Oxazole derivatives for oral administration

Abstract

The present invention relates to a compound of formula (I) or a stereoisomer, or tautomer, wherein R1, R2, and R3 have the same meaning as that defined in the claims and the description, wherein said compound is used as a medicament for oral administration. The present invention also relates to the use of such compounds for the prevention and / or treatment of a disease associated with ferroptosis and / or oxytosis such as liver disease, chronic kidney disease, lung disease, ocular surface diseases, wound healing, multiple organ dysfunction syndrome, neurological disease, acute renal failure, ischemia-reperfusion injury, sepsis, prevention of transplant rejection, iron toxicity, iron metabolism-related disease and genetic disorders of GPX4. The present invention also provides pharmaceutical compositions comprising such compounds, as well as the use of the compounds as medicament for oral administration in methods of prevention and / or treatment of such diseases.

Description

[0001]OXAZOLE DERIVATIVES FOR ORAL ADMINISTRATIONField of the inventionThe present invention relates to oxazole derivative compounds, or pharmaceuticallyacceptable salts thereof, as defined herein, that are useful as medicaments for oral administration for inhibiting undesired cell death occurring in diseases associated withferroptosis and / or oxytosis such as liver disease, chronic kidney disease, lung disease, ocularsurface diseases, wound healing, multiple organ dysfunction syndrome, neurological disease, acute renal failure, ischemia-reperfusion injury, sepsis, iron toxicity, prevention of transplant rejection, iron metabolism-related disease, and genetic disorders of GPX4. Background of the invention Cell death is crucial for normal development, homeostasis, and the prevention of hyperproliferative diseases such as cancer. It was once thought that almost all regulated cell death in mammalian cells resulted from the activation of caspase-dependent apoptosis. This view has been challenged by the discovery of several regulated non-apoptotic cell death pathways activated in specific disease states. Regulated necrosis is defined as a genetically controlled cell death process that eventually results in cellular leakage, and is morphologically characterized by cytoplasmic granulation, as well as organelle and / or cellular swelling.Ferroptosis is one recognized form of regulated necrosis, and its hallmark is the production ofiron-dependent lipophilic reactive oxygen species (ROS). Cell membrane rupture during ferroptotic cell death is characterized by hydrogen abstraction and oxygenation ofpolyunsaturated fatty acids (PUFAs) of phospholipids (PLs), which is catalysed by redox-active iron. This subsequently leads to cell death due to the disruption of membrane stability and the accumulation of lipid hydroperoxides to lethal levels. Although the process of lipid peroxidation has been linked to several regulated cell death modalities, ferroptosis is exclusively driven by excessive lipid peroxidation. Oxidative damage of PUFA-PLs can be initiated either through non-enzymatic free-radical chain reactions involving Fenton chemistry or enzyme-mediated processes catalysed by iron-dependent lipoxygenases (LOXs) orcytochrome P450 oxidoreductase (POR). In addition to ferroptosis, glutamine and oxidativestress induced cell death are inhibited by iron chelation. In line with this, iron-dependent neuronal cell death is blocked by metal protein-attenuating compounds (e.g. clioquinol) and iron chelators (e.g. deferoxamine), which are being explored for the treatment of neurodegenerative diseases. Another type of regulated necrosis is oxytosis which is also induced when the Xc- Cys / Glu antiporter is inhibited through an excess of the neurotransmitterglutamine; the latter process is often designated as excitotoxicity in neuronal cells. Becauseof the clear mechanistic overlaps between oxytosis and ferroptosis, the use of modulators offerroptosis in disease will likely target the same disease processes which are associated withoxytosis. Disease processes where undesired ferroptosis and / or oxytosis occur are typicallydisorders where an oxidative stress factor is involved such as in several neurodegenerativediseases, liver-, cardiac- and kidney-ischemia – reperfusion injury, stroke, sepsis, diabetes,and epilepsy. Oxidative stress due to iron overload is for example highly relevant in organsaccumulating iron such as the brain, kidney, and liver.Several compounds have been described in the art which are able to inhibit ferroptosis suchas, for example in WO2013 / 152039 and in, Skouta R. et al (2014) J. Am. Chem. Soc. 136,4551-4556). The prior art highlights the importance of the ethyl-ester in the maintenance of the potency of the first-in-class compound ferroptosis inhibitor molecule (designated as Ferrostatin-1) and there have been suggestions for chain modifications of the ester for generating improved molecules. Indeed, the latter reference also teaches that esters modified to amides and sulfonamides at the same position have a lower EC50. It has also been suggested that improved pharmacokinetic variants of Ferrostatin-1 could be ester analogues. It would be desirable to generate additional compounds that can inhibit or reduce ferroptosis,in particular compounds with an improved physicochemical and / or pharmacokinetic profile thatallows their use as oral medicaments. There is a need for small molecules that use ferroptosis and / or oxytosis as their target, have strong selectivity, have good oral bioavailability, and have significant efficacy for the treatmentof ferroptosis and / or oxytosis-related diseases.Summary of the invention The present invention is based on the unexpected finding that at least one of the above- mentioned objectives can be attained by small molecules. The present invention provides compounds which have surprisingly been found to be potent inhibitors of ferroptosis and / or oxytosis with excellent oral availability; more particularly, thecompounds of the invention show very potent in vitro anti-ferroptotic activity in the lownanomolar range and good radical-trapping ability. Moreover, the compounds show moderateto high central nervous system (CNS) multiparameter optimization (MPO) scores, blood-brainbarrier (BBB) permeability and in vivo pharmacokinetics (PK) in brain tissue. In view thereof,these compounds can be used to treat diseases where an excess of ferroptosis and / or oxytosis occurs. A first aspect of the present invention provides a compound of formula (I) or a stereoisomer, or tautomer thereof, wherein, R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, C3- 10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3- 10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z1; R2is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, hydrogen, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3- 10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z2;R3 is selected from the group consisting of C3-10cycloalkyl, C3-10cycloalkenyl, C3-10cycloalkynyl,aryl, heterocyclyl, and heteroaryl, wherein said C3-10cycloalkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl or heteroaryl can be unsubstituted or substituted with one or more Z3; each Z1, Z2and Z3is independently selected from the group consisting of halo, haloC1-6alkyl,C1-6alkyl, haloC1-6alkyloxy, C1-10cycloalkyl, aryl, alkyC1-6alkyl, heterocyclyl, heteroaryl,hydroxyl, -OR10, cyano,amino, -NR6R7, -C(O)2R10, -C(O)NR6R7, -C(O)R10, -S(O)R10, -S(O)2R10, -S(O)2NR6R7, nitro;each R6and R7is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; each R10is independently selected from the group consisting of C1-6alkyl, hydrogen, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; or a solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof; for use as a medicament for oral administration.According to a further related aspect, the present invention also encompasses a compound offormula (I) as described in the first aspect of the invention, for use as a medicament for oraladministration in the prevention or treatment of a disease associated with ferroptosis and / oroxytosis. Accordingly, an aspect of the present invention encompasses a compound for useaccording to the first aspect of the invention, which is for use in the prevention or treatment ofa disease associated with ferroptosis and / or oxytosis. A third, related aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described in the first or second aspect of theinvention, and a pharmaceutically acceptable carrier. According to a fourth closely relatedaspect, the present invention also encompasses a compound according to the second aspectof the invention for use in the prevention or treatment of liver disease, chronic kidney disease, lung disease, ocular surface diseases, wound healing, multiple organ dysfunction syndrome, neurological disease, acute renal failure, ischemia-reperfusion injury, sepsis, iron toxicity,prevention of transplant rejection, iron metabolism-related disease and genetic disorders ofGPX4. The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combinedwith any other aspect or aspects unless clearly indicated to the contrary. In particular, anyfeature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. The independent and dependent claims set out particular and preferred features of the invention. Features from the dependent claims may be combined with features of the independent or other dependent claims as appropriate. Detailed description of the invention Before the present invention is described, it is to be understood that this invention is not limited to particular processes, methods, and compounds described, as such processes, methods,and compounds may, of course, vary. It is also to be understood that the terminology usedherein is not intended to be limiting since the scope of the present invention will be limited only by the appended claims. When describing the compounds and processes of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise. As used in the specification and the appended claims, the singular forms "a", "an," and "the" include both singular and plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound. The terms "comprising", "comprises" and "comprised of" as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do notexclude additional, non-recited members, elements or method steps. The terms "comprising","comprises" and "comprised of" also include the term “consisting of”. The term "about" as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of + / -10% or less, preferably + / -5% or less, more preferably + / -1% or less, and still more preferably + / -0.1% or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier "about" refers is itself also specifically, and preferably, disclosed. As used herein, the term "and / or," when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed. For example, if a list is described as comprising group A, B, and / or C, the list can comprise A alone; B alone; C alone; A and B in combination; A and C in combination, B and C in combination; or A, B, and C in combination. The recitation of numerical ranges by endpoints includes all integer numbers and, where appropriate, fractions subsumed within that range (e.g. 1 to 5 can include 1, 2, 3, 4 whenreferring to, for example, a number of elements, and can also include 1.5, 2, 2.75 and 3.80,when referring to, for example, measurements). The recitation of end points also includes the end point values themselves (e.g. from 1.0 to 5.0 includes both 1.0 and 5.0). Any numerical range recited herein is intended to include all sub-ranges subsumed therein. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiments but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or moreembodiments. Furthermore, while some embodiments described herein include some, but notother features included in other embodiments combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments as would be understood by those in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination. Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, definitions for the terms usedin the description are included to better appreciate the teaching of the present invention.When describing the present invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise.The terms described above, and others used in the specification are well understood to thosein the art. Whenever the term “substituted” is used herein, it is meant to indicate that one or more hydrogen atoms on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom’s normal valence is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation from a reaction mixture. Where groups can be substituted, such groups may be substituted with one or more, and preferably one, two or three substituents. Preferred substituents may be selected from but not limited to, for example, the group comprising halo, hydroxyl, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, cyano, amino, nitro,carboxyl, and mono- or dialkylamino.The term “halo” or “halogen” as a group or part of a group is generic for fluoro, chloro, bromo, iodo. The term “hydroxyl” or “hydroxy” as used herein refers to the group -OH. The term “cyano” as used herein refers to the group -C≡N. The term “amino” as used herein refers to the -NH2 group. The term “nitro” as used herein refers to the -NO2 group. The term "carboxy" or “carboxyl” or “hydroxycarbonyl” as used herein refers to the group -CO2H. The term “aminocarbonyl” as used herein refers to the group –CONH2. The term "alkyl", as a group or part of a group, refers to a hydrocarbyl group of formula -CnH2n+1wherein n is a number greater than or equal to 1. Alkyl groups may be linear or branched and may be substituted as indicated herein. Generally, alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 5 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2 carbon atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, “C1-6alkyl” includes all linear or branched alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers. For example, “C1-5alkyl” includes all linear or branched alkyl groups with between 1 and 5 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers. For example, “C1-4alkyl” includes all linear or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl).For example, “C1-3alkyl” includes all linear or branched alkyl groups with between 1 and 3carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl. When the term "alkyl" is used as a suffix following another term, as in "hydroxyalkyl," this is intended to refer to an alkyl group, as defined above, being substituted with one or two (preferably one) substituent(s) selected from the other, specifically-named group, also as defined herein. The term "hydroxyalkyl" therefore refers to a -Ra-OH group wherein Rais alkylene as defined herein. The term "haloalkyl" as a group or part of a group, refers to an alkyl group having the meaning as defined above wherein one, two, or three hydrogen atoms are each replaced with a halogen as defined herein. Non-limiting examples of such haloalkyl groups include chloromethyl, 1- bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, trichloromethyl, tribromomethyl, and the like. The term “alkoxy" or “alkyloxy”, as a group or part of a group, refers to a group having the formula –ORbwherein Rbis alkyl as defined herein above. Non-limiting examples of suitable alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert- butoxy, pentyloxy and hexyloxy. The term “cycloalkyl”, as a group or part of a group, refers to a cyclic alkyl group, that is a monovalent, saturated, hydrocarbyl group having 1 or more cyclic structure, and comprising from 3 to 10 carbon atoms, more preferably from 3 to 9 carbon atoms, more preferably from 3 to 7 carbon atoms; more preferably from 3 to 6 carbon atoms. Cycloalkyl includes all saturated hydrocarbon groups containing 1 or more rings, including monocyclic or bicyclic groups. The further rings of multi-ring cycloalkyls may be either fused, bridged and / or joined through one or more spiro atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term “C3-8cycloalkyl”, a cyclic alkyl group comprising from 3 to 8 carbon atoms. For example, the term “C3-6cycloalkyl”, a cyclic alkyl group comprising from 3 to 6 carbon atoms. Examples of C3-10cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycle[2.2.1]heptan-2yl, (1S,4R)-norbornan-2-yl, (1R,4R)- norbornan-2-yl, (1S,4S)-norbornan-2-yl, (1R,4S)-norbornan-2-yl, 1-adamantyl. The term “cycloalkyloxy”, as a group or part of a group, refers to a group having the formula – ORfwherein Rfis cycloalkyl as defined herein above. The term “cycloalkenyl”, as a group or part of a group, refers to a cyclic alkenyl group, that is a monovalent, unsaturated, hydrocarbyl group having 1 or more cyclic structure, comprising one or more carbon-carbon double bonds; preferably 3 double bonds; preferably 2 double bonds; preferably one double bond. Cycloalkenyl groups according to the present invention comprise from 3 to 10 carbon atoms, more preferably from 3 to 9 carbon atoms, more preferably from 3 to 7 carbon atoms; more preferably from 3 to 6 carbon atoms. Cycloalkenylincludes all unsaturated hydrocarbon groups containing 1 or more rings, including monocyclicor bicyclic groups comprising at least one double bond. The further rings of multi-ring cycloalkenyls may be either fused, bridged and / or joined through one or more spiro atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term “C3-8cycloalkenyl”, a cyclic alkenyl group comprising from 3 to 8 carbon atoms. For example, the term “C3- 6cycloalkenyl”, a cyclic alkenyl group comprising from 3 to 6 carbon atoms. Examples of C3- 10cycloalkeyl groups include but are not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl. The term “cycloalkynyl”, as a group or part of a group, refers to a cyclic alkynyl group, that is a monovalent, unsaturated, hydrocarbyl group having 1 or more cyclic structure, comprising one or more carbon-carbon triple bonds; preferably 3 triple bonds; preferably 2 triple bonds; preferably one double bond. Cycloalkynyl groups according to the present invention comprise from 3 to 10 carbon atoms, more preferably from 3 to 9 carbon atoms, more preferably from 3 to 7 carbon atoms; more preferably from 3 to 6 carbon atoms. Cycloalkynyl includes all unsaturated hydrocarbon groups containing 1 or more rings, including monocyclic or bicyclic groups, comprising at least one triple bond. The further rings of multi-ring cycloalkynyls may be either fused, bridged and / or joined through one or more spiro atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. For example, the term “C3-8cycloalkynyl”, a cyclic alkynyl group comprising from 3 to 8 carbon atoms. For example, the term “C3-6cycloalkynyl”, a cyclic alkynnyl group comprising from 3 to 6 carbon atoms. Examples of C3-10cycloalkynyl groups include but are not limited to cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl, cycloheptynyl, cyclooctynyl. The term “aryl”, as a group or part of a group, refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthyl), or linked covalently, typically comprising 6 to 12 carbon atoms; wherein at least one ring is aromatic, preferably comprising 6 to 10 carbon atoms, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Examples of suitable aryl include C6-12aryl, preferably C6-10aryl, more preferably C6-8aryl. Non-limiting examples of aryl comprise phenyl,biphenylyl, biphenylenyl, or 1-or 2-naphthanelyl; 5- or 6-tetralinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-azulenyl, 4-, 5-, 6 or 7-indenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and 1,4-dihydronaphthyl; 1-, 2-, 3-, 4- or 5-pyrenyl. A “substituted aryl” refers to an aryl group having one or more substituent(s) (for example 1, 2 or 3 substituent(s), or 1 to 2 substituent(s)), at any available point of attachment. The term “aryloxy”, as a group or part of a group, refers to a group having the formula –ORgwherein Rgis aryl as defined herein above.The term "arylalkyl", as a group or part of a group, means an alkyl as defined herein, whereinat least one hydrogen atom is replaced by at least one aryl as defined herein. Non-limiting examples of arylalkyl group include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3-(2-naphthyl)-butyl, and the like. The terms "heterocyclyl" or “heterocycloakyl” or "heterocyclo", as a group or part of a group, refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or comprising a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring; wherein said ring may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Each ring of the heterocyclyl group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from N, O and / or S, where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and wherein at least one carbon atom of heterocyclyl can be oxidized to form at least one C=O. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and / or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, oxetanyl, pyrrolidinyl, thietanyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, chromanyl (also known as 3,4-dihydrobenzo[b]pyranyl), isoindolinyl, 2H- pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4- ylsulfoxide, thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl. The term “aziridinyl” as used herein includes aziridin-1-yl and aziridin-2-yl. The term “oxyranyl” as used herein includes oxyranyl-2-yl. The term “thiiranyl” as used herein includes thiiran-2-yl. The term “azetidinyl” as used herein includes azetidin-1-yl, azetidin-2-yl and azetidin-3-yl. The term “oxetanyl” as used herein includes oxetan-2-yl and oxetan-3-yl. The term “thietanyl” as used herein includes thietan-2-yl and thietan-3-yl. The term “pyrrolidinyl” as used herein includes pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl. The term “tetrahydrofuranyl” as used herein includes tetrahydrofuran-2-yl and tetrahydrofuran-3-yl. The term “tetrahydrothiophenyl” as used herein includes tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl. The term “succinimidyl” as used herein includes succinimid-1-yl and succininmid-3-yl. The term “dihydropyrrolyl” as used herein includes 2,3-dihydropyrrol-1-yl, 2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl, 2,5-dihydropyrrol-1-yl, 2,5-dihydro-1H- pyrrol-3-yl and 2,5-dihydropyrrol-5-yl. The term “2H-pyrrolyl” as used herein includes 2H- pyrrol-2-yl, 2H-pyrrol-3-yl, 2H-pyrrol-4-yl and 2H-pyrrol-5-yl. The term “3H-pyrrolyl” as used herein includes 3H-pyrrol-2-yl, 3H-pyrrol-3-yl, 3H-pyrrol-4-yl and 3H-pyrrol-5-yl. The term “dihydrofuranyl” as used herein includes 2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,3- dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl, 2,5-dihydrofuran-3-yl, 2,5- dihydrofuran-4-yl and 2,5-dihydrofuran-5-yl. The term “dihydrothiophenyl” as used herein includes 2,3-dihydrothiophen-2-yl, 2,3-dihydrothiophen-3-yl, 2,3-dihydrothiophen-4-yl, 2,3- dihydrothiophen-5-yl, 2,5-dihydrothiophen-2-yl, 2,5-dihydrothiophen-3-yl, 2,5- dihydrothiophen-4-yl and 2,5-dihydrothiophen-5-yl. The term “imidazolidinyl” as used herein includes imidazolidin-1-yl, imidazolidin-2-yl and imidazolidin-4-yl. The term “pyrazolidinyl” as used herein includes pyrazolidin-1-yl, pyrazolidin-3-yl and pyrazolidin-4-yl. The term “imidazolinyl” as used herein includes imidazolin-1-yl, imidazolin-2-yl, imidazolin-4-yl and imidazolin-5-yl. The term “pyrazolinyl” as used herein includes 1-pyrazolin-3-yl, 1-pyrazolin-4- yl, 2-pyrazolin-1-yl, 2-pyrazolin-3-yl, 2-pyrazolin-4-yl, 2-pyrazolin-5-yl, 3-pyrazolin-1-yl, 3- pyrazolin-2-yl, 3-pyrazolin-3-yl, 3-pyrazolin-4-yl and 3-pyrazolin-5-yl. The term “dioxolanyl” also known as “1,3-dioxolanyl” as used herein includes dioxolan-2-yl, dioxolan-4-yl and dioxolan-5-yl. The term “dioxolyl” also known as “1,3-dioxolyl” as used herein includes dioxol- 2-yl, dioxol-4-yl and dioxol-5-yl. The term “oxazolidinyl” as used herein includes oxazolidin-2- yl, oxazolidin-3-yl, oxazolidin-4-yl and oxazolidin-5-yl. The term “isoxazolidinyl” as used herein includes isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl and isoxazolidin-5-yl. The term “oxazolinyl” as used herein includes 2-oxazolinyl-2-yl, 2-oxazolinyl-4-yl, 2-oxazolinyl-5-yl, 3- oxazolinyl-2-yl, 3-oxazolinyl-4-yl, 3-oxazolinyl-5-yl, 4-oxazolinyl-2-yl, 4-oxazolinyl-3-yl, 4- oxazolinyl-4-yl and 4-oxazolinyl-5-yl. The term “isoxazolinyl” as used herein includes 2- isoxazolinyl-3-yl, 2-isoxazolinyl-4-yl, 2-isoxazolinyl-5-yl, 3-isoxazolinyl-3-yl, 3-isoxazolinyl-4- yl, 3-isoxazolinyl-5-yl, 4-isoxazolinyl-2-yl, 4-isoxazolinyl-3-yl, 4-isoxazolinyl-4-yl and 4- isoxazolinyl-5-yl. The term “thiazolidinyl” as used herein includes thiazolidin-2-yl, thiazolidin- 3-yl, thiazolidin-4-yl and thiazolidin-5-yl. The term “isothiazolidinyl” as used herein includes isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl and isothiazolidin-5-yl. The term “chromanyl” as used herein includes chroman-2-yl, chroman-3-yl, chroman-4-yl, chroman-5- yl, chroman-6-yl, chroman-7-yl and chroman-8-yl. The term “thiazolinyl” as used herein includes 2-thiazolinyl-2-yl, 2-thiazolinyl-4-yl, 2-thiazolinyl-5-yl, 3-thiazolinyl-2-yl, 3-thiazolinyl- 4-yl, 3-thiazolinyl-5-yl, 4-thiazolinyl-2-yl, 4-thiazolinyl-3-yl, 4-thiazolinyl-4-yl and 4-thiazolinyl- 5-yl. The term “isothiazolinyl” as used herein includes 2-isothiazolinyl-3-yl, 2-isothiazolinyl-4- yl, 2-isothiazolinyl-5-yl, 3-isothiazolinyl-3-yl, 3-isothiazolinyl-4-yl, 3-isothiazolinyl-5-yl, 4- isothiazolinyl-2-yl, 4-isothiazolinyl-3-yl, 4-isothiazolinyl-4-yl and 4-isothiazolinyl-5-yl. The term “piperidyl” also known as “piperidinyl” as used herein includes piperid-1-yl, piperid-2-yl, piperid-3-yl and piperid-4-yl. The term “dihydropyridinyl” as used herein includes 1,2- dihydropyridin-1-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl, 1,4-dihydropyridin-1-yl, 1,4-dihydropyridin-2- yl, 1,4-dihydropyridin-3-yl, 1,4-dihydropyridin-4-yl, 2,3-dihydropyridin-2-yl, 2,3-dihydropyridin- 3-yl, 2,3-dihydropyridin-4-yl, 2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl, 2,5- dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl, 2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl, 2,5-dihydropyridin-6-yl, 3,4-dihydropyridin-2-yl, 3,4-dihydropyridin-3-yl, 3,4-dihydropyridin-4- yl, 3,4-dihydropyridin-5-yl and 3,4-dihydropyridin-6-yl. The term “tetrahydropyridinyl” as used herein includes 1,2,3,4-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydropyridin-2-yl, 1,2,3,4- tetrahydropyridin-3-yl, 1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1,2,3,4- tetrahydropyridin-6-yl, 1,2,3,6-tetrahydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-2-yl, 1,2,3,6- tetrahydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, 1,2,3,6-tetrahydropyridin-5-yl, 1,2,3,6- tetrahydropyridin-6-yl, 2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl, 2,3,4,5- tetrahydropyridin-3-yl, 2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl and 2,3,4,5-tetrahydropyridin-6-yl. The term “tetrahydropyranyl” also known as “oxanyl” or “tetrahydro-2H-pyranyl”, as used herein includes tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl. The term “2H-pyranyl” as used herein includes 2H-pyran-2-yl, 2H- pyran-3-yl, 2H-pyran-4-yl, 2H-pyran-5-yl and 2H-pyran-6-yl. The term “4H-pyranyl” as used herein includes 4H-pyran-2-yl, 4H-pyran-3-yl and 4H-pyran-4-yl. The term “3,4-dihydro-2H- pyranyl” as used herein includes 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-3-yl, 3,4- dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl and 3,4-dihydro-2H-pyran-6-yl. The term “3,6-dihydro-2H-pyranyl” as used herein includes 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H- pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-5-yl and 3,6-dihydro-2H-pyran-6- yl. The term “tetrahydrothiophenyl”, as used herein includes tetrahydrothiophen-2-yl,tetrahydrothiophenyl -3-yl and tetrahydrothiophenyl -4-yl. The term “2H-thiopyranyl” as usedherein includes 2H-thiopyran-2-yl, 2H-thiopyran-3-yl, 2H-thiopyran-4-yl, 2H-thiopyran-5-yl and 2H-thiopyran-6-yl. The term “4H-thiopyranyl” as used herein includes 4H-thiopyran-2-yl, 4H- thiopyran-3-yl and 4H-thiopyran-4-yl. The term “3,4-dihydro-2H-thiopyranyl” as used herein includes 3,4-dihydro-2H-thiopyran-2-yl, 3,4-dihydro-2H-thiopyran-3-yl, 3,4-dihydro-2H- thiopyran-4-yl, 3,4-dihydro-2H-thiopyran-5-yl and 3,4-dihydro-2H-thiopyran-6-yl. The term “3,6-dihydro-2H-thiopyranyl” as used herein includes 3,6-dihydro-2H-thiopyran-2-yl, 3,6- dihydro-2H-thiopyran-3-yl, 3,6-dihydro-2H-thiopyran-4-yl, 3,6-dihydro-2H-thiopyran-5-yl and 3,6-dihydro-2H-thiopyran-6-yl. The term “piperazinyl” also known as “piperazidinyl” as used herein includes piperazin-1-yl and piperazin-2-yl. The term “morpholinyl” as used herein includes morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. The term “thiomorpholinyl” as used herein includes thiomorpholin-2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl. The term “dioxanyl” as used herein includes 1,2-dioxan-3-yl, 1,2-dioxan-4-yl, 1,3-dioxan-2-yl, 1,3- dioxan-4-yl, 1,3-dioxan-5-yl and 1,4-dioxan-2-yl. The term “dithianyl” as used herein includes 1,2-dithian-3-yl, 1,2-dithian-4-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl, 1,3-dithian-5-yl and 1,4- dithian-2-yl. The term “oxathianyl” as used herein includes oxathian-2-yl and oxathian-3-yl. The term “trioxanyl” as used herein includes 1,2,3-trioxan-4-yl, 1,2,3-trioxay-5-yl, 1,2,4-trioxay- 3-yl, 1,2,4-trioxay-5-yl, 1,2,4-trioxay-6-yl and 1,3,4-trioxay-2-yl. The term “azepanyl” as used herein includes azepan-1-yl, azepan-2-yl, azepan-1-yl, azepan-3-yl and azepan-4-yl. The term “homopiperazinyl” as used herein includes homopiperazin-1-yl, homopiperazin-2-yl, homopiperazin-3-yl and homopiperazin-4-yl. The term “indolinyl” as used herein includes indolin-1-yl, indolin-2-yl, indolin-3-yl, indolin-4-yl, indolin-5-yl, indolin-6-yl, and indolin-7-yl. The term “quinolizinyl” as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “isoindolinyl” as used herein includes isoindolin-1-yl, isoindolin- 2-yl, isoindolin-3-yl, isoindolin-4-yl, isoindolin-5-yl, isoindolin-6-yl, and isoindolin-7-yl. The term “3H-indolyl” as used herein includes 3H-indol-2-yl, 3H-indol-3-yl, 3H-indol-4-yl, 3H-indol-5-yl, 3H-indol-6-yl, and 3H-indol-7-yl. The term “quinolizinyl” as used herein includes quinolizidin- 1-yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “quinolizinyl” as used herein includes quinolizidin-1-yl, quinolizidin-2-yl, quinolizidin-3-yl and quinolizidin-4-yl. The term “tetrahydroquinolinyl” as used herein includes tetrahydroquinolin-1-yl, tetrahydroquinolin- 2-yl, tetrahydroquinolin-3-yl, tetrahydroquinolin-4-yl, tetrahydroquinolin-5-yl, tetrahydroquinolin-6-yl, tetrahydroquinolin-7-yl and tetrahydroquinolin-8-yl. The term “tetrahydroisoquinolinyl” as used herein includes tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, tetrahydroisoquinolin-5-yl, tetrahydroisoquinolin-6-yl, tetrahydroisoquinolin-7-yl and tetrahydroisoquinolin-8-yl. The term “1H-pyrrolizine” as used herein includes 1H-pyrrolizin-1- yl, 1H-pyrrolizin-2-yl, 1H-pyrrolizin-3-yl, 1H-pyrrolizin-5-yl, 1H-pyrrolizin-6-yl and 1H-pyrrolizin- 7-yl. The term “3H-pyrrolizine” as used herein includes 3H-pyrrolizin-1-yl, 3H-pyrrolizin-2-yl, 3H-pyrrolizin-3-yl, 3H-pyrrolizin-5-yl, 3H-pyrrolizin-6-yl and 3H-pyrrolizin-7-yl. The term “heterocyclyloxy”, as a group or part of a group, refers to a group having the formula -O-Riwherein Riis heterocyclyl as defined herein above.The term "heterocyclylalkyl", as a group or part of a group, means an alkyl as defined herein,wherein at least one hydrogen atom is replaced by at least one heterocyclyl as defined herein. The term “heteroaryl” as a group or part of a group, refers but is not limited to 5 to 12 carbon- atom aromatic rings or ring systems containing 1 or 2 rings which can be fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by N, O and / or S atoms where the N and S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized, and wherein at least one carbon atom of said heteroaryl can be oxidized to form at least one C=O. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2- b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2- benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl, 2,1- benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3- benzothiadiazolyl, 2,1,3-benzothiadiazolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro- benzofuranyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2- oxopyridin-1(2H)-yl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl; preferably said heteroaryl group is selected from the group consisting of pyridyl, 1,3-benzodioxolyl, benzo[d]oxazol-2(3H)-one, 2,3-dihydro-benzofuranyl, pyrazinyl, pyrazolyl, pyrrolyl, isoxazolyl, thiophenyl, imidazolyl, benzimidazolyl, pyrimidinyl, triazolyl and thiazolyl. The term “pyrrolyl” (also called azolyl) as used herein includes pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl. The term “furanyl” (also called "furyl") as used herein includes furan-2-yl and furan- 3-yl (also called furan-2-yl and furan-3-yl). The term “thiophenyl” (also called "thienyl") as used herein includes thiophen-2-yl and thiophen-3-yl (also called thien-2-yl and thien-3-yl). The term “pyrazolyl” (also called 1H-pyrazolyl and 1,2-diazolyl) as used herein includes pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl. The term “imidazolyl” as used herein includes imidazol-1-yl, imidazol-2-yl, imidazol-4-yl and imidazol-5-yl. The term “oxazolyl” (also called 1,3-oxazolyl) as used herein includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl. The term “isoxazolyl” (also called 1,2-oxazolyl), as used herein includes isoxazol-3-yl, isoxazol-4-yl, andisoxazol-5-yl. The term “thiazolyl” (also called 1,3-thiazolyl), as used herein includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl (also called 2-thiazolyl, 4-thiazolyl and 5-thiazolyl). The term “isothiazolyl” (also called 1,2-thiazolyl) as used herein includes isothiazol-3-yl, isothiazol-4-yl,and isothiazol-5-yl. The term “triazolyl” as used herein includes 1H-triazolyl and 4H-1,2,4-triazolyl, “1H-triazolyl” includes 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5- yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl and 1H-1,2,4-triazol-5-yl. “4H-1,2,4-triazolyl” includes 4H-1,2,4-triazol-4-yl, and 4H-1,2,4-triazol-3-yl. The term “oxadiazolyl” as used herein includes 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl and 1,3,4-oxadiazol-2-yl. The term “thiadiazolyl” as used herein includes 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5- thiadiazol-3-yl (also called furazan-3-yl) and 1,3,4-thiadiazol-2-yl. The term “tetrazolyl” as used herein includes 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, and 2H-tetrazol-5-yl. The term “oxatriazolyl” as used herein includes 1,2,3,4-oxatriazol-5-yl and 1,2,3,5-oxatriazol-4-yl. The term “thiatriazolyl” as used herein includes 1,2,3,4-thiatriazol-5-yl and 1,2,3,5-thiatriazol- 4-yl. The term “pyridinyl” (also called "pyridyl") as used herein includes pyridin-2-yl, pyridin-3- yl and pyridin-4-yl (also called 2-pyridyl, 3-pyridyl and 4-pyridyl). The term “pyrimidyl” as used herein includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl and pyrimid-6-yl. The term “pyrazinyl” as used herein includes pyrazin-2-yl and pyrazin-3-yl. The term “pyridazinyl as used herein includes pyridazin-3-yl and pyridazin-4-yl. The term “oxazinyl” (also called "1,4-oxazinyl") as used herein includes 1,4-oxazin-4-yl and 1,4-oxazin-5-yl. The term “dioxinyl” (also called "1,4- dioxinyl”) as used herein includes 1,4-dioxin-2-yl and 1,4-dioxin-3-yl. The term “thiazinyl” (also called "1,4-thiazinyl”) as used herein includes 1,4-thiazin-2-yl, 1,4-thiazin-3-yl, 1,4-thiazin-4- yl, 1,4-thiazin-5-yl and 1,4-thiazin-6-yl. The term “triazinyl” as used herein includes 1,3,5- triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl and 1,2,3- triazin-5-yl. The term “imidazo[2,1-b][1,3]thiazolyl” as used herein includes imidazo[2,1- b][1,3]thiazoi-2-yl, imidazo[2,1-b][1,3]thiazol-3-yl, imidazo[2,1-b][1,3]thiazol-5-yl and imidazo[2,1-b][1,3]thiazol-6-yl. The term “thieno[3,2-b]furanyl” as used herein includes thieno[3,2-b]furan-2-yl, thieno[3,2-b]furan-3-yl, thieno[3,2-b]furan-4-yl, and thieno[3,2-b]furan- 5-yl. The term “thieno[3,2-b]thiophenyl” as used herein includes thieno[3,2-b]thien-2-yl, thieno[3,2-b]thien-3-yl, thieno[3,2-b]thien-5-yl and thieno[3,2-b]thien-6-yl. The term “thieno[2,3-d][1,3]thiazolyl” as used herein includes thieno[2,3-d][1,3]thiazol-2-yl, thieno[2,3- d][1,3]thiazol-5-yl and thieno[2,3-d][1,3]thiazol-6-yl. The term “thieno[2,3-d]imidazolyl” as used herein includes thieno[2,3-d]imidazol-2-yl, thieno[2,3-d]imidazol-4-yl and thieno[2,3- d]imidazol-5-yl. The term “tetrazolo[1,5-a]pyridinyl” as used herein includes tetrazolo[1,5- a]pyridine-5-yl, tetrazolo[1,5-a]pyridine-6-yl, tetrazolo[1,5-a]pyridine-7-yl, and tetrazolo[1,5- a]pyridine-8-yl. The term “indolyl” as used herein includes indol-1-yl, indol-2-yl, indol-3-yl, - indol-4-yl, indol-5-yl, indol-6-yl and indol-7-yl. The term “indolizinyl” as used herein includes indolizin-1-yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, and indolizin-8-yl. The term “isoindolyl” as used herein includes isoindol-1-yl, isoindol-2-yl, isoindol-3-yl, isoindol-4-yl, isoindol-5-yl, isoindol-6-yl and isoindol-7-yl. The term “benzofuranyl” (also called benzo[b]furanyl) as used herein includes benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl and benzofuran-7-yl. The term “isobenzofuranyl” (also called benzo[c]furanyl) as used herein includes isobenzofuran-1- yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl and isobenzofuran-7-yl. The term “benzothiophenyl” (also called benzo[b]thienyl) as used herein includes 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5- benzo[b]thiophenyl, 6-benzo[b]thiophenyl and -7-benzo[b]thiophenyl (also called benzothien- 2-yl, benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl and benzothien-7-yl). The term “isobenzothiophenyl” (also called benzo[c]thienyl) as used herein includes isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien-5-yl, isobenzothien- 6-yl and isobenzothien-7-yl. The term “indazolyl” (also called 1H-indazolyl or 2-azaindolyl) as used herein includes 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H- indazol-6-yl, 1H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5- yl, 2H-indazol-6-yl, and 2H-indazol-7-yl. The term “benzimidazolyl” as used herein includes benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl and benzimidazol-7-yl. The term “1,3-benzoxazolyl” as used herein includes 1,3-benzoxazol- 2-yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl and 1,3-benzoxazol-7-yl. The term “1,2-benzisoxazolyl” as used herein includes 1,2-benzisoxazol-3-yl, 1,2- benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1,2-benzisoxazol-6-yl and 1,2-benzisoxazol-7-yl. The term “2,1-benzisoxazolyl” as used herein includes 2,1-benzisoxazol-3-yl, 2,1- benzisoxazol-4-yl, 2,1-benzisoxazol-5-yl, 2,1-benzisoxazol-6-yl and 2,1-benzisoxazol-7-yl. The term “1,3-benzothiazolyl” as used herein includes 1,3-benzothiazol-2-yl, 1,3-benzothiazol- 4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl and 1,3-benzothiazol-7-yl. The term “1,2- benzoisothiazolyl” as used herein includes 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl and 1,2-benzisothiazol-7-yl. The term “2,1- benzoisothiazolyl” as used herein includes 2,1-benzisothiazol-3-yl, 2,1-benzisothiazol-4-yl, 2,1-benzisothiazol-5-yl, 2,1-benzisothiazol-6-yl and 2,1-benzisothiazol-7-yl. The term “benzotriazolyl” as used herein includes benzotriazol-1-yl, benzotriazol-4-yl, benzotriazol-5-yl, benzotriazol-6-yl and benzotriazol-7-yl. The term “1,2,3-benzoxadiazolyl” as used herein includes 1,2,3-benzoxadiazol-4-yl, 1,2,3-benzoxadiazol-5-yl, 1,2,3-benzoxadiazol-6-yl and 1,2,3-benzoxadiazol-7-yl. The term “2,1,3-benzoxadiazolyl” as used herein includes 2,1,3- benzoxadiazol-4-yl, 2,1,3-benzoxadiazol-5-yl, 2,1,3-benzoxadiazol-6-yl and 2,1,3- benzoxadiazol-7-yl. The term “1,2,3-benzothiadiazolyl” as used herein includes 1,2,3- benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 1,2,3-benzothiadiazol-6-yl and 1,2,3- benzothiadiazol-7-yl. The term “2,1,3-benzothiadiazolyl” as used herein includes 2,1,3- benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-6-yl and 2,1,3- benzothiadiazol-7-yl. The term “thienopyridinyl” as used herein includes thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl and thieno[3,2-b]pyridinyl. The term “purinyl” as used herein includes purin-2-yl, purin-6-yl, purin-7-yl and purin-8-yl. The term “imidazo[1,2- a]pyridinyl”, as used herein includes imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-4-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl and imidazo[1,2-a]pyridin-7-yl. The term “1,3-benzodioxolyl”, as used herein includes 1,3- benzodioxol-4-yl, 1,3-benzodioxol-5-yl, 1,3-benzodioxol-6-yl, and 1,3-benzodioxol-7-yl. The term “quinolinyl” as used herein includes quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5- yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl. The term “isoquinolinyl” as used herein includes isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. The term “cinnolinyl” as used herein includes cinnolin-3- yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl and cinnolin-8-yl. The term “quinazolinyl” as used herein includes quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl. The term “quinoxalinyl” as used herein includes quinoxalin-2-yl, quinoxalin-5-yl, and quinoxalin-6-yl. The term “heteroaryloxy”, as a group or part of a group, refers to a group having the formula -O-Rkwherein Rkis heteroaryl as defined herein above.The term "heteroarylalkyl", as a group or part of a group, means an alkyl as defined herein,wherein at least one hydrogen atom is replaced by at least one heteroaryl as defined herein.The term “mono- or di-alkylamino”, as a group or part of a group, refers to a group offormula -N(Ro)(Rp) wherein Roand Rpare each independently selected from hydrogen, or alkyl, wherein at least one of Roor Rpis alkyl. Thus, alkylamino include mono-alkyl amino group (e.g. mono-C1-6alkylamino group such as methylamino and ethylamino), and di- alkylamino group (e.g. di-C1-6alkylamino group such as dimethylamino and diethylamino).Non-limiting examples of suitable mono- or di-alkylamino groups include n-propylamino,isopropylamino, n-butylamino, i-butylamino, sec-butylamino, t-butylamino, pentylamino, n- hexylamino, di-n-propylamino, di-i-propylamino, ethylmethylamino, methyl-n-propylamino, methyl-i-propylamino, n-butylmethylamino, i-butylmethylamino, t-butylmethylamino, ethyl-n- propylamino, ethyl-i-propylamino, n-butylethylamino, i-butylethylamino, t-butylethylamino, di- n-butylamino, di-i-butylamino, methylpentylamino, methylhexylamino, ethylpentylamino, ethylhexylamino, propylpentylamino, propylhexylamino, and the like.The term “mono- or di-arylamino”, as a group or part of a group, refers to a group offormula -N(Rq)(Rr) wherein Rqand Rrare each independently selected from hydrogen, or aryl, wherein at least one of Rqor Rris aryl.The term “mono- or di-arylalkylamino”, as a group or part of a group, refers to a group offormula -N(Rq’)(Rr’) wherein Rq’ and Rr’ are each independently selected from hydrogen, or arylalkyl, wherein at least one of Rq’ or Rr’ is arylalkyl.The term “mono- or di-cycloalkylamino”, as a group or part of a group, refers to a group offormula -N(Rs)(Rt) wherein Rsand Rtare each independently selected from hydrogen, or cycloalkyl, wherein at least one of Rsor Rtis cycloalkyl.The term “mono- or di-heteroarylamino”, as a group or part of a group, refers to a group offormula -N(Ru)(Rv) wherein Ruand Rvare each independently selected from hydrogen, or heteroaryl, wherein at least one of Ruor Rvis heteroaryl as defined herein.The term “mono- or di-heterocyclylamino”, as a group or part of a group, refers to a group offormula -N(Rw)(Rx) wherein Rwand Rxare each independently selected from hydrogen, or heterocyclyl, wherein at least one of Rwor Rxis heterocyclyl as defined herein. The term “alkyloxycarbonyl”, as a group or part of a group, refers to a group of formula – COO-Rb, wherein Rbis alkyl as defined herein. The term “cycloakyloxycarbonyl”, as a group or part of a group, refers to a group of formula – COO-Rb, wherein Rbis cycloalkyl as defined herein. The term “aryloxycarbonyl”, as a group or part of a group, refers to a group of formula – COO-Rb, wherein Rbis aryl as defined herein. The term “heterocyclyloxycarbonyl”, as a group or part of a group, refers to a group of formula –COO-Rb, wherein Rbis heterocyclyl as defined herein. The term “heteroaryloxycarbonyl”, as a group or part of a group, refers to a group of formula –COO-Rb, wherein Rbis heteroaryl as defined herein. The term “alkylsulfinyl”, as a group or part of a group, refers to a group of formula –SO-Rb, wherein Rbis alkyl as defined herein. The term “alkylsulfonyl”, as a group or part of a group, refers to a group of formula –S(O)2-Rb, wherein Rbis alkyl as defined herein. The term “cycloalkylsulfonyl”, as a group or part of a group, refers to a group of formula – S(O)2-Rb, wherein Rbis cycloalkyl as defined herein. The term “arylsulfonyl”, as a group or part of a group, refers to a group of formula –S(O)2-Rb, wherein Rbis aryl as defined herein. The term “heterocyclylsulfonyl”, as a group or part of a group, refers to a group of formula – S(O)2-Rb, wherein Rbis heterocyclyl as defined herein. The term “heteroarylsulfonyl”, as a group or part of a group, refers to a group of formula – S(O)2-Rb, wherein Rbis heteroaryl as defined herein.The term “mono- or di-alkylaminosulfonyl”, as a group or part of a group, refers to a group offormula –S(O)2-NNRoRp, wherein RoRpare each independently selected from hydrogen, or alkyl, wherein at least one of Roor Rpis alkyl.The term “mono- or di-cycloalkylaminosulfonyl”, as a group or part of a group, refers to a groupof formula –S(O)2-NNRoRp, wherein RoRpare each independently selected from hydrogen, or alkyl, wherein at least one of Roor Rpis cycloalkyl.The term “mono- or di-arylaminosulfonyl”, as a group or part of a group, refers to a group offormula –S(O)2-NNRoRp, wherein RoRpare each independently selected from hydrogen, or alkyl, wherein at least one of Roor Rpis aryl.The term “mono- or di-heterocyclylaminosulfonyl”, as a group or part of a group, refers to agroup of formula –S(O)2-NNRoRp, wherein RoRpare each independently selected from hydrogen, or alkyl, wherein at least one of Roor Rpis heterocyclyl.The term “mono- or di-heteroarylaminosulfonyl”, as a group or part of a group, refers to agroup of formula –S(O)2-NNRoRp, wherein RoRpare each independently selected from hydrogen, or alkyl, wherein at least one of Roor Rpis heteroaryl.The term “mono- or dialkylaminocarbonyl”, as a group or part of a group, refers to a group offormula –CONRoRpwherein RoRpare each independently selected from hydrogen, or alkyl, wherein at least one of Roor Rpis alkyl.The term “mono- or dicycloalkylaminocarbonyl”, as a group or part of a group, refers to a groupof formula –CONRoRpwherein RoRpare each independently selected from hydrogen, or cycloalkyl, wherein at least one of Roor Rpis cycloalkyl. The term “alkylcarbonyl”, as a group or part of a group, refers to a group of formula –CO-Rb, wherein Rbis alkyl as defined herein. The term “cycloalkylcarbonyl”, as a group or part of a group, refers to a group of formula – CO-Rb, wherein Rbis cycloalkyl as defined herein. The term “arylcarbonyl”, as a group or part of a group, refers to a group of formula –CO-Rb, wherein Rbis aryl as defined herein. The term “heterocyclylcarbonyl”, as a group or part of a group, refers to a group of formula – CO-Rb, wherein Rbis heterocyclyl as defined herein. The term “heteroarylcarbonyl”, as a group or part of a group, refers to a group of formula – CO-Rb, wherein Rbis heteroaryl as defined herein. The term “alkylcarbonylamino”, as a group or part of a group, refers to a group of formula -NRo-CO-Rb, wherein Rois selected from hydrogen, or alkyl and Rbis alkyl as defined herein. The term “alkylsulfonylamino”, as a group or part of a group, refers to a group of formula -NRo-S(O)2-Rb, wherein Rois selected from hydrogen, or alkyl and Rbis alkyl as defined herein. Whenever used in the present invention the term “compounds of the invention” or a similar term is meant to include the compounds of general formula (I), as defined above, as well as(IA), (IB), (IC) as detailed below and any subgroup thereof. This term also refers to thecompounds as depicted in Table 1 and their derivatives, salts, solvates, hydrates, tautomeric forms, analogues, pro-drugs, esters and metabolites, as well as their quaternized nitrogen analogues. As used herein and unless otherwise stated, the term ‘’stereoisomer‘’ refers to all possible different isomeric as well as conformational forms which the compounds of structural formula herein may possess, in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers and / or conformers of the basic molecular structure.Some compounds of the present invention may exist in different tautomeric forms; all of thelatter being included within the scope of the present invention. The present invention includes all possible stereoisomers compounds of formula (I) and any subgroup thereof. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen,and L. N. Mander (Wiley- Interscience, 1994), incorporated by reference with regard tostereochemistry. A structural isomer is a type of isomer in which molecules with the same molecular formula have different bonding patterns and atomic organization. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. The term “prodrug” as used herein means the pharmacologically acceptable derivatives suchas esters, amides and phosphates, such that the resulting in vivo biotransformation product ofthe derivative is the active drug. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed.1992, “Biotransformation of Drugs”, p 13-15) describing pro-drugs generally is hereby incorporated. Prodrugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component. Typical examples of prodrugs are described for instance in WO 99 / 33795, WO 99 / 33815, WO 99 / 33793 and WO 99 / 33792 all incorporated herein by reference. Prodrugs are characterized by increased bio-availability and are readily metabolized into the active inhibitors in vivo. The term “prodrug”, as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the pre-drug reaches the area of the body where administration of the drug is indicated. Preferred statements (features) and embodiments of the compounds and processes of this invention are now set forth. Each statement and embodiment of the invention so defined may be combined with any other statement and / or embodiments unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. 1. A compound of formula (I) or a stereoisomer, or tautomer thereof, wherein, R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z1; R2is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, hydrogen, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z2;R3 is selected from the group consisting of C3-10cycloalkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, and heteroaryl, wherein said C3-10cycloalkyl, C3- 10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl or heteroaryl can be unsubstituted or substituted with one or more Z3; each Z1, Z2and Z3is independently selected from the group consisting of halo, haloC1-6alkyl, C1-6alkyl, haloC1-6alkyloxy, C1-10cycloalkyl, aryl, alkyC1-6alkyl, heterocyclyl,heteroaryl, hydroxyl, -OR10, cyano,amino, -NR6R7, -C(O)2R10, -C(O)NR6R7, -C(O)R10, -S(O)R10, -S(O)2R10, -S(O)2NR6R7, nitro;each R6and R7is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; each R10is independently selected from the group consisting of C1-6alkyl, hydrogen, C3- 10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; or a solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof; for use as a medicament for oral administration. compound of formula (I) or a stereoisomer, or tautomer thereof, wherein, R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, C3- 10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z1; R2is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, hydrogen, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1- 6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z2;R3 is selected from the group consisting of C3-10cycloalkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, and heteroaryl, wherein said C3-10cycloalkyl, C3- 10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl or heteroaryl can be unsubstituted or substituted with one or more Z3; each Z1, Z2and Z3is independently selected from the group consisting of halo, haloC1-6alkyl, C1-6alkyl, haloC1-6alkyloxy, C1-10cycloalkyl, aryl, alkyC1-6alkyl, heterocyclyl,heteroaryl, hydroxyl, -OR10, cyano,amino, -NR6R7, -C(O)2R10, -C(O)NR6R7, -C(O)R10, -S(O)R10, -S(O)2R10, -S(O)2NR6R7, nitro;each R6and R7is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; each R10is independently selected from the group consisting of C1-6alkyl, hydrogen, C3- 10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; or a solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof; for use as a medicament for oral administration in the prevention or treatment of a disease associated with ferroptosis and / or oxytosis. he compound for use according to statement 1 or 2, having structural formula (IA), (IB) or (IC) wherein R1is as defined in any one of statements 1 or 2.4. The compound according to any one of the previous statements, wherein R1 is selectedfrom the group consisting of hydrogen, C3-9cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-9cycloalkyl, arylC1-6alkyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one two or three Z1.5. The compound according to any one of the previous statements, wherein R1 is selectedfrom the group consisting of hydrogen, C3-8cycloalkyl, C6-12arylC1-4alkyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-4alkyl, wherein said C3-8cycloalkyl, arylC1-4alkyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-4alkyl, or heteroarylC1-4alkyl can be unsubstituted or substituted with one two or three Z1.6. The compound according to any one of the previous statements, wherein R2 is selectedfrom the group consisting of hydrogen, C3-9cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-9cycloalkyl, arylC1-6alkyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one two or three Z2.7. The compound according to any one of the previous statements, wherein R2 is selectedfrom the group consisting of hydrogen, C3-8cycloalkyl, C6-12arylC1-4alkyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-4alkyl, wherein said C3-8cycloalkyl, arylC1-4alkyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-4alkyl, or heteroarylC1-4alkyl can be unsubstituted or substituted with one two or three Z2.8. The compound according to any one of the previous statements, wherein R3 is selectedfrom the group consisting of C3-9cycloalkyl, C3-9cycloalkenyl, C3-9cycloalkynyl, C6-12aryl, heterocyclyl, and heteroaryl, wherein said C3-9cycloalkyl, C3-9cycloalkenyl, C3-9cycloalkynyl, C6-12aryl, heterocyclyl or heteroaryl can be unsubstituted or substituted with one, two or three Z3.9. The compound according to any one of the previous statements, wherein R3 is selectedfrom the group consisting of C3-8cycloalkyl, C3-8cycloalkenyl, C3-8cycloalkynyl, or heterocyclyl, wherein said C3-8cycloalkyl, C3-8cycloalkenyl, C3-8cycloalkynyl, or heterocyclyl can be unsubstituted or substituted with one, two or three Z3. 10. The compound according to any one of the previous statements, wherein each Z1is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1-4akyloxy, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, C3-10cycloalkyloxy, C6-12aryloxy, heterocyclyloxy, heteroaryloxy, cyano, amino, mono-C1-4akylamino, mono-C3-10cycloakylamino, mono-C6-12arylamino, di-C1-4akylamino, di-C3-10cycloakylamino, di-C6-12arylamino, hydroxycarbonyl, C1-4akyloxycarbonyl, C3-10cycloakyloxycarbonyl, C6-12aryloxycarbonyl, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3-10cycloakylaminocarbonyl, di-C1-4akylaminocarbonyl, di-C3- 10cycloakylaminocarbonyl, C1-4akylcarbonyl, C3-12cycloakylcarbonyl, C6-12arylcarbonyl, - S(O)H, C1-4akylsulfinyl, -S(O)2H, C1-4akylsulfonyl, -SO2NH2, mono-C1-4akylaminosulfonyl, di-C1-4akylaminosulfonyl nitro. 11. The compound according to any one of the previous statements, wherein each Z1is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1- 4akyloxy, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, hydroxyl, C1- 6alkyloxy, C3-10cycloalkyloxy, C6-12aryloxy, heterocyclyloxy, heteroaryloxy, cyano, amino, mono-C1-4akylamino, mono-C3-10cycloakylamino, mono-C6-12arylamino, hydroxycarbonyl, C1-4akyloxycarbonyl, C3-10cycloakyloxycarbonyl, C6-12aryloxycarbonyl, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3-12cycloakylaminocarbonyl, C1-4akylcarbonyl, C3- 12cycloakylcarbonyl, C6-12arylcarbonyl, -S(O)H, C1-4akylsulfinyl, -S(O)2H, C1- 4akylsulfonyl, -SO2NH2, mono-C1-4akylaminosulfonyl, nitro.12. The compound according to any one of the previous statements, wherein each Z1is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1- 4akyloxy, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, hydroxyl, C1- 6alkyloxy, C3-10cycloalkyloxy, C6-12aryloxy, cyano, amino, mono-C1-4akylamino, mono-C3- 10cycloakylamino, mono-C6-12arylamino, hydroxycarbonyl, C1-4akyloxycarbonyl, C3- 10cycloakyloxycarbonyl, C6-12aryloxycarbonyl, aminocarbonyl, mono-C1- 4akylaminocarbonyl, mono-C3-10cycloakylaminocarbonyl, C1-4akylcarbonyl, C3- 12cycloakylcarbonyl, -S(O)H, C1-4akylsulfinyl, -S(O)2H, C1-4akylsulfonyl, -SO2NH2, mono-C1-4akylaminosulfonyl. 13. The compound according to any one of the previous statements, wherein each Z1is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1-4akyloxy, C3-10cycloalkyl, C6-12aryl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, C3-10cycloalkyloxy, C6-12aryloxy, cyano, amino, mono-C1-4akylamino, hydroxycarbonyl, C1-4akyloxycarbonyl, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3-10cycloakylaminocarbonyl, C1-4akylcarbonyl. 14. The compound according to any one of the previous statements, wherein each Z1is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1-4akyloxy, C3-10cycloalkyl, C6-12aryl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, cyano, amino, mono-C1-4akylamino, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3-10cycloakylaminocarbonyl, C1-4akylcarbonyl. The compound according to any one of the previous statements, wherein each Z1is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, C3- 10cycloalkyl, C6-12aryl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, cyano, amino. The compound according to any one of the previous statements, wherein each Z1is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, C3- 10cycloalkyl, C6-12aryl, hydroxyl, C1-6alkyloxy, cyano. The compound according to any one of the previous statements, wherein each Z2is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1- 4akyloxy, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, hydroxyl, C1- 6alkyloxy, C3-10cycloalkyloxy, C6-12aryloxy, heterocyclyloxy, heteroaryloxy, cyano, amino, mono-C1-4akylamino, mono-C3-10cycloakylamino, mono-C6-12arylamino, di-C1-4akylamino, di-C3-10cycloakylamino, di-C6-12arylamino, hydroxycarbonyl, C1-4akyloxycarbonyl, C3- 10cycloakyloxycarbonyl, C6-12aryloxycarbonyl, aminocarbonyl, mono-C1- 4akylaminocarbonyl, mono-C3-10cycloakylaminocarbonyl, di-C1-4akylaminocarbonyl, di-C3- 10cycloakylaminocarbonyl, C1-4akylcarbonyl, C3-12cycloakylcarbonyl, C6-12arylcarbonyl, - S(O)H, C1-4akylsulfinyl, -S(O)2H, C1-4akylsulfonyl, -SO2NH2, mono-C1-4akylaminosulfonyl, di-C1-4akylaminosulfonyl nitro. The compound according to any one of the previous statements, wherein each Z2is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1- 4akyloxy, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, hydroxyl, C1- 6alkyloxy, C3-10cycloalkyloxy, C6-12aryloxy, heterocyclyloxy, heteroaryloxy, cyano, amino, mono-C1-4akylamino, mono-C3-10cycloakylamino, mono-C6-12arylamino, hydroxycarbonyl, C1-4akyloxycarbonyl, C3-10cycloakyloxycarbonyl, C6-12aryloxycarbonyl, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3-12cycloakylaminocarbonyl, C1-4akylcarbonyl, C3-12cycloakylcarbonyl, C6-12arylcarbonyl, -S(O)H, C1-4akylsulfinyl, -S(O)2H,C1-4akylsulfonyl, -SO2NH2, mono-C1-4akylaminosulfonyl, nitro.The compound according to any one of the previous statements, wherein each Z2is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1-4akyloxy, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, C3-10cycloalkyloxy, C6-12aryloxy, cyano, amino, mono-C1-4akylamino, mono-C3-10cycloakylamino, mono-C6-12arylamino, hydroxycarbonyl, C1-4akyloxycarbonyl, C3-10cycloakyloxycarbonyl, C6-12aryloxycarbonyl, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3-10cycloakylaminocarbonyl, C1-4akylcarbonyl, C3-12cycloakylcarbonyl, -S(O)H, C1-4akylsulfinyl, -S(O)2H, C1-4akylsulfonyl, -SO2NH2, mono-C1-4akylaminosulfonyl. 20. The compound according to any one of the previous statements, wherein each Z2is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1- 4akyloxy, C3-10cycloalkyl, C6-12aryl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, C3- 10cycloalkyloxy, C6-12aryloxy, cyano, amino, mono-C1-4akylamino, hydroxycarbonyl, C1- 4akyloxycarbonyl, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3- 10cycloakylaminocarbonyl, C1-4akylcarbonyl. 21. The compound according to any one of the previous statements, wherein each Z2is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1- 4akyloxy, C3-10cycloalkyl, C6-12aryl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, cyano, amino, mono-C1-4akylamino, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3- 10cycloakylaminocarbonyl, C1-4akylcarbonyl. 22. The compound according to any one of the previous statements, wherein each Z2is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, C3- 10cycloalkyl, C6-12aryl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, cyano, amino. 23. The compound according to any one of the previous statements, wherein each Z2is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, C3- 10cycloalkyl, C6-12aryl, hydroxyl, C1-6alkyloxy, cyano. 24. The compound according to any one of the previous statements, wherein each Z3is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1- 4akyloxy, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, hydroxyl, C1- 6alkyloxy, C3-10cycloalkyloxy, C6-12aryloxy, heterocyclyloxy, heteroaryloxy, cyano, amino, mono-C1-4akylamino, mono-C3-10cycloakylamino, mono-C6-12arylamino, di-C1-4akylamino, di-C3-10cycloakylamino, di-C6-12arylamino, hydroxycarbonyl, C1-4akyloxycarbonyl, C3-10cycloakyloxycarbonyl, C6-12aryloxycarbonyl, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3-10cycloakylaminocarbonyl, di-C1-4akylaminocarbonyl, di-C3-10cycloakylaminocarbonyl, C1-4akylcarbonyl, C3-12cycloakylcarbonyl, C6-12arylcarbonyl, - S(O)H, C1-4akylsulfinyl, -S(O)2H, C1-4akylsulfonyl, -SO2NH2, mono-C1-4akylaminosulfonyl, di-C1-4akylaminosulfonyl nitro. 25. The compound according to any one of the previous statements, wherein each Z3is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1-4akyloxy, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, C3-10cycloalkyloxy, C6-12aryloxy, heterocyclyloxy, heteroaryloxy, cyano, amino, mono-C1-4akylamino, mono-C3-10cycloakylamino, mono-C6-12arylamino, hydroxycarbonyl, C1-4akyloxycarbonyl, C3-10cycloakyloxycarbonyl, C6-12aryloxycarbonyl, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3-12cycloakylaminocarbonyl, C1-4akylcarbonyl, C3-12cycloakylcarbonyl, C6-12arylcarbonyl, -S(O)H, C1-4akylsulfinyl, -S(O)2H,C1-4akylsulfonyl, -SO2NH2, mono-C1-4akylaminosulfonyl, nitro.The compound according to any one of the previous statements, wherein each Z3is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1-4akyloxy, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl, hydroxyl, C1- 6alkyloxy, C3-10cycloalkyloxy, C6-12aryloxy, cyano, amino, mono-C1-4akylamino, mono-C3- 10cycloakylamino, mono-C6-12arylamino, hydroxycarbonyl, C1-4akyloxycarbonyl, C3- 10cycloakyloxycarbonyl, C6-12aryloxycarbonyl, aminocarbonyl, mono-C1- 4akylaminocarbonyl, mono-C3-10cycloakylaminocarbonyl, C1-4akylcarbonyl, C3- 12cycloakylcarbonyl, -S(O)H, C1-4akylsulfinyl, -S(O)2H, C1-4akylsulfonyl, -SO2NH2, mono-C1- 4akylaminosulfonyl. The compound according to any one of the previous statements, wherein each Z3is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1- 4akyloxy, C3-10cycloalkyl, C6-12aryl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, C3- 10cycloalkyloxy, C6-12aryloxy, cyano, amino, mono-C1-4akylamino, hydroxycarbonyl, C1- 4akyloxycarbonyl, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3- 10cycloakylaminocarbonyl, C1-4akylcarbonyl. The compound according to any one of the previous statements, wherein each Z3is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, haloC1- 4akyloxy, C3-10cycloalkyl, C6-12aryl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, cyano, amino, mono-C1-4akylamino, aminocarbonyl, mono-C1-4akylaminocarbonyl, mono-C3- 10cycloakylaminocarbonyl, C1-4akylcarbonyl. The compound according to any one of the previous statements, wherein each Z3is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, C3-10cycloalkyl, C6-12aryl, heterocyclyl, heteroaryl, hydroxyl, C1-6alkyloxy, cyano, amino. The compound according to any one of the previous statements, wherein each Z3is independently selected from the group consisting of halo, C1-6alkyl, haloC1-4akyl, C3-10cycloalkyl, C6-12aryl, hydroxyl, C1-6alkyloxy, cyano. Apharmaceutical composition comprising a compound of formula (I) wherein, R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3- 10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z1; R2is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, hydrogen, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z2; R3is selected from the group consisting of C3-10cycloalkyl, C3-10cycloalkenyl, C3- 10cycloalkynyl, aryl, heterocyclyl, and heteroaryl, wherein said C3-10cycloalkyl, C3- 10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl or heteroaryl can be unsubstituted or substituted with one or more Z3; each Z1, Z2and Z3is independently selected from the group consisting of halo, haloC1- 6alkyl, C1-6alkyl, haloC1-6alkyloxy, C1-10cycloalkyl, aryl, alkyC1-6alkyl, heterocyclyl, heteroaryl, hydroxyl, -OR10, cyano, amino, -NR6R7, -C(O)2R10, -C(O)NR6R7, -C(O)R10, -S(O)R10, -S(O)2R10, -S(O)2NR6R7, nitro; or a solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof; each R6and R7is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; each R10is independently selected from the group consisting of C1-6alkyl, hydrogen, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; and a pharmaceutically acceptable carrier. he compound for use according to any one of statements 2-30, wherein the diseaseassociated with ferroptosis and / or oxytosis is selected from the group consisting of liverdisease, chronic kidney disease, lung disease, ocular surface diseases, wound healing, multiple organ dysfunction syndrome, neurological disease, acute renal failure, ischemia- reperfusion injury, sepsis, iron toxicity, prevention of transplant rejection, iron metabolism-related disease and genetic disorders of GPX4.he compound for use according to statement 32, wherein the liver disease is selected from hemochromatosis, primary biliary cholangitis, non-alcoholic steatohepatitis or liver fibrosis.The compound for use according to statement 32, wherein the neurological disease isselected from Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, Multiple Sclerosis, Huntington’s Disease, Dementia with Lewy bodies, Friedreich’s ataxia, stroke, periventricular leukomalacia, intracerebral haemorrhage, frontotemporal dementia, neurodegeneration with brain iron accumulation, or traumatic brain injury. The compound for use according to statement 32, wherein the ischemia-reperfusion injury is selected from myocardial ischemia-reperfusion injury, liver ischemia-reperfusion injury, renal ischemia-reperfusion injury, intestinal ischemia-reperfusion injury, cerebral ischemia-reperfusion injury, lung ischemia- reperfusion injury, or any surgical ischemia-reperfusion injury. The compound for use according to statement 32, wherein the iron metabolism-related disease is selected from atherosclerosis or diabetes.The compound for use according to statement 32, wherein the lung disease is selectedfrom acute respiratory distress syndrome (ARDS), lung diseases caused by infections such as COVID-19 pulmonary disease, mucoviscidosis, or asthma.The compound for use according to statement 32, wherein the disease is attributable to a genetic disorder of GPX4, preferably the disease is Sedaghatian-type spondylometaphyseal dysplasia. A method of prevention and / or of treatment of a disease associated with ferroptosis and / or oxytosis, said method comprising orally administering to a subject in need thereof an effective amount of a compound according to any one of statements 2 to 30, or apharmaceutical composition according to statement 31. The method according to statement 39, wherein the disease associated with ferroptosis and / or oxytosis is selected from the group consisting of liver disease, chronic kidneydisease, lung disease, ocular surface diseases, wound healing, multiple organ dysfunction syndrome, neurological disease, acute renal failure, ischemia-reperfusion injury, sepsis, iron toxicity, prevention of transplant rejection, iron metabolism-related disease and genetic disorders of GPX4.The method according to statement 39, wherein the liver disease is selected from hemochromatosis, primary biliary cholangitis, non-alcoholic steatohepatitis or liver fibrosis. The method according to statement 39, wherein neurological disease is selected from Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, Multiple Sclerosis, Huntington’s Disease, Dementia with Lewy bodies, Friedreich’s ataxia, stroke, periventricular leukomalacia, intracerebral haemorrhage, frontotemporal dementia, neurodegeneration with brain iron accumulation, or traumatic brain injury.43. The method according to statement 39, wherein the ischemia-reperfusion injury is selectedfrom myocardial ischemia-reperfusion injury, liver ischemia-reperfusion injury, renal ischemia-reperfusion injury, intestinal ischemia-reperfusion injury, cerebral ischemia- reperfusion injury, lung ischemia- reperfusion injury, or any surgical ischemia-reperfusioninjury. 44. The method according to statement 39, wherein the iron metabolism-related disease is selected from atherosclerosis or diabetes. 45. The method according to statement 39, wherein the lung disease is selected from acute respiratory distress syndrome (ARDS), mucoviscidosis, or asthma.46. The method according to statement 39, wherein the genetic disorders of GPX4 is selectedfrom mutation-related disease of GPX4, such as Sedaghatian-type spondylometaphyseal dysplasia. 47. The compound according to any one of statements 1-30, wherein each R6is independently selected from the group consisting of C1-6alkyl, hydrogen, C6-12aryl, and C3-10cycloalkyl.48. The compound according to any one of statements 1-30 or 47, wherein each R7 isindependently selected from the group consisting of C1-6alkyl, hydrogen, C6-12aryl, and C3-10cycloalkyl. 50. The compound according to any one of statements 1-30 or 47-48, wherein each R10is independently selected from the group consisting of C1-6alkyl, hydrogen, C6-12aryl, and C3-10cycloalkyl.51. The compound according to any one of statements 1-30 or 47-50, for use as a medicamentfor oral administration in the prevention or treatment of a disease associated with ferroptosis and / or oxytosis. 52. A compound of formula (I) or a stereoisomer, or tautomer thereof, wherein, R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, C3- 10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z1; R2is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, hydrogen, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z2; R3is selected from the group consisting C3-10cycloalkyl, C3-10cycloalkenyl, C3- 10cycloalkynyl, aryl, heterocyclyl, and heteroaryl, wherein said C3-10cycloalkyl, C3- 10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl or heteroaryl can be unsubstituted or substituted with one or more Z3; each Z1, Z2and Z3is independently selected from the group consisting of halo, haloC1-6alkyl, C1-6alkyl, haloC1-6alkyloxy, C1-10cycloalkyl, aryl, alkyC1-6alkyl, heterocyclyl,heteroaryl, hydroxyl, cyano, amino, nitro; or a solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof; for use as a medicament for oral administration. compound of formula (I) or a stereoisomer, or tautomer thereof, wherein, R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z1; R2is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, hydrogen, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z2; R3is selected from the group consisting of C3-10cycloalkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, and heteroaryl, wherein said C3-10cycloalkyl, C3- 10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl or heteroaryl can be unsubstituted or substituted with one or more Z3; each Z1, Z2and Z3is independently selected from the group consisting of halo, haloC1-6alkyl, C1-6alkyl, haloC1-6alkyloxy, C1-10cycloalkyl, aryl, alkyC1-6alkyl, heterocyclyl,heteroaryl, hydroxyl, cyano, amino, nitro; or a solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof; for use as a medicament for oral administration in the prevention or treatment of a disease associated with ferroptosis and / or oxytosis. he compound for use according to statement 52 or 53, having structural formula (IA), (IB)or (IC) wherein R1 is as defined in any one of statements 52 or 53.pharmaceutical composition comprising a compound of formula (I) according to any oneof statements 52 to 54 and a pharmaceutically acceptable carrier.he compound for use according to statements 53 or 54, wherein the disease associatedwith ferroptosis and / or oxytosis is selected from the group consisting of liver disease,chronic kidney disease, lung disease, ocular surface diseases, wound healing, multiple organ dysfunction syndrome, neurological disease, acute renal failure, ischemia- reperfusion injury, sepsis, iron toxicity, prevention of transplant rejection, iron metabolism-related disease and genetic disorders of GPX4.he compound for use according to statement 56, wherein the liver disease is selected from hemochromatosis, primary biliary cholangitis, non-alcoholic steatohepatitis or liver fibrosis. 58. The compound for use according to statement 56, wherein the neurological disease is selected from Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, Multiple Sclerosis, Huntington’s Disease, Dementia with Lewy bodies, Friedreich’s ataxia, stroke, periventricular leukomalacia, intracerebral haemorrhage, frontotemporal dementia, neurodegeneration with brain iron accumulation, or traumatic brain injury. 59. The compound for use according to statement 56, wherein the ischemia-reperfusion injury is selected from myocardial ischemia-reperfusion injury, liver ischemia-reperfusion injury, renal ischemia-reperfusion injury, intestinal ischemia-reperfusion injury, cerebral ischemia-reperfusion injury, lung ischemia- reperfusion injury, or any surgical ischemia-reperfusion injury. 60. The compound for use according to statement 56, wherein the iron metabolism-related disease is selected from atherosclerosis or diabetes, or wherein the lung disease is selected from acute respiratory distress syndrome (ARDS), lung diseases caused by infections such as COVID-19 pulmonary disease, mucoviscidosis, or asthma.61. The compound for use according to any one of statements 56-60, wherein the disease isattributable to a genetic disorder of GPX4; preferably the disease is Sedaghatian-type spondylometaphyseal dysplasia. The present invention provides a compound of formula (I) or a stereoisomer, or tautomer thereof, wherein, R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, C6-12arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, C6-12aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, C6-12arylC1-6alkyl, C3-10cycloalkenyl, C6-12aryl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R1is selected from the group consisting of hydrogen, C3-8cycloalkyl, C6-12arylC1-6alkyl, C3-8cycloalkenyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R1is selected from the group consisting of hydrogen, C3- 8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; wherein said groups can be unsubstituted or substituted with one or more Z1; preferably said groups are unsubstituted or substituted with one, two or three Z1; R2is selected from the group consisting of hydrogen, C3-10cycloalkyl, C6-12arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, C6-12aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R2is selected from the group consisting of hydrogen, C3- 10cycloalkyl, C6-12arylC1-6alkyl, C3-10cycloalkenyl, C6-12aryl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R2is selected from the group consisting of hydrogen, C3- 8cycloalkyl, C6-12arylC1-6alkyl, C3-8cycloalkenyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R2is selected from the group consisting of hydrogen, C3- 8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; wherein said groups can be unsubstituted or substituted with one or more Z2; preferably said groups are unsubstituted or substituted with one, two or three Z2;R3 is selected from the group consisting of C3-10cycloalkyl, C3-10cycloalkenyl, C3-10cycloalkynyl,C6-12aryl, heterocyclyl, and heteroaryl; preferably R3is selected from the group consisting of C3-8cycloalkyl, C3-8cycloalkenyl and heterocyclyl; wherein said groups can be unsubstituted or substituted with one or more Z3; preferably said groups are unsubstituted or substituted with one, two or three Z3; each Z1, Z2, and Z3is independently selected from the group consisting of halo, haloC1-6alkyl,C1-6alkyl, haloC1-6alkyloxy, C3-10cycloalkyl, 6alkyl, heterocyclyl, heteroaryl,hydroxyl, cyano,amino, -NR8R9, -C(O)2R10, -C(O)NR8R9, 10 8 9 -S(O)2R , -S(O)2NR R , nitro;preferably each Z1, Z2, and Z3is independently selected from the group consisting of halo,haloC1-6alkyl, C1-6alkyl, haloC1-6alkyloxy, C3-8cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl,heterocyclyl, heteroaryl, hydroxyl, -OR10, cyano,amino, -NR8R9, -C(O)2R10, -C(O)NR8R9, -S(O)R10, -S(O)2R10, -S(O)2NR8R9, nitro; preferablyeach Z1, Z2, and Z3is independently selected from the group consisting of halo, haloC1-6alkyl, C1-6alkyl, haloC1-6alkyloxy, hydroxyl, -OR10, cyano, amino, -NR8R9, -C(O)2R10, -C(O)NR8R9, -S(O)2R10, -S(O)2NR8R9; each R6and R7is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; each R10is independently selected from the group consisting of C1-6alkyl, hydrogen, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; or a solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof; for use as a medicament for oral administration. The present invention also provides a compound of formula (I) as described herein for use as a medicament for oral administration in the prevention or treatment of a disease associated with ferroptosis and / or oxytosis. The present invention also provides a compound of formula (I) or a stereoisomer, or tautomer thereof, wherein, R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, C6-12arylC1-6alkyl, C3- 10cycloalkenyl, C3-10cycloalkynyl, C6-12aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, C6-12arylC1-6alkyl, C3-10cycloalkenyl, C6-12aryl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R1is selected from the group consisting of hydrogen, C3-8cycloalkyl, C6-12arylC1-6alkyl, C3-8cycloalkenyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R1is selected from the group consisting of hydrogen, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; wherein said groups can be unsubstituted or substituted with one or more Z1; preferably said groups are unsubstituted or substituted with one, two or three Z1; R2is selected from the group consisting of hydrogen, C3-10cycloalkyl, C6-12arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, C6-12aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R2is selected from the group consisting of hydrogen, C3-10cycloalkyl, C6-12arylC1-6alkyl, C3-10cycloalkenyl, C6-12aryl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R2is selected from the group consisting of hydrogen, C3-8cycloalkyl, C6-12arylC1-6alkyl, C3-8cycloalkenyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; preferably R2is selected from the group consisting of hydrogen, C3-8cycloalkyl, C6-12arylC1-6alkyl, heterocyclyl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl; wherein said groups can be unsubstituted or substituted with one or more Z2; preferably said groups are unsubstituted or substituted with one, two or three Z2;R3 is selected from the group consisting of C3-10cycloalkyl, C3-10cycloalkenyl, C3-10cycloalkynyl,C6-12aryl, heterocyclyl, and heteroaryl; preferably R3is selected from the group consisting of C3-8cycloalkyl, C3-8cycloalkenyl and heterocyclyl; wherein said groups can be unsubstituted or substituted with one or more Z3; preferably said groups are unsubstituted or substituted with one, two or three Z3; each Z1, Z2, and Z3is independently selected from the group consisting of halo, haloC1-6alkyl,C1-6alkyl, haloC1-6alkyloxy, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, heteroaryl,hydroxyl, -OR10, cyano,amino, -NR8R9, -C(O)2R10, -C(O)NR8R9, -C(O)R10, -S(O)R10, -S(O)2R10, -S(O)2NR8R9, nitro;preferably each Z1, Z2, and Z3is independently selected from the group consisting of halo,haloC1-6alkyl, C1-6alkyl, haloC1-6alkyloxy, C3-8cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl,heterocyclyl, heteroaryl, hydroxyl, -OR10, cyano,amino, -NR8R9, -C(O)2R10, -C(O)NR8R9, -S(O)R10, -S(O)2R10, -S(O)2NR8R9, nitro; preferablyeach Z1, Z2, and Z3is independently selected from the group consisting of halo, haloC1-6alkyl, C1-6alkyl, haloC1-6alkyloxy, hydroxyl, -OR10, cyano, amino, -NR8R9, -C(O)2R10, -C(O)NR8R9, -S(O)2R10, -S(O)2NR8R9; each R6and R7is independently selected from the group consisting of hydrogen, C1-6alkyl, C3- 10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; each R10is independently selected from the group consisting of C1-6alkyl, hydrogen, C3- 10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; or a solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof; for use as a medicament for oral administration in the prevention or treatment of a disease associated with ferroptosis and / or oxytosis. Particularly preferred compounds of the invention are those compounds listed in Table 1. Table 1. Compound code Structure CPD-001 CPD-002 Compound code Structure CPD-003 The compounds of the present invention have been found to be potent inhibitors of ferroptosisand / or oxytosis and to have excellent oral bioavailability. Accordingly, the invention providesfor the compounds of the invention for use in therapy by oral administration.In addition, the compounds have been found to have moderate to high solubility and / or showhigh CNS MPO scores and to penetrate the blood brain barrier (BBB) as predicted by theMDR1-MDCK permeability assay, indicating that they are compounds with increased probability of success for use in the CNS. A number of diseases are characterized by a dysregulation of ferroptosis and / or oxytosis, suchas, but not limited to an excess in ferroptosis and / or oxytosis, causing cell-death. Accordingly,the present invention provides compounds of formula (I), and any subgroup thereof such as(I), (IA), (IB), (IC), for use as a medicament for oral administration in the prevention ortreatment of a disease associated with ferroptosis and / or oxytosis, more particularly an excess of ferroptosis and / or oxytosis leading to cell-death. In a particular embodiment the invention provides the compounds of the invention or a pharmaceutical composition comprising one or more compounds of the invention for use as a medicament for oral administration in the treatment of a mammal suffering from excessive ferroptosis in one or more organs. The compounds of the invention are of use in a method of treatment or prevention of a disease characterized by a dysregulation of ferroptosis and / oroxytosis, such as, but not limited to an excess in ferroptosis and / or oxytosis, causing cell-death, which comprises administering one or more of the compounds of the invention to a patient suffering from said disease. The invention also provides for the compounds of the invention for use in the manufacture of a medicament for the treatment of the cited diseases.In some embodiments the disease associated with ferroptosis and / or oxytosis is selected fromthe group consisting of liver disease (NASH, NAFLD), lung disease, chronic kidney disease, ocular surface diseases, wound healing, multiple organ dysfunction syndrome, neurological disease, acute renal failure, ischemia-reperfusion injury, sepsis, iron toxicity or iron poisoning,prevention of transplant rejection, iron metabolism-related disease and genetic disorders ofGPX4. Non-limiting examples of disorders according to the present disclosure include epilepsy, kidney disease, stroke, myocardial infarction, type I diabetes, traumatic brain injury (TBI), periventricular leukomalacia (PVL), and neurological disease. Non-limiting examples of neurological diseases according to the present disclosure include Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, Friedreich's ataxia, Multiple sclerosis, Huntington's Disease, Transmissible spongiform encephalopathy, Charcot-Marie-Tooth disease, Dementia with Lewy bodies, Corticobasal degeneration, Progressive supranuclear palsy, Chronic Traumatic Encephalopathy (CTE), and Hereditary spastic paraparesis. Non-limiting examples of liver disease include hemochromatosis, primary biliary cholangitis, non-alcoholic steatohepatitis or liver fibrosis. Non-limiting examples of neurological disease include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, Multiple Sclerosis, Huntington’s Disease, Dementia with Lewy bodies, Friedreich’s ataxia, multiple sclerosis, stroke, periventricular leukomalacia, intracerebral haemorrhage, frontotemporal dementia, neurodegeneration with brain iron accumulation, or traumatic brain injury.Non-limiting examples of ischemia-reperfusion injury include myocardial ischemia-reperfusioninjury, liver ischemia-reperfusion injury, lung ischemia-reperfusion injury, intestinal ischemia- reperfusion injury, renal ischemia-reperfusion injury, cerebral ischemia-reperfusion injury or any surgical ischemia-reperfusion injury. Non-limiting examples of iron metabolism-related disease include atherosclerosis or diabetes. Non-limiting examples of lung disease include acute respiratory distress syndrome (ARDS),lung diseases caused by infections such as COVID-19 pulmonary disease, mucoviscidosis,or asthma. Non-limiting examples of genetic disorder of GPX4, for instance a mutation-related disease of GPX4, such as Sedaghatian-type spondylometaphyseal dysplasia. In a particular embodiment, the compounds of the invention are envisaged for use as a medicament for oral administration in the treatment or prevention of a disease or disorder such as those described above, wherein the disease or disorder is attributable to a genetic disorder of GPX4, for instance a mutation-related disease of GPX4, such as Sedaghatian-type spondylometaphyseal dysplasia. In a particular embodiment the invention provides the compounds of the invention or a pharmaceutical composition comprising one or more compounds of the invention for use as a medicament for oral administration in the treatment of a mammal suffering from excessive ferroptosis and / or oxytosis in one or more organs. In a particular embodiment the invention provides the compounds of the invention or a pharmaceutical composition comprising one or more compounds of the invention for use as amedicament for oral administration in the treatment of diseases caused by excitatory aminoacids. A well-known example of an excitatory amino acid is glutamate, and the condition isdesignated as glutamine excitotoxicity. In a particular embodiment the invention provides the compounds of the invention or a pharmaceutical composition comprising one or more compounds of the invention for use as a medicament for oral administration in the treatment of diseases caused by increased levels of phospholipid peroxides. In a particular embodiment the invention provides the compounds of the invention or a pharmaceutical composition comprising one or more compounds of the invention for use as amedicament for oral administration in the treatment of liver disease, chronic kidney disease,lung disease, ocular surface diseases, wound healing, multiple organ dysfunction syndrome, neurological disease, acute renal failure, ischemia-reperfusion injury, sepsis, iron toxicity,prevention of transplant rejection, iron metabolism-related disease and genetic disorders ofGPX4. In the present invention the potency of a compound inhibiting (or reducing) ferroptosis and / oroxytosis are determined in (bio)chemical antioxidant activity assays, in vitro assays. Typically,FENIX assay is used to quantify radical trapping antioxidant activity in phospholipid bilayersto predict anti-ferroptotic potency of lipophilic antioxidants in cells. Typically, in vitro assaysare used to measure the potency of a candidate compound. Examples of suitable in vitro assays are cellular assays. One non-limiting example of an assay involves the use of the IMR-32 neuroblastoma cell line. The latter is stimulated to enter ferroptosis upon stimulation with10µM erastin, a documented ferroptosis inducer (see for example Dixon et al (2012) Cell 149,1060-1072 and ferroptosis inhibitors are evaluated for the prevention of erastin induced ferroptosis. Another assay involves the use of ML162-induced ferroptosis in HT1080 human fibrosarcoma cells. Yet another assay is based on the glutamate-induced cell death in the hippocampal cell line HT22 and ferroptosis / oxytosis inhibitors are evaluated for the preventionof cell death (see Henke N. et al (2013) Cell Death and Disease 4, e470). Still another assayis based on the sorafenib induced cell death (described to be iron dependent cell death) in hepatocellular carcinoma cells and ferroptosis inhibitors are evaluated for the prevention ofcell death (see Louandre C. et al (2013) Int. J. Cancer 133, 1732). The calculated potency ofa compound inhibiting ferroptosis and / or oxytosis is typically depicted as an IC50 value.Examples of suitable in vivo assays are typically pre-clinical disease models of for examplemice for the diseases benefiting the application of ferroptosis and / or oxytosis inhibitors, as described herein.One non-limiting example of an in vivo assay is based on inducing organ injury by iron overloador using liver, kidney, lung, brain or intestine-specific Gpx4-deficient mouse lines andferroptosis inhibitors are evaluated based on the level of reduction in plasma injury biomarkersLDH, CK, AST and ALT, and body temperature (see Van Coillie et al. (2022) Nat Comm 13:1046).The compounds for use of this invention can be administered as the sole pharmaceutical agentor in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. The present invention relates also to such combinations. For example, the compounds of this invention can be combined with known therapeutic agents for the treatment of diseases mentioned herein, as well as with admixtures and combinations thereof. Particularly preferred combinations are necroptosis inhibitors (e.g. necrostatin-1) and ferroptosis inhibitors. Examples of these combinations are described inLinkermann et al 2014.The compounds for use of the invention may be in the form of salts, preferably pharmaceutically acceptable salts, as generally described below. Some preferred, but non- limiting examples of suitable pharmaceutically acceptable organic and / or inorganic acids are as hydrochloric acid, trifluoroacetic acid (or triflate), hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids known per se (for which reference is made to the prior art referred to below). When the compounds for use of the invention contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH), the invention also covers salts and / or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of the compounds of formula (I) and any subgroup thereof include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate (or triflate) and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), incorporated herein by reference.The compounds for use of the invention may exist in a continuum of solid states ranging fromfully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibitthe physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order ('melting point'). Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of these methods: (i) by reacting the compound of formula (I) with the desired acid; (ii) by reacting the compound of formula (I) with the desired base;(iii) by removing an acid- or base-labile protecting group from a suitable precursor of thecompound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or (iv) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized. The compounds of the invention may also exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. A currently accepted classification system for organic hydrates is one that defines isolatedsite, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solidsby K. R. Morris (Ed. H. G. Britain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channelsolvates and hygroscopic compounds, the water / solvent content will be dependent onhumidity and drying conditions. In such cases, non-stoichiometry will be the norm. Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug- host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grindingthe components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J.Zaworotko (2004), incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975), incorporated herein by reference. The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as - COO-Na+, -COO-K+, or -SO3-Na+) or non-ionic (such as -N-N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970), incorporated herein by reference. All references to compounds of formula (I) or any subgroups thereof include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi- component complexes and liquid crystals of salts thereof. The compounds of the invention include compounds of formula (I) or any subgroups thereof as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of formula (I). In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and / or purification of the compounds of the invention. A further related aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable” as used herein is consistent with the art and means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof. As used herein, “carrier” or “excipient” includes any and all solvents, diluents, buffers (such as, e.g., neutral buffered saline or phosphate buffered saline), solubilisers, colloids, dispersion media, vehicles, fillers, chelating agents (such as, e.g., EDTA or glutathione), amino acids (such as, e.g., glycine), proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavourings, aromatisers, thickeners, agents for achieving a depot effect, coatings, antifungal agents, preservatives, antioxidants, tonicity controlling agents, absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active substance, its use in the therapeutic compositions may be contemplated. Illustrative, non-limiting carriers for use in formulating the pharmaceutical compositions include, for example, oil-in-water or water-in-oil emulsions, aqueous compositions with or without inclusion of organic co-solvents suitable for intravenous (IV) use, liposomes or surfactant-containing vesicles, microspheres, microbeads and microsomes, powders, tablets, capsules, suppositories, aqueous suspensions, aerosols, and other carriers apparent to one of ordinary skill in the art. Pharmaceutical compositions as intended herein may be formulated for oral administration (such as, e.g., oral ingestion or inhalation). In this way, the therapeutic effects attainable by the methods and compositions can be, for example, systemic, local, tissue-specific, etc., depending of the specific needs of a given application. The dosage or amount of the agent as taught herein, optionally in combination with one or more other active compounds to be administered, depends on the individual case and is, as is customary, to be adapted to the individual circumstances to achieve an optimum effect. Thus, the unit dose and regimen depend on the nature and the severity of the disorder to be treated, and also on factors such as the species of the subject, the sex, age, body weight, general health, diet, mode and time of administration, immune status, and individual responsiveness of the human or animal to be treated, efficacy, metabolic stability and duration of action of the compounds used, on whether the therapy is acute or chronic or prophylactic, or on whether other active compounds are administered in addition to the agent of the invention. In order to optimize therapeutic efficacy, the compound or the pharmaceutical composition as taught herein can be first administered at different dosing regimes. Typically, levels of the agent in a tissue can be monitored using appropriate screening assays as part of a clinical testing procedure, e.g., to determine the efficacy of a given treatment regimen. The frequency of dosing is within the skills and clinical judgement of medical practitioners (e.g., doctors, veterinarians or nurses). Typically, the administration regime is established by clinical trials which may establish optimal administration parameters. However, the practitioner may vary such administration regimes according to the one or more of the aforementioned factors, e.g., subject’s age, health, weight, sex and medical status. The frequency of dosing can be varied depending on whether the treatment is prophylactic or therapeutic. Toxicity and therapeutic efficacy of the agent as described herein or pharmaceutical compositions comprising the same can be determined by known pharmaceutical proceduresin, for example, cell cultures or experimental animals. These procedures can be used, e.g.,for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. Pharmaceutical compositions that exhibit high therapeutic indices are preferred. While pharmaceutical compositions that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to normal cells (e.g., non-target cells) and, thereby, reduce side effects. The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in appropriate subjects. The dosage of such pharmaceutical compositions lies generally within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilised. For a pharmaceutical composition used as described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the pharmaceutical composition which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography. Examples The following examples are provided for the purpose of illustrating the present invention and by no means should be interpreted to limit the scope of the present invention.1. Characterization of representative compounds of the inventionUnless otherwise stated, laboratory reagent grade solvents were used. Reagents were obtained from various commercial sources and were used without any prior purification. Characterisation of all compounds was done with1H and13C NMR and mass spectrometry. NMR spectra were recorded with a 400 MHz Bruker Avance III Nanobay spectrometer with Ultrashield. All obtained spectra were analysed using MestReNova analytical chemistry software. Chemical shifts are displayed in ppm and coupling constants are shown in hertz (Hz). ES mass spectra were obtained from an Esquire 3000plus Ion Trap Mass Spectrometer from Bruker Daltonics. The UPLC (ultra performance liquid chromatography), used to quantify the purity of the products, was an ACQUITY UPLC H-Class system with a TUV detector Waters coupled to an MS detector Waters Qda. Waters Acquity UPLC BEH C181.7 μm, 2.1 mm × 50 mm column was used. The eluent was composed of two different solvents. Solvent C consisted of water with 0.1% formic acid, solvent D was acetonitrile. For most of the experiments, unless stated otherwise, the following general method was used. The column was first equilibrated for 0.15 min with a mixture of 95% solvent C and 5% solvent D. After that, solvent D was increased linearly to 100% over 1.75 min before being held constant for 0.25 min, followed by a mixture of 95% solvent C and 5% solvent D for 0.75 min (flow rate 0.7 ml / min). All mass spectra wererecorded over a m / z range of 100–1000. The wavelength for UV detection was 254 nm.Method II starts with equilibration of column for 0.15 min with a mixture of 95% solvent C and 5% solvent D. After that, solvent D was increased linearly to 100% over 2.50 min before being held constant for 0.75 min, followed by a mixture of 95% solvent C and 5% solvent D for 0.75 min (flow rate 0.7 ml / min).Selected compounds of the invention were analysed by high resolution mass spectrometry:10μL of each sample (concentration = 10–5M) was injected using the CapLC system (Waters, Manchester, UK) and electrosprayed using a standard electrospray source. Samples were injected with an interval of 5 min. Positive ion mode accurate mass spectra were acquired usinga Q-TOF II instrument (Waters, Man-chester, UK). The MS was calibrated prior to use with a 0.2% H3PO4 solution. The spectra were lock mass corrected using the known mass of the nearest H3PO4 cluster.During the chemical synthesis, flash purification was performed when necessary, on a BiotageISOLERA One flash system equipped with an internal variable dual wavelength diode array detector (200−400 nm). Reverse phase purifications were done using Buchi EcoFlex C18 cartridges, dry sample loading was done by self-packing sample cartridges using Celite® 545.Gradients used varied for each purification. Several synthesis procedures that were used inthe preparation of intermediates and final products are summarized here as “GeneralProcedures”. All reactions were performed under argon unless otherwise stated. The finalproducts have a purity above 95% unless otherwise stated. N1-cyclobutyl-4-(oxazol-5-yl)benzene-1,2-diamine (CPD-001) 1H NMR (400 MHz, MeOD) δ 1.78 – 2.00 (m, 4H), 2.45 (ddt, J = 9.7, 6.2, 2.7 Hz, 2H), 3.97 (p,J = 7.4 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 7.05 (s, 1H), 7.18 (s, 1H),8.10 (s, 1H).13C NMR (101 MHz, MeOD) δ 16.16, 31.81, 50.28, 112.48, 112.89, 117.57, 118.33, 118.62,135.76, 138.30, 151.40, 154.66.HRMS (ESI) m / z [M+H]+ calcd for C13H15N3O 230.1288 found 230.1289.N1-cyclopentyl-4-(oxazol-5-yl)benzene-1,2-diamine (CPD-002)1H NMR (400 MHz, MeOD) δ 1.50 – 1.70 (m, 4H), 1.70 – 1.84 (m, 2H), 2.00 – 2.11 (m, 2H),3.84 (tq, J = 11.9, 6.0 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 7.03 – 7.08 (m, 2H), 7.17 (s, 1H), 8.10(s,1H).13C NMR (101 MHz, MeOD) δ 25.22, 34.27, 55.72, 112.65, 113.01, 117.69, 117.89, 118.53,135.71, 139.29, 151.36, 154.70.HRMS (ESI) m / z [M+H]+ calcd for C14H17N3O 244.1444 found 244.1437.N1-cyclohexyl-4-(oxazol-5-yl)benzene-1,2-diamine (CPD-003) 1H NMR (400 MHz, DMSO-d6) δ 1.11 – 1.26 (m, 3H), 1.35 (qt, J = 3.3, 12.8 Hz, 2H), 1.62 (dt,J = 3.7, 12.7 Hz, 1H), 1.73 (dt, J = 3.7, 13.3 Hz, 2H), 1.91 – 2.02 (m, 2H), 3.17 – 3.29 (m, 1H),4.50 (d, J = 7.5 Hz, 1H), 4.75 (br. s, 2H), 6.49 (d, J = 8.1 Hz, 1H), 6.83 – 6.87 (m, 1H), 6.88(d, J = 2.0 Hz, 1H), 7.20 (s, 1H), 8.23 (s, 1H).13C NMR (101 MHz, DMSO-d6) δ 25.19, 26.13, 33.21, 51.26, 110.23, 110.30, 114.78, 115.83,118.34, 135.65, 136.05, 150.44, 152.66;HRMS (ESI) m / z [M+H]+ calcd for C15H19N3O 258.1601, found 258.1602.2. Biological evaluation of the compounds of the inventionFluorescence-Enabled Inhibited Autoxidation (FENIX) (Shah et al. (2019) Cell Chem. Biol.26,1594-1607) Unless otherwise stated, laboratory reagent grade solvents were used. Reagents were obtained from various commercial sources and were used without any prior purification. L-α- phosphatidylcholine (Egg, Chicken), powder was purchased from Merck Life Science B.V. DTUN and STY-BODIPY were synthesized according to methods described in Shah et al. (2019) Cell Chem. Biol. 26, 1594-1607. Fluorescence was measured using the UV / vis spectrophotometer Synergy MX, Biotek with Gen5.To quantify radical trapping antioxidant activity in phospholipid bilayers to a clear bottom black-walled 96-well plate for fluorescence-base assays (Invitrogen by Thermo Fisher Scientific) was added 250 µL of a solution containing liposomes (1 mM), styrene-conjugated BODIPY(STY-BODIPY, 1 µM), and the respective radical trapping antioxidant (RTA, 4 µM). Thesolutions were made in larger volumes in Eppendorfs, pre-mixed and 250 µL aliquot was transferred to each well. The plate was incubated for 10 minutes at 37°C in the BioTek SynergyMx plate reader, followed by a fast-mixing protocol for 5 minutes. The plate wasejected from the plate reader and autoxidation was initiated by the addition of a 50 µL aliquotof (E)-1,2-bis((2-methyldecan-2-yl)oxy)diazene (DTUN, 0.2 mM in EtOH / PBS 3 / 47, v / v),followed by another mixing protocol for 5 minutes. Data were acquired by excitation probes at 488 nm and emission was measured at 518 nm (read intervals 1.0 min). Kinetic readparameters: (i) optic position: bottom, (ii) gain: 80, (iii) bandwidth: 9.0. The results of the FENIXassay are presented in Table 2 as inhibition rate constants (kinh), logkinh and stoichiometries (n) of tested compounds. Table 2. FENIX assay Compound code kinh (104 M-1s-1) ± SD Stoichiometry ± SD Logkinh ± SDCPD-001 1.9 3.0 4.28CPD-002 2.8 3.1 4.44CPD-003 3.4 2.8 4.53Inhibition of ML162-Induced Ferroptosis in HT-1080 human fibrosarcoma cells Human fibrosarcoma cells HT-1080 cells were obtained from American Type Culture Collection (ATCC). HT-1080 cells were cultured in EMEM medium supplemented with 10% FCS and L-glutamine (1 mM), sodium pyruvate and nonessential amino acids. Cell death wasmeasured using Envision multimode plate reader (PE). To determine IC50 values, HT-1080were seeded in a 384-well plate at a density of 3500 cells / well in 40µl in an incubator overnight at 37 °C with 5% CO2. The next day, the cells were pretreated for 1h (in triplicates) with a 1 / 3 dilution series of ferrostatin-1 analogues ranging from 1 µM to 0.5 nM and Sytox Green (1.6 μM). All the compound’s stock solutions were prepared in DMSO at 100 mM concentration. After stimulating the cells with ML-162 1 μM the plate was transferred to the incubator. SytoxGreen intensity was measured after 8, 12, 16 and 24 h using an excitation filter of 485 nm and an emission filter of 535 nm. Dose-response curves were made as % cell death inhibition, taking ML162 treated samples as 0 % inhibition and Fer-1 (1 µM) + ML-162 samplesas 100 % inhibition. Cell death percentage was calculated as 100 – (( x – 100%inh) / ( 0%inh– 100%inh))*100). Curves were plotted in Spotfire software, and IC50 values were calculatedusing logistic regression curves. Data at 16 h is presented in Table 3. Kinetic solubility A turbidimetric method was used. First, a series of DMSO compound stock solutions were prepared (0.15-5 mM) from the stock solution of the compound in DMSO (10 mM). An aliquot of 4μL stock solution was added to 196μL PBS buffer (pH 7.4). A series of concentrations were prepared (3.13-200 μM), including a blank on a microtiter plate. The microtiter plate was shaken for 10 seconds and incubated for 2 hours at 37°C. Turbidity was measured using the UV / vis spectrophotometer Synergy MX, Biotek with Gen5. When there was no turbidity measured at a given concentration the sample was assumed to be dissolved. Data is presented in Table 3. Central nervous system multiparameter optimization (CNS MPO) scoreTo evaluate brain penetration, central nervous system multiparameter optimization (CNSMPO) score was calculated using CDD Vault software (Collaborative Drug Discovery Inc., Burlingame, California, USA). CNS MPO score consists of six fundamental physicochemical properties: lipophilicity, calculated partition coefficient (ClogP), calculated distribution coefficient at pH 7.4 (ClogD), molecular weight (MW), topological polar surface area (TPSA),number of hydrogen-bond donors (HBDs), and most basic centre (pKa). A CNS MPO score of> 4.0 is preferable to penetrate the brain. Data is presented in Table 3. Table 3. Kin. solubility Ferroptosis inhibition CNS MPO Compound code (µM) IC50 (nM) score 15.64 ± 7.05 CDP-001 >2005.2 (n=2) 8.53 ± 4.97 CPD-002 >2005.2 (n=2) 5.20 ± 3.28 CPD-003 >2004.9 (n=2) Human and mouse microsomal stability Pooled liver microsomes (Ultrapool Human Liver microsomes or Mouse CD-1 male Liver microsomes), with a protein concentration of 20 mg / ml, were purchased from CorningGentest™ (now Discovery Life Science – Gentest) and stored at -80°C until use. Themicrosomes (final protein concentration 0.5 mg / ml), 0.1 M phosphate buffer pH 7.4 and test compound (final substance concentration 1 µM), were preincubated at 37°C for 10 min before the addition of NADPH Regenerating System (solution A and B from Corning Gentest™, final concentration 1 mM) to initiate the reaction. For each compound tested, a control without the cofactor was included. In this case, 0.1 M phosphate buffer at pH 7.4 was added instead ofthe NADPH regenerating system. In addition, with each new batch of microsomes, two positivecontrol compounds were incorporated. These controls represented substances with high (verapamil, with human Clint = 178.9 μL / min*mg; diazepam, with mouse Clint = 549 μL / min*mg) and low clearance (dextromethorphan, with human Clint = 34.6 μL / min*mg; diphenhydramine, with mouse Clint = 64.0 μL / min*mg). Each compound was incubated for 45 minutes at 37°C and shaken at 500 rpm. The reactions were stopped by transferring the incubate into acetonitrile, containing an internal standard, in Eppendorfs at the appropriate time points in a 1:3 ratio (0, 5, 10, 15, 30, and 45 minutes for compounds, and 0, 15, and 45 minutes for the negative control of those compounds). Subsequently, the Eppendorfs were centrifuged at 3000 rpm for 20 minutes at 4°C to precipitate the protein. Quantitative AnalysisAfter protein precipitation, the sample supernatant from each time point was analysed usingUPLC-MS / MS. The analysis followed the general UPLC method for microsomal stability described below. The UPLC (ultra-performance liquid chromatography), used to quantify the microsomal stability of the products, was an ACQUITY UPLC H-Class system with a TUV detector Waters (not used in this assay) coupled to an MS / MS detector Xevo Waters TQD. Waters Acquity UPLC BEH C181.7 μm, 2.1 mm × 50 mm column was used. The eluent was composed of two different solvents. Solvent A consisted of water with 0.1% formic acid, solvent B was acetonitrile with 0.1% formic acid. The column was first equilibrated for with a mixture of 95% solvent A and 5% solvent B until the delta of psi decrease below 40 psi. Themethod began with a short equilibration to reach 50% of solvents A and B in 0.15 min.Following this, solvent B was increased linearly to 95% over 2.75 min before being heldconstant for 0.70 min (flow rate 0.7 ml / min). The specific masses of the compounds were tracked using tuning files generated via Intellistart®, and quantification was aided by an internal standard. Data processing All obtained readouts were processed using Microsoft Excel. From a plot of ln peak area ratio (compound peak area / internal standard peak area) against time, the gradient of a line isdetermined by linear regression. Subsequently, several parameters were calculated using theequations below: Elimination rate constant (k) = ( - gradient)Half Time Cl (µL / min / mg of pr^ ^ ^^^int otein) =^^ / ^Where V = (Incubation volume µL) / (Microsomal protein mg / g liver) Data is presented in Table 4. Table 4. Microsomal stability in Microsomal stability in mouse human Compound code Clint in liver Clint in liver t1 / 2t1 / 2amicrosomesamicrosomes (min)^L / min*mg) b (min)( (^L / min*mg) bDiazepam 2.0 707.0 n.d n.dDiphenhydramine 30.7 45.1 n.d n.dVerapamil nd. nd. 16.3 85Dextromethorphan nd. nd. 39.9 34.7CPD-001 44.2 31.3 12.3 11.2CPD-002 11.0 138.4 239 5.8CPD-003 30.9 44.9 121.3 11.4aMetabolism determined in Corning ultra pool human liver microsome (HLM) or Mouse CD-1liver microsome (MLM) activated with NAPDH and expressed as half-life (t1 / 2 in min); b TheClint(liver microsomes) was calculated using the measured microsomal t1 / 2and considers several experimental variables such as the protein concentration and the volume of incubation. Diazepam, diphenhydramine, verapamil and dextromethorphan were used as controls. MDCK-MDR1 Permeability Assay (Unidirectional or Bidirectional). Madin-Darby canine kidney (MDCK) cells are an epithelial cell line of canine kidney origin. These cells can be stably transfected to express active P-glycoprotein (MDCK-MDR1) and areideal for studying drug efflux. Test compound is added to either the apical or basolateral sideof a confluent monolayer of MDCK-MDR1 cells and permeability is measured by monitoringthe appearance of the test compound on the opposite side of the monolayer using LCMS / MS. If performing a bidirectional assay, the efflux ratio (ER) is calculated from the ratio of BA andAB permeabilities. The experiment measures the permeability of test compound in the apicalto basolateral (AB) and / or basolateral to apical (BA) direction across MDCK-MDR1 cells anddetermines the efflux ratio (ER), which shows whether the test compound undergoes activeefflux. The results are reported as apparent permeability coefficients (Papp) along with mean recovery values, and if relevant, the efflux ratio (ER) for the test compound. Experimental procedure MDCK-MDR1 cells obtained from the NIH (Rockville, MD, USA) are used between passagenumbers 6 - 30. Cells are seeded onto Transwell plates at 3.4 x 105 cells / cm2. The cells arecultured in DMEM and media is changed on day 3. On day 4 or 5, the permeability study isperformed. Cell culture and assay incubations are carried out at 37 ºC in an atmosphere of 5 % CO2 with a relative humidity of 95 %. On the day of the assay, the monolayers are prepared by rinsing the apical and basolateral compartment with Hanks Balanced Salt Solution (HBSS) at the desired pH warmed to 37 °C. Cells are then incubated with HBSS at the desired pH in both apical and basolateral compartments for 30 minutes to stabilise physiologicalparameters. The dosing solutions are prepared by diluting the test compound with assay bufferto give the desired final test compound concentration (typically 10 µM). Final DMSOconcentration of 1 % v / v. The fluorescent integrity marker lucifer yellow is also included in thedosing solution. Analytical standards are prepared from test compound DMSO dilutions andtransferred to buffer, maintaining a ≤1 % v / v DMSO concentration. Typical assay buffer is composed of supplemented HBSS pH 7.4 but a range of other buffers and pH values can be used. For assessment of AB permeability, HBSS is removed from the apical compartment andreplaced with test compound dosing solution. The apical compartment insert is then placedinto a companion plate containing fresh buffer (containing ≤1 % v / v DMSO). For assessment of BA permeability, HBSS is removed from the companion plate and replaced with testcompound dosing solution. Fresh buffer (containing ≤1 % v / v DMSO) is added to the apicalcompartment insert, which is then placed into the companion plate. At 60 min the apical compartment inserts and the companion plates are separated and apical and basolateralsamples diluted for analysis. Test compound permeability is assessed in duplicate. Testcompounds of known permeability characteristics are run as controls on each assay plate. Test and control Test compounds are quantified by LC-MS / MS cassette analysis using a 7- point calibration with appropriate dilution of the samples. The express analytical method development procedure is performed using UHPLC on either a Waters XevoTMTQ-MS or a Waters XevoTMTQ-S micro. The procedure is performed in a stepwise manner to assess LC- MS / MS optimization and chromatography. The compound is assessed in clean solution using existing Cyprotex chromatographic methods using a UHPLC C18 column and a gradient consisting of either 10 mM ammonium formate with 0.1 % formic acid in water or 10 mM ammonium acetate in water, with either methanol or acetonitrile.50 nM and 0 µM standards in clean solution are prepared to assess the sensitivity and selectivity of the test article response. The starting concentration (C0) is determined from the dosing solution and the experimental recovery calculated from C0 and both apical and basolateral compartment concentrations. The integrity of the monolayer throughout the experiment is checked by monitoring lucifer yellow permeation using fluorimetric analysis. Data processingThe MDCK-MDR1 assay distinguishes between CNS-positive and CNS-negative compoundsbased on their Papp values (see https: / / www.cyprotex.com / admepk / in-vitro-permeability-and- drug-transporters / mdr1-mdck-permeability for detailed values).The permeability coefficient (Papp) for each test compound is calculated from the followingequation: ^P(dQ / dt) app= (C0 × A)Where dQ / dt is the rate of permeation of the drug across the cells, C0is the donor compartment concentration at time zero and A is the area of the cell monolayer. C0is obtained from analysis of the dosing solution. For bi-directional experiments, an efflux ratio (ER) is calculated from mean A-B and B-A data. This is derived from: If the ER is greater than or equal to 2 then this indicates drug efflux is occurring. Two controlsare screened alongside the test compounds, typically: antipyrine (high permeability) and prazosin (a P-glycoprotein substrate). Data are reported in Table 5. Table 5. Efflux Ratio Direction A2B Direction B2A(ER) Compound code Mean PappMean % Mean % Mean PappMean PappB2A / Mean Recovery Recovery PappA2B) Antypirine 51.4 91.5 57.7 100 1.12 Efflux Ratio Direction A2B Direction B2A(ER) Compound code Mean Papp Mean % Mean % Mean Papp Mean Papp B2A / Mean Recovery Recovery Papp A2B) Prazosin 2.37 75.3 76.6 84.5 32.3CPD-001 62.5 64.5 70.1 71.5 1.12CPD-002 51.1 67.8 53.9 80.4 1.05CPD-003 44.1 58.6 41.3 74.1 0.937High Throughput Aqueous Solubility – MSA 100 µM solution of CPD-003 is made by diluting 5 µL of the 10 mM solution in 495 µL of DMSO. A 5 point standard curve of CPD-003 is made in 75:25 DMSO: water to give a range of concentrations; 5 µM, 500 nM, 50 nM, 5 nM and 0.5 nM.1 mL of aqueous buffer (selected from list above, other buffers are available on request) is added to solid CPD-003 in the vial supplied and placed on a rotary incubator table at room temperature for 24 hr. Following incubation, 200 µL of each of the incubated solutions is removed and filtered using a 96-well 0.4 µM MultiScreen HTS PCF Polycarbonate centrifugal filter plate. The filtrate is serially diluted 1 in 4, 1 in 40 and 1 in 400-fold into 75:25 DMSO:water. The standards and samples are quantified using a Waters Acquity UPLC-MS / MS system. The aqueous solubility of CPD- 003 is quantified from a linear fit of the standard curve. Data is presented in Table 6. LogD Shake Flask CPD-003 (0.5 mg) is dissolved in octanol pre-saturated with 0.1 M phosphate buffer (pH 7.4) and sonicated for 30 min.0.1 M phosphate buffer (pH 7.4) pre-saturated with octanol is added to the octanol solution and shaken at 1000 rpm for 30 min at 22 °C. The mixed samples are then centrifuged at 1000 rpm for 5 min at 22 °C. An aliquot of the octanol fraction is removed from each mixture and diluted into DMSO. The remainder of the octanol fraction is removed, and an aliquot of the aqueous fraction is transferred into a fresh tube. The aqueous aliquot is centrifuged again at 1000 rpm for 5 min at 22 °C and an aliquot of the resulting aqueous fraction is diluted into DMSO. The resulting octanol and aqueous fraction solutions are analysed by LC-MS / MS using Cyprotex generic conditions. The relative amount of CPD-003 in the aqueous fraction solution is quantified against a 5 point standard curve, which is produced by serially diluting the octanol fraction solution. LogD is calculated using the following equation: Where: Coct = Concentration in octanol standard (corrected for dilution); Caq = Concentration in aqueous sample (corrected for dilution). Data is presented in Table 6. Biological stability in plasma Species-specific plasma is adjusted to pH 7.4 at 37 °C and CPD-003 (final substrate concentration 1 µM; final DMSO concentration 0.25 %) is added to initiate the reaction. The final incubation volume is 500 µL. A solvent control incubation is included, along with a positivecontrol known to be metabolised specifically by each species. The solvent control incubationis incubated for 120 min only. CPD-003 is incubated for 0, 5, 15, 30, 60 and 120 min at 37 °C. The reactions are stopped by transferring 50 µL of incubate to 150 µL acetonitrile containing internal standard at the appropriate time points. The termination plates are centrifuged at 3,000 rpm for 30 min at 4 °C to precipitate the protein. This experimental procedure can also be applied to other biological matrices, such as blood, homogenate, simulated biological fluids and buffers. Quantitative Analysis Following protein precipitation, the sample supernatants are combined in cassettes of up to 4 test articles, diluted in a 1:6 ratio of supernatant:water and analysed using Cyprotex generic LC-MS / MS conditions. If the metabolite profiling option is chosen prior to the commencement of the study, samples are set aside for profiling. The level of metabolite profiling chosen depends on amount of knowledge and support required by the client and can include rapid high-resolution analysis to identify whether metabolites are formed, or more in-depth analysis and / or detailed fragmentation analysis to understand metabolite derivation. From a plot of ln peak area ratio (peak area / internal standard peak area) against time, the gradient of the line is determined. Subsequently, half-life is calculated using the equations below: Data is presented in Table 4. Liver Microsomal Stability (by Contract Research Organization) Pooled liver microsomes are purchased from a reputable commercial supplier. A range of species and strains are available upon request. Microsomes are stored at 80 °C prior to use. Microsomes (final protein concentration 0.5 mg / mL), 0.1 M phosphate buffer pH 7.4 and CPD- 003 (final substrate concentration 1 µM; final DMSO concentration 0.25 %) are preincubated at 37 °C prior to the addition of NADPH (final concentration 1 mM) to initiate the reaction. A minus cofactor control incubation is included for each CPD-015 where 0.1 M phosphate buffer pH 7.4 is added instead of NADPH (minus NADPH). Two species-specific positive controls are also incubated alongside CPD-015 for each species. All incubations are performed singularly for CPD-003. CPD-003 is incubated for 0, 5, 15, 30 and 45 min. The control (minusNADPH) is incubated for 45 min only. The reactions are stopped by transferring incubate intoacetonitrile at the appropriate time points, in a 1:3 ratio. The termination plates are centrifuged at 3,000 rpm for 10 min at 4 °C to precipitate the protein. Quantitative Analysis Following protein precipitation, the sample supernatants are combined in cassettes of up to 4 test articles, internal standard is added and samples analysed using Cyprotex generic LCMS / MS conditions. Data analysis From a plot of ln peak area ratio (peak area / internal standard peak area) against time, the gradient of the line is determined. Subsequently, half-life and intrinsic clearance are calculated using the equations below: where V = Incubation volume (µL) / Microsomal protein (mg). Data is presented in Table 6. Mitochondrial Toxicity (Glu / Gal) Objective: To measure the sensitivity and viability (cellular ATP content) of HepG2 cells grown in medium containing either galactose or glucose, in response to CPD-003. Procedure HepG2 human hepatocellular carcinoma cells (other cell types available on request) are plated on an appropriately sized multi-well plate in suitable media at 37 °C in 5 % CO2 for 24 hr priorto dosing of the cells. CPD-003 is diluted in DMSO, or other suitable solvents and serialdilutions are made in 0.5 % DMSO or appropriate solvent in medium supplemented with either galactose or glucose. CPD-003 at 8 concentrations in triplicate is then incubated for 24 hr (other time points available on request). Appropriate controls are run alongside the assay. At the end of the incubation period, cellular ATP is measured using CellTiter-Glo® (Promega) Data The vehicle control wells are used to determine significance limits. The minimum effective concentration (MEC) is determined from the lowest concentration whose mean value exceeds the significance level, provided either a clear dose-response relationship is observed, or at least two consecutive concentration points are above the significance level. AC50 values are also determined provided a clear dose-response relationship is observed. If the AC50 in cells grown with glucose containing medium is >3-fold greater than with galactose containing medium CPD-003 is considered to be a mitochondrial toxicant. Screening Panel (MMP, MP, Cyto C) To assess the potential of CPD-003 to exhibit toxic effects on a panel of cell healthparameters (cell loss, nuclear morphology, cell membrane permeability, mitochondrial membrane potential changes, mitochondrial mass, DNA fragmentation and cytochrome C localisation). These targets have been shown to be predictive for compounds causing various forms of toxicity. Procedure HepG2 human hepatocellular carcinoma cells (other cell lines are available upon request) are plated on appropriately sized multi-well plates in suitable media at 37°C in 5 % CO2 for 24 hr prior to dosing of the cells. CPD-003 is diluted in solvent, and serial dilutions are made in 0.5 % solvent, in growth media. CPD-003 at 8 concentrations (0.04, 0.1, 0.4, 1, 4, 10, 40, 100 µM) in triplicate is then incubated for 72 hr. Appropriate controls are run alongside the assay. At the end of the incubation period, the cells are loaded with the relevant dye / antibody for the appropriate time for each cell health marker. The plate is then scanned using an automated fluorescent cellular imager. The assay provides simultaneous measurement of multiple cell health parameters: ^Cell count: A decreasing number of cells per well indicates toxicity due to necrosis,apoptosis or a reduction in cellular proliferation. ^Nuclear size: An increase in nuclear area can indicate necrosis or G2 cell cycle arrestand a decrease can indicate apoptosis. ^DNA structure: An increase in DNA structure can indicate chromosomal instability andDNA fragmentation. ^Cell membrane permeability: An increase in cell membrane permeability is a generalindicator of cell death.^ Mitochondrial mass: A decrease in mitochondrial mass indicates loss of totalmitochondria and an increase implies mitochondrial swelling or an adaptive response to cellular energy demands. ^Mitochondrial membrane potential (Δψm): A decrease indicates a loss of mitochondrialmembrane potential and mitochondrial toxicity, as well as a potential role in apoptosis signalling, an increase in mitochondrial membrane potential indicates an adaptive response to cellular energy demands. ^Cytochrome c: An increase in cytochrome c release is one of the hallmarks of theapoptosis cascade. Data analysis For readouts other than cell count, a statistical approach to data analysis is used. The solvent controls are used to determine the definitions of “normal” for each parameter, then the software calculates the percentage of cells that are low or high responders (depending on the biological significance of a particular readout). The solvent control wells are then used to determine significance limits for wells that have a greater than expected fraction of low or high responders. The minimum effective concentration is determined from the lowest concentration whose mean value exceeds the significance level, provided either a clear dose-response relationship is observed, or at least two consecutive concentration points are above the significance level. AC50 values are also determined provided a clear dose-response relationship is observed. CardiotoxictyhNav1.5 Sodium Channel Assay Qube APC: After whole cell configuration is achieved, thecells are held at -80mV. Onset and steady state block of peak Nav1.5 current is measured using a pulse pattern consisting of a hyperpolarizing pulse to -120mV for a 200ms duration, depolarization to -15mV amplitude for a 40ms duration, followed by step to 40mV for 200ms and finally a 100ms ramp (1.2 V / s) to a holding potential of -80 mV. Peak current is measured during the step to -15 mV. This paradigm is delivered once every 5s to monitor the current amplitude. Data Analysis: The parameters measured were difference between the peak inward current on stepping to -15mV (i.e. peak of the current) and the leak current. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing theTest compound current amplitude by the Control current amplitude. Control data is the meanNav1.5 current amplitude collected for three pulses (15 seconds) at the end of the vehicle control application; Test compound data is the mean Nav1.5 current amplitude collected for three pulses (15 seconds) at the end of test concentration application for each concentration.hCav1.2 (L-type) CiPA Calcium Channel Assay Qube APC: Onset and steady state block ofpeak hCav1.2 current is measured using a pulse pattern, repeated every 15 sec. Cells were held at -80mV for a 50ms before stepping to -90mV for 100ms to measure leak current andthen stepped back to - 80mV for 50ms, depolarization to 0mV amplitude for a 40ms duration,followed by step to 40mV for 200ms and finally a 100ms ramp (1.2 V / s) to a holding potential of -80 mV. Peak current is measured during the step to 0mV. Each concentration is applied for 5 minutes.Data Analysis: The calcium current amplitude is calculated by measuring the differencebetween the peak inward current on stepping to 0mV or the peak inward current at the ramp (i.e. peak of the current) and the leak current. The calcium current is assessed in vehicle control conditions and at the end of each five (5) minute compound application. hERG Potassium Channel Assay Qube APC: After whole cell configuration is achieved, the cell is held at -80mV. The cell is depolarized to +40mV for 500ms and then to -80mV over a 100ms ramp to elicit the hERG tail current. This paradigm is delivered once every 5s to monitor the current amplitude. Data Analysis: The parameters measured were the maximum tail current evoked on stepping to 40mV and ramping back to -80mV from the test pulse. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean hERG current amplitude collected 15 seconds at the end of the control period; Test compound data is themean hERG current amplitude collected 15 seconds at the end of each 5-minute testcompound application for each concentration. Data is presented in Table 6. Table 6. Properties / Explanation / additional CPD-003 assay information High Throughput analysis via UPLC-MS / MS, 320.2 µM [pH 2] Aqueous @pH 2 and 7.4 6.76 µM [pH 7] Solubility LogD Shake Flask AssaypH 7.4 3.73Plasma Stability Human Highly stable (no degradation over 2h) Properties / Explanation / additional CPD-003 assay information Mouse Highly stable (93% after 2h)Mouse Low CLint= 48.0 µL / min / mg protein CLint Low < 13.1; high > 71.1 t1 / 2 = 28.9 min Microsomal stability Human Low CLint = 10.6 µL / min / mg protein CLint Low < 8.6; high > 47.0 t1 / 2 = 131 min HumanHigh CLint = 24.0 µL / min / 106 cellsCLint Low < 3.5; high > 19.0 t1 / 2 = 57.7 min Mitochondrial Glu / Gal < 2 Glu / Gal: ND toxicity non-mitotoxic Cell health parameter MEC (µM) AC50 (µM)Cell count 15.4 34.1Nuclear size 69.9 (NS) >100 (NS)CytotoxicityDNA structure 4.76 >10screening panel Cell membrane permeability 2.81 >40Cytochrome c 0.936 >40Mitochondrial mass; Mitochondrial membraneNR NRpotential hERG channel inhibition IC50 > 30 µMCardiotoxicityIon channel Nav1.5 N / CIon channel Cav1.2 IC50 > 30 µMGlu / Gal – glucose / galactose ratio; ND not determined due to insufficient response to calculateAC50 values for Glucose. MEC - minimum effective concentration that significantly crossesvehicle control threshold; AC50 - the concentration at which 50% maximum effect is observedfor each cell health parameter; NS - Fit not statistically significant (R 2 < 0.65 ); NR - noresponse observed; N / C - mean max inhibition <25%Pharmacokinetic profiling of CPD-001 and CPD-003 in the CD-1 male mouse following IV andPO dosing. The purpose of this study is to evaluate plasma and tissue concentrations for CPD-001 and CPD-003 and cerebrospinal fluid (CSF) for CDP-003 following intravenous (IV) and oral administration (PO) at 10 mg / kg to male CD-1 mice. Formulation PreparationFormulations were prepared fresh on the day of the in vivo experiment.Pre-weighed CPD-001 and CPD-003 were dissolved in DMSO / Cremophor / PBS (10 / 10 / 80) toreach final concentration of 2 mg / mL for an intravenous dose of 10 mg / kg (IV) and 1 mg / mLfor an oral dose of 10 mg / kg (PO).AnimalsThis study was performed in male CD-1 mice 7 weeks old at the time of administration.Mice were kept in solid bottom cages (TECNIPLAST S.p A., Italy, Type III polysulphone cage;425 mm x 266 mm x 180 mm). The animals were kept on a 4 cm thick layer of corn cob grit,dust-free bedding (Scobis Due - Mucedola, Italy), with a provision of one paper shelter (LillicoBiotechnology, UK). Animals were kept in the holding room with the following environmentalconditions: temperature 22°C ±2, relative humidity 55% ±10, 15 - 20 air changes per hour,artificial light cycle of 12 hours light (7:00 to 19:00). Animals had free access to potable waterand food (SDS VRF 1 (P), UK). All animals were managed similarly and with due regard fortheir well-being according to prevailing practices and the experimental plan approved by CARE Zagreb (Committee for Animal Research Ethics). Treatment / Experimental DesignAnimals were assigned to the groups as in Table 7 below.Table 7. Total Compound No. Feeding Dose Dose Time points sta volume Route(h) Samplesmice tus (mg / kg) (mL / kg) Plasma: 0.05, Plasma, at all t.p. CPD-001 9 fed 10 5 IV0.25, 0.5, 1, 2, Tissue sampling 4, 8 and 24 at 3 timepoints Tissue: 0.5, 4 Plasma, at all t.p. CPD-003 9 fed 10 5 IVand 24 Tissue sampling at 3 timepoints Total Feeding D Dose Time points Compound No. ose statu volume Route(h) Samplesmice s (mg / kg) (mL / kg) Plasma: 0.25, CPD-001 3 fed 10 10 PO0.5, 1, 2, 4, 8 Plasma and 24 CPD-003 3 fed 10 10 POTissue: 0.5, 4 and 24 Plasma CPD-003 3 fed 10 5 IV 4 and 24 CSFCPD-003 3 fed 10 10 PO 4 and 24 CSFCompound administrationIntravenous administration was performed into the lateral tail vein with a volume ofadministration of 5 mL / kg. Oral administration was performed by oral gavage using a syringe and a blunt metal probe, with a volume of administration of 10 mL / kg. Blood and plasma collection Prior to blood sampling from the tail vein, mice were placed in a warming cabinet (up to 10 minutes, maximum at 38˚C). Serial blood samples (ca. 100uL) were collected followingsuccessful puncture of the lateral tail vein using a needle, into K2EDTA-coated tubes.For terminal sampling, before sacrifice, the mice were anesthetized with a cocktail of ketamineand xylazine administered intraperitoneally. For each terminal time point, blood samples werecollected via jugular vein bleeds; ca 0.4 mL of blood were collected and transferred intoK2EDTA-coated tubes.Within 30 minutes after blood collection, samples were centrifuged at 1560 g for 10 min at 4°Cand the resulting plasma samples were aliquoted into polypropylene tubes (two aliquots of 20µL) and stored at -20°C until analysis. Tissue sampling Following terminal blood sampling at 0.5, 4 and 24h, animals were euthanized byexsanguination, Tissues were collected into Precellys® tubes, weighed individually, frozenand stored at –70° until analysis. CSF sampling CSF sampling will be performed in the anesthetized animals, following blood sampling, at 4h and 24h timepoints. Glass capillary will be used to puncture the cisterna magna and withdraw CSF. CSF sample (4-12 μL) will be transferred into pre-weighed LoBind tubes. Following collection and centrifugation (10000 rpm, 10 min, 4°C) samples will be inspected for blood contamination and if present, will be recorded. CSF will be diluted 1:1 with blank plasma, frozen and stored at –20° until analysis. Tubes will be identified with the matrix, animal number and the sampling-time after administration. Bioanalysis Analytical procedurePlasma, tissue concentrations and CSF were determined by research-qualified LC-MS / MSmethods.Samples were analysed on a SCIEX triple quadrupole mass spectrometer operating inTurboIonSpray mode. Blank mouse plasma was used for preparation of blank samples,calibrators and quality control samples (QC samples). Tissue samples were homogenized bythe addition of water. An aliquot of homogenate was diluted with blank plasma and quantified against plasma calibration curve.The study samples were assayed by batch with a calibration curve (six calibration standardlevels at least) including one level corresponding to the target LLOQ and the target ULOQ. A generic internal standard will be used.Each batch included QC samples in duplicate at three concentration levels (one near the limitof quantification, one in the mid-range, and one near the high end of the range).Washing solvent and double blank samples was run to avoid any contamination of a sampleby its preceding one.Back-calculated concentration of calibration and QC samples provided the basis of acceptingor rejecting the batch.The calibration equation was computed by least-squares regression using the selected model,and the concentration of each calibration sample was calculated. If the back-calculatedconcentration of a calibration sample does not fall within ±15% of the nominal concentration(±20% at the LLOQ), that sample was discarded, and the equation was recalculated. For thecalibration and the batch to be valid, the coefficient of determination (r²) must be higher than 0.98 and at least 75% of calibration samples have to remain included. Moreover, for the lowest and the highest levels, only one replicate out of two may be rejected. To qualify the batch, at least 67% of QCs must be within ±15% of their respective nominal, and ≥ 50% of QCs per level should be ±15% of their nominal value. Data analysis Plasma and tissue concentrationsPlasma and CSF concentrations were expressed in ng / mL and tissue concentrations in ng / g.Individual and mean concentrations (n=3 individual values) with standard deviation (SD) and coefficients of variation (CV%).Linear-linear and Log-linear Graphs of concentrations (± SD) are reported for mean data.Pharmacokinetic parametersPharmacokinetic analysis was performed using WinNonlin Phoenix® software (Certara,version 8.3) from animal plasma concentrations, non-compartmental analysis, and the target dose.The following PK parameters were calculated:^ Co (ng / mL): Initial concentration^ Cmax (ng / mL): maximum observed concentration, occurring at Tmax^ Cmax / Dose (ng / mL): dose normalised Cmax^ AUC0-last (ng*h / mL): area under the plasma concentration versus time curve up to lastquantifiable concentration, and / or up to infinity AUC0-inf (ng*h / mL) will be calculated according to the linear up log down method. ^t½ (h): Apparent terminal elimination half-life only reported if three or more time pointsin the elimination phase – excluding the Tmax - were used for linear regression, and ifradj2>0.9, and if % of AUC extrapolation to infinity is lower than 20%, ^CL (mL / min / kg): total clearance determined after intravenous administration^ Vss (L / kg): Apparent volume of distribution at equilibrium determined after intravenousadministration (Vss / F after oral dosing) ^F(%): BioavailabilityTable 8 below shows the mean plasma concentrations after intravenous (IV) administrationfor each compound tested. Table 8. Compound Time (h)Mean concentration (ng / mL) ± SD0.05 13067 ± 1751CPD-0030.25 6540 ± 6010.5 5497 ± 13141 3457 ± 1164Compound Time (h)Mean concentration (ng / mL) ± SD2 650 ± 1194 191 ± 63.68 52.3 ± 9.660.05 11190 ± 54870.25 3130 ± 12850.5 675 ± 229CPD-0011 773 ± 87.82 103 ± 18.44 22.3 ± 5.278 117 ± 105SD = standard deviation of n=6 at t =0.05 h, n=3 at remaining time points.Table 9 below shows the tissue distribution after intravenous (IV) administration for eachcompound tested. Data are expressed as the mean value ± SD (n=3 unless statedotherwise). Table 9. Tissue (ng / kg) Time (h) CPD-003 (ng / g) CPD-001 (ng / g)0.5 10333 ± 3183 1117 ± 587Liver4 714 ±12.9 109 ± 1824 48.5 ± 5.79 BLQ0.5 2467 ± 638 1077 ± 103Lung4 226 ± 131 118 ±18.824 41.3a 83.2 ±1.720.5 859 ± 278 461 ± 107Heart4 68.5 ± 8.05 BLQ24 BLQ 82.5a0.5 9230 ± 3193 3403 ± 1767Kidney4 1015 ± 447 367 ±12724 BLQ BLQ0.5 1123 ± 361 375 ± 27.8Brain4 103 ± 461 132 ± 17.624 123 ± 28.8 175 ± 19.7BLQ - blank, below the detection limit, compound below the lower limit of quantification. BLQcalculated as 0. a For this measurement only one sample of organ homogenate wasprocessed. Table 10 below shows the PK parameters after intravenous administration (IV) for each compound tested. Table 10. Compound AUC0-lastAUC / Dose CL t½ (h) C0( AUC0-infVssCode (µM) ng*h / m (ng*h / mL) / ( (mL / min / k L) mg / kg) (ng*h / mL) g) (L / kg) αt1 / 2 = 0.49 CPD-003 (predominant)60.4 9417 942 9419 17.7 1.41βt1 / 2 = 2.95 αt1 / 2 = 0.11 CPD-001 (predominant) βt1 / 2 = not67.1 3401 340 3420 48.7 3.01calculableTable 11 below shows the mean plasma concentrations after oral administration (PO) foreach compound tested. Data are expressed as the mean value ± SD (n=3 unless statedotherwise). Table 11. Compound Time Mean concentration Code (h)(ng / mL) ± SD0.25 2370 ± 4830.5 2310 ± 4161 2207± 788CPD-0032 1135± 5234 408± 1498 52.2± 27.024 2.34 ± 0.460b0.25 285 ± 78.10.5 289 ± 1141 186 ± 73.2CPD-0012 89 ± 66.64 15.0 ± 1.888 5.41a24 BLQSD = standard deviation of n=3; BLQ = belaow the detection limit, compound below the lowerlimit of quantification. BLQ calculated as 0. bFor this measurement only one sample containedcompound above the detection limit (n=1); n=2.Table 12 below shows the PK parameters after oral administration (PO) for each compoundtested. Table 12. Compound code CPD-003 CPD-001t½ (h) 2.1 ± 0.70 1.05 ± 0.46Tmax (h) 0.5 0.5Cmax (ng / mL) 2773 ± 343 351 ± 75Cmax (µM) 10.8 1.53AUC0-last (ng*h / mL) 5894 ± 1414 445 ± 116AUC0-last / Dose (ng*h / mL) / (mg / kg) 589 ± 141 44.5 ± 11.6AUC0-inf (ng*h / mL) 5923 ± 1381 460 ± 117F (%) 63 ± 15 13 ± 3.4Data were expressed as the mean value (n=3) ± SD.Table 13 below shows the CSF concentrations after intravenous (IV) and oral administration(PO) for CPD-003. Data are expressed as the mean value ± SD (n=3 unless stated otherwise).Table 13. Route Time (h)Mean concentration (ng / mL) ± SDIV 4 2.77 ± 2.3324 BLQ4 5a PO .9724 0.869bBLQ = below the detection limit, compound below the lower limit of quantification. BLQ calculated as 0.aFor this measurement only one sample contained compound above the detection limit (n=1).bn=2.

Claims

Claims 1. A compound of formula (I) or a stereoisomer, or tautomer thereof,wherein, R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, C3- 10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3- 10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z1; R2 is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl,hydrogen, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z2; R3 is selected from the group consisting of C3-10cycloalkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, and heteroaryl, wherein said C3-10cycloalkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl or heteroaryl can be unsubstituted or substituted with one or more Z3; each Z1, Z2and Z3is independently selected from the group consisting of halo, haloC1-6alkyl, C1-6alkyl, haloC1-6alkyloxy, C1-10cycloalkyl, aryl, alkyC1-6alkyl, heterocyclyl,heteroaryl, hydroxyl, -OR10, cyano, amino, -NR6R7, -C(O)2R10, -C(O)NR6R7, -C(O)R10, -S(O)R10, -S(O)2R10, -S(O)2NR6R7, nitro;or a solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof; each R6and R7is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; each R10is independently selected from the group consisting of C1-6alkyl, hydrogen, C3- 10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; for use as a medicament for oral administration.

2. A compound for use according to claim 1, which is for use as a medicament for oraladministration in the prevention or treatment of a disease associated with ferroptosis and / or oxytosis.

3. The compound for use according to claim 1 or 2, having structural formula (IA), (IB) or (IC)wherein R1is as defined in any one of claims 1 or 2.

4. A pharmaceutical composition comprising a compound of formula (I)wherein, R1is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, C3- 10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl, C3-10cycloalkenyl, C3- 10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z1; R2is selected from the group consisting of hydrogen, C3-10cycloalkyl, arylC1-6alkyl, hydrogen, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, and heteroarylC1-6alkyl, wherein said C3-10cycloalkyl, arylC1-6alkyl,C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, heteroaryl, heterocyclylC1-6alkyl, or heteroarylC1-6alkyl can be unsubstituted or substituted with one or more Z2; R3is selected from the group consisting of C3-10cycloalkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl, and heteroaryl, wherein said C3-10cycloalkyl, C3-10cycloalkenyl, C3-10cycloalkynyl, aryl, heterocyclyl or heteroaryl can be unsubstituted or substituted with one or more Z3; each Z1, Z2and Z3is independently selected from the group consisting of halo, haloC1- 6alkyl, C1-6alkyl, haloC1-6alkyloxy, C1-10cycloalkyl, aryl, alkyC1-6alkyl, heterocyclyl,heteroaryl, hydroxyl, -OR10, cyano, amino, -NR6R7, -C(O)2R10, -C(O)NR6R7, -C(O)R10, -S(O)R10, -S(O)2R10, -S(O)2NR6R7, nitro; or a solvate, hydrate, pharmaceutically acceptable salt, or prodrug thereof; each R6and R7is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; each R10is independently selected from the group consisting of C1-6alkyl, hydrogen, C3- 10cycloalkyl, C6-12aryl, C6-12arylC1-6alkyl, heterocyclyl, and heteroaryl; and a pharmaceutically acceptable carrier.

5. The compound for use according to claims 2 or 3, wherein the disease associated withferroptosis and / or oxytosis is selected from the group consisting of liver disease, chronickidney disease, lung disease, ocular surface diseases, wound healing, multiple organ dysfunction syndrome, neurological disease, acute renal failure, ischemia-reperfusion injury, sepsis, iron toxicity, prevention of transplant rejection, iron metabolism-related disease and genetic disorders of GPX4.

6. The compound for use according to claim 5, wherein the liver disease is selected from hemochromatosis, primary biliary cholangitis, non-alcoholic steatohepatitis or liver fibrosis.

7. The compound for use according to claim 5, wherein the neurological disease is selected from Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, Multiple Sclerosis, Huntington’s Disease, Dementia with Lewy bodies, Friedreich’s ataxia, stroke, periventricular leukomalacia, intracerebral haemorrhage, frontotemporal dementia, neurodegeneration with brain iron accumulation, or traumatic brain injury.

8. The compound for use according to claim 5, wherein the ischemia-reperfusion injury isselected from myocardial ischemia-reperfusion injury, liver ischemia-reperfusion injury, renal ischemia-reperfusion injury, intestinal ischemia-reperfusion injury, cerebral ischemia-reperfusion injury, lung ischemia- reperfusion injury, or any surgical ischemia-reperfusion injury.

9. The compound for use according to claim 5, wherein the iron metabolism-related disease is selected from atherosclerosis or diabetes, or wherein the lung disease is selected from acute respiratory distress syndrome (ARDS), lung diseases caused by infections such as COVID-19 pulmonary disease, mucoviscidosis, or asthma.

10. The compound for use according to any one of claims 5-9, wherein the disease is attributable to a genetic disorder of GPX4; preferably the disease is Sedaghatian-type spondylometaphyseal dysplasia.

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