Organoselenium compounds, preparation and implementations thereof

Abstract

The present disclosure provides a compound of Formula (I), 5 Formula (I) its polymorphs, stereoisomers, prodrugs, solvates, metabolites, intermediates, and pharmaceutically acceptable salts thereof. The compound of Formula (I) of the present disclosure is selected from Formula (Ia) or Formula (Ib). The present disclosure further provides a process for preparation of the compound of Formula 10 (Ia) and Formula (Ib), its pharmaceutical composition and uses thereof.

Description

ORGANOSELENIUM COMPOUNDS, PREPARATION AND IMPLEMENTATIONS THEREOFFIELD OF INVENTION

[0001] The present disclosure relates to the field of medicinal chemistry and more particularly to compounds that catalytically mimic the activity of glutathione peroxidases (GPX4), in particular organoselenium compounds and pharmaceutical compositions containing these compounds as the active ingredient. The present disclosure further relates to a process of preparation of the aforementioned compounds. The compounds of the present disclosure are useful as medicaments for the treatment, prevention or suppression of neurodegenerative diseases.BACKGROUND OF THE INVENTION

[0002] Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, traumatic brain injury, hemorrhagic stroke, ischemic stroke, and cardiovascular diseases including cardiomyopathy and cardiac hypertrophy are the leading causes of death, contributing to high morbidity and mortality rates worldwide and being extremely debilitating to human health and life. They create a huge burden for a patient's family and society, which requires effective treatment and preventative strategies to alleviate the global burden. Emerging evidence suggests that ferroptosis plays a key role in the onset and progression of cardiovascular and neurodegenerative diseases. Thus, targeting ferroptosis has attracted considerable attention over the years. The selenoenzyme glutathione peroxidase 4 (GPX4) is the master regulator of ferroptosis, which suppresses ferroptosis by reducing lipid hydroperoxides in cellular membranes to their corresponding alcohols. Organoselenium compounds have attracted immense attention towards their ability to cure such types of neurodegenerative disease. These compounds can reduce hydrogen peroxide by mimicking the function of glutathione peroxidase (GPx), a selenoenzyme, using thiol cofactors.

[0003] The benzisoselenazole compounds belong to organoselenium class compounds. The core of benzisoselenazole contains a bicyclic fused isoselenazole ring with benzene ring. These compounds have the potential to be used as therapeutic agents for disorders mediated by reactive oxygen species. There are previous reports on systematic investigation of these compounds towards high glutathione peroxidase (GPx) and peroxiredoxin (Prx) activities, provides remarkable cytoprotection to human cells, mainly by exhibiting antioxidant activities in the presence of cellular thiols.

[0004] Over the last few decades, there has been significant progress in developing benzisoselenazole based molecular systems for the treatment of neurodegenerative diseases, such as ferroptosis. These small molecule functional mimetics of GPX4 provide novel cytoprotective strategies that can translate into improved therapeutics in pathologically relevant scenarios; however, there have been no such effective molecules reported yet. Therefore, there is scope for improvement in the thorough understanding of the antioxidant activities of benzisoselenezole derivatives which requires molecular engineering. Also, there is a need in the state of art for developing novel small organoselenium compounds that catalytically mimic the activity of GPX4 and help in the treatment of various diseases caused by ferroptosis.SUMMARY OF THE INVENTION

[0005] In an aspect of the present disclosure, a compound of Formula (I),Formula (I) its polymorphs, stereoisomers, prodrugs, solvates, metabolites, intermediates, and pharmaceutically acceptable salts thereof, wherein,Ri is selected from hydrogen, C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl or C3-20 cycloalkyl, wherein C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, or C3-20 cycloalkyl, is optionally substituted with one or more substituent selected from oxo, hydroxyl,carboxyl, C1-5 alkylamino, Ce-15 arylamino, Ci-20 alkyl, Ci-10 alkoxy, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl, wherein Ce-15 arylamino, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, carboxyl, oxo, carbonyl, Ci-20 alkyl, or - COO(Ci-2o alkyl);R2 is selected from hydrogen, hydroxyl, C1-5 alkylamino, C6-20 aryl, C3-15 heterocyclyl, C3-15 heteroaryl, Ci-10 alkoxy or Ci-10 alkylthio, wherein the C6-20 aryl, C3-15 heterocyclyl, or C3-15 heteroaryl is optionally substituted with one or more substituent selected from hydroxy, amino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, C6-20 aryl, Ci-10 alkoxy,wherein amino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, cyano, Ci-20 alkyl-Ce-is arylamino, Ce-15 arylamino, C3-20 cycloalkylamino, or C3-15 heterocyclyl, wherein amino, Ci-20 alkyl-Ce-is arylamino, Ce-15 arylamino, or C3-15 heterocyclyl is optionally substituted with one or more substituent selected from hydroxy, oxo, amino, Ci-20 alkyl, -COO(Ci-2o alkyl), or C3-20 cycloalkylamino;R3 is selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl;R4 and R5 are independently selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl or R4 and R5 are taken together to form an oxo or C3-20 cycloalkyl.

[0006] In another aspect of the present disclosure, there is provided a process of preparation of compound of Formula I, or its polymorphs, stereoisomers, prodrugs, solvates, metabolites, intermediates, and pharmaceutically acceptable salts thereof.

[0007] In yet another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula I, its polymorphs, stereoisomers, prodrugs, solvates, metabolites, intermediates, or pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

[0008] In another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula I, as disclosed herein and a pharmaceutically acceptable carrier.

[0009] In yet another aspect of the present disclosure, there is provided a method of treating a disease or condition in a patient, said method comprising administering to the patient an effective amount of a compound of Formula (I), or its polymorphs, stereoisomers, prodrugs, solvates, metabolites, intermediates, or pharmaceutically acceptable salt thereof, wherein said disease or condition is caused by dysregulation of iron, thiol, lipid peroxidation metabolism, redox homeostasis and accumulation of overt levels of reactive oxidation species (ROS) or lipid ROS due to impairment in the level or activity of antioxidant enzymes particularly GPX4 or GPX3.

[0010] These and other features, aspects, and advantages of the present subject matter will be better understood with reference to the following description. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify key features or essential features of the disclosed subject matter, nor is it intended to be used to limit the scope of the disclosed subject matter.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The following drawings form a part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.

[0012] Figure 1 depicts the (A) GPX activity of compounds of Formula I (2.5 pM) in the presence of 1.5 mM hydrogen peroxide (H2O2), cumene hydroperoxide (Cum-OOH) and tertiary butyl hydroperoxide (t-BuOOH) in comparison with Ferrostatin 1 (Fer-1; ferroptosis inhibitor); (B) GPX4 activity of compounds of Formula I (2.5 pM) in the presence of 50 pM of free fatty acid lipid hydroperoxides (15-HpETE) and esterified phospholipid hydroperoxides (15-HpETE-SAPE); (C)effect of varying concentrations (0-100 pM) of 15-HpETE and 15-HpETE-SAPE on the catalytic activity of compound 5 (2.5 pM); and (D) effect of varying concentrations of GSH (0-3 mM) on the catalytic reduction of free fatty acid lipid hydroperoxides (15-HpETE) and esterified phospholipid hydroperoxides (15- HpETE-SAPE) by compound 5 (2.5 pM), in accordance with an implementation of the present disclosure.

[0013] Figure 2 depicts the (A) phase contrast image showing the effect of compounds 1 and 5 of Formula I on GPX4 depletion-induced ferroptosis in HT1080 cells; (B) effect of compounds of Formula I on shGPX4 induced accumulation of lipid peroxides; (C) phase contrast image of HT1080 cells in the presence or absence of compounds 1 and 5 of Formula I (1 pM) for 24 h; and (D) effect of lipid peroxidation in the presence of compounds of Formula 1 (1 pM) on HT1080 cells using Cl l-BODIPY by flow cytometry, in accordance with an implementation of the present disclosure.

[0014] Figure 3 depicts (A) phase contrast image of HT1080 cells left untreated or treated with Erastin (10 pM) in the presence or absence of GPX mimicking disclosed compounds 1 and 5 of Formula I (1 pM) for 24 h; and assessment of lipid peroxidation in HT1080 cells left untreated (UT) or treated with Erastin (10 pM) in the presence or absence of GPX mimicking disclosed compounds 1 to 5 of Formula I (1 pM) for 8 h and using (B) Cl l-BODIPY and (C) cytosolic (reactive oxidation species) ROS using 2’,7’-dichlorofluorescin diacetate (DCFDA) by flow cytometry, in accordance with an implementation of the present disclosure.

[0015] Figure 4 depicts phase contrast images of primary cortical neurons(A) left untreated or treated with GPX4 inhibitors RSE3 (1 pM); (B) left untreated or treated with Erastin (10 pM) in the presence or absence of the compounds 1 and 5 of Formula I; and (C) in the presence or absence of GPX mimicking disclosed compounds 1 and 5 of Formula 1 (1 pM) or glutamate analogue homocysteic acid (HCA) (5mM) for 24 h and then cell viability was assessed using live dead imaging, in accordance with an implementation of the present disclosure.

[0016] Figure 5 depicts the cell viability of (A)compounds 6, 7, 8 and 9; and(B) compounds 11 to 14 in HT1080 cells against erastin-induced ferroptosis.

[0017] Figure 6 depicts the cell viability of (A) compounds 6, 7, 8 and 9; and (B) compounds 10 to 14 in HT1080 cells against RSL3-induced ferroptosis.

[0018] Figure 7 depicts the cell viability of (A) compounds 6, 7, 8 and 9; and (B) compounds 10 to 14 along with the compound Oxa_Se in HT1080 cells against FINCh-induced ferroptosis.DETAILED DESCRIPTION OF THE INVENTION

[0019] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such steps, features, compositions, and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any or more of such steps or features. Definitions

[0020] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are delineated here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.

[0021] The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0022] The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.

[0023] Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.

[0024] The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.

[0025] The term “pharmaceutically acceptable” refers to compounds or compositions that are physiologically tolerable and do not typically produce allergic or similar untoward reactions, including but not limited to gastric upset or dizziness when administered to subjects. It will be appreciated that pharmaceutically acceptable salts of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the disclosure, pharmaceutically acceptable salts of the compounds according to Formula (I), may be preferred over the respective free base because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Accordingly, the disclosure is further directed to compounds of Formula (I) and pharmaceutically acceptable salts thereof.

[0026] The compounds of the present disclosure shall also exist as tautomers, wherein one or more forms of the compounds of Formula I shall exist in equilibrium and are interchangeable by migration of an atom or group within the compound. Tautomers are structural isomers wherein more frequently there is a transfer of proton(s) from one group to another within the compound.

[0027] Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Zn and Mn, ammonium, substituted ammonium salts, aluminum salts and the like; salts of organic bases, such as N, N’ -diacetylethylenediamine, glucamine, triethylamine, choline, dicyclohexylamine, benzylamine, trialkylamine, thiamine, guanidine, diethanolamine, a-phenylethylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine and the like, salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc. Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, fumarates, citrates, succinates, lactates, mesylates, trifluoroacetates, acetates, besylates, propionates, mandelates, hydrobromides, hydrochlorides, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.

[0028] The term “pharmaceutically acceptable carriers” refers to a material, composition or vehicle which might be a solid, liquid, diluent, solvent or an excipient that is compatible with the active ingredients of the pharmaceutical composition and is acceptable to the physiology. These carriers help in maximum absorption of the pharmaceutically active ingredient onto the tissues and organs without causing any allergic conditions.

[0029] The term "pharmaceutical composition" refers to a composition comprising the essential components along with additives, carriers, colorants and preservatives, which can be used as a pharmaceutical or medical treatment composition. In an aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula I as disclosed herein or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

[0030] The term "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and / or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s) / carrier(s) utilized, the route of administration, and like factors within the knowledge and expertise of the attending physician.

[0031] The term "substituted" refers to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic, and heterocyclic, aromatic, and nonaromatic substituents of organic compounds. Illustrative substituents, for example, include those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents, and / or any permissible substituents of organic compounds describedherein which satisfy the valences of the heteroatoms. It is understood that the substituent may be further substituted.

[0032] The term “alkyl” refers to straight or branched aliphatic hydrocarbon groups having specified number of carbon atoms in a range of 2 to 20, which are attached to the rest of the molecule by a single atom, and may be optionally substituted by one or more substituents. Preferred alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.

[0033] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group having specified number of carbon atoms in a range of 2 to 20, with one or more carbon-carbon double bonds, which are attached to the rest of the molecule by a single atom, and are optionally substituted by one or more substituent. Preferred alkenyl groups include, without limitation ethenyl, propenyl and like that.

[0034] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group having specified number of carbon atoms in a range of 2 to 20, with one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally one or more double bonds. These moeities are attached to the rest of the molecule by a single atom, and are optionally substituted by one or more substituent. Preferred alkenyl groups include, without limitation ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, and the like that.

[0035] The term “cycloalkyl” refers to non-aromatic mono or polycyclic ring system of about 3 to 20 carbon atoms, which may be optionally substituted by one or more substituents. The polycyclic ring denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctanyl, bridged cyclic groups or spirobicyclic groups e.g spiro [4.4] non-2-yl and the like.

[0036] The term “carboxyl” refers to a type of functional group where carbon atom is bonded to both an oxygen atom via a double bond (-C=O) and a hydroxyl group (-OH). The general structure of a carboxyl group can be represented as - C(=O)-OH.

[0037] The term “carbonyl” refers to a functional group where a carbon atom double-bonded to an oxygen atom (C=O). The general representation of a carbonyl group is: R-C(=O)-R'.

[0038] The term “-COO(Ci-2o alkyl)” refers to a carboxyl group substituted with Ci-io alkyl group at its hydrogen position.

[0039] The term “C3-20 cycloalkylamino” refers to C3-20 cycloalkyl group attached to a molecule or a moiety through an amino linkage.

[0040] The term “alkoxy” refers to an alkyl group attached via an oxygen linkage to the rest of the molecule, which may be optionally substituted by one or more substituents. Alkoxy groups refer to compounds with 1 to 10 carbon atoms and preferred alkoxy groups include, without limitation, -OCH3, -OC2H5 and the like.

[0041] The term “amino” refers to -NH2 group.

[0042] The term “alkylamino” refers to the amine groups substituted with alkyl chains such as NMe2, NEt2, etc., wherein the linkage of the alkylamino group on a moiety is through the N atom of the alkylamino group. Similarly, the term “arylamino” refers to the amine groups substituted with aryl rings such as -NH-CeHs, -N(C6HS)2. Aryl amino groups include carbon atoms in a range of 6 to 15.

[0043] The term “alkylaryl” refers to the alkyl groups substituted with one or more aryl rings such as -CH2-CH2-PI1, -CH2-CH(CH2)-Ph, etc., wherein the linkage of the alkylaryl group on a moiety is through the alkyl end. Alkylaryl groups include carbon atoms in a range of 7 to 20.

[0044] The term “alkylthio” refers to the alkyl groups substituted with one or more thio such as -CH2-SH, -CH2-CH2-SH, etc., wherein the linkage of the alkylthio group on a moiety is through the alkyl end. Alkylthio groups include carbon atoms in a range of 1 to 10.

[0045] The term “oxo” refers to a =0 group and includes the radical form of the oxo group (-O’).

[0046] The term “hydroxy / hydroxyl” refers to -OH group.

[0047] The term “cyano” refers to a -CN group.

[0048] The term "heteroatom" as used herein designates a sulfur, nitrogen or oxygen atom.

[0049] The term “aryl” refers to aromatic radicals having 6 to 20 carbon atoms, which may be optionally substituted by one or more substituents. Preferred aryl groups include not limited to phenyl and the like.

[0050] The term “heteroaryl” refers to an aromatic heterocyclic ring radical as defined above. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom resulting in the creation of a stable structure. The heteroaryl refers to an aromatic ring with one or more hetero atoms selected from N, O or S with carbon ranging between 3 to 15.

[0051] The term “heterocyclyl” refers to a heterocyclic ring radical that may be optionally substituted by one or more substituents. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom resulting in the creation of a stable structure. Furthermore, the term “heterocyclyl” refers to a stable 3 to 15 membered ring radical, which consists of carbon atoms and heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention the heterocyclic ring radical may be monocyclic, bicyclic or tricyclic ring systems, and the nitrogen, phosphorus, carbon, or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quatemized; and the ring radical may be partially or fully saturated. The term “heterocyclyl” refers to monocyclic or polycyclic ring, polycyclic ring system refers to a ring system containing 2 or more rings, preferably bicyclic or tricyclic rings, in which rings can be fused, bridged or spiro rings or any combinations thereof. A fused ring as used herein means that the two rings are linked to each other through two adjacent ring atoms common to both rings. The fused ring can contain 1-4 hetero atoms independently selected from N, O, or S. The rings can be either fused by nitrogen or -CH- group. Preferred heterocyclyl groups include, without limitation, oxazolinyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, qunioxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, homopiperazinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, thienyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, furyl, tetrahydrofuryl, tetrahydropyranyl, chromanyl, and isochromanyl.

[0052] Furthermore, the compound of Formula (I) can be its polymorphs, stereoisomers, prodrugs, solvates, metabolites, intermediates, and pharmaceutically acceptable salts and its compositions.

[0053] The compounds described herein may also exhibit polymorphism. This invention further includes different polymorphs of the compounds of the present invention. The term polymorph refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. It will be appreciated that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

[0054] The compounds described herein may contain one or more chiral centers and / or double bonds and therefore, may exist as stereoisomers, such as double -bond isomers (i.e., geometric isomers), regioisomers, enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure ordiastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the person skilled in the art.

[0055] It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereomers, enantiomers, tautomers, and geometrical isomers in “E” or “Z” configurational isomer or a mixture of ‘E’ and ‘Z’ isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers and geometrical isomers can be separated by physical and / or chemical methods and by those skilled in the art.

[0056] Compounds disclosed herein may exist as single stereoisomers, and or mixtures of enantiomers and / or diastereomers. All such single stereoisomers and mixtures thereof are intended to be within the scope of the subject matter described.

[0057] Described herein are prodrugs of the compound of Formula (I), which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of a compound of the invention, which are readily convertible in vivo into a compound of the invention.

[0058] Compounds disclosed herein include isotopes of hydrogen, carbon, oxygen, fluorine, chlorine, iodine and sulfur which can be incorporated into the compounds, such as not limited to 2H (D), 3H (T), 11C, 13C, 14C, 15N, 18F, 35S, 36C1 and 1251. Compounds of this invention wherein atoms were isotopically labeled for example radioisotopes such as 3H, 13C, 14C, and the like can be used in metabolic studies, kinetic studies. Compounds of the invention where hydrogen is replaced with deuterium may improve the metabolic stability and pharmacokinetics properties of the drug such as in vivo half-life.

[0059] The compounds described herein can also be prepared in any solid or liquid physical form, for example, the compound can be in a crystalline form, in amorphous form and have any particle size. Furthermore, the compound particles may be micronized or nanonized, or may be agglomerated, particulate granules, powders, oils, oily suspensions, or any other form of solid or liquid physical forms.

[0060] The term “solvate”, as used herein, refers to a crystal form of a substance which contains solvent. The term “hydrate” refers to a solvate wherein the solvent is water.

[0061] The term “prodrug” refers to the precursor of the compound of Formula I which on administration to a patient undergoes chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of a compound of Formula I of the present disclosure, which are readily convertible in vivo into a compound of the Formula I of the present disclosure.

[0062] The term “polymorphs” refers to crystal forms of the same molecule, and different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates and / or vibrational spectra as a result of the arrangement or conformation of the molecules in the crystal lattice.

[0063] In the structural formulae given herein and throughout the present disclosure, the following terms have been indicated meaning, unless specifically stated otherwise.

[0064] The term “lipid peroxidation” refers to the conversion of lipids to peroxide and hydroperoxide derivatives. These lipid oxidation products (LOPs), are susceptible to further reactions. Lipid peroxidation mainly applies to unsaturated fats, especially polyunsaturated fats such as those derived from linoleic acid.

[0065] The term “inhibitor” refers to the substance which prevents or slows down a particular chemical reaction or other process or which reduces the activity of a particular reactant, catalyst, or enzyme.

[0066] The term “ferroptosis” refers to a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. It is initiated by the failure of the glutathione-dependent antioxidant defenses, resulting in unchecked lipid peroxidation and eventual cell death.

[0067] Ratios, concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to includenot only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub -ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a temperature range of 80 °C to 130 °C should be interpreted to include not only the explicitly recited limits of 80 °C to 130 °C, but also to include subranges, such as 81 °C to 130 °C, 100 °C to 130 °C, 85 °C to 110°C and so forth, as well as individual amounts, including fractional amounts, within the specified ranges, such as 87 °C, 110 °C, 115.5 °C and 125 °C, for example.

[0068] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.

[0069] Ferroptosis is a newly discovered nonapoptotic form of regulated cell death characterised by iron-dependent accumulation of lipid peroxides. Glutathione peroxidase 4 (GPX4) is the only known cellular antioxidant enzyme capable of directly eliminating lipid peroxides using glutathione (GSH) as a reducing cosubstrate. Insufficiency of GSH or GPX4 causes loss of GPX4 activity and subsequent accumulation of lipid hydroperoxides, leading to ferroptosis. Small molecule functional mimetics of GPX4 provide novel cytoprotective strategies that can translate into improved therapeutics in pathologically relevant scenarios; however, there have been no such molecules reported yet. The present disclosure provides design and synthesis of novel, small organoselenium compounds that catalytically mimic the activity of GPX4. The synthetic strategies for these compounds include the introduction of alkyl chains such as dodecyl group on the nitrogen atom of an isoselanozole and substitutions on the benzyl ring of the isoselenazole. The alkyl substitutions on the N atom of the benzisoselenazole induce hydrophobicity for favourable interaction with the plasma membrane. The substitutions on the benzyl ring of the benzisoselenazole induce steric hindrance thereby avoiding side reactions to preserve the cyclic moiety comprising Se-N andthereby preventing toxicity in cells. These compounds actively reduce lipid hydroperoxides and suppress ferroptosis induced by classic ferroptosis inducers, such as RSL3, FIN56, FINO2, Erastin, cystine deprivation, and homocysteic acid (HCA). These compounds are efficacious in preventing ferroptosis in the ferroptosis- model cell line HT1080 as well as in primary cortical neurons. The antiferroptotic effect is due to the direct reduction of the phospholipid hydroperoxides. Also, these compounds are the first small molecule antiferroptotic agent that mitigates ferroptosis via catalytically mimicking GPX4. The studies using HT1080 cells and primary cortical neurons suggest that these compounds could pave the way to the development of an entirely new and effective therapeutic arena for combating ferroptosis and associated pathologies.

[0070] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally-equivalent products, compositions, and methods are clearly within the scope of the disclosure, as described herein.

[0071] In an embodiment of the present disclosure, there is provided a compound of Formula (I),Formula (I) or its polymorphs, stereoisomers, prodrugs, solvates, metabolites, intermediates, and pharmaceutically acceptable salts thereof, wherein,Ri is selected from hydrogen, C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl or C3-20 cycloalkyl, wherein C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, or C3-20 cycloalkyl, is optionally substituted with one or more substituent selected from oxo, hydroxyl, carboxyl, -COO(C 1-20 alkyl), C1-5 alkylamino, Ce-15 arylamino, Ci-20 alkyl, Ci-10 alkoxy, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl, wherein Ce-15 arylamino, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl is optionally substituted with one ormore substituent selected from hydroxyl, amino, carboxyl, oxo, carbonyl, Ci-20 alkyl, or -COO(Ci-2o alkyl);R2 is selected from hydrogen, hydroxyl, C1-5 alkylamino, C6-20 aryl, C3-15 heterocyclyl, C3-15 heteroaryl, Ci-10 alkoxy or Ci-10 alkylthio, wherein the C6-20 aryl, C3-15 heterocyclyl, or C3-15 heteroaryl is optionally substituted with one or more substituent selected from Ci-20 alkyl, C7-20 alkylaryl, C6-20 aryl, or Ci-10 alkoxy, wherein Ci-20 alkyl, C7-20 alkylaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, or cyano;R3 is selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl;R4 and R5 are independently selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl or R4 and R5 are taken together to form an oxo or C3-20 cycloalkyl.

[0072] In an embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, wherein,Ri is selected from hydrogen, C2-15 alkyl, C2-15 alkenyl, C2-15 alkynyl or C3-15 cycloalkyl, wherein C2-15 alkyl, C2-15 alkenyl, C2-15 alkynyl or C3-15 cycloalkyl, is optionally substituted with one or more substituent selected from oxo, hydroxyl, carboxyl, -COO(C 1-20 alkyl), C1-5 alkylamino, C6-12 arylamino, Ci-15 alkyl, C1-5 alkoxy, C3-12 heterocyclyl, C3-10 heteroaryl, or Ce-15 aryl, wherein C6-12 arylamino, C3-12 heterocyclyl, C3-10 heteroaryl, or Ce-15 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, carboxyl, oxo, carbonyl, Ci-15 alkyl, or -COO(Ci-2o alkyl);R2 is selected from hydrogen, hydroxyl, C1-5 alkylamino, Ce-15 aryl, C3-12 heterocyclyl, C3-12 heteroaryl, C1-5 alkoxy or C1-5 alkylthio, wherein the Ce-15 aryl, C3-12 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituent selected from Ci-10 alkyl, C7-18 alkylaryl, Ce-15 aryl, or C1-5 alkoxy, wherein Ci-10 alkyl, C7-18 alkylaryl, or Ce-15 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, or cyano;Rs is selected from hydrogen, Ci-io alkyl, C3-I8 cycloalkyl, Ce-15 aryl, C3-12 heterocyclyl, C1-4 alkylamino or C1-5 alkoxy, wherein C3-12 heterocyclyl is optionally substituted with C1-10 alkyl; andR4 and R5 are independently selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl and R5 is selected from hydrogen or oxo or Ci-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with C1-20 alkyl or R4 and R5 are taken together to form an oxo or C3-20 cycloalkyl.

[0073] In an embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, wherein the compound is selected from Formula (la) or Formula (lb),Formula (la) or Formula (lb) and its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, wherein,Ri is selected from hydrogen, C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl or C3-20 cycloalkyl, wherein C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, or C3-20 cycloalkyl, is optionally substituted with one or more substituent selected from oxo, hydroxyl, carboxyl, -COO(C 1-20 alkyl), C1-5 alkylamino, Ce-15 arylamino, Ci-20 alkyl, Ci-10 alkoxy, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl, wherein Ce-15 arylamino, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, carboxyl, oxo, carbonyl, Ci-20 alkyl, or -COO(Ci-2o alkyl);R2 is selected from hydrogen, hydroxyl, C1-5 alkylamino, C6-20 aryl, C3-15 heterocyclyl, C3-15 heteroaryl, Ci-10 alkoxy or Ci-10 alkylthio, wherein the C6-20 aryl, C3-15 heterocyclyl, or C3-15 heteroaryl is optionally substituted with one or moresubstituent selected from hydroxy, amino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, C6-20 aryl, Ci-10 alkoxy,, wherein amino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, cyano, Ci-20 alkyl-Ce-is arylamino, Ce-15 arylamino, C3-20 cycloalkylamino, or C3-15 heterocyclyl, wherein amino, Ci-20 alkyl-Ce-is arylamino, Ce-15 arylamino, or C3-15 heterocyclyl is optionally substituted with one or more substituent selected from hydroxy, oxo, amino, Ci-20 alkyl, -COO(Ci-2o alkyl), or C3-20 cycloalkylamino; andR3 is selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl.

[0074] In another embodiment of the present disclosure, there is provided a compound of Formula la as disclosed herein, wherein Ri is C2-15 alkyl, R2 is hydrogen or C1-5 alkoxy, and R3 is hydrogen. In yet another embodiment of the present disclosure, there is provided a compound of Formula la as disclosed herein, wherein Ri is C2-12 alkyl, R2 is hydrogen or C1-3 alkoxy, and R3 is hydrogen. In one another embodiment of the present disclosure, the Ri is C2-12 alkyl; R2 is hydrogen or Ci alkoxy; and R3 is hydrogen. In still another embodiment of the present disclosure, for compound 2, Ri is C4 alkyl, R2 is Ci alkoxy, and R3 is hydrogen; for compound 3, Ri is Ci, alkyl, R2 is Ci alkoxy, and R3 is hydrogen; for compound 4 Ri is Cs alkyl, R2 is Ci alkoxy; and R3 is hydrogen; for compound 5 Ri is C12 alkyl, R2 is Ci alkoxy, and R3 is hydrogen.

[0075] In an embodiment of the present disclosure, there is provided a compound of Formula la as disclosed herein, wherein the compound is selected from 7-methoxy-2-dodecyl-2,3-dihydro-l,2-benzoselenazole; 7-methoxy-2-octyl-2,3- dihydro- 1 ,2-benzoselenazole; and 7 -methoxy-2-hexyl-2,3-dihydro- 1 ,2- benzoselenazole.

[0076] In an embodiment of the present disclosure, there is provided a compound of Formula la as disclosed herein that acts as a potent inhibitor of ferroptosis. In another embodiment of the present disclosure, the use of thecompound of Formula I where Ri is C3-C12 alkyl, R2 is -OCH3, R3 is hydrogen, R4 is hydrogen and R5 is hydrogen as a potent inhibitor ferroptosis is disclosed.

[0077] In an embodiment of the present disclosure, there is provided a compound of Formula la as disclosed herein, wherein the compound of Formula I as disclosed herein prevents lipid peroxidation. In another embodiment of the present disclosure, the use of the compound of Formula la where Ri is C3-C12 alkyl, R2 is - OCH3, R3 is hydrogen, R4 is hydrogen and R5 is hydrogen prevents lipid peroxidation.

[0078] In an embodiment of the present disclosure, there is provided a process of preparation of compound of Formula la as disclosed herein, or its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, the process comprising: cyclizing an aryl diselenide with an amine, in the presence of at least one reactant and a first solvent to obtain the compound of Formula I. In one another embodiment of the present disclosure, there is a process of preparation of compound of Formula la as disclosed herein, where Ri is aryl substituted alkyl, R2 is -OCH3, R3 is hydrogen, R4 is hydrogen and R5 is hydrogen, the process comprising: cyclizing an aryl diselenide with an amine, in the presence of at least one reactant and a first solvent to obtain the compound of Formula la. In yet another embodiment of the present disclosure, there is a process of preparation of compound of Formula la as disclosed herein, where Ri is C3-C12 alkyl, R2 is -OCH3, R3 is hydrogen, R4 is hydrogen and R5 is hydrogen, the process comprising: cyclizing an aryl diselenide with an amine, in the presence of at least one reactant and a first solvent to obtain the compound of Formula I.

[0079] In an embodiment of the present disclosure, there is provided a process of preparation of compound of Formula la as disclosed herein, or its polymorphs, stereoisomers, prodrugs, solvates, metabolites, intermediates, and pharmaceutically acceptable salts thereof, the process comprising: cyclizing an aryl diselenide with an amine, in the presence of at least one reactant and a first solvent to obtain the compound of Formula la wherein the at least one reactant is selected from dichloromethane, methylcyanide, hydrochloric acid, sodium borohydride, orcombinations thereof; and the first solvent is selected from acetonitrile, methanol, or combinations thereof.

[0080] In an embodiment of the present disclosure, there is provided a process of preparation of compound of Formula la as disclosed herein, or its polymorphs, stereoisomers, prodrugs, solvates, metabolites, intermediates, and pharmaceutically acceptable salts thereof, wherein the process is carried out at a temperature in a range of 0 to 20 °C and for a time period in a range of 4 to 6 hours.

[0081] In an embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, wherein the compound is of Formula (lb),Formula (lb) and its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, wherein, Ri is selected from hydrogen, C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl or C3- 20 cycloalkyl, wherein C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, or C3-20 cycloalkyl, is optionally substituted with one or more substituent selected from oxo, hydroxyl, carboxyl, -COO(C 1-20 alkyl), C1-5 alkylamino, Ce-15 arylamino, Ci-20 alkyl, Ci-10 alkoxy, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl, wherein Ce-15 arylamino, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, carboxyl, oxo, carbonyl, Ci-20 alkyl, or -COO(Ci-2o alkyl);R2 is selected from hydrogen, hydroxyl, C1-5 alkylamino, C6-20 aryl, C3-15 heterocyclyl, C3-15 heteroaryl, Ci-10 alkoxy or Ci-10 alkylthio, wherein the C6-20 aryl, C3-15 heterocyclyl, or C3-15 heteroaryl is optionally substituted with one or more substituent selected from hydroxy, amino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, C6-20 aryl, Ci-10 alkoxy,, whereinamino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, cyano, C1-20 alkyl-Ce-is arylamino, Ce-15 arylamino, C3-20 cycloalkylamino, or C3-15 heterocyclyl, wherein amino, Ci-20 alkyl-Ce-is arylamino, Ce-15 arylamino, or C3-15 heterocyclyl is optionally substituted with one or more substituent selected from hydroxy, oxo, amino, Ci-20 alkyl, -COO(Ci-2o alkyl), or C3-20 cycloalkylamino; and R3 is selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl.

[0082] In another embodiment of the present disclosure, there is provided a compound of Formula lb as disclosed herein, wherein Ri is selected from hydrogen, C2-15 alkyl, C2-15 alkenyl, or C3-15 cycloalkyl, wherein C2-15 alkyl, C2-15 alkenyl, or C3-15 cycloalkyl, is optionally substituted with one or more substituent selected from oxo, hydroxyl, carboxyl, -COO(Ci-2o alkyl), Ci-20 alkyl, Ci-10 alkoxy, C3-15 heterocyclyl, C3-15 heteroaryl, C6-12 arylamino, or C6-20 aryl, wherein C3-15 heterocyclyl, C3-15 heteroaryl, C6-12 arylamino, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, carboxyl, oxo, carbonyl, C1-20 alkyl, or -COO(Ci-2o alkyl); R2 is selected from hydrogen, C3-15 heterocyclyl, or C3-15 heteroaryl, wherein the C6-20 aryl, C3-15 heterocyclyl, or C3-15 heteroaryl is optionally substituted with one or more substituent selected from Ci-15 alkyl, or Ce- 15 aryl, wherein Ci-15 alkyl or Ce-15 aryl is optionally substituted with one or more substituent selected from hydroxyl, or nitro; and R3 is hydrogen. In yet another embodiment of the present disclosure, the Ri is selected from hydrogen, C2-12 alkyl, C2-12 alkenyl, or C3-12 cycloalkyl, wherein C2-12 alkyl, C2-12 alkenyl, or C4-12 cycloalkyl, is optionally substituted with one or more substituent selected from hydroxyl, carboxyl, -COO(Ci-2o alkyl), Ci-20 alkyl, Ci-10 alkoxy, C3-15 heterocyclyl, C3-15 heteroaryl, Ce-io arylamino, or C6-20 aryl, wherein C3-15 heterocyclyl, C3-15 heteroaryl, Ce-io arylamino, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, Ci-20 alkyl, or -COO(Ci-2o alkyl); R2 is selected from hydrogen, or C3-10 heterocyclyl, wherein the C6-20 aryl, or C3-10 heterocyclyl, is optionally substituted with one or more substituent selected from Ci-io alkyl, or Ce-io aryl wherein Ci-io alkyl or Ce-io aryl is optionally substituted with one or more substituent selected from hydroxyl; and R3 is hydrogen. In still another embodiment of the present disclosure, for compound 6, Ri is C2 alkyl, wherein C2 alkyl is substituted with -COO(Ci alkyl), and Ci, aryl, R2 is C5 heterocyclyl, wherein C5 heterocyclyl is substituted with two Ci alkyl groups, and R3 is hydrogen; for compound 7, Ri is C2 alkenyl, wherein C2 alkenyl is substituted with - COO(Ci alkyl), and Ci, aryl, R2 is C5 heterocyclyl, wherein C5 heterocyclyl is substituted with two Ci alkyl groups, and R3 is hydrogen; for compound 8, Ri is Ci, cycloalkyl, wherein Ci, cycloalkyl is substituted with Ge arylamino, wherein Ci, arylamino is substituted with amino, and -COO(Ci alkyl), R2 is C5 heterocyclyl, wherein C5 heterocyclyl is substituted with two Ci alkyl groups, and R3 is hydrogen; for compound 9, Ri is Ci, cycloalkyl, R2 is C5 heterocyclyl, wherein C5 heterocyclyl is substituted with two Ci alkyl groups, and R3 is hydrogen; for compound 10, Ri is hydrogen, R2 is C5 heterocyclyl, wherein C5 heterocyclyl is substituted with two Ci alkyl groups, and R3 is hydrogen; for compound 11, Ri is C4 alkyl, wherein C4 alkyl is substituted with two hydroxyl groups, R2 is C5 heterocyclyl, wherein C5 heterocyclyl is substituted with two Ci alkyl groups, and R3 is hydrogen; for compound 12, Ri is C4 alkyl, wherein C4 alkyl is substituted with one hydroxyl group, R2 is C5 heterocyclyl, wherein C5 heterocyclyl is substituted with two Ci alkyl groups, wherein one Ci alkyl is substituted with hydroxyl, and R3 is hydrogen; for compound 13, Ri is C4 alkyl, wherein C4 alkyl is substituted with two hydroxyl groups, R2 is C5 heterocyclyl, wherein C5 heterocyclyl is substituted with two Ci alkyl, wherein one of C4 alkyl group is substituted with hydroxyl, and R3 is hydrogen; and for compound 14, Ri is C4 alkyl, wherein C4 alkyl is substituted with three hydroxyl groups, R2 is C5 heterocyclyl, wherein C5 heterocyclyl is substituted with two Ci alkyl groups, and R3 is hydrogen.

[0083] In an embodiment of the present disclosure, there is a process of preparation of compound of Formula lb as disclosed herein, or its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, the process comprising: reacting an arylamide with a selenium source, in the presence of at least one reagent and a second solvent to obtain the compound of Formula lb. In another embodiment of the present disclosure, there is a process of preparation of compound of Formula lb as disclosed herein, the process comprising: reacting an arylamide with a selenium source, in the presence of at least one reagent and a second solvent to obtain the compound of Formula lb.

[0084] In an embodiment of the present disclosure, there is provided a process for preparation of the compound of Formula lb as disclosed herein, wherein the arylamide is substituted with R2 and R3, wherein R2 is selected from hydrogen, hydroxyl, C1-5 alkylamino, C6-20 aryl, C3-15 heterocyclyl, C3-15 heteroaryl, Ci-10 alkoxy or C 1-10 alkylthio, wherein the C6-20 aryl, C3-15 heterocyclyl, or C3-15 heteroaryl is optionally substituted with one or more substituent selected from hydroxy, amino, Ce- 15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, C6-20 aryl, Ci-10 alkoxy,, wherein amino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, cyano, Ci-20 alkyl-Ce-is arylamino, Ce-15 arylamino, C3-20 cycloalkylamino, or C3-15 heterocyclyl, wherein amino, Ci-20 alkyl- Ce-15 arylamino, Ce-15 arylamino, or C3-15 heterocyclyl is optionally substituted with one or more substituent selected from hydroxy, oxo, amino, Ci-20 alkyl, -COO(Ci-2o alkyl), or C3-20 cycloalkylamino; and R3 is selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl.

[0085] In an embodiment of the present disclosure, there is a process of preparation of compound of Formula lb as disclosed herein, or its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, the process comprising: reacting an arylamide with a selenium source, in the presence of at least one reagent and a second solvent to obtainthe compound of Formula lb, wherein the selenium source is selenium powder; the at least one reagent is selected from amine, copper halide, 1,10-phenanthroline, potassium carbonate, or combinations thereof; and the second solvent is selected from dicyclohexylcarbodiimide (DCC), dimethyl formamide, dimethyl sulfoxide, or combinations thereof.

[0086] In an embodiment of the present disclosure, there is a process of preparation of compound of Formula lb as disclosed herein, or its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, the process comprising: treating a benzoic acid derivative with a first reagent to obtain an aryl amide; reacting the aryl amide with a selenium source, in the presence of at least one second reagent and a second solvent to obtain the compound of Formula lb, wherein the selenium source is selenium powder; the at least one first reagent is selected from amine, N,N'- tertiary butyl alcohol, triethyl amine, ethylacetate, or combinations thereof; at least one second reagent is selected from copper halide, 1,10-phenanthroline, potassium carbonate, or combinations thereof; and the second solvent is selected from dicyclohexylcarbodiimide (DCC), dimethyl formamide, dimethyl sulfoxide, or combinations thereof.

[0087] In an embodiment of the present disclosure, there is a process of preparation of compound of Formula lb as disclosed herein, or its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, wherein the process is carried out at a temperature in a range of 25 to 110 degree C and for a time period in a range of 12 to 36 hours.

[0088] In an embodiment of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula I as disclosed herein or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions. In an another embodiment of the present disclosure there is provided the pharmaceutical composition is in the form selected from the group consisting of a tablet, capsule, powder, syrup, solution, aerosol, and suspension.

[0089] In an embodiment of the present disclosure, there is provided a compound of Formula I as disclosed herein, its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, for use as a medicament. In another embodiment of present disclosure, there is provided a compound of Formula I, its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof for use as an antiferroptotic agent.

[0090] In an embodiment of the present disclosure, there is provided a use of the compound of Formula I as disclosed herein, the pharmaceutical composition, for the treatment and / or prevention of various diseases including functional, behavioural, cardiovascular, or neurodegenerative disorders, together with other clinically relevant cytotoxic agents or non-cytotoxic agents. In another embodiment of the present disclosure, the use in the neurodegenerative disorder is selected from the group of Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, traumatic brain injury, hemorrhagic stroke, and ischemic stroke; and cardiovascular diseases is selected from the group of cardiomyopathy and cardiac hypertrophy. In another embodiment of the present disclosure, the use of the compound Formula la, in effectively preventing GPX4 depletion-induced ferroptosis in primary cortical neurons is disclosed. In one another embodiments, these compounds effectively eliminate lipid peroxides and offer significant cytoprotective effects against ferroptosis induced by diverse classes of ferroptosis inducers such as RSL3, FIN56, FINO2, erastin, cystine deprivation, and HCA in both HT1080 cells and primary cortical neurons.

[0091] In an embodiment of present disclosure there is provided a method of treating a disease or condition in a patent, said method comprising administering to a patient a compound of Formula (I) as disclosed herein, or its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, wherein said disease or condition is caused by dysregulation of iron, thiol, lipid peroxidation metabolism and redox homeostasis and accumulation of overt levels of ROS / lipid ROS due to impairment in the level / activity of antioxidant enzymes particularly GPX4 / GPX3.

[0092] Although the subject matter has been described in considerable detail with reference to certain examples and implementations thereof, other implementations are possible.EXAMPLES

[0093] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may apply.

[0094] The forthcoming examples explain the preparation of isoselenazole compounds of Formula I. The compounds are modified with judicially selected groups such that these compounds work as potential candidates for glutathione peroxidase 4 mimetics as therapeutics for the treatment of ferroptosis-induced neurodegenerative diseases and other human pathologies. The present disclosure also provides a process for preparing the compounds and their activity.Materials and Methods

[0095] For the purpose of the present disclosure, the raw materials dimethyl formamide (DMF), acetonitrile (CH3CN), sodium sulfate (Na2SO4), copper iodide (CuL), 1,10-phenanthroline, N-alkyl, aryl benzamides, potassium carbonate, selenium powder, aryl diselenides, butyl amine, hexyl amine, octyl amine, dodecyl amine and sodium borohydride, were commercially procured and used.EXAMPLE 1

[0096] The general method of preparing the compounds of Formula I and Formula la is given below.Preparation of compounds of Formula I and Formula la:

[0097] The below Scheme 1 depicts the mechanistic route for the preparation of the compound of Formula lai) R1- NH2, MeCN, HC1, 4h; and ii) NaBFU, MeOH, 30 min, O2.Scheme 1

[0098] The aryl diselenides were dissolved in dry acetonitrile in the presence of dry dichloromethane to obtain a reaction mixture. In this reaction mixture, HC1 was added, which was followed by 15 minutes of stirring. The methyl amine (primary amine; R^Fh, 2.5 equiv.) was added and stirred continuously. The solvent was evaporated after 4 hours of stirring. The whole content was dissolved in dry methanol. The temperature was maintained at 0 °C and sodium borohydride was added followed by 6 hrs of stirring. The solvent was evaporated under pressure and the organic compound was extracted with dichloromethane, followed by washing with water and drying on Na2SO4. The diselenides thus obtained were purified by flash chromatography using petroleum ether and ethyl acetate as the eluents. However, during purification, the diselenides slowly cyclize to produce the corresponding isoselenazole compound 1 (compound of Formula la), which was found to be the major product. The purified isoselenazole of 7-methoxy-2-methyl- 2,3-dihydro-l,2-benzoselenazole was characterized by NMR spectroscopy and mass spectrometry.

[0099] Similarly, compound 2 (7-methoxy-2-butyl-2,3-dihydro-l,2- benzoselenazole), compound 3 (7-methoxy-2-hexyl-2,3-dihydro-l,2- benzoselenazole), compound 4 (7-methoxy-2-octyl-2,3-dihydro-l,2- benzoselenazole), and compound 5 (7-methoxy-2-dodecyl-2,3-dihydro-l,2- benzoselenazole) were prepared by using butyl amine, hexyl amine, octyl amine,and dodecyl amine respectively as the primary amine R1-NH2. The confirmation of the above compounds were carried out using NMR and mass spectrometry.[000100] The compounds of Formula la prepared by the process explained herein are depicted in below Table 1.Synthesis of N-alkyl and N-aryl substituted compounds of Formula lb:[000101] The mechanistic route of the above synthesis is depicted in Scheme 2.Scheme 2[000102] The copper iodide (0.25 equiv.) and 1,10-phenanthroline (0.25 equiv.) were added into dimethyl formamide (DMF; 3 mL). The resulting solution was stirred for 30 min under a nitrogen atmosphere, and then N-alkyl, aryl benzamides (1 equiv.), selenium powder (1.2 equiv.), and potassium carbonate powder (2 equiv.) were added sequentially to the same reaction mixture. The reaction mixture was refluxed at 110 °C for 24 hrs. using a refluxed condenser under a nitrogen atmosphere and the progress of the reaction was monitored by thin layer chromatography (TLC). After which, the reaction mixture was poured over a brine solution and stirred for 3 hrs. The obtained precipitate was collected by filtration, followed by washing and drying. Further dissolved in ethyl acetate followed by purification through column chromatography using hexane / ethyl acetate over silica gel. The purified compounds were characterized by NMR spectroscopy and mass spectrometry. The obtained compound 7 of Formula lb, oxazoline substituted 4-oxo-2-butyl-l,2- benzoselenazole as depicted below.Formula lbWhere R1=[000103] Similarly other compounds (6-14) were also prepared using the process of Example 2, as depicted in Table 1.Table 1[000104] Further, for comparative purposes, a compound 1 was prepared. Compounc1 was prepared with Ci alkyl at R1position.EXAMPLE 2GPx-like activity of Formula I compounds :[000105] GPx activity of compounds 1 to 5 (2.5 pM) was studied in the presence of reactive oxidative species (ROS) such as 1.5 mM hydrogen peroxide (H2O2), cumene hydroperoxide (Cum-OOH), and tertiary butyl hydroperoxide (t-BuOOH) separately in comparison with Fer-1 and Ebselen (Figure 1 A). Fer-1 and Ebselen are ferroptosis inhibitors by trapping radicals. Further, the GPX4 activity of compounds 1 to 5 (2.5 pM) was studied in the presence of 50 pM of free fatty acid lipid hydroperoxides (15-HpETE) and esterified phospholipid hydroperoxides (15-HpETE-SAPE) observation and compiled results are shown in Figure IB. The catalytic activity of GPX4 mimetic compound 5 (2.5 pM) was analysed by varying concentrations (0- 100 pM) of free fatty acid lipid hydroperoxides (15-HpETE) and esterified phospholipid hydroperoxides (15-HpETE-SAPE) and observations and results are shown in Figure 1C. The catalytic reduction of free fatty acid lipid hydroperoxides (15-HpETE) and esterified phospholipid hydroperoxides (15-HpETE-SAPE) exhibited by the compound 5 (2.5 pM) was studied and the results obtained by varying the concentrations of GSH (0-3 mM) was analysed and depicted in Figure ID.[000106] The Figure 1A confirmed that as the chain length of Ri substitution increased, the substrate preference of the compound changed from hydrophilic peroxide (i.e., H2O2) to hydrophobic organic peroxide (i.e., cumene hydroperoxide). Hence compound 5 was confirmed to possess more ability to reduce organic hydroperoxide owing to the longer alkyl chain at R1position. The GPX activity of these molecules was checked by using GSH coupled assay, as the GPX4 plays a central role in the prevention of ferroptosis and nervous system diseases. Therefore, GPX4 activity of these compounds along with known GPX-mimetic Ebselen were studied simultaneously as shown in Figures 1A-B. The compound 5 showed enhanced GPX4 activity. Hence, it led to the conclusion that Ri induced hydrophobicity for the favourable interaction with the plasma membrane and lead to better GPX4 activity. Therefore, by systematically varying the hydrocarbon chainlength of the substituent of the N atom, the GPX4 activity of the compound could be varied.EXAMPLE 3Cell viability studies:[000107] The studies related to GPX4 depletion-induced ferroptosis in HT1080 cells were carried out to analyse the cell viability effect of the compounds 1 to 5. As shown in Phase contrast image (Figure 2A), the cells showed different morphological changes under different conditions. Further, the effect of GPX mimicking compounds 1 to 5 on shGPX4 induced accumulation of lipid peroxides was also studied. The HT1080 cells were infected and treated with these compounds and by using Cl l-BODIPY technique, lipid peroxidation was assessed (Figure 2B). Cl l- BODIPY is a fluorescent fatty acid analogue with fluorescent properties in the red range of the visible spectrum allowing the use of this fluorescent probe in fast- and medium-throughput screening of antioxidants in living cells and model membranes in a multiwell / fluorescence reader approach. The phase contrast image and analysis of lipid peroxidation effect were recorded for HT1080 cells left untreated (UT) or treated with RSL3 (2 pM; ferroptosis inducer) in the presence or absence of compounds 1 and 5 of Formula 1 (1 pM) for 24 h. The cell viability was also assessed using live dead imaging (Figure 2C), where the HT1080 cells were left untreated or treated with RSL3 (2 pM) in the presence or absence of indicated GPX mimicking disclosed compounds 1 to 5 of Formula I (1 pM) for 24 h. Further, the lipid peroxidation of these cells was assessed using Cl l-BODIPY by flow cytometry (Figure 2D) left untreated (UT) or treated with RSL3 (2 pM; ferroptosis inducer) in the presence or absence of compounds 1 and 5 of Formula 1 (1 pM) for 24 h for 2 h. The green live cells was found to be higher when compound 5 was treated. All these results (Figure 2A-2D) revealed that in the presence of compound 5 the cell death was remarkably decreased.[000108] In another study on cell viability, the HT1080 cells were assessed using live dead imaging (Figure 3A), in which these cells were left untreated or treated with Erastin (10 pM), in the presence or absence of GPX mimicking disclosed compounds 1 to 5 of Formula 1 (1 pM) for 24 h. In one another set of experiments,these HT1080 cells were left untreated or treated with Erastin (10 |iM) in the presence or absence of GPX mimicking disclosed compounds 1 to 5 of Formula 1 (1 pM) for 8 h, followed by assessment of lipid peroxidation by using Cl l-BODIPY (Figure 3B). The cytosolic ROS was also assessed using DCFDA by flow cytometry (Figure 3C). Results indicated that the compound 5 potentially inhibited lipid peroxidation and ferroptosis in GPX4 -deficient HT1080 cells.[000109] Further studies in this direction were carried out on the primary cortical neurons. The cell viability was assessed using live dead imaging in the primary cortical neurons when they were left untreated or treated with GPX4 inhibitor RSE3 (1 pM) (Figure 4A), or Erastin (10 pM) (Figure 4B), or glutamate analogue homocysteic acid (HCA) (5mM) (Figure 4C) in the presence or absence of GPX mimicking disclosed compounds 1 to 5 of Formula I (1 pM) for 24 h. Results indicated that the compound 5 was effective in preventing GPX4 depletion-induced ferroptosis in primary cortical neurons as well. Furthermore, the compound 5 effectively eliminated lipid peroxides and offered significant cytoprotective effects against ferroptosis induced by diverse classes of ferroptosis inducers such as RSE3, FIN56, FINO2, erastin, cystine deprivation, and HCA in both HT1080 cells and primary cortical neurons.[000110] Furthermore, the cell viability studies of HT1080 cells treated with Compounds 6 to 14 against, (a) erastin-induced ferroptosis (Figure 5A and 5B), (b) RSE3-induced ferroptosis (Figure 6A and 6B), and (c) FINO2-induced ferroptosis (Figure 7), with respect to Oxa_Se as reference molecule were carried out.[000111] From the Figure 5A, and 5B, it was observed that the HT1080 cells treated with compounds 8 and 11-14 exhibited higher percentage of cell viability at lower concentrations than Oxa-Se against erastin-induced ferroptotic cell death. This suggested that the compounds 8 and 11-14 possessed significant protective effects.The high viability indicates that these compounds can effectively mitigate cellular stress or damage, functioning as a potential antioxidant, likely enhancing cell survival from erastin induced ferroptosis.[000112] Further, it was observed that, HT1080 cells treated with compound 9 exhibited no cell viability, irrespective of the concentration of the compound in the cell. Thus, it can be inferred that the compound 9 was uniformly toxic to the cells, completely inhibiting their ability to survive. This complete lethality indicated that the compound 9 did not offer any protective effects against cellular stressors. The outcome implied that it may not prevent ferroptosis induced by erastin, regardless of the dose administered.[000113] Similarly, from Figure 6A and 6B also, it was found that the HT1080 cells treated with compounds 8, 11, 12, 13 and 14 exhibited higher percentage of cell viability at lower concentrations than Oxa-Se. This finding suggested that they could prevent cell death via RSL3 -induced ferroptosis.[000114] In addition, from Figure 7 also, it was established that, that the HT1080 cells treated with compounds 8, 11, 12, 13 and 14, demonstrated higher percentage of cell viability at lower concentrations relative to Oxa-Se, suggesting that these compounds can likely enhancing cell survival from FINO2 induced ferroptosis.ADVANTAGES OF THE PRESENT DISCLOSURE[000115] The present disclosure provides the isoselenazole small-molecule functional mimetics of GPX4. This disclosure also unfolds a novel antiferroptotic strategy and upholds that these compounds can be harnessed for treating numerous organ injuries and degenerative pathologies linked to extensive lipid peroxidation and ferroptosis. These developed GPX4 isoform- specific small molecule mimetics to inhibit ferroptosis, may provide novel therapeutic opportunities for the treatment and prevention of diverse human pathologies associated with neurodegenerative diseases.

Claims

I / We Claim:

1. A compound of Formula (I),Formula (I) or its polymorphs, stereoisomers, prodrugs, solvates, metabolites, intermediates, and pharmaceutically acceptable salts thereof, wherein Ri is selected from hydrogen, C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl or C3- 20 cycloalkyl, wherein C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, or C3-20 cycloalkyl, is optionally substituted with one or more substituent selected from oxo, hydroxyl, carboxyl, - COO(C1 -20 alkyl), C1-5 alkylamino, Ce-15 arylamino, Ci-20 alkyl, Ci-10 alkoxy, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl, wherein Ce-15 arylamino, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, carboxyl, oxo, carbonyl, Ci-20 alkyl, or -COO(Ci-2o alkyl);R2 is selected from hydrogen, hydroxyl, C1-5 alkylamino, C6-20 aryl, C3-15 heterocyclyl, C3-15 heteroaryl, Ci-10 alkoxy or Ci-10 alkylthio, wherein the C6-20 aryl, C3-15 heterocyclyl, or C3-15 heteroaryl is optionally substituted with one or more substituent selected from hydroxy, amino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, C6-20 aryl, Ci-10 alkoxy,, wherein amino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, cyano, Ci-20 alkyl-Ce-is arylamino, Ce-15 arylamino, C3-20 cycloalkylamino, or C3-15 heterocyclyl, wherein amino, Ci-20 alkyl-Ce-is arylamino, Ce-15 arylamino, or C3-15heterocyclyl is optionally substituted with one or more substituent selected from hydroxy, oxo, amino, Ci-20 alkyl, -COO(Ci-2o alkyl), or C3-20 cycloalkylamino;R3 is selected from hydrogen, C1-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl; andR4 and R5 are independently selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, Ce- 20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or C 1-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl, or R4 and R5 are taken together to form an oxo or C3-20 cycloalkyl.

2. The compound as claimed in claim 1, wherein, Ri is selected from hydrogen, C2- 15 alkyl, C2-15 alkenyl, C2-15 alkynyl or C3-15 cycloalkyl, wherein C2-15 alkyl, C2-15 alkenyl, C2-15 alkynyl or C3-15 cycloalkyl, is optionally substituted with one or more substituent selected from oxo, hydroxyl, carboxyl, -COO(Ci-io alkyl), C1-5 alkylamino, C6-12 arylamino, Ci-15 alkyl, C1-5 alkoxy, C3-12 heterocyclyl, C3-10 heteroaryl, or Ce-15 aryl, wherein C6-12 arylamino, C3-12 heterocyclyl, C3-10 heteroaryl, or Ce-15 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, carboxyl, oxo, carbonyl, Ci-15 alkyl, or -COO(Ci-io alkyl);R2 is selected from hydrogen, hydroxyl, C1-5 alkylamino, Ce-15 aryl, C3-12 heterocyclyl, C3-12 heteroaryl, C1-5 alkoxy or C1-5 alkylthio, wherein the Ce-15 aryl, C3-12 heterocyclyl, or C3-12 heteroaryl is optionally substituted with one or more substituent selected from Ci-10 alkyl, C7-18 alkylaryl, Ce-15 aryl, or C1-5 alkoxy, wherein Ci-10 alkyl, C7-18 alkylaryl, or Ce-15 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, cyano;R3 is selected from hydrogen, Ci-10 alkyl, C3-I8 cycloalkyl, Ce-15 aryl, C3-12 heterocyclyl, C1-4 alkylamino or C1-5 alkoxy, wherein C3-12 heterocyclyl is optionally substituted with Ci-10 alkyl; andR4 and R5 are independently selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, Ce- 20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or C 1-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl, or R4 and R5 are taken together to form oxo or C3-20 cycloalkyl.

3. The compound as claimed claim 1, wherein the compound is Formula (I) is selected from Formula (la) or Formula (lb),Formula (la) or Formula (lb) and its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, wherein, Ri is selected from hydrogen, C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl or C3- 20 cycloalkyl, wherein C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, or C3-20 cycloalkyl, is optionally substituted with one or more substituent selected from oxo, hydroxyl, carboxyl, -COO(C 1-20 alkyl), C1-5 alkylamino, Ce-15 arylamino, Ci-20 alkyl, Ci-10 alkoxy, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl, wherein Ce-15 arylamino, C3-15 heterocyclyl, C3-15 heteroaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, carboxyl, oxo, carbonyl, Ci-20 alkyl, or -COO(Ci-2o alkyl);R2 is selected from hydrogen, hydroxyl, C1-5 alkylamino, C6-20 aryl, C3-15 heterocyclyl, C3-15 heteroaryl, Ci-10 alkoxy or Ci-10 alkylthio, wherein the C6-20 aryl, C3-15 heterocyclyl, or C3-15 heteroaryl is optionally substituted with one or more substituent selected from hydroxy, amino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, C6-20 aryl, Ci-10 alkoxy,, wherein amino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, cyano, Ci-20 alkyl-Ce-is arylamino, Ce-15 arylamino, C3-20 cycloalkylamino, or C3-15 heterocyclyl, wherein amino, Ci-20 alkyl-Ce-is arylamino, Ce-15 arylamino, or C3-15 heterocyclyl is optionally substituted with one or more substituent selected from hydroxy, oxo, amino, Ci-20 alkyl, -COO(Ci-2o alkyl), or C3-20 cycloalkylamino; andRs is selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with C1-20 alkyl.

4. The compound as claimed in claim 3, wherein Ri is selected from hydrogen, C2-15 alkyl, C2-15 alkenyl, C3-20 cycloalkyl, wherein C2-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, or C3-20 cycloalkyl, is optionally substituted with one or more substituent selected from hydroxyl, -COO(Ci-io alkyl), Ce-15 arylamino, Ci-20 alkyl, or C6-20 aryl, wherein Ce-15 arylamino, or C6-20 aryl is optionally substituted with one or more substituent selected from hydroxyl, amino, carboxyl, or -COO(Ci-2o alkyl); R2 is selected from hydrogen, C3-15 heterocyclyl, or C1-5 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with one or more substituent selected from Ci- 20 alkyl, wherein Ci-20 alkyl, is optionally substituted with one or more substituent selected from hydroxyl; and R3 is hydrogen.

5. The compound as claimed in claim 1, wherein the compound is selected from a. 7-methoxy-2-hexyl-2,3-dihydro-l,2-benzoselenazole; b. 7-methoxy-2-octyl-2,3-dihydro-l,2-benzoselenazole; c. 7-methoxy-2-dodecyl-2,3-dihydro-l,2-benzoselenazole; d. methyl 2-(7-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3- oxobenzo[d][l,2]selenazol-2(3H)-yl)-3-phenylpropanoate; e. methyl -2-(7-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3- oxobenzo [d] [ 1 ,2] selenazol-2(3 H) -y 1) - 3 -phenylacrylate ; f. methyl 3-amino-4-((4-(7-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3- oxobenzo[d][l,2]selenazol-2(3H)-yl)cyclohexyl)amino)benzoate; g. 2-cyclohexyl-7-(4,4-dimethyl-4,5-dihydrooxazol-2- yl)benzo [d] [ 1 ,2] selenazol-3 (2H)-one; h. 7-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)benzo[d][l,2]selenazol-3(2H)- one; i. 2-(l,3-dihydroxy-2-methylpropan-2-yl)-7-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)benzo[d][l,2]selenazol-3(2H)-one; j . 2-( 1 -hydroxy-2-methylpropan-2-yl)-7 -(4-(hydroxymethyl)-4-methyl- 4,5-dihydrooxazol-2-yl)benzo[d][l,2]selenazol-3(2H)-one;k. 2-(l,3-dihydroxy-2-methylpropan-2-yl)-7-(4-(hydroxymethyl)-4- methyl-4,5-dihydrooxazol-2-yl)benzo[d][l,2]selenazol-3(2H)-one; and l. 2-(l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-7-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)benzo[d][l,2]selenazol-3(2H)-one.

6. The compound as claimed in any one of the claims 1 to 5, wherein the compound of Formula I acts as a potent inhibitor of ferroptosis.

7. The compound as claimed in any one of the claims 1 to 5, wherein the compound of Formula I prevents lipid peroxidation.

8. A process of preparation of compound of Formula (la) as claimed in claim 3, its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, the process comprising: cyclizing an aryl diselenide with an amine in presence of at least one reactant and a first solvent to obtain the compound of Formula (la).

9. The process as claimed in claim 8, wherein the at least one reactant is selected from dichloromethane, methylcyanide, hydrochloric acid, sodium borohydride, or combinations thereof; and the first solvent is selected from acetonitrile, methanol, or combinations thereof.

10. A process of preparation of compound of Formula (lb) as claimed in claim 3, its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, the process comprising: reacting an arylamide with a selenium source, in presence of at least one reagent and a second solvent to obtain the compound of Formula (lb).

11. The process as claimed in claim 10, wherein the arylamide is a benzamide substituted with R2 and R3, wherein R2 is selected from hydrogen, hydroxyl, C1-5 alkylamino, C6-20 aryl, C3-15 heterocyclyl, C3-15 heteroaryl, Ci-10 alkoxy or Ci-10 alkylthio, wherein the C6-20 aryl, C3-15 heterocyclyl, or C3-15 heteroaryl is optionally substituted with one or more substituent selected from hydroxy, amino, Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, C6-20 aryl, Ci-10 alkoxy, or, wherein amino,Ce-15 arylamino, C3-20 cycloalkyl, Ci-20 alkyl, C7-20 alkylaryl, or C6-20 aryl is optionallysubstituted with one or more substituent selected from hydroxyl, nitro, amino, cyano, Ci-20 alkyl-Ce-15 arylamino, Ce-15 arylamino, C3-20 cycloalkylamino, or C3-15 heterocyclyl, wherein amino, C1-20 alkyl-Ce-is arylamino, Ce-15 arylamino, or C3-15 heterocyclyl is optionally substituted with one or more substituent selected from hydroxy, oxo, amino, Ci-20 alkyl, -COO(Ci-2o alkyl), or C3-20 cycloalkylamino; and R3 is selected from hydrogen, Ci-20 alkyl, C3-20 cycloalkyl, C6-20 aryl, C3-15 heterocyclyl, C1-5 alkylamino or Ci-10 alkoxy, wherein C3-15 heterocyclyl is optionally substituted with Ci-20 alkyl.

12. The process as claimed in claim 10, wherein the selenium source is selenium powder; at least one reagent is selected from copper halide, 1,10-phenanthroline, potassium carbonate, or combinations thereof; and the second solvent is selected from dicyclohexylcarbodiimide (DCC), dimethyl formamide (DMF), dimethyl sulfoxide, or combinations thereof.

13. A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7, together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

14. The pharmaceutical composition as claimed in claim 13, wherein the composition is in a form selected from the group consisting of a tablet, capsule, powder, syrup, solution, aerosol, and suspension.

15. The compound as claimed in any one of the claims 1 to 7, its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition as claimed in any one of the claims 13 to 14, for use as a medicament.

16. The compound as claimed in any one of the claims 1 to 7, its polymorphs, stereoisomers, prodrugs, solvates, intermediates, metabolites, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition as claimed in any one of the claims 13 to 14, for use as an antiferroptotic agent.

17. Use of the compounds as claimed in any one of the claims 1 to 7, or the pharmaceutical composition as claimed in any one of the claims 13 to 14, for the treatment and / or prevention of various diseases including functional, behavioural,cardiovascular, or neurodegenerative disorders, together with other clinically relevant cytotoxic agents or non-cytotoxic agents.

18. The use as claimed in claim 17, wherein the neurodegenerative disorder is selected from the group of Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, traumatic brain injury, hemorrhagic stroke, and ischemic stroke; and cardiovascular diseases is selected from the group of cardiomyopathy and cardiac hypertrophy.

19. A method of treating a disease or condition in a patent, said method comprising administering to a patient an effective amount of a compound of Formula (I) as claimed in claim 1, its polymorphs, stereoisomers, prodrugs, solvates, metabolites, intermediates, or pharmaceutically acceptable salts thereof, wherein said disease or condition is caused by dysregulation of iron, thiol, or lipid peroxidation metabolism, redox homeostasis, or accumulation of reactive oxidation species (ROS), or lipid ROS due to impairment in the activity of antioxidant enzymes selected from the group of GPX4, and GPX3.

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