Urolithin derivatives and therapeutic uses

Abstract

Disclosed are compounds, compositions, and methods useful for inhibiting ferroptosis in a subject in need thereof.

Description

Cross - reference to related applications

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 392,611, filed on July 27, 2022.

Background Art

[0002] Urolithin has potential effects on the improvement of a number of health conditions and has been shown to be highly biologically active in vitro and in vivo. Urolithin has been proposed as a therapeutic agent for various conditions, including those related to insufficient mitochondrial activity, such as obesity, memory decline, reduced metabolic rate, metabolic syndrome, type 2 diabetes, cardiovascular disease, hyperlipidemia, neurodegenerative diseases, cognitive impairment, mood disorders, stress, anxiety disorders, and fatty liver disease, for the improvement of liver function and weight management. In particular, urolithin has been shown to have beneficial effects on improving muscle function.

Summary of the Invention

Means for Solving the Problems

[0003] One aspect of the present invention provides compounds, compositions, and methods useful for inhibiting ferroptosis.

[0004] Accordingly, a compound having the structure of formula (I):

Chemical Formula

[0005] Also provided herein is a compound having the structure of formula (II): [Chemical formula] [wherein, X1 and X2 are each alkyl or, in combination with the carbon to which they are attached, form an unsubstituted or substituted spirocycloalkyl, R1’, R4’, R5’, and R8’ are independently selected from -H, -OH, -NH2, alkyl, and halogen, R2’, R3’, R6’, and R7’ are independently selected from -H, -OH, -OAc, -NH2, halogen, -CN, -CF3, -CO2H, -NO2, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, and -OR8’, R8’ is selected from alkyl, hydroxyalkyl, aminoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.] Also provided herein is a pharmaceutically acceptable salt thereof.

[0006] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0007] Other features, objects, and advantages of the present invention will become apparent from the detailed description and the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0008]

Figure 1

Mode for Carrying Out the Invention

[0009] Definitions For convenience, before further description of the present invention, specific terms used in the specification, examples, and appended claims are summarized herein. These definitions should be read in light of the remainder of the present disclosure and should be understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0010] To more quickly understand the present invention, specific terms and phrases are defined below and throughout this specification.

[0011] The articles "a" and "an" are used herein to refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, "(an) element" means one element or more than one element.

[0012] As used in this specification and the claims, the phrase "and / or" is to be understood to mean "either or both" of the recited elements, i.e., elements that may be conjunctively present in some cases and disjunctively present in other cases. The multiple elements recited in "and / or" are to be construed in the same fashion, i.e., as being composed of "one or more" of the conjoined elements. Other elements may optionally be present, whether or not related to the specifically identified elements, in addition to the elements specifically identified in the "and / or" clause. Thus, by way of non-limiting example, when used in combination with open-ended words such as "comprising", a reference to "A and / or B" can, in one embodiment, refer to only A (optionally including elements other than B); in another embodiment, to only B (optionally including elements other than A); and in yet another embodiment, to both A and B (optionally including other elements).

[0013] In the specification and claims, as used herein, "or" is to be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" is to be interpreted as inclusive, i.e., including not only one or at least one of the number of elements or list, but also two or more, optionally including additional items not in the list. In contrast, terms specifically indicating exclusivity, such as "only one of", or "exactly one of", or "consisting of" when used in the claims, mean including exactly one element out of a number of elements or a series of elements. Generally, as used herein, the term "or" is to be interpreted as indicating exclusive alternatives (i.e., "not both, either one or the other") only when preceded by terms indicating exclusivity, such as "any of", "one of", "only one of", or "exactly one of". As used in the claims, "consisting essentially of" shall have the ordinary meaning as used in the field of patent law.

[0014] In the specification and claims, as used herein, the phrase "at least one" with respect to the recitation of one or more elements shall be understood to mean at least one element selected from any one or more of the recited elements, but not necessarily each and every one of the at least one specifically recited in the recitation of elements, and not necessarily including all, and not excluding any combinations of elements in the recitation of elements. This definition also allows for the possibility that, optionally, elements other than those specifically identified in the list of elements referred to by the phrase "at least one" may be present, whether or not related to those specifically identified elements. Thus, by way of non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B", or equivalently "at least one of A and / or B") can, in one embodiment, refer to at least one, optionally, two or more of A, with no B present (and, optionally, including elements other than B), in another embodiment, can refer to at least one, optionally, two or more of B, with no A present (and, optionally, including elements other than A), and in yet another embodiment, can refer to at least one, optionally, two or more of A, and at least one, optionally, two or more of B (and, optionally, including other elements), and so on.

[0015] Unless otherwise expressly indicated, in any method claimed herein that includes two or more steps or acts, it must also be understood that the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts are recited.

[0016] In the claims and the above specification, transitional phrases such as "comprising", "including", "carrying", "having", "containing", "involving", "holding", "composed of", etc. are all non-limiting, that is, it should be understood to mean including, but not limited to. As stipulated in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03, only the transitional phrases "consisting of" and "consisting essentially of" are restrictive or semi-restrictive transitional phrases respectively.

[0017] The specific compounds contained in the compositions of the present invention may in particular exist in geometric forms or stereoisomers. In addition, the polymers of the present invention may also be optically active. The present invention contemplates that all such compounds, including cis and trans isomers, (R)-enantiomers and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, their racemic mixtures, and other mixtures, are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. It is intended that all such isomers, as well as their mixtures, are included in the present invention.

[0018] "Geometric isomers" mean isomers in which the orientation of substituent atoms is different in relation to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. The atoms (other than H) on each side of a carbon-carbon double bond may be in the E configuration (substituents on opposite sides of the carbon-carbon double bond) or the Z configuration (substituents on the same side). "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" indicate the structure with respect to the core molecule. The specific compounds disclosed can exist in "atropisomeric" form or as "atropisomers". Atropisomers are stereoisomers resulting from rotational hindrance about a single bond where the steric hindrance to rotation is sufficiently high to allow separation of conformational isomers. The compounds of the present invention can be prepared as individual isomers either by enantioselective synthesis or by separation from a mixture of isomers. Conventional separation techniques include using an optically active acid to form salts of the free bases of each isomer of an isomer pair (subsequently followed by fractional crystallization and regeneration of the free base), using an optically active amine to form salts of the acid form of each isomer of an isomer pair (subsequently followed by fractional crystallization and regeneration of the free acid), using an optically pure acid, amine or alcohol to form esters or amides of each of the isomers of an isomer pair (subsequently followed by separation by chromatography and removal of the chiral auxiliary), or using various well-known chromatographic methods to separate a mixture of isomers of either the starting material or the final product.

[0019] For example, if a specific enantiomer in the compound of the present invention is desired, the enantiomer can be prepared by asymmetric synthesis or by induction using a chiral auxiliary group. The resulting mixture of diastereomers is separated, the auxiliary group is cleaved, and the desired pure enantiomer is obtained. Alternatively, when the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomeric salt is formed using an optically active appropriate acid or base, and then the diastereomers thus formed are resolved by fractional crystallization or chromatography methods well known in the art, and subsequently, the pure enantiomer is recovered.

[0020] The purity ratio by mole fraction is the molar ratio of the enantiomer (or diastereomer), or the ratio of the mole of the enantiomer (or diastereomer) to the mole of its optical isomer. When the stereochemistry of the disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction relative to other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure by mole fraction.

[0021] The disclosed compounds are named or depicted by structure without indicating stereochemistry, and when a compound has at least one chiral center, its name or structure is understood to encompass any enantiomer of the compound, the racemic mixture of the compound, or a mixture enriched in one enantiomer relative to its corresponding optical isomers. When the disclosed compounds are named or depicted by structure without indicating stereochemistry and have two or more chiral centers, its name or structure is understood to encompass a diastereomer that does not include other diastereomers, a number of diastereomers that do not include other diastereomer pairs, a mixture of diastereomers, a mixture of diastereomer pairs, a mixture of diastereomers in which one diastereomer is enriched relative to other diastereomer(s), or a mixture of diastereomers in which one or more diastereomers are enriched relative to other diastereomers. The present invention encompasses all of these forms.

[0022] The structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds generated by replacing hydrogen with deuterium or tritium, or carbon with 13 C or 14 C enriched carbon are within the scope of the present invention.

[0023] The term "prodrug" as used herein encompasses compounds that are converted to a therapeutically active agent under physiological conditions. A common method for making a prodrug is to include a selected moiety that hydrolyzes under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal.

[0024] As used herein, the terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" mean pharmaceutically acceptable materials, compositions or vehicles such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials involved in carrying or transporting the subject chemical substance from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not deleterious to the patient, and substantially nonpyrogenic. Some examples of materials that can function as pharmaceutically acceptable carriers are as follows: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, sesame oil, coconut oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffers; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the invention are nonpyrogenic, i.e., they do not cause a significant increase in temperature when administered to a patient.

[0025] The term "pharmaceutically acceptable salt" means relatively non-toxic inorganic and organic acid addition salts of a compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free base form with a suitable organic or inorganic acid and isolating the salt so formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfate, among others (see, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

[0026] In other cases, compounds useful in the methods of the present invention may contain one or more acidic functional groups, thereby enabling the formation of pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salt" in these cases means relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine, among others. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, among others. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, e.g., Berge et al. supra).

[0027] The term "pharmaceutically acceptable cocrystal" refers to a coformer of a solid that does not form formal ionic interactions with small molecules.

[0028] A "therapeutically effective amount" (or "effective amount") of a compound for use in a treatment means an amount of the compound(s) in a preparation that, when administered as part of a desired dosing regimen (for a mammal, preferably a human), treats a disease or condition, or alleviates symptoms, ameliorates a condition, or delays the onset of a disease condition, according to clinically acceptable standards for any medical treatment, e.g., with a reasonable benefit / risk ratio applicable to any medical treatment.

[0029] The term "preventive or therapeutic" treatment is recognized in the art and includes administration of one or more of the subject compositions to a host. The treatment is preventive (i.e., protects the host from the development of an undesirable condition) when administered before the clinical symptoms of an undesirable condition (e.g., a disease or other undesirable condition of the host animal) appear, whereas the treatment is therapeutic (i.e., is intended to reduce, ameliorate, or stabilize an existing undesirable condition or its side effects) when administered after the appearance of the undesirable condition.

[0030] The term "patient" or "subject" refers to a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is a human.

[0031] Aliphatic chains include the classes of alkyl, alkenyl, and alkynyl as defined below. A straight-chain aliphatic chain is limited to an unbranched carbon chain moiety. As used herein, the term "aliphatic group" refers to a straight-chain, branched-chain, or cyclic aliphatic hydrocarbon group, including saturated and unsaturated aliphatic groups such as alkyl groups, alkenyl groups, or alkynyl groups.

[0032] "Alkyl" means a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the specified number of carbon atoms, or, when not specified, up to 30 carbon atoms. For example, alkyl having 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as moieties that are positional isomers of these moieties. Alkyl having 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, a straight-chain or branched-chain alkyl has up to 30, and more preferably up to 20 carbon atoms in its main chain (e.g., C1-C 30 , and in the case of a branched chain, C3-C 30 ). The alkyl group may be substituted or unsubstituted.

[0033] As used herein, the term "heteroalkyl" means an alkyl moiety as defined above that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.

[0034] As used herein, the term "haloalkyl" means an alkyl group as defined above that is substituted with at least one halogen.

[0035] As used herein, the term "hydroxyalkyl" means an alkyl group as defined above that is substituted with at least one hydroxyl.

[0036] As used herein, the term "alkylene" means an alkyl group having the specified number of carbons, e.g., 2 to 12 carbon atoms, and containing two points of attachment to the remainder of the compound on the longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, and the like. The alkylene group can be a cyclic or acyclic, branched or unbranched carbon chain moiety and can be optionally substituted with one or more substituents.

[0037] "Cycloalkyl" means a monocyclic or bicyclic or bridged or spirocyclic, or polycyclic saturated carbon cyclic ring, each having 3 to 12 carbon atoms. Preferred cycloalkyls have 3 to 10 carbon atoms in the cyclic structure, and more preferably, 3 to 6 carbons in the cyclic structure. The cycloalkyl group can be substituted or unsubstituted.

[0038] As used herein, the term "halocycloalkyl" means a cycloalkyl group as defined above substituted with at least one halogen.

[0039] "Cycloheteroalkyl" or "heterocycloalkyl" means a cycloalkyl moiety as defined above containing one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have 4 to 8 carbon atoms and heteroatoms in the cyclic structure, and more preferably, 4 to 6 carbons and heteroatoms in the cyclic structure. The cycloheteroalkyl or heterocycloalkyl group can be substituted or unsubstituted.

[0040] Unless otherwise specified, as used herein, "lower alkyl" means an alkyl group as defined above having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms in its main chain structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" also have similar chain lengths. Throughout the present application, the preferred alkyl group is lower alkyl. In certain embodiments, the substituents described herein as alkyl are lower alkyl.

[0041] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the specified number of carbon atoms, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified, and having one or more double bonds in that moiety. Alkenyls having 6 to 26 carbon atoms are exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and tetracosenyl, and in various isomeric forms, the unsaturated bond(s) can be located at any position in that moiety and can have either a (Z) configuration or an (E) configuration about the double bond(s).

[0042] "Alkynyl" is a hydrocarbyl moiety within the scope of alkenyl but having one or more triple bonds in that moiety.

[0043] As used herein, the term "aryl" includes 3- to 12-membered substituted or unsubstituted monocyclic aromatic groups, where each atom of the ring is carbon (i.e., carbocyclic aryl), or one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, the aryl group includes a 5- to 12-membered ring, more preferably a 6- to 10-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings where two or more carbons are common to two adjacent rings, and at least one of those rings is aromatic. For example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline. Examples of heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, and the cyclic structure contains 1 to 4 heteroatoms. Examples of heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0044] As used herein, the term "halo", "halide", or "halogen" means halogen and includes, for example, but not limited to, fluoro, chloro, bromo, iodo, etc. in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro, and bromo.

[0045] The term "heterocyclyl" or "heterocyclic group" means a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, still more preferably a 5- to 10-membered ring, and the cyclic structure contains 1 to 4 heteroatoms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam, for example, azetidinone and pyrrolidinone, sultam, sultone, and the like. The heterocyclic ring can be substituted at one or more positions with substituents such as those described above, for example, halogen, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, and the like.

[0046] The term "substituted" refers to a moiety having a substituent that replaces a hydrogen on one or more carbons of a backbone. "Substitution" or "substituted with" is understood to include the implicit condition that such substitution is in accordance with the allowable bonding valences of the atom being substituted and the substituent, and that the substitution gives a stable compound (i.e., one in which conversions such as rearrangement, cyclization, elimination, etc. do not occur spontaneously). As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compound substituents. Permissible substituents are one or more and may be the same or different for a suitable organic compound. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any permissible substituent of an organic compound described herein that satisfies the valence of the heteroatom. Substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioglycolate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, arylalkyl, or an aromatic or heteroaromatic moiety. In a preferred embodiment, the substituent of a substituted alkyl is C 1-6 alkyl, C 3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In a preferred embodiment, the substituent on a substituted alkyl is selected from fluoro, carbonyl, cyano, or hydroxyl. One of ordinary skill in the art will understand that, where appropriate, the substituent itself may be substituted. Unless specifically stated to be "unsubstituted", references herein to chemical moieties are understood to include substitution variants. For example, a reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0047] As used herein, each expression, such as alkyl, m, n, etc., when it appears two or more times in any structure, means that it is independent of the definition at other places of the same structure.

[0048] As used herein, "low molecule" means a low organic or inorganic molecule having a molecular weight of less than about 3,000 daltons. Generally, the low molecules useful in the present invention have a molecular weight of less than 3,000 daltons (Da). The low molecule can be, for example, at least about 100 Da to about 3,000 Da (e.g., about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).

[0049] In some embodiments, "low molecule" means an organic, inorganic, or organometallic compound that usually has a molecular weight of less than about 1000. In some embodiments, the low molecule is an organic compound having a size on the order of 1 nm. In some embodiments, the low molecular drugs of the present invention include oligopeptides and other biomolecules having a molecular weight of less than about 1000.

[0050] "Effective amount" means an amount sufficient to achieve a beneficial or desired result. For example, a therapeutic amount is an amount that achieves a desired therapeutic effect. This amount can be the same as, or different from, a prophylactically effective amount which is an amount necessary to prevent the onset of a disease or a symptom of a disease. An effective amount can be administered in one or more administrations, applications, or dosages. The therapeutically effective amount of a composition will vary depending on the composition selected. The composition can be administered one or more times per day to once or more per week (including once every other day). One of ordinary skill in the art will recognize that certain factors, such as, but not limited to, the severity of the disease or disorder, past treatments, the overall health and / or age of the subject, and other diseases present, can affect the dosage and timing required to effectively treat the subject. Further, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment, or a series of treatments.

[0051] The terms "decrease", "reduce", "reduced", "reduction", "decreasing", and "inhibit" are all generally used herein to mean a statistically significant decrease as compared to a reference. However, for the avoidance of doubt, "reduce", "reduction", or "decrease", or "inhibit" generally means at least a 10% decrease as compared to a reference level, for example, including any decrease between 10% and 99% as compared to the complete absence of a given element or parameter, or as compared to the non - performance of a given treatment, including, for example, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% decrease.

[0052] The terms "increased", "increasing", "enhanced", or "activated" are all used herein generally to mean an increase in a statistically significant amount, and to avoid doubt, the terms "increased", "increasing", "enhanced", or "activated" mean an increase of at least 10%, for example, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to 100% (including this value), or any increase between 10 - 100% compared to the reference level, or at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 10-fold, or any increase between 2-fold - 10-fold or more compared to the reference level.

[0053] As used herein, the term "modulate" includes upregulation and downregulation, e.g., enhancing or inhibiting a response.

[0054] As defined herein, "radiopharmaceutical" means a pharmaceutical agent containing at least one radiation-emitting radioisotope. Radiopharmaceuticals are routinely used in nuclear medicine for the diagnosis and / or treatment of various diseases. A radiolabeled pharmaceutical agent, e.g., a radiolabeled antibody, contains a radioisotope (RI) that functions as a radiation source. The term "radioisotope" as contemplated herein includes metallic and non-metallic radioisotopes. The radioisotope is selected based on the medical use of the radiolabeled pharmaceutical agent. When the radioisotope is a metallic radioisotope, a chelating agent is usually used to bind the metallic radioisotope to the remainder of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is usually bound directly to the remainder of the molecule or via a linker.

[0055] For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986 - 87.

[0056] The compounds of the present invention One embodiment of the present invention is a compound of formula (I): [Chem.] [wherein, Y1 and Y2 are each alkyl or, in combination with the carbon to which they are attached, form an unsubstituted or substituted spirocycloalkyl, R1, R4, R5, and R8 are independently selected from -H and halogen, R2 and R7 are -H, -OH, -OAc, -NH2, halogen, -CN, -CF3, -CO2H, -NO2, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R9, alkenyl-R9, alkynyl-R9, -OR 10 , -NHR 10 , -NR 11 C(O)R 12 , -C(O)NR 11 R 12 , and -NR 11 SO2R 12 independently selected from, R3 and R6 are independently selected from alkyl and cycloalkyl, each R9 present is independently selected from OH, NH2, O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH3)C(O)-alkyl, NHSO2-alkyl, N(CH3)SO2-alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, R 10is selected from alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, SO3H, SO2-alkyl, and SO2-haloalkyl, each R present 11 is selected from H and alkyl, each R present 12 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl, provided that when R1, R4, R5, and R8 are each -H, R2 and R7 are each -OH, and R3 and R6 are each CH3, then Y1 and Y2 are each not -Me, or together with the carbon to which they are attached, do not form an unsubstituted spirocyclobutyl] or a pharmaceutically acceptable salt thereof is provided.

[0057] In certain embodiments, R3 and R6 are alkyl.

[0058] In certain embodiments, Y1 and Y2 are each independently C1-C4 alkyl.

[0059] In certain embodiments, Y1 and Y2 are each -CH3.

[0060] In certain embodiments, Y1 and Y2 combine together with the carbon to which they are attached to form an unsubstituted spirocycloalkyl.

[0061] In certain embodiments, Y1 and Y2 combine together with the carbon to which they are attached to form an unsubstituted spirocyclopropyl, cyclobutyl, or cyclopentyl.

[0062] In certain embodiments, R3 and R6 are each independently C1-C4 alkyl.

[0063] In certain embodiments, R3 and R6 are each independently selected from -CH3 and -CH2CH3.

[0064] In certain embodiments, R3 and R6 are each -CH3.

[0065] In certain embodiments, R3 and R6 are each -CH2CH3.

[0066] In certain embodiments, one of R3 and R6 is -CH3 and the other of R3 and R6 is -CH2CH3.

[0067] In certain embodiments, R3 and R6 are cycloalkyl.

[0068] In certain embodiments, R3 and R6 are each independently C3-C5 cycloalkyl.

[0069] In certain embodiments, R3 and R6 are each cyclopropyl.

[0070] In certain embodiments, one of R3 and R6 is C1-C4 alkyl and the other of R3 and R6 is C3-C5 cycloalkyl.

[0071] In certain embodiments, one of R3 and R6 is -CH3 and the other of R3 and R6 is cyclopropyl.

[0072] In certain embodiments, the compound has a structure selected from the following:

Chemical Formula

[0073] In certain embodiments, the compound has a structure selected from the following: [Chemical formula]

[0074] In certain embodiments, R2 and R7 are independently selected from -OH, -NH2, alkylamino, and -OR 10 and the like.

[0075] In certain embodiments, R2 and R7 are each OH.

[0076] In certain embodiments, R2 is -OH and R7 is -OCH3.

[0077] In certain embodiments, R7 is -OH and R2 is -OCH3.

[0078] In certain embodiments, R2 is selected from -NH2, -NHCH3, and -NH(CH3)2, and R7 is OH.

[0079] In certain embodiments, R7 is selected from -NH2, -NHCH3, and -NH(CH3)2, and R2 is OH.

[0080] In certain embodiments, R1, R4, R5, and R8 are each -H.

[0081] Another aspect of the present invention is a compound of formula (II): [Chemical formula] [wherein, X1 and X2 are each alkyl or, in combination with the carbon to which they are attached, form an unsubstituted or substituted spirocycloalkyl, R1’, R4’, R5’, and R8’ are independently selected from -H, -OH, -NH2, alkyl, and halogen, R2’, R3’, R6’, and R7’ are independently selected from -H, -OH, -OAc, -NH2, halogen, -CN, -CF3, -CO2H, -NO2, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, and -OR8’; R8’ is selected from alkyl, hydroxyalkyl, aminoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. or a pharmaceutically acceptable salt thereof is provided.

[0082] In certain embodiments, X1 and X2 are each independently C1-C4 alkyl.

[0083] In certain embodiments, X1 and X2 are each -CH3.

[0084] In certain embodiments, X1 and X2 combine with the carbon to which they are attached to form an unsubstituted spirocycloalkyl.

[0085] In certain embodiments, X1 and X2 combine with the carbon to which they are attached to form an unsubstituted spirocyclopropyl, cyclobutyl, or cyclopentyl.

[0086] In certain embodiments, the compound has a structure selected from the following:

Chemical formula

[0087] In certain embodiments, R2’ and R7’ are independently selected from -OH, -NH2, alkylamino, and -OR 10 selected therefrom.

[0088] In certain embodiments, R2’ and R7’ are each OH.

[0089] In certain embodiments, R2’ is -OH and R7’ is -OCH3.

[0090] In certain embodiments, R7’ is -OH and R2’ is -OCH3.

[0091] In certain embodiments, R2’ is selected from -NH2, -NHCH3, and -NH(CH3)2, and R7’ is OH.

[0092] In certain embodiments, R7’ is selected from -NH2, -NHCH3, and -NH(CH3)2, and R2’ is OH.

[0093] In certain embodiments, R3’ and R6’ are each independently -H or C1-C4 alkyl.

[0094] In certain embodiments, R3’ and R6’ are each independently -H or -CH3 alkyl.

[0095] In certain embodiments, R1’ and R8’ are each independently -H or C1-C4 alkyl.

[0096] In certain embodiments, R1’ and R8’ are each independently -H or -CH3 alkyl.

[0097] In certain embodiments, R4’ and R5’ are each independently -H or -OH.

[0098] In certain embodiments, the compound is selected from Table 1.

Table 1-1

Table 1-2

[0099] In certain embodiments, the compound is selected from Table 2.

Table 2

[0100] In some embodiments, the compound is an atropisomer. Unless otherwise specifically noted, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds generated by replacing hydrogen with deuterium or tritium, or carbon with 13 C or 14 C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes for biological assays, or therapeutic agents according to the present invention. For example, in the case of variable R 1 , (C1-C4)alkyl, or -O-(C1-C4)alkyl can be appropriately deuterated (e.g., -CD3, -OCD3).

[0101] Any compound of the present invention can also be radiolabeled for the preparation of radiopharmaceuticals.

[0102] Method of treatment One aspect of the present invention relates to a method of inhibiting ferroptosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or (II).

[0103] Another aspect of the present invention relates to a method of treating an inflammatory disease, a neurological disease, or a neurodegenerative disease that is at least partially mediated by ferroptosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or (II).

[0104] Another aspect of the present invention relates to a method of treating an inflammatory disease that is at least partially mediated by ferroptosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or (II).

[0105] Another aspect of the invention relates to a method for treating a neurological disorder mediated at least in part by ferroptosis, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or (II).

[0106] Another aspect of the invention relates to a method for treating a neurodegenerative disorder mediated at least in part by ferroptosis, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or (II).

[0107] A further aspect of the invention relates to a method for treating mitochondrial disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) or (II).

[0108] In one embodiment, the mitochondrial disease affects the subject's muscles (e.g., mitochondrial myopathy). In another embodiment, the mitochondrial disease affects the subject's eyes (e.g., external progressive ophthalmoplegia). In other embodiments, the mitochondrial disease is Alzheimer's disease, Barth syndrome, β-oxidation deficiency, carnitine deficiency, carnitine-acyl-carnitine deficiency, chronic progressive external ophthalmoplegia syndrome, or coenzyme Q10 deficiency.

[0109] In one aspect, the present invention relates to a method for treating a muscular or neuromuscular disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formulas (I) or (II). In one embodiment, the muscular or neuromuscular disease is sarcopenia. In another embodiment, the muscular or neuromuscular disease is muscular dystrophy. In another embodiment, the muscular or neuromuscular disease is myopathy. In another embodiment, the muscular or neuromuscular disease is Duchenne muscular dystrophy. In another embodiment, the muscular or neuromuscular disease is inclusion body myositis (IBM) or sporadic inclusion body myositis (sIBM). In another embodiment, the muscular or neuromuscular disease is selected from mitochondrial myopathies. In other embodiments, the muscular or neuromuscular disease is muscle aging and wasting, weakness, sarcopenia, mitochondrial myopathy, or muscle rhabdomyolysis.

[0110] In one aspect, the present invention relates to a method of treating a neurological or neurodegenerative disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formulas (I) or (II). In some embodiments, the neurological or neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), as well as AIDS dementia complex, adrenoleukodystrophy, Alexander disease, Alpers disease, ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy (BSE), Canavan disease, corticobasal degeneration, Creutzfeldt-Jakob disease, and dementia with Lewy bodies. These include: Fatal Familial Insomnia, Frontotemporal Lobar Degeneration, Kennedy Disease, Krabbe Disease, Lyme Disease, Macado-Joseph Disease, Multiple Sclerosis, Multiple System Atrophy, Chorea Acanthocytosis, Niemann-Pick Disease, Pick's Disease, Primary Lateral Sclerosis, Progressive Supranuclear Palsy, Refsum Disease, Sandhoff Disease, Diffuse Myelinating Sclerosis, Spinocerebellar Ataxia, Subacute Combined Spinal Cord Degeneration, Tabes Dorsalis, Tay-Sachs Disease, Toxic Encephalopathy, Transmissible Spongiform Encephalopathy, and Wobble Hedgehog Syndrome.

[0111] In one aspect, the present invention relates to a method for treating reperfusion injury in a subject in need of treatment for reperfusion injury, the method comprising administering to the subject an effective amount of a compound of any one of formula (I) or (II).

[0112] Pharmaceutical composition, route of administration, and dosage In certain embodiments, the present invention is directed to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, the present invention relates to a pharmaceutical composition comprising a compound of any one of formula (I) or (II) and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the present invention and a pharmaceutically acceptable carrier.

[0113] In certain embodiments, the pharmaceutical composition of the present invention further comprises at least one additional pharmaceutically active agent other than the compound of the present invention. The at least one additional pharmaceutically active agent can be an agent useful for treating ischemia-reperfusion injury.

[0114] The pharmaceutical composition of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0115] As described above, "effective amount" means any amount sufficient to achieve the desired biological effect. By combining the teachings provided herein, selecting from among various active compounds, and weighting factors such as potential, relative bioavailability, patient body weight, severity of adverse side effects, and method of administration, an effective prophylactic or therapeutic treatment regimen can be planned that is effective in treating a particular subject without causing substantially undesirable toxicity. The effective amount for any particular use can vary depending on factors such as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can experimentally determine the effective amount of a particular compound of the invention and / or other therapeutic agents without undue experimentation. The maximum dose, i.e., the maximum safe dose according to some medical judgment, can be used. Multiple administrations per day may be contemplated to achieve an appropriate systemic amount of the compound. For example, an appropriate systemic amount can be determined by measuring the peak or sustained plasma concentration of the drug in the patient. "Dosage" and "dose" are used interchangeably herein.

[0116] The formulations of the present invention can be administered in a pharmaceutically acceptable solution which may routinely contain salts, buffers, preservatives, compatible carriers, adjuvants, and optionally other therapeutic components at pharmaceutically acceptable concentrations.

[0117] The pharmaceutical compositions of the present invention contain an effective amount of the compounds described herein and optionally a therapeutic agent contained in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers, diluents, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" means a natural or synthetic, organic or inorganic component which facilitates the application of the active ingredient. The components of the pharmaceutical composition can be mixed with the compounds of the present invention and with each other without interacting to substantially impair the desired pharmaceutical efficiency.

[0118] Other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent to those skilled in the art from the perspective of information known to them, and it will be understood by those skilled in the art that it is possible to make them without departing from the scope of the present invention, or any embodiment thereof. Although the present invention has been described in detail heretofore, the present invention will be more clearly understood by referring to the following examples. The examples are included herein for illustrative purposes only and are not intended to limit the present invention.

Examples

[0119] The present invention will be further described by the following examples. These do not limit the scope of the present invention described in the claims.

[0120] Example 1: Synthesis of an Exemplary Compound of the Present Invention Unless otherwise stated, all reactions were carried out under an inert atmosphere (nitrogen) using oven-dried glassware. Unless otherwise stated, all solvents were used as purchased. Commercially available reagents were used as purchased without further purification. Organic solutions were concentrated under vacuum using a Buchi rotary evaporator.

[0121] Thin layer chromatography was performed using fluorescently treated silica gel Merck Kieselgel 60 F254 (230 - 400 mesh), and visualization was carried out under ultraviolet light (254 and 366 nm) and / or by staining with an aqueous potassium permanganate solution. 1H NMR spectra in deuterated solvents were recorded at 400 MHz on a spectrometer manufactured by Bruker or at 60 MHz on an Nanalysis NMReady - 60PRO spectrometer using the remaining protic solvent as an internal standard. 13C NMR spectra in deuterated solvents were recorded at 100 MHz on a spectrometer manufactured by Bruker, with the central peak of the deuterated solvent as the internal standard. Chemical shifts (δ) were shown in parts per million (ppm) of 1000 million, and coupling constants (J) were shown in hertz (Hz) rounded to the nearest 0.1 Hz. The 1H NMR spectra were reported as δ / ppm from tetramethylsilane (multiplicity, number of protons, coupling constant J / Hz) on the low - magnetic - field side. 13 13C NMR spectra were reported as δ / ppm. TLC - MS data were obtained on an Advion Expression CMS integrated with a Plate Express TLC - plate reader. Medium - pressure liquid chromatography (MPLC) was carried out on a Biotage Isolera Four equipped with a UV detector and a fraction collector with an Interchim silica gel column.

[0122] 1. Synthesis of ((8 - (benzyloxy)-2,6,6,9 - tetramethyl - 6H - benzo[c]chromen - 3 - yl)oxy)(tert - butyl)dimethylsilane

Chemical formula

[0123] Scheme 1

Chemical formula

[0124] Step 1: Synthesis of Methyl 3-Hydroxy-4-methylbenzoate

Chem.

[0125] Step 2: Synthesis of Methyl 3-(Benzyloxy)-4-methylbenzoate

Chem.

[0126] Step 3: Synthesis of Methyl 5-(Benzyloxy)-2-bromo-4-methylbenzoate

Chem.

[0127] Step 4: Synthesis of 5-(Benzyloxy)-2-bromo-4-methylbenzoic Acid

Chem.

[0128] Step 5: Synthesis of 8-(benzyloxy)-3-hydroxy-2,9-dimethyl-6H-benzo[c]chromen-6-one

Chemical Structure

[0129] Step 6: Synthesis of 8-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-2,9-dimethyl-6H-benzo[c]chromen-6-one

Chemical Structure

[0130] Step 7: Synthesis of ((8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl)oxy)(tert-butyl)dimethylsilane

Chemical Structure

[0131] 2. Synthesis of 2,6,6,9-tetramethyl-8-(methylamino)-6H-benzo[c]chromen-3-ol (2a)

Chemical Structure

[0132] Scheme 2

Chemical Structure

[0133] Step 1: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-ol

Chemical Structure

[0134] Step 2: Synthesis of 3-3-((tert-butyldimethylsilyl)oxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-yl trifluoromethanesulfonate

Chemical formula

[0135] Step 3: Synthesis of 3-((tert-butyldimethylsilyl)oxy)-N,2,6,6,9-pentamethyl-6H-benzo[c]chromen-8-amine

Chemical formula

[0136] Step 4: Synthesis of 2,6,6,9-tetramethyl-8-(methylamino)-6H-benzo[c]chromen-3-ol (2a)

Chemical Structure

[0137] Synthesis of 3.8-amino-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-ol (2)

Chemical Structure

[0138] Scheme 3

Chemical Structure

[0139] Step 1: Synthesis of tert-butyl (3-((tert-butyldimethylsilyl)oxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-yl)carbamate

Chemical Structure

[0140] Step 2: Synthesis of 8-amino-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-ol (2)

Chemical formula

[0141] 4. Synthesis of 3-amino-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-ol (1)

Chemical formula

[0142] Scheme 4

Chemical formula

[0143] Step 1: Synthesis of 8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-ol

Chemical formula

[0144] Step 2: Synthesis of 8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate

Chemical Structure

[0145] Step 3: Synthesis of tert-butyl (8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl)carbamate

Chem.

[0146] The crude product was loaded onto silica and purified by FC eluent (EA / cyclohexane 0%→5%→10% 20%) to give tert-butyl (8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl)carbamate (60 mg, 0.13 mmol, 21%). R f 0.5 (EtOAc / cyclohexane 20%). MS (APCI+): m / z = 460.

[0147] Step 4: Synthesis of tert-butyl 8-(benzyloxy)-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-amine

Chemical formula

[0148] Step 5: Synthesis of 3-amino-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-ol (1)

Chemical Structure

[0149] Synthesis of 5,2,6,6,9 - tetramethyl - 3 - (methylamino) - 6H - benzo[c]chromen - 8 - ol (8)

Chem.

[0150] Scheme 5

Chem.

[0151] Step 1: Synthesis of tert - butyl (8 - (benzyloxy) - 2,6,6,9 - tetramethyl - 6H - benzo[c]chromen - 3 - yl)(methyl) carbamate

Chem.

[0152] Step 2: Synthesis of 8-(benzyloxy)-N,2,6,6,9-pentamethyl-6H-benzo[c]chromen-3-amine

Chemical Structure

[0153] Step 3: Synthesis of 2,6,6,9-tetramethyl-3-(methylamino)-6H-benzo[c]chromen-8-ol (8)

Chemical Structure

[0154] 6. Synthesis of 3-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-ol (6)

Chemical formula

[0155] Scheme 6

Chemical formula

[0156] Step 1: Synthesis of 8-(benzyloxy)-3-methoxy-2,9-dimethyl-6H-benzo[c]chromen-6-one

Chemical formula

[0157] Step 2: Synthesis of 8-(benzyloxy)-3-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chrome

Chemical formula

[0158] Step 3: Synthesis of 3-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-ol (6)

Chemical Structure

[0159] Synthesis of 7.3-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-amine (4)

Chemical Structure

[0160] Scheme 7

Chemical Structure

[0161] Project 1: Synthesis of 3-Methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-yl trifluoromethanesulfonate

Chem.

[0162] Project 2: Synthesis of tert-Butyl (3-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-yl) carbamate

Chem.

[0163] Step 3: Synthesis of 3-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-amine (4)

Chem.

[0164] Synthesis of 8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-ol (5)

Chemical formula

[0165] Scheme 8

Chemical formula

[0166] Step 1: Synthesis of 3-hydroxy-8-methoxy-2,9-dimethyl-6H-benzo[c]chromen-6-one

Chemical formula

[0167] Step 2: Synthesis of 3-(benzyloxy)-8-methoxy-2,9-dimethyl-6H-benzo[c]chromen-6-one

Chemical Structure

[0168] Step 3: Synthesis of 3-(benzyloxy)-8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromene [ka] 3-(Benzyloxy)-8-methoxy-2,9-dimethyl-6H-benzo[c]chromen-6-one (200 mg, 1 equiv., 555 μmol) was dissolved in THF (40.0 mg, 7.93 mL, 0.07 molar, 1 equiv., 555 μmol), and methylmagnesium bromide (304 mg, 851 μL, 3 molar, 4.6 equiv., 2.55 mmol) was added dropwise. Stirring at room temperature was continued overnight. The rm was poured into HCl (1 M), extracted twice with EtOAc, dried over sodium sulfate, and concentrated in vacuo to give the ring-opened intermediate (170 mg). The ring-opened intermediate was heated at 70 °C in the presence of PTSOH (10.6 mg, 0.1 equiv., 55.5 μmol) in toluene for 1 h. The toluene was evaporated, and the crude product was extracted with saturated NaHCO3 solution and dried over sodium sulfate to give 3-(benzyloxy)-8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromene (160 mg, 427 μmol, 77.0%) as a brownish oil. MS (APCI+): m / z = 375. 1 H NMR(400MHz,CDCl3)δ7.55-7.29(m,7H),6.65(s,1H),6.53(s,1H),5.06(s, 2H),3.86(s,3H),2.28(d,J=0.7Hz,3H),2.26(d,J=0.7Hz,3H),1.62(s,6H).

[0169] Step 4: Synthesis of 8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-ol (5) [Chemical formula] A suspension of 3-(benzyloxy)-8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromene (800 mg, 1 equivalent, 2.14 mmol) and palladium on carbon hydroxide (300 mg, 20 wt%, 0.2 equivalent, 427 μmol) in MeOH (5 mL) was hydrogenated under atmospheric pressure for 2 hours. The suspension was filtered through a Celite pad, and the solvent was evaporated under vacuum to obtain 8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-ol (600 mg, 2.11 mmol, 98.8%) as a white foam. R f 0.5 EA / hexane 10 / 90. 1 1H NMR (400 MHz, CDCl3) δ 14.11 (s, 1H), 12.22 (d, J = 0.9 Hz, 1H), 12.18 (s, 1H), 11.55 (s, 1H), 11.07 (s, 1H), 8.57 (s, 3H), 8.08 (s, 2H), 6.92 (d, J = 0.7 Hz, 3H), 6.86 (d, J = 0.7 Hz, 3H), 6.28 (s, 6H).

[0170] Synthesis of 9.8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-amine (3) [Chemical formula] 3 was prepared from 6 in 3 steps.

[0171] Step 1: Synthesis of 8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate [Chemical formula] Triflic anhydride (570 mg, 342 μL, 2.5 eq., 2.02 mmol) was added dropwise to a solution of 8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-ol (230 mg, 1 eq., 809 μmol) and pyridine (640 mg, 654 μL, 10 eq., 8.09 mmol) in DCM (10 mL) at 0 °C, and the mixture was stirred at room temperature for 3 h. The DCM was evaporated under vacuum, and the crude product was extracted with saturated NH4Cl solution and EA. The organic phase was washed once with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by FC eluent (EA / cyclohexane 0%→15%) to give 8-methoxy-6-oxo-6H-benzo[c]chromen-3-yl trifluoromethanesulfonate (550 mg, 1.47 mmol, 42%) as a white solid. R f 0.6 (EA / cyclohexane 40%) was used as the crude product.

[0172] Step 2: Synthesis of tert-butyl (8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl) carbamate

Chemical Structure

[0173] Step 3: Synthesis of 8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-amine (3)

Chemical formula

[0174] Synthesis of 10.7-amino-1,6,9,9-tetramethyl-9H-fluorene-2,4-diol (14a)

Chem.

[0175] Scheme 9

Chem.

[0176] BBr3 (235.2 mg, 938.7 μL, 1 molar concentration, 4 equivalents, 938.7 μmol) was added to a suspension of tert-butyl (3-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-yl) carbamate (90.00 mg, 1 equivalent, 234.7 μmol) in DCM (19.93 mg, 4.694 mL, 0.05 molar concentration, 1 equivalent, 234.7 μmol) at -78 °C over 5 minutes, and the mixture was warmed at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 solution, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, and the organic residue was passed through column chromatography biotage FCE (from tOAc / cyclohexane 0% to 20%, to obtain MeOH / DCM 0% to 20%), and 7-amino-1,6,9,9-tetramethyl-9H-fluorene-2,4-diol (20 mg, 74 μmol, 32%) was obtained as a white solid. Rf 0.5 (MeOH / DCM 10%). 1 1H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 8.89 (s, 1H), 7.40 (s, 1H), 6.62 (s, 1H), 6.32 (s, 1H), 4.78 (s, 2H), 2.16 (s, 3H), 2.06 (s, 3H), 1.39 (d, J = 2.1 Hz, 6H).

[0177] Synthesis of 11,2,6,6,9-tetramethyl-8-(methylamino)-6H-benzo[c]chromen-3-ol (14)

[0178] Scheme 10

Chemical Structure

[0179] BBr3 (100.8 mg, 402.5 μL, 1 molar concentration, 4 equivalents, 402.5 μmol) was added to a suspension of tert-butyl (3-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-8-yl)(methyl)carbamate (40.00 mg, 1 equivalent, 100.6 μmol) in DCM (8.546 mg, 1.006 mL, 0.1 molar concentration, 1 equivalent, 100.6 μmol) at -78 °C over 5 minutes, and the mixture was warmed to room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 solution, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, and the organic residue was passed through column chromatography biotage FCE (from tOAc / cyclohexane 0% to 20%, to obtain MeOH / DCM 0% to 20%), and 2,6,6,9-tetramethyl-8-(methylamino)-6H-benzo[c]chromen-3-ol (19 mg, 67 μmol, 67%) was obtained as a pale brown solid. R f 0.5 (MeOH / DCM 10%). 1 1H NMR (400 MHz, DMSO) δ 9.15 (s, 1H), 8.91 (s, 1H), 7.45 (s, 1H), 6.50 (s, 1H), 6.33 (s, 1H), 4.86 (s, 1H), 2.78 (s, 3H), 2.17 (s, 3H), 2.09 (s, 3H), 1.44 (s, 3H), 1.43 (s, 3H). MS (APCI+): m / z = 284.

[0180] Synthesis of 12.3,8,9,9-tetramethyl-7-(methylamino)-9H-fluorene-2,5-diol (15) Scheme 11

Chemical Structure

[0181] BBr3 (0.11 g, 0.45 mL, 1 molar concentration, 3 equivalents, 0.45 mmol) was added to a suspension of tert-butyl (8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl)(methyl)carbamate (60 mg, 1 equivalent, 0.15 mmol) in DCM (13 mg, 3.0 mL, 0.05 molar concentration, 1 equivalent, 0.15 mmol) at -78 °C over 2 minutes, and the mixture was warmed at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 solution, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, and the organic residue was passed through column chromatography biotage FCE (from tOAc / cyclohexane 0% to 20%, obtaining MeOH / DCM 0% to 20%), and 3,8,9,9-tetramethyl-7-(methylamino)-9H-fluorene-2,5-diol (20 mg, 71 μmol, 47%) was obtained as a white solid. R f 0.5 (MeOH / DCM 10%). 1 1H NMR (400 MHz, DMSO) δ 9.14 (s, 1H), 8.88 (s, 1H), 7.49 (s, 1H), 6.75 (s, 1H), 6.03 (s, 1H), 4.88 (s, 1H), 2.77 - 2.70 (m, 3H), 2.16 (s, 3H), 2.14 (s, 3H), 1.44 (s, 3H), 1.44 (s, 3H). MS (APCI+): m / z = 284.

[0182] Synthesis of 3,7-amino-3,8,9,9-tetramethyl-9H-fluorene-2,5-diol (13) Scheme 12

Chemical Structure

[0183] BBr3 (0.18 g, 0.73 mL, 1 molar concentration, 4 equivalents, 0.73 mmol) was added to a suspension of tert-butyl (8-methoxy-2,6,6,9-tetramethyl-6H-benzo[c]chromen-3-yl) carbamate (70 mg, 1 equivalent, 0.18 mmol) in DCM (13 mg, 3.0 mL, 0.05 molar concentration, 1 equivalent, 0.15 mmol) at -78 °C over 2 minutes, and the mixture was warmed at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 solution, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, and the organic residue was passed through column chromatography biotage FCE (from tOAc / cyclohexane 0%→20% to obtain MeOH / DCM 0%→20%), and 7-amino-3,8,9,9-tetramethyl-9H-fluorene-2,5-diol (20 mg, 71 μmol, 41%) was obtained as a white solid. R f 0.5 (MeOH / DCM 10%). 1 1H NMR (400 MHz, DMSO) δ 9.00 (s, 1H), 8.82 (s, 1H), 7.44 (s, 1H), 6.70 (s, 1H), 6.13 (s, 1H), 4.66 (s, 2H), 2.11 (d, J = 0.7 Hz, 3H), 2.09 (s, 3H), 1.39 (s, 6H). MS (APCI+): m / z = 270.

[0184] 14.2,9-Dimethylspiro[benzo[c]chromene-6,1'-cyclopropane]-3,8-diol

Chemical Structure

[0185] Scheme 13

Chemical Structure

[0186] Project 1: Synthesis of Methyl 4,4’-Bis(benzyloxy)-2’-fluoro-5,5’-dimethyl-[1,1’-biphenyl]-2-carboxylate

Chem.

[0187] Step 2: Synthesis of 1-(4,4'-bis(benzyloxy)-2'-fluoro-5,5'-dimethyl-[1,1'-biphenyl]-2-yl)cyclopropan-1-ol

Chem.

[0188] Step 3: Synthesis of 3,8-bis(benzyloxy)-2,9-dimethylspiro[benzo[c]chromene-6,1'-cyclopropane]

Chem.

[0189] Step 4: Synthesis of 2,9-dimethylspiro[benzo[c]chromene-6,1'-cyclopropane]-3,8-diol (7)

Chem.

[0190] 15. Synthesis of 2,9-dimethylspiro[benzo[c]chromene-6,1'-cyclopentane] (9)

Chem.

[0191] Scheme 14

Chem.

[0192] Step 1: Synthesis of 1-(4,4'-bis(benzyloxy)-2'-fluoro-5,5'-dimethyl-[1,1'-biphenyl]-2-yl)cyclopentan-1-ol [Chemistry] To magnesium anhydride (39.7 mg, 4.8 equivalents, 1.6322 mmol) in anhydrous diethyl ether (25.20 mg, 6.8007 mL, 0.05 molar concentration, 1 equivalent, 340.03 μmol), 1,4-dibromobutane (440.52 mg, 242.0 μL, 6 equivalents, 2.0402 mmol) was added at room temperature, and the reaction mixture was stirred for 2 hours. To this turbid solution, a solution of methyl 4,4'-bis(benzyloxy)-2'-fluoro-5,5'-dimethyl-[1,1'-biphenyl]-2-carboxylate (160.00 mg, 1 equivalent, 340.03 μmol) in anhydrous THF (1 mL) was added, and the reaction solution was stirred for 5 hours. TLC showed that some SM still remained (a polar product was formed. TLC MS showed M-18). The reaction solution was quenched with a saturated NH4Cl solution, extracted with EtOAc, dried over sodium sulfate, evaporated under vacuum to obtain a crude product of methyl 4,4'-bis(benzyloxy)-2'-fluoro-5,5'-dimethyl-[1,1'-biphenyl]-2-carboxylate (160.00 mg, 1 equivalent, 340.03 μmol), which was used in the next step without further purification. R f = 0.2 (EA / cyclohexane 10%).

[0193] Step 2: Synthesis of 3,8-bis(benzyloxy)-2,9-dimethylspiro[benzo[c]chromene-6,1'-cyclopentane] [Chemistry] In a round-bottomed flask, 1-(4,4'-bis(benzyloxy)-2'-fluoro-5,5'-dimethyl-[1,1'-biphenyl]-2-yl)cyclopentan-1-ol (100 mg, 1 equivalent, 201 μmol) was dissolved in anhydrous DMF (3 mL), heated to 120 °C, and then NaH (40 mg, 60 wt%, 5 equivalents, 1.01 mmol) was added portionwise. Stirring was continued at 120 °C for 10 minutes. The mixture was cooled to room temperature, saturated NaHCO3 solution was added, and the aqueous phase was extracted twice with EA. The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The crude product was loaded onto silica gel and purified with an FC eluent (EtOAc / Cyh 0%→10%) to obtain 3,8-bis(benzyloxy)-2,9-dimethylspiro[benzo[c]chromene-6,1'-cyclopentane] (60 mg, 0.13 mmol, 63%) as a white solid. R f 0.6 (EA / cyclohexane 10%). MS(APCI+): m / z = 476. 1 H NMR(400 MHz, CDCl3) δ 7.51 - 7.42 (m, 6H), 7.39 (td, J = 7.4, 1.7 Hz, 4H), 7.33 (td, J = 7.0, 1.8 Hz, 2H), 6.72 (s, 1H), 6.52 (s, 1H), 5.10 (s, 2H), 5.05 (s, 2H), 2.32 (d, J = 0.7 Hz, 3H), 2.27 (d, J = 0.9 Hz, 3H), 2.25 - 2.15 (m, 2H), 2.03 - 1.82 (m, 4H), 1.81 - 1.70 (m, 2H).

[0194] Step 3: Synthesis of 2,9-dimethylspiro[benzo[c]chromene-6,1'-cyclopentane]-3,8-diol (9)

Chemical Structure

[0195] Synthesis of 16.9-Ethyl-2-methylspiro[benzo[c]chromene-6,1'-cyclobutane]-3,8-diol (10) 11 was prepared from 1-(benzyloxy)-5-bromo-2-ethyl-4-iodobenzene and (4-(benzyloxy)-2-fluoro-5-methylphenyl)boronic acid (see Patent 1·amazentis) in 4 steps.

[0196] Scheme 15

Chemical formula

[0197] Project 1: Synthesis of 4,4'-bis(benzyloxy)-2-bromo-5-ethyl-2'-fluoro-5'-methyl-1,1'-biphenyl

Chemical formula

[0198] Project 2: Synthesis of 4,4'-bis(benzyloxy)-2-bromo-5,5'-diethyl-2'-fluoro-1,1'-biphenyl

Chemical formula

[0199] Step 3: Synthesis of 3,8-bis(benzyloxy)-9-ethyl-2-methylspiro[benzo[c]chromene-6,1'-cyclobutane]

Chemical Structure

[0200] Step 4: Synthesis of 9-ethyl-2-methylspiro[benzo[c]chromene-6,1'-cyclobutane]-3,8-diol (10)

Chemical Structure

[0201] Synthesis of 17.2-Ethyl-9-methylspiro[benzo[c]chromene-6,1'-cyclobutane]-3,8-diol (11)

Chemical Structure

[0202] Synthesis of 2-(4-(Benzyloxy)-5-ethyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Chem.

[0203] Scheme 16

Chem.

[0204] Step 1: Synthesis of 2-Ethyl-5-fluorophenol

Chem.

[0205] Engineering b-TFA (7.40 g, 5.00 mL, 10 equivalents, 64.9 mmol) was added dropwise at 0 °C to a solution of 5-fluoro-2-(1-hydroxyethyl)phenol (intermediate) (4 g) and triethylsilane (1.51 g, 2.07 mL, 2 equivalents, 13.0 mmol) in 15 mL of dichloromethane. The reaction mixture was stirred at room temperature for 15 hours. Next, the reaction mixture was evaporated under vacuum, and the crude product was extracted twice with saturated Na2CO3 solution and EtOAc. The organic solvent was dried over sodium sulfate and evaporated under vacuum. The crude product was purified by FC eluent EtOAc / cyclohexane (0%→7%) to obtain 5-bromo-2-ethylphenol (2.2 g, 11 mmol, 55%) as a yellowish oil. This was crystallized at room temperature. 1 1H NMR (400 MHz, CDCl3) δ 7.11 - 6.99 (m, 1H), 6.59 (td, J = 8.4, 2.5 Hz, 1H), 6.52 (dd, J = 9.9, 2.5 Hz, 1H), 4.09 (s, 1H), 2.59 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H).

[0206] Step 2: Synthesis of 2-(benzyloxy)-1-ethyl-4-fluorobenzene

Chemical formula

[0207] Step 3: Synthesis of 1-(Benzyloxy)-4-bromo-2-ethyl-5-fluorobenzene

Chem.

[0208] Step 4: Synthesis of 2-(4-(Benzyloxy)-5-ethyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Chem.

[0209] Synthesis of 18.2-Ethyl-9-methylspiro[benzo[c]chromene-6,1’-cyclobutane]-3,8-diol (11) Scheme 17

Chem.

[0210] Step 1: Synthesis of 4,4’-Bis(benzyloxy)-2-bromo-5’-ethyl-2’-fluoro-5-methyl-1,1’-biphenyl

Chem.

[0211] Step 2: Synthesis of 4,4'-bis(benzyloxy)-2-bromo-5'-ethyl-2'-fluoro-5-methyl-1,1'-biphenyl

Chemical Structure

[0212] Step 3: Synthesis of 3,8-bis(benzyloxy)-2-ethyl-9-methylspiro[benzo[c]chromene-6,1'-cyclobutane]

Chemical Structure

[0213] Step 4: Synthesis of 2-ethyl-9-methylspiro[benzo[c]chromen-6,1'-cyclobutane]-3,8-diol (11)

Chemical Structure

[0214] 19. Step 7: Synthesis of 2,9-diethylspiro[benzo[c]chromene-6,1'-cyclobutane]-3,8-diol (12) 13 was prepared in 4 steps from 1-(benzyloxy)-5-bromo-2-ethyl-4-iodobenzene and 2-(4-(benzyloxy)-5-ethyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0215] Scheme 18

Chemical Structure

[0216] Project 1: Synthesis of 4,4'-Bis(benzyloxy)-2-bromo-5,5'-diethyl-2'-fluoro-1,1'-biphenyl

Chem.

[0217] Project 2: Synthesis of 1-(4,4'-Bis(benzyloxy)-5,5'-diethyl-2'-fluoro-[1,1'-biphenyl]-2-yl)cyclobutan-1-ol

Chem.

[0218] Step 3: Synthesis of 3,8-bis(benzyloxy)-2,9-diethylspiro[benzo[c]chromene-6,1'-cyclobutane]

Chemical Structure

[0219] Step 4: Synthesis of 2,9-diethylspiro[benzo[c]chromene-6,1'-cyclobutane]-3,8-diol (12)

Chemical Structure

[0220] Synthesis of 20.1’,6’-Dimethylspiro[cyclopentane-1,9’-fluorene]-2’,4’,7’-triol (16) 16 was prepared in 4 steps from methyl 2-bromo-5-methoxy-4-methylbenzoate and methyl 5-(benzyloxy)-2-bromo-4-methylbenzoate, and 2-(4-(benzyloxy)-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0221] Scheme 19

Chemical Structure

[0222] Step 1: Synthesis of Methyl 4'-(Benzyloxy)-2'-fluoro-4-methoxy-5,5'-dimethyl-[1,1'-biphenyl]-2-carboxylate

Chem.

[0223] Step 2: Synthesis of 1-(4'-(Benzyloxy)-4-methoxy-3',5-dimethyl-[1,1'-biphenyl]-2-yl)cyclopentan-1-ol

Chem.

[0224] Step 3: Synthesis of 3-(benzyloxy)-8-methoxy-2,9-dimethylspiro[benzo[c]chromene-6,1'-cyclopentane] [Chemical formula] 1-(4'-(Benzyloxy)-2'-fluoro-4-methoxy-5,5'-dimethyl-[1,1'-biphenyl]-2-yl)cyclopentan-1-ol (120 mg, 1 equiv, 285 μmol) was dissolved in DMF (3 mL) and heated at 120 °C. NaH (57 mg, 60 wt%, 5 equiv, 1.43 mmol) was added portionwise at 120 °C and stirring was continued at 120 °C for 15 min. The mixture was cooled to room temperature and saturated NH4Cl solution was added, and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by FC eluent EtOAc / cyclohexane (0%→10%) to give 3-(benzyloxy)-8-methoxy-2,9-dimethylspiro[benzo[c]chromen-6,1'-cyclopentane] (40 mg, 0.10 mmol, 35%) as a white solid. R f 0.5. (EA / cyclohexane 10%). MS (APCI+): m / z = 401. 1 H NMR (400 MHz, CDCl3) δ 7.48 - 7.28 (m, 7H), 6.67 (s, 1H), 6.52 (s, 1H), 5.06 (s, 2H), 3.86 (d, J = 1.4 Hz, 3H), 2.26 (s, 6H), 2.22 (m, 2H), 2.03 - 1.88 (m, 4H), 1.82 (d, J = 7.6 Hz, 2H).

[0225] Step 4: Synthesis of 1',6'-dimethylspiro[cyclopentane-1,9'-fluorene]-2',4',7'-triol (16)

Chem.

[0226] Synthesis of 2,9-dicyclopropylspiro[benzo[c]chromene-6,1'-cyclobutane]-3,8-diol (17) 17 was prepared in 4 steps from 1-(benzyloxy)-5-bromo-2-cyclopropyl-4-iodobenzene and 2-(4-(benzyloxy)-5-cyclopropyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Chemical Structure

[0227] Project 1: Synthesis of 4,4'-bis(benzyloxy)-2-bromo-5,5'-dicyclopropyl-2'-fluoro-1,1'-biphenyl [Chemical formula] 1-(Benzyloxy)-5-bromo-2-cyclopropyl-4-iodobenzene (340 mg, 1 equivalent, 792 μmol) and 2-(4-(benzyloxy)-5-cyclopropyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (379 mg, 1.3 equivalents, 1.03 mmol) were dissolved in dioxane (10 mL). Bis-(triphenylphosphino)-palladium(II) chloride (55.6 mg, 0.1 equivalent, 79.2 μmol) was added, and the solution was degassed for 5 minutes. Then, sodium bicarbonate (200 mg, 2.38 mL, 1 molar concentration, 3 equivalents, 2.38 mmol) was dissolved in water (4 mL) and added dropwise. The mixture was heated at 90 °C for 2 hours. Water was added, and the mixture was extracted twice with EtOAc. The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by FC biotage (EtOAc / cyclohexane 0%→5%) to obtain 4,4'-bis(benzyloxy)-2-bromo-5,5'-dicyclopropyl-2'-fluoro-1,1'-biphenyl (330 mg, 607 μmol, 76.6%) as a colorless oil. Rf 0.3 EtOAc / cyclohexane 2%. 1 H NMR (400 MHz, CDCl3) δ 7.67 - 7.28 (m, 11H), 7.18 (s, 1H), 6.82 (dd, J = 5.7, 3.8 Hz, 1H), 6.75 (d, J = 3.9 Hz, 1H), 6.72 (d, J = 6.0 Hz, 4H), 2.28 - 2.09 (m, 2H), 0.92 (dddd, J = 7.4, 5.5, 4.4, 1.8 Hz, 4H), 0.69 - 0.60 (m, 4H). 19 F NMR (376 MHz, CDCl3) δ -116.77.

[0228] Step 2: Synthesis of 1-(4,4'-Bis(benzyloxy)-5,5'-dicyclopropyl-2'-fluoro-[1,1'-biphenyl]-2-yl)cyclobutan-1-ol

Chemical formula

[0229] Step 3: Synthesis of 3,8-Bis(benzyloxy)-2,9-dicyclopropylspiro[benzo[c]chromene-6,1'-cyclobutane] [Chemical formula]

[0230] NaH (18 mg, 60 wt%, 3 equiv., 0.45 mmol) was added to a solution of 1-(4,4'-bis(benzyloxy)-5,5'-dicyclopropyl-2'-fluoro-[1,1'-biphenyl]-2-yl)cyclobutan-1-ol (80 mg, 1 equiv., 0.15 mmol) in DMF (7 mL) at 110 °C. Stirring was continued at 110 °C for 15 minutes. TLC indicated that there was no more starting material.

[0231] The reaction mixture was cooled to room temperature. A 1 / 2 saturated solution of NaHCO3 was slowly added, and the aqueous phase was extracted twice with EtOAc. The combined organic phases were successively washed with water and brine, and dried over sodium sulfate. The solvent was evaporated, and the crude product was purified by FC eluent (EtOAc / cyclohexane 0%→5%) to give 3,8-bis(benzyloxy)-2,9-dicyclopropylspiro[benzo[c]chromene-6,1'-cyclobutane] (65 mg, 0.13 mmol, 84%). Rf 0.7 EtOAc / cyclohexane 5%. 1 H NMR (400 MHz, CDCl3) δ 7.53 - 7.31 (m, 10H), 7.13 (s, 1H), 7.09 (s, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 5.20 (s, 2H), 5.11 (s, 2H), 2.57 - 2.44 (m, 2H), 2.42 - 2.31 (m, 2H), 2.26 (ddd, J = 8.5, 5.3, 3.1 Hz, 1H), 2.15 (ddd, J = 8.5, 5.4, 3.1 Hz, 1H), 2.05 - 1.92 (m, 1H), 1.73 (dt, J = 11.4, 8.7 Hz, 1H), 1.05 - 0.82 (m, 4H), 0.80 - 0.61 (m, 4H).

[0232] Step 4: Synthesis of 2,9-dicyclopropylspiro[benzo[c]chromene-6,1'-cyclobutane]-3,8-diol [Chemical formula] 3,8-Bis(benzyloxy)-2,9-dicyclopropylspiro[benzo[c]chromene-6,1'-cyclobutane] (60.00 mg, 1.00 equiv, 116.6 μmol) was dissolved in MeOH (4 mL). Nickel(II) chloride hexahydrate (138.5 mg, 5 equiv, 582.9 μmol) was added. Sodium borohydride (88.20 mg, 82.51 μL, 20 equiv, 2.332 mmol) was added portionwise (evolution of gas). The mixture was filtered, and the crude product was loaded onto silica gel and purified by FC eluent MeOH / DCM (0%→10%) to give 2,9-dicyclopropylspiro[benzo[c]chromene-6,1'-cyclobutane]-3,8-diol (34 mg, 0.10 mmol, 87%) as a white solid. Rf 0.4 MeOH / DCM 4%. MS: m / z: [M+H] + 335. 1 H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 9.36 (s, 1H), 7.04 (s, 1H), 7.00 (s, 1H), 6.86 (s, 1H), 6.37 (s, 1H), 2.43 - 2.31 (m, 2H), 2.27 - 2.14 (m, 2H), 2.13 - 2.03 (m, 1H), 2.01 - 1.89 (m, 2H), 1.73 (dt, J = 11.0, 8.5 Hz, 1H), 0.91 - 0.83 (m, 2H), 0.83 - 0.78 (m, 2H), 0.77 - 0.73 (m, 2H), 0.73 - 0.64 (m, 2H).

[0233] Synthesis of 22.2-Cyclopropyl-9-methylspiro[benzo[c]chromene-6,1'-cyclobutane]-3,8-diol (18) 18 was prepared in 4 steps from 1-(benzyloxy)-5-bromo-4-iodo-2-methylbenzene and 2-(4-(benzyloxy)-5-cyclopropyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Chemical Structure

[0234] Synthesis of 1-(benzyloxy)-5-bromo-4-iodo-2-methylbenzene

Chem.

[0235] Step 1: Synthesis of 5-bromo-4-iodo-2-methylphenol

Chem.

[0236] Step 2: Synthesis of 1-(benzyloxy)-5-bromo-4-iodo-2-methylbenzene

Chem.

[0237] Synthesis of 2-(4-(benzyloxy)-5-cyclopropyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4-(Benzyloxy)-5-cyclopropyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was prepared in four steps from commercially available 2-bromo-5-fluorophenoline. [Chemical formula]

[0238] Step 1: Synthesis of 2-cyclopropyl-5-fluorophenol [Chemical formula] Phosphine, tricyclohexyl-(147 mg, 164 μL, 0.2 equiv, 524 μmol) and palladium(II) diacetate (58.8 mg, 0.1 equiv, 262 μmol) were suspended and stirred for 5 minutes in degassed toluene (241 mg, 26.2 mL, 0.1 M, 1 equiv, 2.62 mmol). 2-Bromo-5-fluorophenol (500 mg, 292 μL, 1 equiv, 2.62 mmol) and cyclopropylboronic acid (899 mg, 4 equiv, 10.5 mmol) were subsequently added successively to tribasic potassium phosphate (3.33 g, 1.30 mL, 6 equiv, 15.7 mmol) dissolved in water (47.2 mg, 13.1 mL, 0.2 M, 1 equiv, 2.62 mmol). The reaction mixture was stirred at 110 °C overnight. The reaction mixture was extracted with EA and saturated NH4Cl solution. The combined organic phases were dried over sodium sulfate and then concentrated under vacuum. The crude product was purified by FC biotage (EA / cyclohexane 0%→35%) to give 2-cyclopropyl-5-fluorophenol (340 mg, 2.23 mmol, 85.4%) as a pale brown oil. Rf 0.3 eluent EA / cyclohexane 10%. 1 1H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 6.75 (dd, J = 8.5, 6.8 Hz, 1H), 6.55 (dd, J = 10.8, 2.7 Hz, 1H), 6.48 (td, J = 8.6, 2.7 Hz, 1H), 1.98 (ddd, J = 8.5, 4.9, 3.1 Hz, 1H), 0.86 - 0.77 (m, 2H), 0.62 - 0.42 (m, 2H).

[0239] Step 2: Synthesis of 4-bromo-2-cyclopropyl-5-fluorophenol

Chem.

[0240] Step 3: Synthesis of 1-(benzyloxy)-4-bromo-2-cyclopropyl-5-fluorobenzene

Chem.

[0241] Step 4: Synthesis of 2-(4-(benzyloxy)-5-cyclopropyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Chemical Structure

[0242] Synthesis of 18 Step 1: Synthesis of 4,4’-bis(benzyloxy)-2-bromo-5’-cyclopropyl-2’-fluoro-5-methyl-1,1’-biphenyl

Chemical Structure

[0243] Step 2: Synthesis of 1-(4,4’-bis(benzyloxy)-5’-cyclopropyl-2’-fluoro-5-methyl-[1,1’-biphenyl]-2-yl)cyclobutan-1-ol

Chemical Structure

[0244] Step 3: Synthesis of 1-(4,4'-bis(benzyloxy)-5'-cyclopropyl-2'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)cyclobutan-1-ol

Chemical Structure

[0245] Step 4: Synthesis of 2-cyclopropyl-9-methylspiro[benzo[c]chromene-6,1'-cyclobutane]-3,8-diol

Chemical formula

[0246] Synthesis of 23.9-Cyclopropyl-2-methylspiro[benzo[c]chromene-6,1'-cyclobutane]-3,8-diol (19)

Chem.

Chem.

[0247] Synthesis of 1-(Benzyloxy)-5-bromo-2-cyclopropyl-4-iodobenzene

Chem.

Chem.

[0248] Step 1: Synthesis of 5-bromo-2-cyclopropylphenol

Chem.

[0249] Step 2: Synthesis of 5-Bromo-2-cyclopropyl-4-iodophenol

Chem.

[0250] Step 3: Synthesis of 1-(Benzyloxy)-5-bromo-2-cyclopropyl-4-iodobenzene

Chem.

[0251] Synthesis of 19 Step 1: Synthesis of 4,4'-bis(benzyloxy)-2-bromo-5-cyclopropyl-2'-fluoro-5'-methyl-1,1'-biphenyl

Chemical Structure

[0252] Project 2: Synthesis of 1-(4,4'-bis(benzyloxy)-5-cyclopropyl-2'-fluoro-5'-methyl-[1,1'-biphenyl]-2-yl)cyclobutan-1-ol

Chemical Structure

[0253] Step 3: Synthesis of 3,8 - bis(benzyloxy) - 9 - cyclopropyl - 2 - methylspiro[benzo[c]chromene - 6,1'-cyclobutane]

Chemical Structure

[0254] Step 4: Synthesis of 9 - cyclopropyl - 2 - methylspiro[benzo[c]chromene - 6,1'-cyclobutane]-3,8 - diol

Chemical Structure

[0255] 3,8 - Bis(benzyloxy)-9 - cyclopropyl - 2 - methylspiro[benzo[c]chromene - 6,1'-cyclobutane] (40.00 mg, 1.00 equivalent, 81.86 μmol) was dissolved in MeOH (4 mL). Nickel(II) chloride hexahydrate (97.28 mg, 5 equivalents, 409.3 μmol) was added. Sodium borohydride (61.94 mg, 57.94 μL, 2 times the equivalent amount, 20 equivalents, 1.637 mmol) was added in small portions (evolution of gas). The mixture was filtered, and the crude product was loaded onto silica gel and purified by FC eluent MeOH / DCM (0% → 20%) to give 9 - cyclopropyl - 2 - methylspiro[benzo[c]chromene - 6,1'-cyclobutane]-3,8 - diol (10 mg, 32 μmol, 40%) as a white solid. Rf 0.4 MeOH / DCM 4%. MS: m / z: [M + H] + 309. 11H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 9.32 (s, 1H), 7.42 (s, 1H), 7.04 (s, 1H), 6.85 (s, 1H), 6.38 (s, 1H), 2.44 - 2.35 (m, 2H), 2.26 - 2.17 (m, 2H), 2.16 (d, J = 0.7 Hz, 3H), 2.05 - 1.86 (m, 2H), 1.79 - 1.66 (m, 1H), 0.91 - 0.75 (m, 2H), 0.67 (dt, J = 5.5, 2.9 Hz, 2H).

[0256] Example 2: Anti-ferroptosis assay The anti-ferroptosis activity of the compound was measured by measuring cell viability after co-treatment with the ferroptosis inducer 1S,3R-RSL 3 (CAS number: 1219810-16-8; hereinafter RSL3). Cell viability was measured using the CellTiter-Glo® 2.0 assay. The assay provides a homogeneous method for measuring the number of viable cells in the culture medium by quantifying the amount of ATP present, which indicates the presence of metabolically active cells.

[0257] On day 1, C2C12 myoblasts (ATCC #CRL-1772) were seeded at 1,500 cells / well in normal DMEM medium in white-walled, clear-bottom 96-well plates, and 10% heat-inactivated fetal bovine serum (FBS) and penicillin-streptomycin (100 U / mL) were added. On day 2, the cells were treated with 0.1% DMSO (vehicle, n = 8 per plate), RSL3 at 1.25 μM as a positive control (n = 8 per plate), and the test compound in a 5-point concentration-response curve starting at 50 μM with 2-fold dilutions (n = 4 per plate and per concentration) in the presence or absence of RSL3 (1.25 μM). On day 3, CellTiter-Glo reagent (2× stock solution) (Promega) was added, mixed on an orbital shaker for 2 minutes, incubated at room temperature in the dark for 10 minutes, and then luminescence was measured using a FLUOstar OPTIMA reader (0.25 seconds). The percentage efficacy (PE) for each test compound concentration corresponded to rescue in cell viability compared to RSL3 (1.25 μM) only and test compound concentration only.

Number

[0258] A score of 0% means the compound has no anti-ferroptosis activity. A score of 100% means the compound completely rescues cell viability and has the maximum possible anti-ferroptosis activity.

[0259] The concentration (EC50) at which the compound shows 50% efficacy against ferroptosis-induced cell death was calculated using GraphPad Prism v9.4.0. Non-linear regression of log10-transformed concentration (log(agonist) vs response - variable slope (four parameters)) with constraints of lower = 0 and upper = 100 was used. pEC 50 values correspond to the 50 -log10 of the EC

[0260] Incorporation by reference All U.S. applications cited in this specification, as well as U.S. and PCT patent application publications, are hereby incorporated by reference into this specification.

[0261] Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. Compound of formula (I): 【Chemistry 1】 [In the formula, Y １ and Y ２ Each of these is either alkyl, or they combine with the carbon to which they are bonded to form an unsubstituted or substituted spirocycloalkyl group. R １ , R ４ , R ５ , and R ８ It is selected independently of -H and halogen, R ２ and R ７ are independently selected from -H, -OH, -OAc, -NH ２ , halogen, -CN, -CF ３ , -CO ２ H, -NO ２ , -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, alkyl-R ９ , alkenyl-R ９ , alkynyl-R ９ , -OR １０ , -NHR １０ , -NR １１ C(O)R １２ , -C(O)NR １１ R １２ , and -NR １１ SO ２ R １２ and are independently selected from R ３ and R ６ It is independently selected from alkyl and cycloalkyl groups. Each has an R ９ OH, NH ２ O-alkyl, O-alkyl-O-alkyl, alkylamino, NHC(O)-alkyl, N(CH ３ ) C(O)-alkyl, NHSO ２ - Alkyl, N(CH ３ ) SO ２ - Independently selected from alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, R １０ Alkyl, hydroxyalkyl, aminoalkyl, alkyl-O-alkyl, alkyl-O-alkyl-OH, alkyl-O-alkyl-O-alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, alkyl-heterocycloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Reuters ３ H, SO ２ - Alkyl and SO ２ - Selected from haloalkyl groups, Each has an R １１ is selected from H and alkyl, Each has an R １２ These are selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, O-alkyl, aminoalkyl, arylalkyl, heteroarylalkyl, alkyl-cycloalkyl, and alkyl-heterocycloalkyl. However, R １ , R ４ , R ５ , and R ８ Each of these is -H, and R ２ and R ７ Each of them is -OH, and R ３ and R ６ CH ３ If Y １ and Y ２ These are not -Me, and they do not form unsubstituted spirocyclobutyl with the carbon atoms to which they are bonded. or a pharmaceutically acceptable salt thereof.

2. Y １ and Y ２ Each is independent of C １ -C ４ The compound according to claim 1, wherein Y1 and Y2 are alkyl, or Y1 and Y2 combine with the carbons to which they are bonded to form an unsubstituted spirocycloalkyl group.

3. Y １ and Y ２ These are, respectively, -CH ３ The compound according to claim 1, wherein Y1 and Y2, together with the carbons to which they are bonded, form an unsubstituted spirocyclopropyl, cyclobutyl, or cyclopentyl.

4. R ３ and R ６ Each is independent of C １ -C ４ Alkyl, or R3 and R6 are each independently a C3-C5 cycloalkyl, or The compound according to claim 1, wherein one of R3 and R6 is a C1-C4 alkyl group, and the other of R3 and R6 is a C3-C5 cycloalkyl group.

5. R ３ and R ６ Each is independent of the other, -CH ３ and -CH ２ CH ３ Selected from, R3 and R6 are cyclopropyl, or The compound according to claim 1, wherein one of R3 and R6 is -CH3 and the other of R3 and R6 is cyclopropyl.

6. The following structure: 【Chemistry 2】 The compound according to claim 1, having a structure selected from the above.

7. R ２ and R ７ is -OH, -NH ２ , alkylamino, and -OR １０ A compound according to claim 1, independently selected from the above.

8. R ２ and R ７ Each of these is an OH, or R2 is -OH, and R7 is -OCH3, or R7 is -OH, and R2 is -OCH3, or R2 is selected from -NH2, -NHCH3, and -NH(CH3)2, and R7 is OH, or The compound according to claim 1, wherein R7 is selected from -NH2, -NHCH3, and -NH(CH3)2, and R2 is OH.

9. R １ , R ４ , R ５ , and R ８ The compound according to claim 7, wherein each of these is -H.

10. The following structure: 【Transformation 3】 The compound according to claim 1, having a structure selected from the above.

11. Compound of formula (II): 【Chemistry 4】 [In the formula, X １ and X ２ Each of these is either alkyl, or they combine with the carbon to which they are bonded to form an unsubstituted or substituted spirocycloalkyl group. R １ ', R ４ ', R ５ ', and R ８ ' is -H, -OH, -NH ２ Independently selected from alkyl and halogen, R ２ ’, R ３ ’, R ６ ’, and R ７ ’ are independently selected from -H, -OH, -OAc, -NH ２ , halogen, -CN, -CF ３ , -CO ２ H, -NO ２ , -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylamino, and -OR ８ ’ and are independently selected, R ８ ' is selected from alkyl, hydroxyalkyl, aminoalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. or a pharmaceutically acceptable salt thereof.

12. X １ and X ２ Each is independent of C １ -C ４ The compound according to claim 11, wherein X1 and X2 are alkyl, or X1 and X2 combine with the carbons to which they are bonded to form an unsubstituted spirocycloalkyl group.

13. X １ and X ２ each is, -CH ３ or X1 and X2, together with the carbon to which they are attached, combine to form an unsubstituted spirocyclopropyl, cyclobutyl, or cyclopentyl, the compound of claim 11.

14. The following structure: 【Transformation 5】 The compound according to claim 11, having a structure selected from the above.

15. R ２ 'and R ７ ' is -OH, -NH ２ , alkylamino, and -OR １０ A compound according to claim 11, independently selected from the above.

16. R ２ 'and R ７ Each of the ' is OH, or R2' is -OH, and R7' is -OCH3, or R7' is -OH, and R2' is -OCH3, or R2' is selected from -NH2, -NHCH3, and -NH(CH3)2, and R7' is OH, or The compound according to claim 11, wherein R7' is selected from -NH2, -NHCH3, and -NH(CH3)2, and R2' is OH.

17. R ３ 'and R ６ 'Each of these is independently -H or C １ -C ４ Alkyl and / or The compound according to claim 11, wherein R1' and R8' are each independently -H or C1-C4 alkyl.

18. R ３ 'and R ６ ' are independent of each other, -H or -CH ３ is, and / or R1' and R8' are independently -H or -CH3, and / or The compound according to claim 11, wherein R4' and R5' are each independently -H or -OH.

19. The following structure: 【Transformation 6】 The compound according to claim 11, having a structure selected from the above.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable carrier.

21. A composition for inhibiting ferroptosis, comprising a compound according to any one of claims 1 to 19.

22. A composition for treating an inflammatory disease, neurological disease, or neurodegenerative disease that is at least partially ferroptosis-mediated, comprising a compound according to any one of claims 1 to 19.

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