroblastoma cells). Elastin and RSL3 are well-described molecules that have been used as chemical tools to study the regulation of ferroptosis and neuronal pathology [Lewerenz et al., Front. Neurosci., 2018, 12:214; Reichert et al., Int. J. Mol. Sci., 2020, 21, 8765].

[0206] material and method Mouse hippocampal neuronal cell line (HT22, ATCC) and human neuroblastoma cell line (SH-SY5Y, ATCC) were grown in Dulbecco's modified Eagle's medium (DMEM, Gibco) supplemented with 10% fetal bovine serum (FBS, Gibco) at 37°C in a 5% CO2 atmosphere. Neurotoxicity was induced by erastin or RSL3, and excitotoxicity was induced by glutamate. Cells were seeded in 96-well plates at 5,000 cells / well and 10,000 cells / well for HT22 and SH-SY5Y cell lines, respectively. Cells were treated with 0.5-1 μM erastin (HT22 cells) or 10 μM erastin (SH-SY5Y cells) or 5-10 mM glutamate (HT22 cells) or 0.5 μM RSL3 (HT22 cells) or 5 μM RSL3 (SH-SY5Y cells) for 24 h in the presence of increasing concentrations of inhibitors. Cells treated with DMSO only were used as control. Cell viability was assessed by MTS assay (CellTiter96® Aqueous One Solution Cell Proliferation Assay, Promega).

[0207] result In Figures 1, 2A, and 2B, inhibitors were added to HT22 cells (Figure 1: compound 6) or SH-SY5Y cells (Figure 2A: compound 6, Figure 2B: compound 25) in the presence or absence of cell death inducers (erastin, glutamate, or RSL3). The curves show the cell viability measured after 24 hours of treatment and the addition of tetrazolium salts (CellTiter96 Aqueous One Solution Cell Proliferation Assay (MTS), #G3582, Promega). The results obtained without cell death inducers showed a potential cytotoxic effect of the molecule alone. It can be noticed that compounds 6 and 25 do not affect cell viability at the doses tested (up to 50 μM or 100 μM). Results obtained in the presence of ferroptosis inducers showed that increasing concentrations of compound 6 increased cell viability, with 10 μM in HT22 cells (EC 50 EC = 2.05 μM, and in the presence of 10 mM glutamate 50 = 1.64 μM, and in the presence of 0.5 μM RSL3 50 = 2.31 μM) in SH-SY5Y cells at 1 μM (EC 50 = 0.18 μM), leading to almost complete inhibition. Similarly, increasing concentrations of compound 25 increased cell viability, with 10 μM in SH-SY5Y cells (EC 50 EC = 1.4 μM and in the presence of 5 μM RSL3 50 = 5.25 μM), resulting in almost complete inhibition.

[0208] The EC of compounds 1–28 was determined using Graphpad Prism software. 50 Values ​​were calculated from dose-response curves and the results are reported in Table 1 below. [Table 2]

[0209] II.2. In vitro cold hypoxia / reoxygenation assay Model Renal tubular necrosis that occurs during ischemia-reperfusion is cell death by ferroptosis [Linkermann et al., PNAS, 2014, 11(47)16836-16841]. To mimic the ischemia-reperfusion that occurs in organs during transplantation, renal cells were treated with increasing concentrations of the compound of interest diluted in University of Wisconsin (UW) solution, followed by incubation for 24 hours at 4°C in a 95% N2 / 5% CO2 atmosphere. It should be noted here that UW is the solution most commonly used in hospitals for the preservation of organs before transplantation. After 24 hours, the culture medium was replaced with PBS buffer solution or the culture medium recommended for these renal cells. The cells were then incubated for 6 hours at 37°C in the presence of oxygen and 5% CO2 in an incubator. The viability of the remaining cells was quantified using the MTS reduction assay. Hypoxia-induced cell mortality was then estimated by quantifying the reduction in cell viability. These molecules were considered to be effective if they maintained high and significant levels of cell viability after hypoxic shock.

[0210] material and method Human renal glomerular endothelial cells (hRGEC) were grown to 80% confluency and then synchronized with FBS (fetal bovine serum)-depleted medium for 16 hours (M200 medium + 2% serum). For hypothermia / hypoxia, cells were washed twice with PBS and then incubated for 24 hours at 4°C in UW solution in an atmosphere of 95% N2 / 5% CO2 (Bactal 2 gaz, Air Liquide, France). Cells were treated with increasing concentrations of inhibitors during the hypoxic phase. For the reoxygenation phase, cells were washed and incubated for 6 hours at 37°C in PBS + 2% serum or in M200 medium + 4% serum in an atmosphere of 5% CO2 and 21% O2. Controls were cells that were not subjected to this protocol and were continuously oxygenated and incubated in PBS supplemented with 2% FBS. After 6 h of reoxygenation, cell viability was assessed by the XTT test (Sigma-Aldrich, Saint-Quentin-Fallavier, France).

[0211] result Each of the 14 compounds tested in this model had a dose-dependent cytoprotective effect, as shown in FIGS.

[0212] II.3. Cisplatin-induced nephrotoxicity Model Nephrotoxicity associated with the use of cisplatin in the treatment of various cancers (specifically ear, nose, throat, and lung cancers) occurs due to accumulation of cisplatin in the kidney before it can be eliminated. High cisplatin concentrations in the kidney are known to induce cell death by ferroptosis, leading to acute tubular necrosis and acute kidney injury [Hu et al., Cell Death Dis., 2020, 11:73].

[0213] To mimic this pathology, we used non-cancerous rat proximal tubule kidney cells (NRK-52E) supplemented with a high dose of cisplatin (200 μM) in the presence of increasing doses of inhibitors. Ferrostatin-1 (Fer-1) was used as a positive control for ferroptosis inhibition. After 24 h of treatment, a cell viability assay (MTS) was performed.

[0214] material and method Rat renal proximal tubule epithelial cell line (NRK-52E) was grown in high glucose Dulbecco's Modified Eagle Medium (DMEM, ATCC) supplemented with 5% FBS. Cells were maintained at 37°C under 5% CO2 atmosphere. NRK-52E cells were seeded at 10,000 cells / well in 96-well plates. Cells were treated with 200 μM cisplatin (Sigma) for 24 h in the presence of increasing doses of inhibitors or DMSO for control cells. Cell viability was assessed by MTS assay (CellTiter96® Aqueous One Solution Cell Proliferation Assay, Promega).

[0215] result Each of the 24 compounds tested in this model had a dose-dependent cytoprotective effect against cisplatin-induced cell death, as shown in Figures 19-24.

[0216] II.4. Cellular models of age-related macular degeneration (AMD) Model Age-related macular degeneration, or AMD, is characterized by a loss of vision due to the degeneration of the central cells of the retina, called the macula. Oxidative stress has been shown to play a key role in the loss of retinal cells, particularly by initiating ferroptosis [Totsuka et al., Exp. Eye Res., 2019, 181-316-324]. One of the models used to study retinal cell death is the human ARPE-19 cell line, a pigmented retinal epithelial cell line, in the presence of sodium iodate (NaIO3, a strong oxidant) [Hanus et al. Cell Death Discov. 2016, 2, 16054][Chan et al., J. Biomed. Sci., 2019, 26:40]. Resveratrol is used as a positive control, to the extent that it inhibits ferroptosis by playing its well-documented role as an antioxidant.

[0217] material and method ARPE-19 cells were seeded at 10,000 cells / well in 96-well plates. Cells were treated with 10 mM NaIO3 in the presence of increasing doses of inhibitors or in the presence of resveratrol or ferrostatin-1 for control cells. Cell viability was assessed by MTS assay (CellTiter96® Aqueous One Solution Cell Proliferation Assay, Promega).

[0218] result As shown in FIG. 25, the test compound exhibited a significant protective effect against NaIO3-induced death in ARPE-19 cells (n=3, mean ± standard deviation, ***P<0.001).

[0219] II.5. Cellular models of retinal pigment epithelium (RPE) phototoxicity material and method Primary cultures of porcine RPE are prepared weekly and tested on 96-well culture plates after one week in vitro. Cells are incubated with the molecules for 10 minutes before inducing phototoxicity. 19 hours after adding A2E (30 μM) to the culture medium, cells are illuminated by a device equipped with a blue light-emitting LED (λ=430 nM). 24 hours after induction of phototoxicity, cell viability and death are detected by staining cells with Hoechst (nuclear marker) and ethidium (marker for dead cell nuclei). Images of each well are acquired with a fluorescent microscope equipped with a motorized stage driven by Metamorph® software, and cell viability is quantified by an in-house program. Molecules are tested at 10 μM and 30 μM unless they are toxic concentrations. Negative controls include cells treated with A2E and vehicle. Positive controls include cells treated with A2E and crocetin (100 μM) for 48 hours prior to illumination. These treatments are performed in quadruplicate and experiments are performed in quadruplicate.

[0220] result The results shown in FIG. 29 indicate that compound 1 (referred to as SBL-02 in FIG. 29) can significantly protect RPE cells from phototoxicity at 10 μM and 30 μM.

[0221] II.6. In vivo models of Stargardt's disease and age-related macular degeneration (AMD) Model As described in Parmar et al., Invest Ophthalmol Vis Sci., 2016, 57(7), mice lacking ATP-binding cassette transporter 4 (ABCA4) and retinol dehydrogenase 8 (RDH8) mimic features of human Stargardt disease and age-related macular degeneration.

[0222] Exposure to intense light causes Abca4 ー / ー Rdh8 ー / ー It can accelerate retinal degeneration in mice.

[0223] Experimental Protocol Blue light damage (BLD) experiments were performed on 7-week-old Abca4 mice. ー / ー Rdh8 ー / ー The study was carried out in mice. The animals were acclimated to low light levels (4000 lux for 30 min). Six days after BLD, an optical coherence tomography (OCT) examination was performed on each eye, which gives a "snapshot" of the state of the retinal cell layers in living mice. OCT is based on the use of low-coherence optical interference. This imaging technique allows cross-sectional images of tissues in vivo to be taken with a resolution of a few microns. It is performed under light gas anesthesia (5% isoflurane during induction, then 2% during maintenance) and is non-invasive. The pupils of the mice are dilated with 0.5% Midriaticum. Representative images of each eye were extracted and included in separate report documents (4 OCT inserts). In the following days, measurements of the electrical activity of the retina were performed by measuring scotopic and photopic electroretinograms (ERG). Scotopic ERG is performed after a night in the dark to measure the electrical response of the rods, which represent 97% of the photoreceptors in mice. At higher intensities, the cones also respond. This is followed by a photopic ERG, which records the response of only the cones. These measurements are taken as a function of the activity of 1) rod and cone photoreceptors, 2) intraretinal bipolar cells, and 3) cones only. The eyes are then harvested and prepared for subsequent histological analysis. For IP experiments, one eye is dissected and the retina and RPE are frozen separately. These tissues can be used for further measurements.

[0224] Intravitreal treatment with Compound 1 Compound 1 in powder form is placed in DMSO to obtain a 20 mM solution. These solutions are stored at -20°C and immediately thawed to prepare an 89-fold dilution in PBS. These solutions provide a final intraocular concentration of Compound 1 of approximately 50 μM and 0.25% DMSO. Vehicle is prepared from pure DMSO to a final intravitreal concentration of 0.25%. During the IVT procedure, mice are lightly anesthetized with isoflurane. A volume of 1.5 μL is injected intravitreally into the left eye.

[0225] ERG results Abca4 ー / ー Rdh8 ー / ー The effect of intravitreal administration of compound 1 (referred to as SBL2 in Figures 30-32) on induced retinal phototoxicity in scotopic and photopic ERG measurements in mice shows that Abca4 ー / ー Rdh8 ー / ー Intravitreal injection of 50 μM compound 1 in mice appears to preserve the electrical response of retinal cells. In FIG. 30, the results are presented as intensity histograms for scotopic and photopic ERGs. Scotopic A-wave in SBL2-injected eyes (SBL2 I) compared to uninjected eyes (SBL2 NI) was 10 cd.s / m 2 and 30 cd.s / m 2 There is a striking difference in the response of SBL2 injected eyes compared to vehicle injected eyes (VEH I) and non-injected eyes (VEH NI) (Figure 31). This is also observed when comparing vehicle injected eyes (VEH I) and non-injected eyes (VEH NI). A clear difference is observed when comparing the response of SBL2 injected eyes to vehicle injected eyes, which is greater than the response of SBL2 I at 10 cd.s / m 2 Scotopic B waves appear to be preserved in injected eyes compared to non-injected eyes in SBL2-treated mice (Figure 32). 2 There is a significant difference in SBL2 I (p=0.048) compared with VEH NI. 2In SBL2 I, the b-wave amplitude is very close to that of NINI (naive and non-injected) mice. The photopic ERG of the injected eye is partially preserved compared to the non-injected eye (Figure 30). The same is true when comparing SBL2 I to VEH I.

[0226] Quantification of total retinal thickness from OCT Image processing was performed using Image J software to measure the thickness of the retina and photoreceptor layer. Measure the total retinal thickness between the outer segment layer and the ganglion cell layer. Measure the photoreceptor layer thickness between the outer plexiform layer and the outer segment layer. Take an average of six measurements along the length of the OCT image representing the top or bottom half of the retina. To prepare plates of ocular sections from the SBL2 IVT experiments, one eye corresponding to each condition, i.e., one NINI eye and both eyes (I and NI) of SBL2-injected mice, are sectioned on a cryostat.

[0227] Quantification of retinal thickness in SBL2 IVT treated mice shows significant differences between the thickness of SBL2 injected and non-injected eyes of the same mice, and the results are shown in FIG.

[0228] Intraperitoneal treatment with compound 7 Solutions are extemporaneously prepared from the water-soluble lyophilizate of compound 7 (SBL1)-cyclodextrin (final CD concentration, 15%) and the corresponding placebo. The solutions are prepared by injecting a given volume of 0.9% NaCl into the vial. The vial is then vortexed and the solution is filtered into a new sterile tube. Two groups of 3 mice are used in these studies. These groups receive either SBL1 (20 mg / kg) (n=3) or placebo-SBL1 (n=3). The volume injected is calculated according to the mouse's weight and corresponds to 10 mL / kg. Mice were injected 3 and 1 h before the start of BLD, and 1 and 3 h after.

[0229] ERG results For scotopic and photopic ERG measurements, Abca4 - / -Rdh8 - / - Multiple injections of SBL1 at 20 mg / kg before and after induction of BLD in mice have been shown to slightly protect the electrical responses of retinal cells compared to placebo-treated mice. The trend for protection was at 30 cd.s / m 2 A tendency for protection was observed in response to a flash intensity of 100 nm, which corresponds to a mixed "rod-cone" response with a high proportion of cones (Figures 34 and 35). At higher intensities of scotopic B waves, a tendency for protection was observed in response to intraretinal responses, specifically bipolar cell responses, which corresponds to an intraretinal response stimulated by a mixed response of photoreceptors (Figure 35).

[0230] Quantification of whole retinal thickness from OCT Quantification of retinal thickness in SBL1 IP treated mice shows differences between the whole retina of injected and non-injected mice (FIG. 36).

[0231] II.7.Protective effects of compounds on survival of rat primary dopaminergic neurons after 6-OHDA injury Model As described in Ding et al., J. Neurochem., 2004, (89), administration of the neurotoxin 6-hydroxydopamine (6-OHDA) has been widely used to induce selective degeneration of dopamine (DA) neurons in in vitro and in vivo models. These models are used as models of Parkinson's disease, which is characterized by the progressive loss of DA neurons in the substantia nigra.

[0232] material and method Rat dopaminergic neurons were cultured as described by Schinelli et al., J Neurochem., 1988, 50(6). Cells were seeded at a density of 40000 cells / well in 96-well plates (precoated with poly-D-lysine, Greiner, ref: 655940, batch: E20093UL) and cultured at 37°C in a humidified air (95%) / CO2 (5%) atmosphere. Half of the medium was replaced with fresh medium every 2 days. In these conditions, after 5 days of culture, astrocytes are present in the cultures, releasing growth factors that allow the differentiation of neurons. In these conditions, 2-5% of the neurons are dopaminergic neurons.

[0233] 6-OHDA (Sigma, Reference Number: 162957, Batch: MKCK5243) was reconstituted in the restrictive culture medium at 40 μM (stock solution). Control medium was prepared under the same conditions. After 7 days of culture, primary midbrain neurons were pretreated with test compound or reference compound (BDNF, 50 ng / mL) for 1 hour, and then toxicized with 6-OHDA at a final concentration of 20 μM for 2 days of incubation to induce approximately 50% + / - 5% neuronal cell death.

[0234] After 2 days of toxicity in the presence or absence of test compounds, cells were fixed with a solution of 4% paraformaldehyde (Sigma, ref. no. 6148, batch: SZBE2390V) for 20 minutes at room temperature, and control conditions were fixed similarly following the same procedure. Cells were then permeabilized and non-specific sites were blocked with a solution of phosphate-buffered saline (PBS, Panbiotech, ref. no. P04-36500, batch: 7701020) containing 0.1% saponin (Sigma, ref. no. S7900, batch: BCBL8667V) and 1% FCS for 15 minutes at room temperature. Cells were incubated overnight at 4°C with a solution of mouse monoclonal anti-tyrosine hydroxylase antibody (TH, 1 / 10000, Sigma, ref. no. T1299, batch: 014M4835) in PBS. Dopaminergic neurons were stained with an antibody against TH. The staining was revealed by adding Alexa Fluor® 488 goat anti-mouse IgG (1 / 400, Molecular Probes, ref: A11001, batch: 2247988) in PBS containing 1% FCS and 0.1% saponin for 1 h at room temperature. In the same solution, the nuclei of the cells were labeled with a fluorescent marker (Hoechst, Sigma, ref: B1155, batch: 046M4048V). 20 images per well were taken for each condition using an InCell Analyzer™ 2200 (GE Healthcare) at 20× magnification. Images of each culture well were taken under the same conditions. Analysis of the cell bodies of TH-positive neurons was performed using the developer's software (GE Healthcare). A total of 6 data were obtained per experimental condition.

[0235] result As can be seen in FIG. 37, 6-OHDA induces a significant decrease in the viability of dopaminergic neurons at 20 μM (48% cell death, p<0.0001). As expected, the reference molecule BDNF at 50 ng / mL can partially rescue neurons from cell death (15% cell death, p<0.0001). These results make it possible to validate the culture conditions. Compound 7 (SBL-01) at the tested concentrations of 10 μM, 1 μM, and 0.1 μM, treated 1 hour before 6-OHDA exposure and during 2 days of 6-OHDA exposure, can partially and significantly rescue dopaminergic neurons from cell death (16% at p<0.001 and 24% at p<0.001, respectively). Similarly, treatment with compound 1 (SBL-02) at the tested concentrations of 10 μM, 1 μM, and 0.1 μM, 1 hour prior to 6-OHDA injury and during 2 days of 6-OHDA exposure, was able to partially and significantly rescue dopaminergic neurons from cell death (25% at p<0.001, respectively).

[0236] The results obtained with compounds 14 (SBL-571), 22 (SBL-962), and 3 (SBL-1495) are shown in Figures 38 and 39 (mean ± standard deviation; statistics relative to 6-OHDA). * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001; one-way ANOVA followed by Dunnett's test. # indicates toxicity condition).

[0237] II.8. In vivo model of ischemic acute renal failure induced by transient bilateral renal artery occlusion in rats material and method Experiments were performed using male Wistar rats (Institut Janvier, CS4105, Saint-Berthe-Vin F-53941, France) weighing 200-260 g on the day of surgery. Prior to surgery, the animals were housed in polysulfone cages (floor area = 1500 cm) under standard conditions as follows: 2The rats were housed in groups 2-4 in a 10-m2 lab at 12°C for 12 h and 12 h for 24 h, with room temperature (22±2°C), hygrometer (55±10%), light / dark cycle (12h / 12h), ventilation (15-20 volumes / h), water and food (SAFE, ref. A04) ad libitum. The animals were allowed to acclimate to the environmental conditions for at least 5 days before the experiment. The rats were anesthetized with sodium pentobarbital (60mg / kg, i.p.) and placed on a servo-controlled heating platform to maintain a rectal temperature close to 37°C. After endotracheal intubation, the animals were mechanically ventilated. The abdominal cavity was exposed by a median laparotomy and both the right and left renal arteries were identified and carefully dissected from the renal vein and fixed with clamps for 40 min. The abdominal cavity was kept closed during this clamping. The clamps were released, the perfusion to the kidneys was reestablished, and the abdominal cavity was sutured. Animals with poor reperfusion, as judged by visual inspection, were excluded. Post-surgical analgesia was ensured by subcutaneous administration of buprenorphine (1050 μg / kg, subcutaneous) twice daily for 2 days (including the day of surgery). After surgery, animals were housed individually. Animals were observed and weighed daily, and sutures were inspected and disinfected with antiseptic solution (povidone-iodine) if necessary.

[0238] All animals were followed for body weight and mortality on the day of surgery and for 7 days after ischemia. Six blood samples of at least 0.3 mL were taken from each animal for determination of plasma creatinine and blood urea nitrogen (BUN) concentrations before surgery and then on days 1, 2, 3 (before vehicle / SBL01 administration), 4 and 7 after surgery. The following parameters were measured: plasma creatinine concentration, blood urea nitrogen concentration, and body weight. Dosing protocol: Using a group size of n=10, animals received the following treatments: Vehicle 1 (5% Tween 80 in phosphate buffer, intraperitoneally) / Compound 7 (15 mg / kg, intraperitoneally).

[0239] All treatments were administered via intraperitoneal route with a dose volume of 5mL / kg. Administration was performed: 10 minutes before ischemia (=T-10 minutes: treatment shall be administered directly into the peritoneal cavity before clamping the renal artery), then immediately after reperfusion (=T45 minutes: treatment shall be administered directly into the peritoneal cavity before suturing the peritoneal cavity), then 3 hours, 24 hours, and 48 hours after the beginning of ischemia. At the end of the experiment, deeply anesthetized animals were sacrificed by cervical dislocation. Compound 7 was prepared in 5% Tween in phosphate buffer as vehicle.

[0240] result As shown in Figures 40 and 41, a significant reduction in plasma levels of creatinine and urea 2 days after administration of compound 7 (sibiriline).

[0241] These results strongly demonstrate the protective effect of compound 7 compared to vehicle on renal function during arterial occlusion and therefore protection from renal ischemic failure.

Claims

1. A compound of the following general formula (I): 【Chemistry 1】 or a pharma- ceutical composition for use in inhibiting ferroptosis comprising said compound or a pharma- ceutical acceptable salt and / or solvate thereof. (In the above formula, 【Chemistry 2】 teeth 【Chemistry 3】 and (iii) 【Chemistry 4】 but 【Chemistry 5】 When X is N and Y is N(R ２ ) and Z is C(H); (iv) 【Chemistry 6】 but 【Chemistry 7】 When -X is N(R １ ) and -Y is N or N ＋ (O － ) and Z is C(R ３ ) or Y is CH and Z is N, or Y and Z are CH; ・R １ and R ２ are each independently a hydrogen atom, CN, NO ２ , OR ７ , S.R. ８ , N.R. ９ R １０ , C(O)R １１ , CO ２ R １２ , O.C.(O)R １３ , N.R. １４ C(O)R １５ , C(O)NR １６ R １７ , S(O)R Ｓ , S.O. ２ R Ｓ ', (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, aryl, heterocyclyl, aryl-(C １ -C ６ ) alkyl, or heterocyclyl-(C １ -C ６ ) alkyl group, said aryl or heterocyclyl group being free of halogen atoms, CN, NO ２ , OR １８ , S.R. １９ , N.R. ２０ R ２１ , C(O)R ２２ , CO ２ R ２３ , O.C.(O)R ２４ , N.R. ２５ C(O)R ２６ , C(O)NR ２７ R ２８ , (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups; ・R ３ , R ４ , R ４ｂ and R ５ are each independently a hydrogen atom, a halogen atom, CN, OR ２９ , S.R. ３０ , N.R. ３１ R ３２ , C(O)R ３３ , CO ２ R ３４ , O.C.(O)R ３５ , N.R. ３６ C(O)R ３７ , C(O)NR ３８ R ３９ , (C １ -C ６ ) alkyl, or (C １ -C ６ ) a haloalkyl group, wherein the alkyl or haloalkyl group is OR ４０ , S.R. ４１ and N.R. ４２ R ４３ or R ３ , R ４ , R ４ｂ and R ５ are each independently an aryl, a heterocyclyl, an aryl-(C １ -C ６ ) alkyl, or heterocyclyl-(C １ -C ６ ) alkyl group, wherein the aryl or heterocyclyl group is not a halogen atom, CN, NO ２ , OR ４４ , S.R. ４５ , N.R. ４６ R ４７ , C(O)R ４８ , CO ２ R ４９ , O.C.(O)R ５０ , N.R. ５１ C(O)R ５２ , C(O)NR ５３ R ５４ , (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups; ・R ６ is a hydrogen atom, (C １ -C ６ ) alkyl or aryl-(C １ -C ６ ) an alkyl group, or OH, SH, NH ２ , (C １ -C ６ ) alkoxy, (C １ -C ６ ) thioalkoxy, (C １ -C ６ ) alkylamino, and di((C １ -C ６ (C ) alkyl) amino groups, which may be optionally substituted with one or more substituents selected from the group consisting of １ -C ６ ) an alkylcarbonyl group; ・R Ｓ and R Ｓ ' are each independently １ -C ６ ) alkyl, aryl, or aryl-(C １ -C ６ ) represents an alkyl group; ・R ７ ~R １０ , R １２ , R １４ , and R １６ ~R １７ are each independently a hydrogen atom, (C １ -C ６ ) alkyl, aryl, or aryl-(C １ -C ６ ) represents an alkyl group; ・R １１ , R １３ , and R １５ are each independently a hydrogen atom, (C １ -C ６ ) alkyl, aryl, aryl-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylamino, or di((C １ -C ６ ) alkyl) amino group; ・R １８ From R ２８ are each independently a hydrogen atom, (C １ -C ６ ) alkyl, or represents an aryl group, ・R ２９ From R ３９ are each independently a hydrogen atom, (C １ -C ６ ) alkyl, aryl, or aryl-(C １ -C ６ ) an alkyl group, and the aryl group is a halogen atom, CN, NO ２ , OR ５５ , S.R. ５６ , N.R. ５７ R ５８ , C(O)R ５９ , CO ２ R ６０ , O.C.(O)R ６１ , N.R. ６２ C(O)R ６３ , C(O)NR ６４ R ６５ , (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups; ・R ４０ From R ４３ are each independently a hydrogen atom or (C １ -C ６ ) represents an alkyl group; ・R ４４ From R ５４ are each independently a hydrogen atom, (C １ -C ６ ) an alkyl or aryl group; ・R ５５ From R ６５ are each independently a hydrogen atom, (C １ -C ６ ) alkyl, or aryl groups).

2. 2. The pharmaceutical composition of claim 1 for use in the prevention and / or treatment of a disorder associated with ferroptosis.

3. ・R １ is a hydrogen atom, CN, NO ２ , OR ７ , S.R. ８ , N.R. ９ R １０ , C(O)R １１ , CO ２ R １２ , O.C.(O)R １３ , N.R. １４ C(O)R １５ , C(O)NR １６ R １７ , S(O)R Ｓ , S.O. ２ R Ｓ ', (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, aryl, heterocyclyl, aryl-(C １ -C ６ ) alkyl, or heterocyclyl-(C １ -C ６ ) alkyl group, said aryl or heterocyclyl group being free of halogen atoms, CN, NO ２ , OR １８ , S.R. １９ , N.R. ２０ R ２１ , (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups, Preferably, R １ is a hydrogen atom, CN, OR ７ , C(O)R １１ , CO ２ R １２ , O.C.(O)R １３ , S.O. ２ R Ｓ ', (C １ -C ６ ) alkyl, heterocyclyl, or heterocyclyl-(C １ -C ６ ) alkyl group, the heterocyclyl group being NO ２ and optionally substituted with; ・R Ｓ and R Ｓ ' are each independently (C １ -C ６ ) represents an alkyl or aryl group, preferably an aryl group, ・R １８ From R ２１ are each independently a hydrogen atom or (C １ -C ６ ) represents an alkyl group, The pharmaceutical composition according to claim 1 or 2.

4. ・R ２ is C(O)R １１ , CO ２ R １２ , C(O)NR １６ R １７ , (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, aryl, heterocyclyl, aryl-(C １ -C ６ ) alkyl, or heterocyclyl-(C １ -C ６ ) alkyl group, said aryl or heterocyclyl group being selected from halogen atoms, OR １８ , S.R. １９ , N.R. ２０ R ２１ , (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups; Preferably, R ２ CO ２ R １２ , C(O)NR １６ R １７ , or aryl-(C １ -C ６ ) alkyl group, the aryl group being a halogen atom, OR １８ , S.R. １９ , and N.R. ２０ R ２１ , especially OR １８ and optionally substituted with one or more substituents selected from the group consisting of: ・R １８ From R ２１ are each independently a hydrogen atom or (C １ -C ６ ) represents an alkyl group, The pharmaceutical composition according to claim 1 or 2.

5. ・R ３ is a hydrogen atom, a halogen atom, CN, OR ２９ , S.R. ３０ , N.R. ３１ R ３２ , C(O)R ３３ , CO ２ R ３４ , O.C.(O)R ３５ , N.R. ３６ C(O)R ３７ , C(O)NR ３８ R ３９ , aryl, heterocyclyl, aryl-(C １ -C ６ ) alkyl, or heterocyclyl-(C １ -C ６ ) alkyl group, said aryl or heterocyclyl group being selected from halogen atoms, OR ４４ , S.R. ４５ , N.R. ４６ R ４７ , (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups, preferably hydrogen atoms, halogen atoms, CN, OR ２９ , S.R. ３０ , N.R. ３１ R ３２ , O.C.(O)R ３５ , N.R. ３６ C(O)R ３７ , heterocyclyl, or heterocyclyl-(C １ -C ６ ) alkyl group, the heterocyclyl group being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, OR ４４ , S.R. ４５ , N.R. ４６ R ４７ , and (C １ -C ６ ) alkyl groups, more preferably hydrogen atoms, halogen atoms, CN, NR ３１ R ３２ , O.C.(O)R ３５ , heterocyclyl, or heterocyclyl-(C １ -C ６ ) alkyl group, and said heterocyclyl group is optionally substituted by one or more substituents selected from the group consisting of OR ４４ , S.R. ４５ , and N.R. ４６ R ４７ , especially OR ４４ and optionally substituted with one or more substituents selected from the group consisting of: ・R ２９ From R ３７ are each independently a hydrogen atom or (C １ -C ６ ) represents an alkyl group; ・R ４４ From R ４７ are each independently a hydrogen atom or (C １ -C ６ ) represents an alkyl group, The pharmaceutical composition according to any one of claims 1 to 3.

6. ・R ４ is a hydrogen atom, a halogen atom, CN, OR ２９ , S.R. ３０ , N.R. ３１ R ３２ , (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl group, aryl, heterocyclyl, aryl-(C １ -C ６ ) alkyl, or heterocyclyl-(C １ -C ６ ) alkyl group, said aryl or heterocyclyl group being free of halogen atoms, CN, NO ２ , OR ４４ , S.R. ４５ , N.R. ４６ R ４７ , C(O)R ４８ , CO ２ R ４９ , O.C.(O)R ５０ , N.R. ５１ C(O)R ５２ , C(O)NR ５３ R ５４ , (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups; Preferably, R ４ is a hydrogen atom, a halogen atom, OR ２９ , S.R. ３０ , N.R. ３１ R ３２ , aryl, or heterocyclyl group, the aryl or heterocyclyl group being selected from the group consisting of a halogen atom, OR ４４ , S.R. ４５ , N.R. ４６ R ４７ , C(O)R ４８ , CO ２ R ４９ , C(O)NR ５３ R ５４ , (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups; More preferably, R ４ is a hydrogen atom, a halogen atom, NR ３１ R ３２ , aryl, or heterocyclyl group, said aryl or heterocyclyl group being C(O)R ４８ and (C １ -C ６ ) alkyl groups, ・R ４ｂ is a hydrogen atom, a halogen atom, OR ２９ , or N.R. ３１ R ３２ , preferably a hydrogen atom, a halogen atom, or OR ２９ , more preferably a hydrogen atom, ・R ２９ From R ３２ are each independently a hydrogen atom, (C １ -C ６ ) alkyl, aryl, or aryl-(C １ -C ６ ) alkyl group, the aryl group being a halogen atom, OR ５５ , S.R. ５６ , N.R. ５７ R ５８ , C(O)R ５９ , CO ２ R ６０ , O.C.(O)R ６１ , N.R. ６２ C(O)R ６３ , C(O)NR ６４ R ６５ , (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups, particularly C(O)R ５９ , CO ２ R ６０ , C(O)NR ６４ R ６５ , (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups, specifically C(O)R ５９ and optionally substituted with one or more substituents selected from the group consisting of: ・R ４８ is a hydrogen atom, (C １ -C ６ ) an alkyl or aryl group, in particular an aryl group, ・R ５５ From R ６５ are each independently a hydrogen atom, (C １ -C ６ ) alkyl or aryl radicals, in particular aryl radicals, The pharmaceutical composition according to any one of claims 1 to 5.

7. ・R ５ is a hydrogen atom, a halogen atom, CN, OR ２９ , S.R. ３０ , N.R. ３１ R ３２ , (C １ -C ６ ) alkyl, or (C １ -C ６ ) a haloalkyl group, wherein the alkyl or haloalkyl group is OR ４０ , S.R. ４１ , and N.R. ４２ R ４３ or R ５ is an aryl, heterocyclyl, aryl-(C １ -C ６ ) alkyl, or heterocyclyl-(C １ -C ６ ) alkyl group, wherein the aryl or heterocyclyl group is selected from the group consisting of halogen atoms, OR ４４ , S.R. ４５ , N.R. ４６ R ４７ , (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups; Preferably, R ５ represents a hydrogen atom, a halogen atom, (C １ -C ６ ) alkyl, or (C １ -C ６ ) a haloalkyl group, wherein the alkyl or haloalkyl group is OR ４０ , S.R. ４１ , and N.R. ４２ R ４３ or R ５ is aryl-(C １ -C ６ ) alkyl, or heterocyclyl-(C １ -C ６ ) alkyl group, wherein the aryl or heterocyclyl group is selected from the group consisting of halogen atoms, (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl groups; More preferably, R ５ represents a hydrogen atom, a halogen atom, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl group, or heterocyclyl-(C １ -C ６ ) alkyl group, said alkyl or haloalkyl group being OR ４０ wherein the heterocyclyl is optionally substituted with one or more (C １ -C ６ ) may be optionally substituted with an alkyl group, specifically R ５ represents a hydrogen atom, ・R ２９ From R ３２ are each independently a hydrogen atom or (C １ -C ６ ) represents an alkyl group; ・R ４０ From R ４３ are each independently a hydrogen atom or (C １ -C ６ ) an alkyl group, in particular a hydrogen atom, The pharmaceutical composition according to any one of claims 1 to 6.

8. R ６ is a hydrogen atom, (C １ -C ３ ) alkyl or aryl-(C １ -C ３ ) an alkyl group, or OH, SH, NH ２ , (C １ -C ３ ) alkoxy, (C １ -C ３ ) thioalkoxy, and (C １ -C ３ ) alkylamino groups, which may be optionally substituted by one or more substituents selected from the group consisting of １ -C ６ ) an alkylcarbonyl group, preferably R ６ is a hydrogen atom, methyl, ethyl, benzyl, or OH, NH ２ and a thiomethyl group (C １ -C ６ ) represents an alkylcarbonyl group, specifically R ６ The pharmaceutical composition according to any one of claims 1 to 7, wherein represents a hydrogen atom or an ethyl group, in particular an ethyl group.

9. The compound of claim 1, wherein 【Chemistry 8】 【change】 【change】 The pharmaceutical composition according to any one of claims 1 to 8, wherein the compound is selected from the group consisting of: and pharma- ceutically acceptable salts and / or solvates thereof.

10. The compound of claim 1, wherein 【Chemistry 9】 【change】 【change】 and pharma- ceutically acceptable salts and / or solvates thereof.

11. The ferroptosis-related disorders include myocardial ischemia-reperfusion injury, particularly occurring after arterial ligation; cardiomyopathies, particularly doxorubicin-induced cardiomyopathy; stroke, particularly ischemic stroke or hemorrhagic stroke; traumatic brain injury; contusion spinal cord injury; neurodegenerative disorders, particularly chronic neurodegenerative disorders, more particularly Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease), Friedreich's ataxia, and dementia; retinal disorders, particularly Stargardt's disease or age-related jaundice. macular degeneration (AMD), particularly dry AMD; chronic liver disease, particularly non-alcoholic steatohepatitis (NASH), chronic infections such as hepatitis, and alcoholic liver disease; acute liver failure, particularly due to drug-induced liver injury (DILI), such as acetaminophen (APAP)-induced liver injury, or due to ischemia-reperfusion injury induced by septic or hemorrhagic shock; skin inflammatory diseases, such as psoriasis; toxic epidermal necrolysis (Lyell's syndrome); acute kidney injury (AK) I), renal ischemia-reperfusion injury, such as oxalate-induced, folic acid (FA)-induced, and cisplatin-induced AKI, and acute tubular necrosis; chronic obstructive pulmonary disease (COPD); bronchial asthma; lung damage due to bacterial infections, particularly those caused by Pseudomonas aeruginosa or Mycobacterium tuberculosis; pulmonary fibrosis, such as radiation-induced pulmonary fibrosis (RILF) and paraquat-induced lung injury; necrotizing enterocolitis; inflammatory bowel disease, such as Chronic Kidney Disease (CDD), Chronic Kidney Disease (CDD), Chronic Kidney Disease (KDDI ... The pharmaceutical composition according to any one of claims 2 to 10, wherein the therapeutic agent is selected from the group consisting of: Rohn's disease, hemochromatosis, hemolytic disorders, cytokine storm during viral infections, radiation-induced necrosis, rheumatoid arthritis, type I diabetes, insulin resistance associated with obesity, epilepsy, such as mitochondrial disease-associated epilepsy and intractable epilepsy, and disease conditions associated with stress-induced premature tissue aging, such as atherosclerosis, hypertension, and type II diabetes.

12. The disorders associated with ferroptosis include cardiomyopathy, in particular doxorubicin-induced cardiomyopathy; contusion spinal cord injury; neurodegenerative disorders, in particular chronic neurodegenerative disorders, more particularly Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (Charcot's disease), Friedreich's ataxia, and dementia; retinal disorders, in particular Stargardt's disease or age-related macular degeneration (AMD), in particular dry AMD; acute liver failure, in particular due to drug-induced liver injury (DILI), such as acetaminophen (APAP)-induced liver injury, or due to ischemia-reperfusion injury induced by septic or hemorrhagic shock; skin inflammatory diseases, such as psoriasis; toxic epidermal necrolysis (Lyell's syndrome); acute kidney injury (AKI), for example oxalate-induced, folate-induced (FA) ...

12. The pharmaceutical composition according to claim 2, wherein the therapeutic agent is selected from the group consisting of: bronchial asthma; lung damage caused by bacterial infections, in particular those caused by Pseudomonas aeruginosa or Mycobacterium tuberculosis; pulmonary fibrosis, such as radiation-induced pulmonary fibrosis (RILF) and paraquat-induced lung injury; necrotizing enterocolitis; hemochromatosis; hemolytic disorders; cytokine storm during viral infections; radiation-induced necrosis; rheumatoid arthritis; type I diabetes; insulin resistance associated with obesity; epilepsy, such as mitochondrial disease-associated epilepsy and refractory epilepsy; and pathologies associated with stress-induced premature tissue aging, such as hypertension and type II diabetes.

13. The ferroptosis-related disorders include myocardial ischemia-reperfusion injury, particularly occurring after arterial ligation; stroke, particularly ischemic stroke or hemorrhagic stroke; traumatic brain injury; neurodegenerative disorders, particularly chronic neurodegenerative disorders, more particularly Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis (Charcot's disease); retinal disorders, particularly Stargardt's disease or age-related macular degeneration (AMD), particularly dry AMD; chronic liver diseases, particularly non-alcoholic fatty liver disease. The pharmaceutical composition according to any one of claims 2 to 11, wherein the pharmaceutical composition is selected from the group consisting of acute liver injury (NASH); acute liver failure, particularly due to drug-induced liver injury (DILI) such as acetaminophen (APAP)-induced liver injury, or due to ischemia-reperfusion injury induced by septic or hemorrhagic shock; and acute kidney injury (AKI), such as folic acid (FA)-induced AKI and cisplatin-induced AKI, renal ischemia-reperfusion injury, and acute tubular necrosis.

14. 11. An agent for use in inhibiting ferroptosis-induced cell death in biological material such as a cell or tissue sample, comprising a compound according to any one of claims 1 to 10 or a pharma- ceutically acceptable salt and / or solvate thereof.

15. 【Catalog 10】 【change】 【change】 or a pharma- ceutically acceptable salt or solvate thereof.

16. A pharmaceutical composition comprising the compound of claim 15 or a pharma- ceutically acceptable salt or solvate thereof.

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