Compositions and methods for inducing ferroptosis

Abstract

The disclosure provides compounds, e.g., compounds of Formula I, and their use in treating medical diseases or disorders, such as cancer. The compounds are contemplated to be modulators of, e.g., inducers of, ferroptosis.

Description

COMPOSITIONS AND METHODS FOR INDUCING FERROPTOSISCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 550,701, filed on February 7, 2024; the content of which is hereby incorporated by reference herein in its entirety.BACKGROUND

[0002] Diseases such as cancer, autoimmune diseases, and fibrosis manifest when cells in the body exhibit uncontrolled, abnormal cell growth and proliferation. In order to treat hyperproliferative diseases, the standard of care therapies induce cell death by a cellular process called apoptosis. The apoptosis pathway is engaged by many common types of anticancer therapies and ionizing radiation, which contributes to the regression of tumors or the toxic side effects of treatment.

[0003] Given the ability for hyperproliferative cells to resist cell death by current apoptosis-driven therapeutics, there is a need for the development of new methods, compounds, and compositions of and for inducing cell death in hyperproliferative cells.SUMMARY

[0004] The disclosure is directed, in part, to compounds that modulate, for example, induce, ferroptosis in a cell, a tissue, or a tumor in a patient or subject. Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier or excipient. In some embodiments, the present disclosure provides a method of treating a disease or disorder amenable to modulation, e.g., induction, of ferroptosis. In some embodiments, the disease or disorder is a cancer.

[0005] For example, disclosed herein is a compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is NR4or O;R1is selected from the group consisting of -COOH, a 5-membered heteroaryl, a 5- membered heterocyclyl, -C(O)ORn, -C(O)NR12R13, -S(O)2Rn, -S(O)2NR12R13, -CF3, -C(=N- ORN1)NHRN1, and -C(=NH)NHRN1; wherein the heteroaryl or heterocyclyl bears at least two ring heteroatoms each independently selected from the group consisting of S, O, N, and NRN1; and wherein the heterocyclyl or heteroaryl may optionally be substituted on an available carbon atom with one or more substituents each independently selected from R14;R2is selected from the group consisting of -N(RN2)2, -CH2(RN2)2, and -OH;RN1is selected from the group consisting of hydrogen and Ci-Csalkyl;RN2is selected from the group consisting of hydrogen, Ci-Cealkyl, -C(O)Ci-Cealkyl, and -C(O)OCi-C6alkyl;R11is selected from the group consisting of Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Cs-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocyclyl; wherein R11may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, - C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, and -O(C=O)OCi-C6alkyl;R12is selected from the group consisting of hydrogen and Ci-Csalkyl;R13is selected from the group consisting of Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Cs-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocyclyl; wherein R13may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, - C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, and -O(C=O)OCi-C6alkyl; orR12and R13, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl which may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R14is independently selected for each occurrence from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Csalkyl, and Ci-Csalkoxy;L is selected from the group consisting of -C(O)-O-Ci-C3alkylene-, -Ci-Csalkylene- O-C(O)-, -O-Ci-Csalkylene-, and -Ci-Csalkylene-O-; wherein Ci-Csalkylene may be interrupted in the alkylene chain by -C(O)NRa- or -NRaC(O)-; and wherein Ci-Csalkylene may optionally be substituted with one or two substituents each independently selected from - CF3and -NRaRb;R3is Cs-C27alkyl optionally substituted with one or more halogens;R4is selected from the group consisting of hydrogen and Ci-Csalkyl;Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci-Cealkyl, wherein Ci-Cealkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci-Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy; and t is 0, 1 or 2.

[0006] Also disclosed herein is a compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein R1is Cs-Ci9alkyl optionally substituted with one or more halogens.

[0007] Also disclosed herein are pharmaceutical compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions comprise at least one additional therapeutic agent.

[0008] Further disclosed herein are methods of modulating, e.g., inducing, ferroptosis in a cell, tissue, or tumor, or a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0009] For example, disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit from induction of ferroptosis in a cell, tissue, or tumor, or a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0010] In some embodiments, the methods described herein may be useful to treat cancers including, but not limited to, a carcinoma, a sarcoma, or a melanoma. In some embodiments, the cancer may be, for example, a clear cell renal carcinoma, a non-clear cell renal carcinoma, or a liver carcinoma. In some embodiments, the methods described herein may be useful to treat, for example, a fibrosis or a kidney disorder.DETAILED DESCRIPTION

[0011] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Definitions

[0012] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0013] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci-ealkyl, Ci-4alkyl, and Ci-3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -butyl, 3-methyl-2-butyl, 2-methyl-l-pentyl, 3-methyl-l- pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1 -butyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0014] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms,referred to herein as Ci-Csalkenyl, C2-Cealkenyl, and C3-C4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0015] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, and Cs-ealkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0016] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as Ci-Csalkoxy, Ci-Cealkoxy, and C2-Cealkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[0017] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g, bicyclic or tricyclic) 4n+2 aromatic ring system (e.g, having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cuaryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from Ci-Cs alkyl, Ci-Cs haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-Cs alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SChalkyl, Saryl, SOaryl, SCharyl; or R56and R57may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60and R61are each independently hydrogen, Ci-Cs alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cio aryl, substituted Ce-Cio aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0018] The term “carbonyl” as used herein refers to the radical -C(O)-.

[0019] The term “cyano” as used herein refers to the radical -CN.

[0020] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as Cs-Ciocycloalkyl, Cs-ecycloalkyl or C4-6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[0021] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

[0022] The terms “haloalkyl” as used herein refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms substituted with a halogen (i.e., Cl, F, Br and I), referred to herein as Ci-ehaloalkyl, Ci-4 haloalkyl, and Ci-3haloalkyl, respectively.

[0023] The term “hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g.,heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0024] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.

[0025] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art- recognized and refer to saturated or partially unsaturated 3-12 membered ring structures, for example, 4-10 membered ring structures, for example, 4-8 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur, wherein the sulfur atom may be oxidized to SO or SO2.. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. Further examples include Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyi, piperidonyl, 4-piperidinonyl, quinudidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), and azaspiroheptanyls. In some embodiments, the heterocycle is a spiro heterocycle. In some embodiments, the heterocycle is a bridged heterocycle. "Spiro heterocyclyl," or “spiro heterocycle” refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is an integer of 0 to 2) as ring atoms.

[0026] The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH.

[0027] The term “oxo” as used herein refers to the radical =0.

[0028] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0029] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0030] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0031] “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). “Modulation” includes antagonism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signal transduction, functionally selective agonism, partial antagonism and / or partial agonism.

[0032] In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect.

[0033] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, -toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0034] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0035] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol — denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carboncarbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0036] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans,” where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0037] Compounds described herein may be depicted to show stereochemistry using hashed or wedged bonds as shown below. For compounds with a stereogenic atom, when only one substituent is hashed or wedged, a 4thsubstituent can be interpreted to have the opposite orientation in space. For compounds with a stereogenic sulfoximine sulfur atom, when two substituents are both hashed or both wedged, the third and fourth substituents can be interpreted to have the opposite orientation in space.

[0038] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also beresolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0039] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0040] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0041] Certain isotopically labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0042] The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-s)alkyl, (C2- i2)alkylcarbonyloxymethyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-l-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxy carbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 -(alkoxy carbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3 -phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-2)alkylamino(C2-3)alkyl (such as P- dimethylaminoethyl), carbamoyl-(Ci-2)alkyl, N,N-di(Ci-2)alkylcarbamoyl-(Ci-2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3)alkyl.

[0043] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-6)alkylcarbonyloxym ethyl, l-((Ci-6)alkylcarbonyloxy)ethyl, 1 -methyl- l-((Ci-6)alkylcarbonyloxy)ethyl (Ci-6)alkoxycarbonyloxymethyl, N-(Ci- 6)alkoxycarbonylaminomethyl, succinoyl, (Ci-e)alkylcarbonyl, a-amino(Ci-4)alkylcarbonyl, arylalkylcarbonyl and a-aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a- aminoalkylcarbonyl, where each a -aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(Ci-e)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0044] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N- alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate abioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio, et al., Molecules 2008, 13, 519 and references therein.

[0045] Throughout this disclosure, various embodiments can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of any embodiments. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range to the tenth of the unit of the lower limit unless the context clearly dictates otherwise. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual values within that range, for example, 1.1, 2, 2.3, 5, and 5.9. This applies regardless of the breadth of the range. The upper and lower limits of these intervening ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, unless the context clearly dictates otherwise.

[0046] Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. “About” can be understood as within plus or minus: 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.” Where particular values are described in the application and claims, unless otherwise stated, the term “about” is implicit and in this context means within an acceptable error range for the particular value.

[0047] The term “anti-cancer agent” or “chemotherapeutic agent” and its grammatical equivalents as used herein refer to an agent that is capable of killing cells that divide rapidly (e.g., cancer cells), preventing the cells that divide rapidly from further dividing, of slowing the division of rapidly dividing cells. Exemplary anti-cancer agents provided herein can include ferroptosis inducing agents, can be used be used in combination with one or more additional ferroptosis inducing agents, can be used in combination with an iron-dependent cell death inducing agent, and / or can be used in combination with a second therapeutic agentor second active agent. The second therapeutic agent or second active agent can be in the form of a prodrug. The second therapeutic agent or second active agent can be in the form of a pharmaceutically acceptable salt. The second therapeutic agent or second active agent can be an alkylating agent such as a nitrogen mustard, can be chlorouracil, cyclophosphamide, isosfamide, melphalan, or bisulfan; a nitrosourea, which can be, for example, streptozocin, carmustine, or lomustine; an alkyl sulfonate such as busulfan; a triazine, such as dacarbazine or temozolomide; or an ethylenimine, such as thiotepa- or altretamine. The second therapeutic agent or second active agent can be an antimetabolite, which can be a purine antagonist, a pyrimidine antagonist or a folate antagonist, for example, 5-fluorouracil, 6-mercaptopurine, capecitabine, cladribine, or clofarabine. The second therapeutic agent or second active agent can be an anti-tumor antibiotic. The second therapeutic or second active agent can be a mitotic inhibitor. The second therapeutic or second active agent can be a corticosteroid. The second therapeutic agent or second active agent can be a plant alkaloid, for example, actinomycin D, a doxorubicin, or a mitomycin, such as mitomycin C. The second therapeutic agent or second active agent can be an antitumor antibiotic, for example, a doxorubicin, a mitoxantrone, or a bleomycin. The second therapeutic or the second active agent can be, for example, mechlorethamine, leucovorin, methotrexate, mercaptopurine, busulfan, chlorambucil, cyclophosphamide, vincristine, dactinomycin, vinblastine, thioguanine, procarbazine, floxuridine, fluorouracil, mitotane, bleomycin, doxorubicin, dacarbazine, lomustine, carmustine, cisplatin, asparaginase, streptozocin etoposide, ifosfamide, carboplatin, altretamine, fludarabine, pentostatin, paclitaxel, melphalan, teniposide, cladribine, vinorelbine, pegaspargase, thiotepa, docetaxel, gemcitabine, irinotecan, toptecan, idarubicin, capecitabine, daunorubicin, valrubicin, temozolomide, cytarabine, epirubicin, arsenic trioxide, mitomycin, oxaliplatin, pemetrexed disodium, clofarabine, nelarabine, ixabepilone, bendamustine hydrochloride, paratrexate, carbazitazel, erbulin mesylate, asparaginaseerwinia chrsanthemi, omacetaxine mepesuccinate, radium 223 dichloride, fluoxymesterone, methyltestosterone, tamoxifen, tamoxifen citrate, estramustine, interferon alpha 2b (recombinant), gosrelin, flutamide, aldeslukin, bicalutamide, anastrozole, porfimer, nilutamide, imiquimod, letrazole, rituximab. Toremifene, thalidomide, trastuzmad, alitretinonin, bexarotene, denileukin diftitox, exemestane, gemfluzumab ozogamicin, exemestane, gemtuzumab ozogamicin, triptorelin, alemtuzamub, imatinib, imatinim mesylate, peginterferon alpha 2-B, fulvestrant, iron, an iron comprising nanoparticle, ibritumomab tiuxetan, leuprolide, leuprolide acetate, abarelix, bortezomib, genfitinib, tositumomab and iodine 1 131, tositumomab, bevacizumab,cetuximab, erlotinib, erlotinib hydrochloride, lenalidomide, sorafenib, sorafenib tosylate, dasatinib, decitabine, panitumamab, sunitinib, sunitinib malate, vorinostat, lapatinib, lapatinib ditosylate, nilotinib, temsirolimus, degarelix, everolimus, ofatumumab, pazopanib, pazopanib hydrochloride, romidepsin, denosumab, hydroxyurea, spuleucel-T, abiraterone, abiratone acetate, brentuximab vedotin, crizotinib, iplimumab, ruxolitinib, ruxolitinib phosphate, vandetanib, vemurafenib, pertuzumab, axitinib, bosutinib, carbozantinib, carfilzomib, enzalutamide, ponatinib, ponatinib hydrochloride, regorafenib, vismodegrib, ziv-afhbercept, dabrafenib, trametinib, obinutuzumab, adotrastuzumab emtansine, afatinib, ibrutinib, pomalidomide, idelalisib, belinostat, ceritinib, perbrolizumab, ramucirumab, lanreotide, blinatumomab, nivolumab, olaparib, a checkpoint inhibitor, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, a chimeric antigen receptor T cell therapy (CAR-T cell therapy), CAR natural killer cell therapy (CAR NK therapy), tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel, or ciltacabtegene autoleucel.

[0048] The term “cancer” and its grammatical equivalents as used herein refer to a hyperproliferation of cells whose unique trait — loss of normal controls — results in unregulated growth, lack of differentiation, local tissue invasion, and metastasis. With respect to the methods provided herein, the cancer can be any cancer, including but not limited to any one of: acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bladder cancer, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, rectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vulva, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, esophageal cancer, cervical cancer, fibrosarcoma, gastrointestinal cancer, Hodgkin lymphoma, hypopharynx cancer, kidney cancer, larynx cancer, leukemia, liquid tumors, liver cancer, lung cancer, lymphoma, malignant mesothelioma, mastocytoma, melanoma, dedifferentiated melanoma, multiple myeloma, nasopharynx cancer, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, peritoneum, omentum, and mesentery cancer, pharynx cancer, prostate cancer, colorectal cancer, renal cancer, a carcinoma, renal carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, skin cancer, small intestine cancer, soft tissue cancer, solid tumors, stomach cancer, testicular cancer, thyroid cancer, ureter cancer, and / or urinary bladder cancer. As used herein, the term “tumor” refers to an abnormal growth of cells or tissues,e.g., of malignant type or benign type. Any cancer or neoplastic condition, tumor, or population of cancerous cells can be SWI / SNF deficient. In some instances, any cancer or neoplastic condition, tumor, or population of cancerous cells is not SWI / SNF deficient.

[0049] The term “drug resistant cancer” and its grammatical equivalents as used herein refers to a cancer that does not respond, or exhibits a decreased response to, one or more chemotherapeutic agents.

[0050] The term “expression” and its grammatical equivalents as used herein refers to the biosynthesis of a gene product. For example, in the case of a structural gene, expression involves transcription of the structural gene into mRNA and the translation of mRNA into one or more polypeptides.

[0051] The term “zzz vitro" and its grammatical equivalents as used herein refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc., rather than within a multi-cellular organism.

[0052] The term “zzz vzvo” and its grammatical equivalents as used herein refers to events that occur within a multi-cellular organism, such as a non-human animal.

[0053] The term “iron-dependent cell death agent” and its grammatical equivalents as used herein refers to an agent which induces, promotes or activates cell death mediated by iron. In some cases, within the disclosure, the term “iron-dependent cell death agent” is used interchangeably with ferroptosis-inducing agent. The term “normal cells” and its grammatical equivalents as used herein refers to cells that undergo controlled cell division, controlled activation, or quiescent cells.

[0054] The term “hyperproliferative cells” and its grammatical equivalents as used herein refers to cells characterized by unwanted cell proliferation, or abnormally high rate or sustained cell division, unrelated or uncoordinated with that of surrounding normal tissue. The term “normal cells” and its grammatical equivalents as used herein refers to cells that undergo controlled cell division, controlled activation, or quiescent cells.Ferroptosis

[0055] The term “ferroptosis” refers to a form of cell death involving generation of reactive oxygen species mediated by iron, and characterized by, in part, lipid peroxidation. The term “ferroptosis-inducing agent” or “ferroptosis activator” or “ferroptosis inducer” or“ferroptosis-inducing compound” or “ferroptosis modulator” refers to an agent which promotes or activates or modulates ferroptosis in a cell.

[0056] Cell death is a cellular process involved in development, cellular homeostasis, and prevention of proliferative diseases such as cancer. Programmed cell death can take different forms, such as apoptosis, mitotic catastrophe, necrosis, senescence, and autophagy. While each of these processes ultimately lead to cell death, the pathways and mechanisms appear to be unique, both at the molecular and cellular level.

[0057] Ferroptosis is a non-apoptotic, oxidative form of regulated cell death involving lipid hydroperoxides and the accumulation of lipid peroxide at the cellular plasma membrane. Cells undergoing ferroptosis do not display the cellular characteristics or functions associated with apoptosis, the canonical form of cell death. Examples of apoptotic cell features include, e.g., mitochondrial cytochrome c release, caspase activation, and chromatin fragmentation. Ferroptosis is also characterized by increased levels of intracellular reactive oxygen species (ROS) which can be prevented by iron chelation and genetic inhibition of cellular iron uptake. Addition of iron, but not by other divalent transition metal ions, can potentiate ferroptosis signaling in cells.

[0058] Cellular components implicated in and regulating ferroptosis include, among others, cysteine-glutamate antiporter (system Xc), glutathione peroxidase 4 (GPX4), p53, cargo receptor NCOA4, glutathione synthetase (GSH), glutamate-cysteine ligase (GCL). The inactivation or inhibition of some of these molecules, for example, system Xc, GPX4, or glutathione synthetase leads to iron-dependent cell death or ferroptosis.

[0059] Hyperproliferative cells in a drug -resistant state, such as, e.g., drug resistant cancer cells have been found to exhibit a dysregulation in apoptosis cellular pathways. Surprisingly, drug-resistance to apoptotic agents by hyperproliferative cells can have an enhanced ability to undergo ferroptosis. Apoptosis-resistant cells can be killed via ferroptosis induction due to their “flammable” ferroptosis-sensitive state.Compounds

[0060] The disclosure is directed, in part, to compounds that modulate, for example, induce, ferroptosis in a cell, a tissue, or a tumor in a patient or subject. In some embodiments, the present disclosure provides a method of treating a disease or disorder amenable to modulation, e.g., induction, of ferroptosis. In some embodiments, the disease or disorder is a cancer.

[0061] For example, disclosed herein is a compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is NR4or O;R1is selected from the group consisting of -COOH, a 5-membered heteroaryl, a 5- membered heterocyclyl, -C(O)ORn, -C(O)NR12R13, -S(O)2Rn, -S(O)2NR12R13, -CF3, -C(=N- 0RN1)NHRN1, and -C(=NH)NHRN1; wherein the heteroaryl or heterocyclyl bears at least two ring heteroatoms each independently selected from the group consisting of S, O, N, and NRN1; and wherein the heterocyclyl or heteroaryl may optionally be substituted on an available carbon atom with one or more substituents each independently selected from R14;R2is selected from the group consisting of -N(RN2)2, -CH2(RN2)2, and -OH;RN1is selected from the group consisting of hydrogen and Ci-Csalkyl;RN2is selected from the group consisting of hydrogen, Ci-Cealkyl, -C(O)Ci-Cealkyl, and -C(O)OCi-C6alkyl;R11is selected from the group consisting of Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Cs-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocyclyl; wherein R11may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, - C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, and -O(C=O)OCi-C6alkyl;R12is selected from the group consisting of hydrogen and Ci-Csalkyl;R13is selected from the group consisting of Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Cs-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocyclyl; wherein R13may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, - C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, and -O(C=O)OCi-C6alkyl; orR12and R13, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl which may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R14is independently selected for each occurrence from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Csalkyl, and Ci-Csalkoxy;L is selected from the group consisting of -C(O)-O-Ci-C3alkylene-, -Ci-Csalkylene- O-C(O)-, -O-Ci-Csalkylene-, and -Ci-Csalkylene-O-; wherein Ci-Csalkylene may be interrupted in the alkylene chain by -C(O)NRa- or -NRaC(O)-; and wherein Ci-Csalkylene may optionally be substituted with one or two substituents each independently selected from - CF3and -NRaRb;R3is Cs-C27alkyl optionally substituted with one or more halogens;R4is selected from the group consisting of hydrogen and Ci-Csalkyl;Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci-Cealkyl, wherein Ci-Cealkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci-Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy; and t is 0, 1 or 2.

[0062] In some embodiments, L is selected from the group consisting of, for example,wherein * indicated the point of attachment to R3.

[0063] In other embodiments, R1is COOH. In still other embodiments, R1is a 5- membered heteroaryl having two or three ring nitrogens. For example, in certain embodiments R1is selected from the group consisting of

[0064] In further embodiments, R1is a 5-membered heterocyclyl having one, two, or three ring nitrogens. For example, in certain embodiments R1is selected from the group consisting of

[0065] In some embodiments, R1is -C(=N-OH)NH2, and -C(=NH)NH2. In other embodiments, R2is -NH2. In still other embodiments, R3is Cs-Cwalkyl optionally substituted with one, two, or three fluoros. In further embodiments, R3is selected from the group consisting of -(CH2)eCH3, -(CH2)IOCH3, -(CH2)I4CH3, and -(CH2)4CF3. In certain embodiments, R4is hydrogen. In certain other embodiments, t is 1.

[0066] Also disclosed herein is a compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein R1is Cs-Ci9alkyl optionally substituted with one or more halogens.

[0067] In some embodiments, R3is selected from the group consisting of, for example, -(CH2)6CH3, -(CH2)IOCH3, -(CH2)I4CH3, and -(CH2)4CF3.

[0068] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.Table 1. Exemplary compounds.

[0069] Procedures for making compounds described herein are provided in the examples below. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio or carboxyl groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds as disclosed herein. Starting materials used in the following scheme can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

[0070] Compounds disclosed herein, or any of the intermediates described in the schemes above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify disclosed compounds or any preceding intermediates by modifying, introducing or removing appropriate functional groups.

[0071] Where it is desired to obtain a particular enantiomer of a disclosed compound, this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example, diastereomeric derivatives (such as salts) can be produced by reaction of a mixture of enantiomers of a disclosed compound (such a racemate) and an appropriate chiralcompound (such as a chiral base). The diastereomers can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety of biocatalysts (for example, see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0072] In another resolution process a racemate of disclosed compounds can be separated using chiral High Performance Liquid Chromatography. Alternatively, a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the disclosure.

[0073] In an alternative embodiment, disclosed compounds may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.Methods

[0074] Further disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit from inducing ferroptosis, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0075] For example, provided herein is a method of treating a disease or condition in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the disease or condition can be a cancer, for example in a tissue of the subject. The cancer can be comprised in a mammal, or contained in a tissue of a mammal, which canbe a human, which can be male, female. In other embodiments, the disease or condition can be an inflammatory disease, or a fibrosis.

[0076] For example, provided herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the cancer is a carcinoma, a sarcoma, or a melanoma. In some embodiments, the carcinoma is a liver carcinoma. In some embodiments, the cancer is a clear cell renal carcinoma or non-clear cell renal carcinoma. In some embodiments, the cancer is an SWI / SNF deficient-complex cancer.

[0077] Further provided herein is a method of modulating, e.g., inducing, ferroptosis in a cell or tissue, which can be in a patient in need thereof, comprising contacting, for example directly or indirectly, optionally in a sustained manner, the cell or tissue with a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. Also provided herein is a method of modulating, e.g., inducing, ferroptosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0078] In addition, disclosed herein is a method of modulating, inhibiting, or partially inhibiting a target comprising glutamate-cysteine ligase (GCL) in a cell or tissue, which can be in a patient in need thereof, comprising contacting, for example directly or indirectly, optionally in a sustained manner, the cell or tissue with a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. Also provided herein is a method of modulating, inhibiting, or partially inhibiting a target comprising glutamate-cysteine ligase (GCL) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0079] For example, the methods described herein may be useful to treat, for example, a cancer. In some embodiments, the patient has, is suspected of having, or is at risk of developing cancer. In some embodiments, the patient has a benign tumor. In some embodiments, the patient has a pre-cancerous lesion. In some embodiments, the patient has a basal cell carcinoma (BCC) or a squamous cell carcinoma (SCC). In some embodiments, the patient has a metastatic tumor. In some embodiments, the cancer is a solid cancer or ablood cancer. In some embodiments, the blood cancer is a leukemia or a lymphoma. In some embodiments, the patient has a solid tumor. In some embodiments, the solid tumor is a carcinoma, a melanoma, or a sarcoma. In some embodiments, the melanoma is a dedifferentiated melanoma or amelanotic melanoma. In some embodiments, the patient has a melanoma with a B-Raf proto-oncogene, serine / threonine kinase (BRAF) mutation. In some embodiments the patient has a sarcoma with a Kirsten rat sarcoma (KRAS) mutation. In some embodiments, the sarcoma is a soft tissue sarcoma. In some embodiments, the sarcoma is leiomyosarcoma. In some embodiments, the carcinoma is a colon adenocarcinoma. In some embodiments, the carcinoma is a liver carcinoma. In some embodiments, the carcinoma is renal carcinoma. In some embodiments, the carcinoma is clear cell renal carcinoma. In some embodiments, the carcinoma is non-clear cell renal carcinoma.

[0080] Non-limiting examples of cancer that can be treated with an agent provided herein include: acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B cell ALL, T cell ALL), acute myelocytic leukemia (AML) (e.g., B cell AML, T cell AML), chronic myelocytic leukemia (CML) (e.g., B cell CIVIL, T cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B cell CLL, Tcell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B cell HL, T cell HL) and non Hodgkin lymphoma (NHL) (e.g., B cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B cell lymphomas (e.g., mucosa associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B cell lymphoma, splenic marginal zone B cell lymphoma), primary mediastinal B cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T cell NHL such as precursor T lymphoblastic lymphoma / leukemia, peripheral T cell lymphoma (PTCL) (e.g., cutaneous T cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T cell lymphoma, extranodal natural killer T cell lymphoma, enteropathy type T cell lymphoma, subcutaneous panniculitis like T cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma, clear cell renal carcinoma, non-clear cell renal carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), angiogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CIVIL), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumors); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes;intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); colorectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0081] In other embodiments, the patient has, is suspected of having, or is at risk of developing a hyperproliferative disease or condition. In some embodiments, methods provided herein further comprise a step of obtaining a biopsy of the tissue for histological analysis. In some embodiments, the tissue comprises a histological abnormality, wherein the histological abnormality is hyperplasia or fibrosis.

[0082] In further embodiments, the patient has, is suspected of having, or is at risk of developing a disease or condition associated with abnormal angiogenesis or vascularization. Diseases or conditions associated with abnormal angiogenesis or vascularization can include but are not limited to: ocular neovascularization, macular degeneration, retinopathy, sarcomas, polycystic kidney disease, benign hyperplasias, leiomyomas, adenomas, lipomas, hemangiomas, fibromas, vascular occlusion, restenosis, atherosclerosis, pre-neoplastic lesions, carcinoma in situ, and cancer. In some embodiments, the patient has, is suspected of having, or is at risk of developing an autoimmune disease. Non-limiting examples of relevant autoimmune diseases include: rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, oral hairy leukoplakia, and psoriasis. In some embodiments, the patient has, is suspected of having, or is at risk of developing fibrosis. Non-limiting examples of diseases and conditions associated with fibrosis include: keloid scars, hypertrophic scars, systemic sclerosis, pulmonary arterial hypertension, cardiac fibrosis, hypertrophic cardiomyopathy valvular disease, myelofibrosis, myelodysplastic syndrome, chronic myelogenous leukemia, portal hypertension, hepatocellular carcinoma, retroperitoneal fibrosis, intestinal fibrosis, enteropathies, subretinal fibrosis, epiretinal fibrosis, cystic fibrosis, emphysema, pancreatic fibrosis, chronic pancreatitis, duct obstruction, arthrofibrosis, renal fibrosis, nephrogenic systemic fibrosis, renal anemia, chronic kidney disease, Dupuytren’s disease, Ledderhosedisease (plantar fibromatosis), primary biliary cholangitis (PBC), non-alcoholic steatohepatitis (NASH), scleroderma, diabetic neuropathy, hypertensive nephrosclerosis, allograft nephropathy, cirrhosis, and pulmonary fibrosis.

[0083] Further disclosed herein is a method of inducing immune cell recruitment to a tumor, the method comprising: administering to a patient in need thereof a compound disclosed herein by any of the methods provided herein. In some embodiments, the administering is sustained administration for at least about 10 hours, thereby recruiting immune cells to the tumor site. In some embodiments, the immune cells are leukocytes. In some embodiments, following contact with a mammalian tissue or administration of a ferroptosis-inducing agent, immune cell recruitment can be detected at a time point at or after contacting the mammalian tissue with the ferroptosis-inducing agent. In some embodiments, the administering reduces the size of the tumor and / or increases the number of leukocytes within the tumor.

[0084] Further disclosed herein is a method of inducing weight loss, fat loss, or both, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the method is inducing weight loss. In other embodiments, the method is inducing fat loss. In still other embodiments, the method is inducing weight loss and inducing fat loss. In certain embodiments, the patient is obese or overweight. In some embodiments, the patient is suffering from one or more conditions selected from the group consisting of, for example, obesity, metabolic syndrome, elevated blood glucose, a diabetes, diabetes type 2, diabetes type 3, insulin resistance, high blood pressure, a cardiovascular disease, a coronary artery disease, a cerebrovascular disease, a stroke, a rheumatic heart disease, an arteriosclerosis, an atherosclerosis, a liver disease, a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).

[0085] For example, disclosed herein is a method of treating one or more conditions selected from the group consisting of obesity, metabolic syndrome, elevated blood glucose, a diabetes, diabetes type 2, diabetes type 3, insulin resistance, high blood pressure, a cardiovascular disease, a coronary artery disease, a cerebrovascular disease, a stroke, a rheumatic heart disease, an arteriosclerosis, an atherosclerosis, a liver disease, a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), in a patient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0086] Also disclosed herein is a method of inducing, regulating, or modulating weight loss, body composition, or fat loss or fat reduction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0087] Also disclosed herein is a method of treating, inducing, regulating, modulating, or diminishing cholesterol metabolism or a disease associated with cholesterol metabolism in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0088] In particular, in certain embodiments, the disclosure provides a method of treating the medical indications contemplated herein comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein.Combination Therapy

[0089] The compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein. For clarity, contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a disclosed compound and one additional therapeutic agent is administered. In some embodiments, a disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a disclosed compound and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, a disclosed compound and an additional therapeutic agent can be administered in a single formulation. Othercombinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.

[0090] Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y- X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.

[0091] In some embodiments, the methods provided herein comprise administering at least one additional treatment to a subject. In some embodiments, the additional treatment is surgery. In some embodiments, the additional treatment is radiation therapy. In some embodiments, the additional treatment is radioligand therapy. In some embodiments, the additional treatment is a dietary supplement. Non-limiting examples of dietary supplements include: probiotics, selenium, iron, vitamins (e.g., vitamin A, vitamin C, vitamin E), curcumin, fish oils, beta carotene, hydrogen sulfides, fatty acids, methionine, cysteine, homocysteine, taurine, cystine or di-cysteine. In some embodiments, the dietary supplement is a high-selenium nutritional supplement.

[0092] In certain embodiments, the methods described herein further comprises administering to the patient one or more additional therapeutic agents that treats a disease or disorder that is affected by, associated with, or would benefit from modulating, e.g., inducing, ferroptosis.

[0093] In some embodiments, the methods provided herein comprise administering an additional agent in combination with a ferroptosis-inducing agent (e.g., a compound disclosed herein), an iron-dependent cell death inducing agent, and / or a priming agent provided herein. I n some embodiments, the additional agent is a cell-death inducing agent.In some embodiments, the additional agent is an anti-cancer agent. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. A chemotherapeutic agent or compound is any agent or compound useful in the treatment of cancer. The chemotherapeutic cancer agents that can be used in combination with ferroptosis-inducing agents or iron-dependent cell death agents provided herein which include, but are not limited to, mitotic inhibitors (vinca alkaloids). These include, for example, vincristine, vinblastine, vindesine and Navelbine™ (vinorelbine, 5’-noranhydroblastine). In yet other cases, chemotherapeutic cancer agents include topoisomerase I inhibitors, such as camptothecin compounds. As used herein, “camptothecin compounds” include Camptosar™ (irinotecan HCL), Hycamtin™ (topotecan HCL) and other compounds derived from camptothecin and its analogues. Another category of chemotherapeutic cancer agents that can be used in the methods and compositions disclosed herein are podophyllotoxin derivatives, such as etoposide, teniposide and mitopodozide. The present disclosure further encompasses other chemotherapeutic cancer agents known as alkylating agents, which alkylate the genetic material in tumor cells. These include without limitation cisplatin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacarbazine. The disclosure encompasses antimetabolites as chemotherapeutic agents. Examples of these types of agents include, for example, cytosine arabinoside, fluorouracil, methotrexate, mercaptopurine, azathioprime, and procarbazine.

[0094] In some embodiments, an additional category of therapeutic agents, e.g., chemotherapeutic cancer agents, that may be used in the methods and compositions disclosed herein include, for example, aldehyde dehydrogenase inhibitors. Examples of contemplated aldehyde dehydrogenase inhibitors include, but are not limited to, e.g., 4- amino-4-methyl-2-pentyne-l-al (AMP AL), N-acetyl-N-acetoxy-4- chlorobenzenesulfonamide, 2-allyl-6-(((l-propyl-lH-benzo[d]imidazol-2- yl)amino)methyl)phenol, 5-(l,3-benzodioxol-5-yl)-2-phenyl-pyrazolo[l,5-a]pyrimidine-7- carboxylic acid methyl ester, A-(l,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide, calcium carbamide, captan, 3-(4-chloro-2-methoxyphenyl)-l-(2'-methoxy-[l,l'-biphenyl]-4- yl)-l,5,6,7-tetrahydroimidazo[l,2-a]pyrimidine, chlorpropamide, citral, coprine, 8-[[4- (cyclopropylcarbonyl)-l-piperazinyl]methyl]-3,7-dihydro-l,3-dimethyl-7-(3-methylbutyl)- U / -purine-2, 6-dione hydrochloride, cyanamide, daidzin, daidzein, 2,6-diphenyl- imidazo[l,2-a]pyridine, dyclonine, dyclonine hydrochloride, disulfiram, diethylaminobenzaldehyde, 4-(diethylamino)-3-nitrobenzaldehyde, diethyldithiocarbamate,ethyl 2-[[3,4-dihydro-4-oxo-3-[3-( l -pyrrolidinyl)propyl][ l ]benzothieno[3,2-t / ]pyrimidin-2- yl]thio]acetate, 3-ethyl-N-(7-fluoro-l,2,3,4-tetrahydro-2-oxo-6-quinolinyl)-4- pyridinecarboxamide, eugenol, fomepizole, 1- [4- [6-fluoro-3-(4-methyl sulfonylpiperazine- 1- carbonyl)quinolin-4-yl]phenyl]cyclopropane-l -carbonitrile, 6-[(3- fluorophenyl)methylsulfanyl]-5-(2 -methylphenyl)- lH-pyrazolo[3,4-d]pyrimidin-4-one, furazolidone, glyceryl trinitrate, gossypol, 3 -hydroxybenzaldehyde N- hydroxybenzenesulfonamide, 4-hydroxynonenal, 3 -hydroxypropionamide, kynurenine, 3- hydroxykynurenine, 3-hydroxyanthranilic acid, kynurenic acid, indol-3-ylpyruvic acid, methyl-[l-[(butylamino)carbonyl]-17 / -benzimidazol-2-yl]carbamate (benomyl), 3-[[[3-[4- [(methylsulfonyl)amino]phenyl]-4-oxo-4J / -l-benzopyran-7-yl]oxy]methyl]benzoic acid, methyltetrazolethiol, molinate, 2-(a-naphthoyl)ethyltrimethylammonium iodide, nitrefazole, 7V,7V-l,8-octanediylbis(2,2-dichloroacetamide, omeprazole, oxyfedrine, pargyline, phenylglyoxal, prunetin, puerarin, purgiline, a-pyridoin, quercetin, (£)-5-(2-(quinolin-4- yl)vinyl)benzene-l,3-diol, taraxerone, tolbutamide, trichloroacetaldehyde monohydrate, and pharmaceutically acceptable salts and / or analogs of any of the foregoing. For example, an aldehyde dehydrogenase inhibitor contemplated herein may be selected from those disclosed in W02020 / 230701 Al, which is incorporated herein by reference in its entirety. In certain embodiments, the aldehyde dehydrogenase inhibitor is, for example, oxyfedrine.

[0095] For example, disclosed herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an aldehyde dehydrogenase inhibitor, for example, oxyfedrine. Also disclosed herein is a pharmaceutical composition comprising: a compound disclosed herein, or a pharmaceutically acceptable salt thereof; an aldehyde dehydrogenase inhibitor, for example, oxyfedrine; and a pharmaceutically acceptable excipient. Further disclosed herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising: a compound disclosed herein, or a pharmaceutically acceptable salt thereof; an aldehyde dehydrogenase inhibitor, for example, oxyfedrine; and a pharmaceutically acceptable excipient.

[0096] An additional category of chemotherapeutic cancer agents that may be used in the methods and compositions disclosed herein include antibiotics. Examples include without limitation doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerous liposomal formulationscommercially available for these compounds. The present disclosure further encompasses other chemotherapeutic cancer agents including without limitation anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, ifosfamide and mitoxantrone.

[0097] The disclosed agents provided herein can be administered in combination with other anti-tumor agents, including cytotoxic / antineoplastic agents and anti-angiogenic agents. Cytotoxic / anti -neoplastic agents can be defined as agents who attack and kill cancer cells. Some cytotoxic / anti-neoplastic agents can be alkylating agents, which alkylate the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine. Other cytotoxic / anti-neoplastic agents can be antimetabolites for tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine. Other cytotoxic / anti-neoplastic agents can be antibiotics, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerous liposomal formulations commercially available for these compounds. Still other cytotoxic / anti-neoplastic agents can be mitotic inhibitors (vinca alkaloids). These include, for example, vincristine, vinblastine and etoposide. Miscellaneous cytotoxic / anti-neoplastic agents include, for example, taxol and its derivatives, L- asparaginase, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

[0098] Anti-angiogenic agents can also be used. Suitable anti -angiogenic agents for use in the disclosed methods and compositions include, for example, anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense oligonucleotides. Other inhibitors of angiogenesis include, for example, angiostatin, endostatin, interferons, interleukin 1 (including a and P) interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinase- 1 and -2. (TIMP-1 and -2). Small molecules, including topoisomerases such as razoxane, a topoisomerase II inhibitor with anti -angiogenic activity, can also be used.

[0099] Other anti-cancer agents that can be used in combination with the ferroptosis- inducing agents provided herein can include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; avastin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bevacizumab; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; folinic acid; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer agents include, but are not limited to: 20-epi-l,25dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara- CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophy cin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B;itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinumtriamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B 1 ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Any of the aforementioned chemotherapeutics can be administered at a clinically effective dose. A chemotherapeutic can also be administered from about day: -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, - 1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or up to about day 14 after administration of an agent provided herein. In some cases, a subject can have a refractory cancer that is unresponsive to a chemotherapeutic.

[0100] The methods described herein include administering to the patient a therapeutically effective amount of at least one compound as described herein, which is optionally formulated in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the patient an additional therapeutic agent that treats a cancer, or that treats a disease or disorder that is affected by, associated with, or would benefit from modulating, e.g., inducing, ferroptosis.

[0101] In some embodiments, administering the compound(s) described herein to the patient allows for administering a lower dose of the additional therapeutic agent as comparedto the dose of the additional therapeutic agent alone that is required to achieve similar results in treating, ameliorating, and / or preventing cancer, or in treating, ameliorating, and / or preventing a disease or disorder that is affected by, associated with, or would benefit from modulating, e.g., inducing, ferroptosis. For example, in certain embodiments, the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect.

[0102] In some embodiments, a compound disclosed herein can be comprised as a ligand in a proteolysis-targeting chimera (PROTAC) protein degrader. In some instance, a bifunctional PROTAC molecule can comprise the ligand of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). In some instances, the POI can be any protein herein. In some instances, the POI can be cysteine-glutamate antiporter (system Xc), a glutathione peroxidase 4 (GPX4), a p53, a cargo receptor NCOA4, a glutathione synthetase (GSH), or a glutamate-cysteine ligase (GCL). The inactivation or inhibition of some of these molecules, for example, system Xc, GPX4, or glutathione synthetase PROTAC protein degraders can work by recruiting a chosen E3 ligase into close proximity with a specific disease-causing protein so that it can be tagged with ubiquitin and sent off for degradation by the proteasome. After the protein is degraded, the PROTAC can be released to continue to elicit further degradation.

[0103] In some embodiments, a compound described herein can be part of an antibodydrug conjugate (ADC) where the compound is optionally linked to the antibody by a linker.Dosing and Administration

[0104] A typical human dose of compound provided herein (e.g., a ferroptosis-inducing agent) may be from about 10 pg / kg body weight / day to 10,000 mg / kg / day. In some embodiments, the dose of an agent provided herein is from about 0.1 mg / kg to about 1000 mg / kg, from 1 mg / kg to 1000 mg / kg, 1 mg / kg to 800 mg / kg, from about 1 mg / kg to about 700 mg / kg, from about 2 mg / kg to about 500 mg / kg, from about 3 mg / kg to about 400 mg / kg, 4 mg / kg to about 300 mg / kg, or from about 5 mg / kg to about 200 mg / kg. In certain embodiments, the suitable dosages of the agent can be about 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 250 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, 600 mg / kg, 700 mg / kg, 800 mg / kg,900 mg / kg, 1000 mg / kg, 2,000 mg / kg, 3,000 mg / kg, 4,000 mg / kg, 5,000 mg / kg, 6,000 mg / kg, 7,000 / mg / kg, 8,000 mg / kg, 9,000 mg / kg, up to 9,600 mg / kg. In some embodiments, the dose of compound provided herein is from about 100 mg / kg / day to about 6,400 mg / kg / day four times per day. In some embodiments, the dose of a compound provided herein is from about 50 mg / kg / day to about 25 mg / kg / day. In some embodiments, the dose of a compound provided herein is from about 400 mg / kg / day to about 800 mg / kg / day. In certain embodiments, the dose of the compound can be administered once per day or divided into subdoses and administered in multiple doses, e.g., twice, three times, or four times per day.

[0105] In some embodiments, compounds provided herein are administered in an amount of at least about 10 nanograms (ng) or more, about 20 ng or more, about 30 ng or more, about 40 ng or more, about 50 ng or more, about 60 ng or more, about 70 ng or more, about 80 ng or more, about 90 ng or more, up to 100 ng. In some embodiments, the compound is administered in an amount of at least about 1 microgram (pg) or more, about 5 pg or more, about 10 pg or more, about 20 pg or more, about 30 pg or more, about 40 pg or more, about 50 pg or more, about 60 pg or more, about 70 pg or more, about 80 pg or more, about 90 pg or more, up to 100 pg.

[0106] In some embodiments, compounds provided herein are administered at a concentration of at least about 0.1 micromolar (pM) or more, about 1 pM or more, about 2 pM or more, about 3 pM or more, about 4 pM or more, about 5 pM or more, about 6 pM or more, about 7 pM or more, about 8 pM or more, about 9 pM or more, about 10 pM or more, about 15 pM or more, about 20 pM or more, about 25 pM or more, about 30 pM or more, about 35 pM or more, about 40 pM or more, about 45 pM or more, about 50 pM or more, about 55 pM or more, about 60 pM or more, about 65 pM or more, about 70 pM or more, about 75 pM or more, about 80 pM or more, about 85 pM or more, about 90 pM or more, about 95 pM or more, about 100 pM or more, about 110 pM or more, about 120 pM or more, about 130 pM or more, about 140 pM or more, about 150 pM or more, about 160 pM or more, about 170 pM or more, about 180 pM or more, about 190 pM or more, about 200 pM or more, about 300 pM or more, about 400 pM or more, about 500 pM or more, up to 1 mM. In some embodiments, compounds provided herein are administered at a concentration of at least about 0.1 pM up to about 500 pM. In some embodiments, compounds provided herein are administered at a concentration of at least about 1 pM up to 500 pM. In some embodiments, compounds provided herein are administered at a concentration of at leastabout 0.1 pM up to 10 pM. In some embodiments, compounds provided herein are administered at a concentration of at least about 1 pM up to 10 pM.

[0107] In some embodiments, ferroptosis-inducing agents provided herein, e.g., compounds provided herein, are administered intravenously. In some embodiments, compounds provided herein are administered intravenously at a concentration of at least about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, about 1000 mg / kg, about 1100 mg / kg, about 1200 mg / kg, about 1300 mg / kg, about 1400 mg / kg, about 1500 mg / kg, about 2000 mg / kg, about 2200 mg / kg, about 2400 mg / kg, up to about 2500 mg / kg. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 25 mg / kg once per day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 25 mg / kg twice per day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 450 mg / kg / day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 650 mg / kg / day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 650 mg / kg / day for 3 continuous days. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 1300 mg / kg / day. In some embodiments, compounds provided herein are administered intravenously at a concentration of about 2400 mg / kg / day.

[0108] In some embodiments, compounds provided herein are administered orally. In some embodiments, compounds provided herein are administered orally at a concentration of at least about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, about 1000 mg / kg, about 1100 mg / kg, about 1200 mg / kg, about 1300 mg / kg, about 1400 mg / kg, about 1500 mg / kg, about 2000 mg / kg, about 2200 mg / kg, about 2400 mg / kg, up to about 2500 mg / kg. In some embodiments, compounds provided herein are administered orally at a concentration of about 25 mg / kg once per day. In some embodiments, compounds provided herein are administered orally at a concentration of about 25 mg / kgtwice per day. In some embodiments, compounds provided herein are administered orally at a concentration of about 1300 mg / kg / day. In some embodiments, compounds provided herein are administered orally at a concentration of about 2400 mg / kg / day.

[0109] The methods provided herein can be characterized by or further comprise measuring the distribution of an agent in a target tissue. Distribution of a compound provided herein can be determined by the amount or concentration of the agent within a square millimeter (mm2) or cubic millimeter (mm3) of tissue. For example, for local administration of the compound to a tumor, the tissue may be from about 6 to 7 mm in diameter, 36 to 42 mm2, or 216 to 294 mm3. The data obtained from animal studies may be used in formulating a range of drug distribution in a mammalian tissue. Methods of determining tissue distribution of a compound include, for example, mass spectrometry, chromatography, imaging techniques, and immunoassays. The distribution of a compound provided herein can be determined using a system provided herein.

[0110] In some embodiments, the tissue is administered a therapeutic amount of a compound disclosed herein, wherein administration of comprises providing to a tissue the compound in an amount sufficient to achieve a desired drug distribution. In some embodiments, the compound may achieve a distribution within a tissue of at least about 1 ng / mm2or more, about 5 ng / mm2or more, about 10 ng / mm2or more, about 15 ng / mm2or more, about 20 ng / mm2or more, about 25 ng / mm2or more, about 30 ng / mm2or more, about 35 ng / mm2or more, about 40 ng / mm2or more, about 45 ng / mm2or more, about 50 ng / mm2or more, about 55 ng / mm2or more, about 60 ng / mm2or more, about 65 ng / mm2or more, about 70 ng / mm2or more, about 75 ng / mm2or more, about 80 ng / mm2or more, about 85 ng / mm2or more, about 90 ng / mm2or more, about 95 ng / mm2or more, about 100 ng / mm2or more, about 110 ng / mm2or more, about 120 ng / mm2or more, about 130 ng / mm2or more, about 140 ng / mm2or more, about 150 ng / mm2or more, about 160 ng / mm2or more, about 170 ng / mm2or more, about 180 ng / mm2or more, about 190 ng / mm2or more, about 200 ng / mm2or more, about 300 ng / mm2or more, about 400 ng / mm2or more, up to 500 ng / mm2. In some embodiments, the compound may achieve a distribution within a tissue of at least about 1 ng / mm3or more, about 5 ng / mm3or more, about 10 ng / mm3or more, about 15 ng / mm3or more, about 20 ng / mm3or more, about 25 ng / mm3or more, about 30 ng / mm3or more, about 35 ng / mm3or more, about 40 ng / mm3or more, about 45 ng / mm3or more, about 50 ng / mm3or more, about 55 ng / mm3or more, about 60 ng / mm3or more, about 65 ng / mm3or more, about 70 ng / mm3or more, about 75 ng / mm3or more, about 80 ng / mm3or more,about 85 ng / mm3or more, about 90 ng / mm3or more, about 95 ng / mm3or more, about 100 ng / mm3or more, about 110 ng / mm3or more, about 120 ng / mm3or more, about 130 ng / mm3or more, about 140 ng / mm3or more, about 150 ng / mm3or more, about 160 ng / mm3or more, about 170 ng / mm3or more, about 180 ng / mm3or more, about 190 ng / mm3or more, about 200 ng / mm3or more, about 300 ng / mm3or more, about 400 ng / mm3or more, up to 500 ng / mm3.

[0111] In some embodiments, a compound disclosed herein may be administered at least about once per day, twice per day, three times per day, four times per day, or five times per day. In some embodiments of any of the aspects, compounds are administered at least about every week, at least about every 2 weeks, or at least about every 3 weeks. The amount of compound administered depends on the size of the tissue, the type of disease being treated, and the type of administration (e.g., local administration to a tissue in vivo using a system provided herein). Effective doses will vary, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments. In some embodiments, administering comprises, for example, intratumoral injection, oral administration, transdermal injection, inhalation, nasal administration, topical administration, vaginal administration, ophthalmic administration, intracerebral administration, rectal administration, intravenous administration, intra-arterial administration, intramuscular administration, or subcutaneous administration.Pharmaceutical Compositions and Kits

[0112] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and / or may be formulated for oral or subcutaneous administration.

[0113] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0114] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0115] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employedas fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0116] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0117] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0118] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0119] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0120] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0121] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0122] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0123] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.Aerosols generally are prepared from isotonic solutions.

[0124] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0125] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0126] In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenumjejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g. , Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials iseither known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure.

[0127] The disclosure also provides kits for use by a e.g., a consumer in need of treatment of a disease or disorder described herein. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0128] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . “ etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.EXAMPLES

[0129] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. At least some of the compounds identified as “Intermediates” herein are contemplated as compounds of the disclosure.Example 1: Synthesis of (2S)-2-amino-4-[[(3R)-4,4,4-trifluoro-3-octanoyloxy- butyljsulfonimidoyl] butanoic acid (Compound 101)Step 1: octanoy I chloride:

[0130] To a solution of octanoic acid (176 mg, 1.22 mmol, 193.41 pL, 1 eq) in DCM (2 mL) was added DMF (8.92 mg, 122.04 pmol, 9.39 pL, 0.1 eq) and oxalyl dichloride (387.26 mg, 3.05 mmol, 267.08 pL, 2.5 eq) at 0 °C, the mixture was stirred at 0-15 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a colorless oil.Step 2: (2S)-2-(tert-butoxycarbonylamino)-4-[N-tert-butoxycarbonyl-S-[(3R)-4,4,4- trifluoro-3-octanoyloxy-butyl sulfonimidoyl butanoic acid) :

[0131] A solution of (S)-4-((R,3R)-N-(tert-butoxycarbonyl)-4,4,4-trifluoro-3- hydroxybutylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoic acid (0.3 g, 609 pmol, 1 eq), pyridine(241 mg, 3.05 mmol, 246 pL, 5 eq) in DCM (3 mL) was degassed with N2 for 3 times, and then compound 2 (119 mg, 731 pmol, 125 pL, 1.2 eq) in DCM (0.3 mL) was added at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL*2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 pm; mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: 25%-55% B over 15.0 min) to afford the title compound (180 mg, 290.93 pmol, 47.76% yield) as a white solid.Step 3: (2S)-2-amino-4-[[(3R)-4,4,4-trifluoro-3-octanoyloxy-butyl]sulfonimidoyl]butanoic acid:

[0132] A solution of compound 3 (180 mg, 290.93 pmol, 1 eq) in HClZEtOAc (2 mL) was stirred at 15 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 pm; mobile phase: [H2O (10mM NH4HCO3)-MeCN]; gradient: 20%-50% B over 15.0 min) to afford the title compound (80 mg, 191.17 pmol, 65.71% yield, 100% purity) as a white solid. LCMS: Rt = 2.356 min, (ES+) m / z (M+H)+= 419.1. 'H NMR (400 MHz, MeOD-tL) 5 5.60 (ddd, J= 3.5, 6.3, 9.6 Hz, 1H), 3.69 (t, J= 6.2 Hz, 1H), 3.50 - 3.36 (m, 1H), 3.28 - 3.12 (m, 2H), 2.53 - 2.21 (m, 6H), 1.65 (quin, J= 7.1 Hz, 2H), 1.32 (br dd, J= 2.7, 6.7 Hz, 8H), 0.97 - 0.84 (m, 3H).Example 2: Synthesis of (2S)-2-amino-4-[[(3R)-3-dodecanoyloxy-4,4,4-trifluoro- butyljsulfonimidoyl] butanoic acid (Compound 102)Step 1: dodecanoyl chloride:

[0133] A solution of dodecanoic acid (75 mg, 374.41 pmol, 1 eq) in SOCh (1 mL) was stirred at 78 °C for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown oil.Step 2: (2S)-2-(tert-butoxycarbonylamino)-4-[N-tert-butoxycarbonyl-S-[(3R)-3- dodecanoyloxy-4, 4, 4-trifluoro-butyl ] sulfonimidoyl Jbutanoic acid:

[0134] To a solution of (S)-4-((R,3R)-N-(tert-butoxycarbonyl)-4,4,4-trifluoro-3- hydroxybutylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoic acid (138.54 mg, 281 pmol, 1 eq in DCM (2 mL) was added pyridine (111 mg, 1.41 mmol, 114 pL, 5 eq) and compound 2 (80 mg, 366 pmol, 84.6 pL, 1.3 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 pm; mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: 50%-80% B over 12.0 min) to afford the title compound (30 mg, 39.57 pmol, 14.07% yield, 89% purity) as a white solid. 'H NMR (400 MHz, CDCh-tZ) 5 5.44 (br d, J= 6.9 Hz, 1H), 4.41 (br d, J= 3.9 Hz, 1H), 3.58 - 3.46 (m, 2H), 3.45 - 3.37 (m, 2H), 2.43 (br t, J= 7.6 Hz, 3H), 2.37 - 2.24 (m, 2H), 1.70 - 1.61 (m, 2H), 1.47 (br d, J= 8.9 Hz, 18H), 1.34 - 1.24 (m, 16H), 0.89 (br t, J= 6.7 Hz, 3H).Step 3: (2S)-2-amino-4-[[(3R)-3-dodecanoyloxy-4, 4, 4-trifluoro- butyl J sulfonimidoyl butanoic acid:

[0135] A solution of compound 3 (30 mg, 44.5 pmol, 1 eq) in HClZEtOAc (0.5 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 pm; mobile phase: [H2O (10mM NH4HCO3)-MeCN]; gradient:40%-70% B over 12.0 min) to afford the title compound (6.8 mg, 14.28 pmol, 32.13% yield, 99.69% purity) as a white solid. LCMS: Rt = 2.733 min, (ES+) m / z (M+H)+= 475.2.1H NMR (400 MHz, DMSO-de) 5 7.64 - 7.29 (m, 2H), 5.71 - 5.55 (m, 1H), 4.08 - 3.86 (m, 1H), 3.27 - 3.23 (m, 1H), 3.18 - 2.98 (m, 3H), 2.47 - 2.40 (m, 2H), 2.23 - 1.98 (m, 4H), 1.54 (br t, J= 7.0 Hz, 2H), 1.24 (s, 16H), 0.90 - 0.80 (m, 3H).Example 3: Synthesis of (S)-2-amino-4-((R,3R)-4,4,4-trifluoro-3-(palmitoyloxy) butylsulfonimidoyl)butanoic acid (Compound 103)Step 1: hexadecanoyl chloride:

[0136] A solution of palmitic acid (118 mg, 460 pmol, 139 pL, 1 eq) in SOCI2 (2 mL) was stirred at 80 °C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was used directly in the next step.Step 2: (S)-4-( (R, 3R)-N-( tert-butoxycarbonyl)-4, 4, 4-trifluoro-3-(palmitoyloxy) butylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoic acid:

[0137] To a solution of (S)-4-((R,3R)-N-(tert-butoxycarbonyl)-4,4,4-trifluoro-3- hydroxybutylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoic acid (150 mg, 305 pmol, 1 eq) and pyridine (120 mg, 1.52 mmol, 123 pL, 5 eq) in DCM (2 mL) was added compound 2 (126 mg, 457 pmol, 139 pL, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (lOmM NH4HCO3)-MeCN]; gradient: 50%-80% B over 12.0 min) to afford the title compound (70 mg, 95.77 pmol, 31.45% yield) as a colorless oil. 'H NMR (400 MHz, MeOD-t / v) 5 5.64 - 5.52 (m, 1H), 4.11 (br s, 1H), 3.65 - 3.43 (m, 4H), 2.47 (dt, J= 5.1, 7.3 Hz, 2H), 2.39 - 2.23 (m, 3H), 2.15 (br dd, J= 2.0, 8.1 Hz, 1H), 1.70 - 1.57 (m, 3H), 1.45 (s, 17H), 1.33 - 1.28 (m, 25H), 0.90 (s, 3H).Step 3: (S)-2-amino-4-( (R, 3R)-4, 4, 4-trifluoro-3-(palmitoyloxy)butylsulfonimidoyl)butanoic acid:

[0138] A solution of compound 3 (70 mg, 96.03 pmol, 1 eq) in HClZEtOAc (1 mL) was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 pm; mobile phase: [H2O (10mM NH4HCO3)-MeCN]; gradient:50%-80% B over 12.0 min) to afford the title compound (15 mg, 28.27 pmol, 29.43% yield) as a white solid. LCMS: Rt = 3.770 min, (ES+) m / z (M+H)+ = 531.3.1H NMR (400 MHz, MeOD-t / v) 5 4.42 (br dd, J = 5.0, 6.7 Hz, 1H), 4.17 - 4.08 (m, 1H), 2.49 - 2.01 (m, 7H), 1.73 - 1.56 (m, 2H), 1.29 (br s, 27H), 0.90 (br t, J= 6.6 Hz, 3H).Example 4: (S)-2-amino-4-((R,3R)-4,4,4-trifluoro-3-((6,6,6- trifluorohexanoyl)oxy)butylsulfonimidoyl)butanoic acid (Compound 104)Step 1: 6,6,6-trifluorohexanoyl chloride:

[0139] To a solution of 6,6,6-trifluorohexanoic acid (69 mg, 406 pmol, 1 eq) in DCM (1 mL) was added oxalyl dichloride (103 mg, 811 pmol, 71.0 pL, 2 eq) and DMF (1.48 mg, 20.3 pmol, 1.56 pL, 0.05 eq) at 0°C. The resulting mixture was stirred at 15°C for 1 hr. The reaction mixture was concentrated under reduced pressure to afford the title compound (76 mg, 403 pmol, 99.4% yield) as a yellow oil.Step 2: (S)-4-( (R, 3R)-N-( ter tdmtoxy carbonyl) -4, 4, 4-trifluoro-3-( t) 6, 6, 6- trijluorohexanoyl)oxy) butylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoic acid:

[0140] To a solution of compound 2 (50 mg, 102 pmol, 1 eq) and Pyridine (40.2 mg, 508 pmol, 40.9 pL, 5 eq) in DCM (1 mL) was added Compound 2A (38.3 mg, 203 pmol, 2 eq) at 0°C. The resulting mixture was stirred at 15°C for 1 hr. The reaction mixture was poured into water (3 mL) and extracted with DCM (3 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm 10 pm; mobile phase: [FLO (lOmM NH4HCO3)-MeCN]; gradient: 35%-65% B over 9.0 min) to afford the title compound (28 mg, 43.4 pmol, 42.8% yield) as a white solid. H NMR (400MHz, CDCh-t / ) 5 5.76 - 5.59 (m, 1H), 5.53 - 5.38 (m, 1H), 4.25 (br d, J= 4.0 Hz, 1H), 3.54 - 3.39 (m, 4H), 2.50 - 2.26 (m, 6H), 2.17 - 2.05 (m, 2H), 1.79 - 1.71 (m, 2H), 1.65 - 1.59 (m, 2H), 1.47 (s, 9H), 1.44 (s, 9H).Step 3: (S)-2-amino-4-( (R, 3R)-4, 4, 4-trifluoro-3-( ( 6, 6, 6-trifluorohexanoyl)oxy) butylsulfonimidoyl) butanoic acid:

[0141] Compound 3 (28 mg, 43.4 pmol, 1 eq) in HCl / EtOAc (5 mL) was stirred at 25°C for Ihr. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 pm; mobile phase: [H2O (10mM NH4HCO3)-MeCN]; gradient: 15%-45% B over 12.0 min) to afford the title compound (5.08 mg, 11.2 pmol, 25.7% yield, 97.8% purity) as a white solid. LCMS: Rt = 2.483 min, (ES+) m / z (M+H)+= 445.1. 'H NMR (400 MHz, MeOD-t / 4) 5 5.67 - 5.55 (m, 1H), 3.69 (t, J = 6.0 Hz, 1H), 3.47 - 3.36 (m, 1H), 3.33 (br s, 1H), 3.29 - 3.16 (m, 2H), 2.63 - 2.47 (m, 2H), 2.44 - 2.25 (m, 4H), 2.24 - 2.09 (m, 2H), 1.81 - 1.69 (m, 2H), 1.68 - 1.56 (m, 2H).Example 12: GCL Enzyme Profiling Assay

[0142] The GCL enzyme assay was run in 50 mM HEPES, pH 7.5, containing 150 mM NaCl, 30 mM MgCh, 0.5 mM EDTA, 1 mM DTT, 0.1 mg / mL BSA, and 0.2% F-127 in a total assay volume of 10 pL. Compound in pure DMSO was stamped in assay plates (Greiner black 384-well) using a D300e digital dispenser (TEC AN) and the final DMSO concentration was normalized to 1%. A 5 pL mixture of human recombinant GCL (final concentration: 5 nM) and ATP (final concentration: 0.6 mM) was added and the solution was incubated at room temperature (22 °C) for 1 h. The GCL enzyme reaction was initiated by addition of a 5 pL mixture of mono sodium glutamate (final concentration: 1 mM) and a- aminobutyrate (final concentration: 1.2 mM). The reaction was stopped after 2 h by addition of 5 pL ADP GLO Reagent (Promega). The resulting solution was incubated for 2 h at room temperature. This was then followed by the addition of 5 pL ADP GLO Detection. After incubation at room temperature for 30 min, the plates were read on a plate reader (PheraStar) using a luminescence protocol to quantify the GCL enzyme activity from each reaction solution. The data was analyzed using a four-parameter logistic equation to calculate IC50. The results are shown in Table 2, where A is < 1 pM; B is > 1 pm and < 10 pM; C is > 10 pM and < 100 pM; and D is > 100 pM.Table 2.INCORPORATION BY REFERENCE

[0143] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS AND SCOPE

[0144] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0145] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits theinclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0146] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0147] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound represented by Formula I:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is NR4or O;R1is selected from the group consisting of -COOH, a 5-membered heteroaryl, a 5- membered heterocyclyl, -C(O)ORn, -C(O)NR12R13, -S(O)2Rn, -S(O)2NR12R13, -CF3, - C(=N-ORN1)NHRN1, and -C(=NH)NHRN1; wherein the heteroaryl or heterocyclyl bears at least two ring heteroatoms each independently selected from the group consisting of S, O, N, and NRN1; and wherein the heterocyclyl or heteroaryl may optionally be substituted on an available carbon atom with one or more substituents each independently selected from R14;R2is selected from the group consisting of -N(RN2)2, -CH2(RN2)2, and -OH;RN1is selected from the group consisting of hydrogen and Ci-Csalkyl;RN2is selected from the group consisting of hydrogen, Ci-Cealkyl, -C(O)Ci-Cealkyl, and -C(O)OCi-C6alkyl;R11is selected from the group consisting of Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Cs-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocyclyl; wherein R11may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, - C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, and -O(C=O)OCi-C6alkyl;R12is selected from the group consisting of hydrogen and Ci-Csalkyl;R13is selected from the group consisting of Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Cs-Cecycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocyclyl; wherein R13may optionally be substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -CN, -NO2, -NRaRb, oxo, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, - (C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, and -O(C=O)OCi-C6alkyl; orR12and R13, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl which may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy;R14is independently selected for each occurrence from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Csalkyl, and Ci-Csalkoxy;L is selected from the group consisting of -C(O)-O-Ci-C3alkylene-, -Ci-Csalkylene- O-C(O)-, -O-Ci-Csalkylene-, and -Ci-Csalkylene-O-; wherein Ci-Csalkylene may be interrupted in the alkylene chain by -C(O)NRa- or -NRaC(O)-; and wherein Ci-Csalkylene may optionally be substituted with one or two substituents each independently selected from - CF3and -NRaRb;R3is Cs-C27alkyl optionally substituted with one or more halogens;R4is selected from the group consisting of hydrogen and Ci-Csalkyl;Raand Rbare each independently selected for each occurrence from the group consisting of hydrogen and Ci-Cealkyl, wherein Ci-Cealkyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, and Ci-Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, deuterium, hydroxyl, -NRaRb, Ci-Cealkyl, and Ci-Cealkoxy; and t is 0, 1 or 2.O CF32. The compound of claim 1, wherein L is selected from the group consisting ofo o and; wherein * indicated the point of attachment to R3.

3. The compound of claim 1 or 2, wherein R1is COOH.

4. The compound of claim 1 or 2, wherein R1is a 5-membered heteroaryl having two or three ring nitrogens.

5. The compound of claim 4, wherein R1is selected from the group consisting of6. The compound of claim 1 or 2, wherein R1is a 5-membered heterocyclyl having one, two, or three ring nitrogens.

7. The compound of claim 6, wherein R1is selected from the group consisting of8. The compound of claim 1 or 2, wherein R1is -C(=N-0H)NH2, and -C(=NH)NH2.

9. The compound of any one of claims 1-8, wherein R2is -NH2.

10. The compound of any one of claims 1-8, wherein R3is Cs-Ci9alkyl optionally substituted with one, two, or three fluoros.

11. The compound of any one of claims 1-10, wherein R3is selected from the group consisting of -(CH2)6CH3, -(CH2)IOCH3, -(CH2)i4CH3, and -(CH2)4CF3.

12. The compound of any one of claims 1-11, wherein R4is hydrogen.

13. The compound of any one of claims 1-12, wherein t is 1.

14. A compound represented by Formula II:or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein R1is Cs-Ci9alkyl optionally substituted with one or more halogens.

15. The compound of claim 14, wherein R3is selected from the group consisting of - (CH2)6CH3, -(CH2)IOCH3, -(CH2)I4CH3, and -(CH2)4CF3.

16. A compound selected from the group consisting of:or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

17. A pharmaceutical composition comprising a compound of any one of claims 1-16, or a pharmaceutically acceptable salt and / or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

18. A method of treating a cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-16, or the pharmaceutical composition of claim 17.

19. The method of claim 18, wherein the cancer is selected from the group consisting of a carcinoma, a sarcoma, or a melanoma.

20. The method of claim 18 or 19, wherein the cancer is selected from the group consisting of clear cell renal carcinoma, a nonclear cell renal carcinoma, and a liver carcinoma.

21. A method of treating an inflammatory disease, a fibrosis, or a kidney disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-16, or the pharmaceutical composition of claim 17.

22. The method of claim 21, wherein the fibrosis is liver fibrosis.

23. A method of modulating ferroptosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-16, or the pharmaceutical composition of claim 17.

24. The method of claim 23, wherein modulating ferroptosis comprises inducing ferroptosis.

25. The method of claim 23 or 24, wherein the patient is suffering from a cancer.

26. The method of any one of claims 23-25, wherein the patient is suffering from clear cell renal carcinoma, a nonclear cell renal carcinoma, and a liver carcinoma.

27. The method of any one of claims 23-25, wherein the patient is suffering from an inflammatory disease, a fibrosis, or a kidney disorder.

28. A method of inducing weight loss, fat loss, or both, in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-16, or the pharmaceutical composition of claim 17.

29. A method of treating a patient suffering from one or more of the conditions selected from the group consisting of obesity, metabolic syndrome, elevated blood glucose, a diabetes, diabetes type 2, diabetes type 3, insulin resistance, high blood pressure, a cardiovascular disease, a coronary artery disease, a cerebrovascular disease, a stroke, a rheumatic heart disease, an arteriosclerosis, an atherosclerosis, a liver disease, a fatty liver disease, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), comprising administering to the patient an effective amount of a compound of any one of claims 1-16, or the pharmaceutical composition of claim 17.

30. The method of claim 28 or 29, wherein the patient is obese or overweight.

31. A method of treating obesity in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of claims 1-16, or the pharmaceutical composition of claim 17.

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