Compositions and methods for inducing ferroptosis

Abstract

Methods and systems as well as compounds and agents for inducing or modulating ferroptosis in a cell, tissue or tumor of a subject are provided. Various agents and compounds are described. Various methods of administration for optimal ferroptosis modulation, such as induction and killing of target cells, are described. Methods of making, purifying, and characterizing various compounds are described.

Description

Cross - References

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 370,293, filed on August 3, 2022, the disclosure of which is incorporated herein by reference in its entirety. Incorporation of Sequence Listing by Reference

[0002] This application contains a sequence listing that has been submitted via the Patent Center. The sequence listing, entitled 203718 - 715601.xml, was created on June 29, 2023, and is 2,935 bytes in size and is incorporated herein by reference in its entirety. Background

[0003] Diseases such as cancer, autoimmune diseases, and fibrosis occur when cells in the body exhibit uncontrolled abnormal cell growth and proliferation. To treat hyperproliferative diseases, standard of care therapies induce cell death through a cellular process called apoptosis. Many common types of anti - cancer therapies and ionizing radiation are involved in the apoptosis pathway, which contributes to tumor regression or the toxic side effects of treatment. Given the ability of hyperproliferative cells to resist cell death through current apoptosis - driven therapies, there is a need to develop new methods, compounds, and compositions for inducing cell death in hyperproliferative cells. Overview

[0004] The present disclosure provides compounds of formula I: their diastereomers or enantiomers, or pharmaceutically acceptable salts of any of the foregoing, or deuterated derivatives of any of the foregoing, wherein: R1 is: C(O)OH; or C(O)OX, where X is an organic cation, an inorganic cation, Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ or Mn 2+ ; or C(O)OR3, where R3 is a straight - chain or branched - chain alkyl, cycloalkyl, cycloether, or straight - chain or branched - chain alkyl ether, where any of these is optionally and independently substituted; or R3 is or R3 is or R1 is C(O)N(R4R5) where R4 is H; or R4 is a straight-chain or branched-chain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; any of which is optionally and independently substituted; and R5 is H; or R5 is a straight-chain or branched-chain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; any of which is optionally and independently substituted; or R5 is S(O)2alkyl; or R5 is S(O)2CF3; or R5 is S(O)2NH2; or R5 is S(O)2cycloalkyl, S(O)2cyclopropyl, S(O)2cyclobutyl, S(O)2cyclopentyl, S(O)2cyclohexyl or S(O)2cycloheptyl; or R5 is or R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or R5 is pyrrolidinyl; or R5 is 2-tetrahydropyranyl, 3-tetrahydropyranyl; or 4-tetrahydropyranyl; or R5 is or R5 is alkylaryl or benzyl; or R5 is or R5 is 2-pyridyl, 3-pyridyl; or 4-pyridyl; or R5 is or R5 is or R5 is or R5 is or R5 is or CN; or or or or and R2 is: NH2, NHC(O)OMe or NHMe; and R6 is: H, C(O)Me or P(O)(OH)2; and R7 is: C1-C3 or C5-C 10 a straight-chain or branched-chain alkyl, C1-C 10 a straight-chain or branched-chain alkenyl or C1-C 10A straight-chain or branched alkynyl group, any of which may be substituted with an alkyl ring or an alkyl ether ring, said alkyl ring or alkyl ether ring containing said C1-C3 or C5-C 10 A straight-chain or branched alkyl group, said C1-C 10 A straight-chain or branched alkenyl group or one carbon atom of said C1-C 10 A straight-chain or branched alkynyl group; wherein any of the foregoing may be independently and optionally substituted, wherein when a straight-chain C3-alkyl group is substituted with a methyl group at the terminal carbon atom, said straight-chain C3-alkyl group substituted with a methyl group at the terminal carbon atom contains a further substitution; wherein when a C2-alkyl group is substituted with an ethyl group at the terminal carbon atom, said C2-alkyl group substituted with an ethyl group at the terminal carbon atom contains a further substitution; wherein when a C1-alkyl group is substituted with a n-propyl group at the terminal carbon atom, said C1-alkyl group substituted with a n-propyl group at the terminal carbon atom contains a further substitution; or R7 is:

[0005] In some cases, in a compound of formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R1 is: C(O)H; or C(O)OH; or C(O)OR3, wherein R3 is C1-C 10 A straight-chain or branched alkyl group, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, C1-C 10 A cycloalkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, an alkyl cycloalkyl group, an alkyl cyclohexyl group, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl, a straight-chain or branched alkyl ether, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypropyl, a cycloalkyl ether, a tetrahydropyranyl group, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, a tetrahydrofuranyl group, 2-tetrahydrofuranyl, 2-tetrahydrofuranyl, an alkyl aryl group, benzyl; And any of these is optionally and independently substituted with one or more C1-C 10 An alkyl group, one or more halogen atoms, one or more fluorine atoms, one or more chlorine atoms, one or more deuterium atoms, bromine, one or more iodine atoms, an aryl group, a C6 aryl group, C 10Substituted with aryl, heteroaryl, C1-C7 alkyl cycloalkyl, unsubstituted tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl, or any combination thereof.

[0006] In some cases, in a compound of formula I, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing R1 is C(O)N(R4R5) Wherein R5 is: C1-C 10 Straight or branched alkyl, methyl, ethyl, propyl or butyl; any of them is optionally or independently substituted with one or more deuteriums, C1-C 10 Straight or branched alkyl, one or more halogens, one or more fluorines, one or more chlorines, one or more iodines, or any combination thereof.

[0007] In some cases, in a compound of formula I, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R1 is C(O)N(R4R5) and Wherein R5 is: heteroaryl, 2-pyridyl, 3-pyridyl or 4-pyridyl; or R5 is S(O)2Me.

[0008] In some cases, in a compound of formula I, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing R7 is: C1-C3 or C5-C 10 Straight or branched alkyl, C1-C 10 Straight or branched alkenyl or C1-C 10 Straight or branched alkynyl, any of which may carry an alkyl ring or an alkyl ether ring, said alkyl ring or alkyl ether ring containing the C1-C3 or C5-C 10 Straight or branched alkyl, the C1-C 10 Straight or branched alkenyl or the C1-C 10 Straight or branched alkynyl of one carbon; wherein any of the foregoing may be independently and optionally substituted with one or more of the substituents, which may be: deuterium, C1-C 10 Straight alkyl, methyl, ethyl, C1-C 10Branched alkyl, halogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxylic acid or a pharmaceutically acceptable salt thereof, amide, carbamate, urea, ester, alkoxy, methoxy, ethoxy, trifluoromethoxy, ether, cyclic ether, C1-C7 alkyl ether, C1-C7 cycloalkyl ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, fused aryl, biaryl, fused aryl-heteroaryl, fused diaryl, fused aryl-heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic group, tricyclic aliphatic group, adamantyl, cyano, acetal; ketal; or any combination thereof; Wherein: When a straight-chain C3-alkyl is substituted with a methyl substituent at the terminal carbon atom, the straight-chain C3-alkyl substituted with a methyl substituent at the terminal carbon atom contains a further substitution; When a C2-alkyl is substituted with an ethyl substituent at the terminal carbon atom, the C2-alkyl substituted with an ethyl substituent at the terminal carbon atom contains a further substitution; When a C1-alkyl is substituted with a n-propyl substituent at the terminal carbon atom, the C1-alkyl substituted with a n-propyl substituent at the terminal carbon atom contains a further substitution; and Wherein said C1-C 10 Straight-chain alkyl substituent, methyl substituent, ethyl substituent, C1-C 10 Branched alkyl substituent, hydroxyl substituent, amino substituent, carboxylic acid or a pharmaceutically acceptable salt thereof substituent, amide substituent, carbamate substituent, urea substituent, ester substituent, alkoxy substituent, methoxy substituent, ethoxy substituent, ether substituent, cyclic ether substituent, C1-C7 alkyl ether substituent, C1-C7 cycloalkyl ether substituent, aryl substituent, heteroaryl substituent, fused aryl substituent, biaryl substituent, fused aryl-heteroaryl substituent, fused diaryl substituent, fused aryl-heteroaryl substituent, 5-membered heteroaryl substituent, 6-membered heteroaryl substituent, naphthyl substituent, cycloalkyl substituent, cyclopropyl substituent, cyclobutyl substituent, cyclopentyl substituent, cyclohexyl substituent, cycloheptyl substituent, tert-butyl substituent, bicyclic aliphatic group substituent, tricyclic aliphatic group substituent, adamantyl substituent, or any combination thereof may be independently and optionally substituted with one or more of the following: C1-C 10 Straight-chain alkyl, methyl, ethyl, C1-C 10Branched alkyl, halogen, fluorine, chlorine, bromine, iodine, hydroxyl, alkoxy, methoxy, ethoxy, carbamate, urea, amide, ester, amine, trifluoromethoxy, ether, C1-C7 alkyl ether, C1-C7 cyclic ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic group, tricyclic aliphatic group, adamantyl, cyano, acetal, ketal or any combination thereof.

[0009] There is also provided a compound of formula I: Its diastereomers or enantiomers, or pharmaceutically acceptable salts of any of the foregoing, or deuterated derivatives of any of the foregoing, wherein: R1 is: C(O)OH; or C(O)OX, where X is an organic cation, an inorganic cation, Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ or Mn 2+ ; or C(O)OR3, where R3 is a straight-chain or branched alkyl, cycloalkyl, cyclic ether or straight-chain or branched alkyl ether, any of which is optionally and independently substituted; or R3 is or R3 is or C(O)N(R4R5) where R4 is H; or R4 is a straight-chain or branched alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; any of which is optionally and independently substituted; and R5 is H or absent; or R5 is a straight-chain or branched alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; any of which is optionally and independently substituted; or R5 is S(O)2alkyl; or R5 is S(O)2CF3; or R5 is S(O)2NH2; or R5 is S(O)2 cycloalkyl, S(O)2 cyclopropyl, S(O)2 cyclobutyl, S(O)2 cyclopentyl, S(O)2 cyclohexyl or S(O)2 cycloheptyl; or R5 is or R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or R5 is pyrrolidinyl; or R5 is 2-tetrahydropyranyl, 3-tetrahydropyranyl; or 4-tetrahydropyranyl; R5 is or R5 is alkylaryl or benzyl; or R5 is or R5 is 2-pyridyl, 3-pyridyl; or 4-pyridyl; or R5 is or R5 is or R5 is or R5 is or R5 is or CN; or R2 is: NH2, NHC(O)OMe or NHMe; and R6 is: H, C(O)Me or P(O)(OH)2; and R7 is: a straight-chain or branched alkyl, alkenyl or alkynyl, any of which may be optionally and independently substituted; or R7 is: and wherein the compound of formula I is not buthionine sulfoximine (BSO) or a salt of BSO.

[0010] In some cases, in the compound of formula I, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R1 is: C(O)OH; or C(O)OR3, wherein R3 is alkyl, C1-C 10 a straight-chain or branched alkyl, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, cycloalkyl, C1-C 10Cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, alkylcyclohexyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl, alkyl ether, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl, cycloalkyl ether, tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, tetrahydrofuranyl, 2-tetrahydrofuranyl, 2-tetrahydrofuranyl, alkylaryl, benzyl; wherein any of these is optionally and independently substituted by one or more deuteriums, C1-C 10 a straight-chain or branched alkyl, one or more halogens, one or more fluorines, one or more chlorines, one or more bromines, one or more iodines, aryl, C6 aryl, C 10 aryl, heteroaryl, C1-C7 alkylcycloalkyl, unsubstituted tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl or any combination thereof.

[0011] In some cases, in a compound of formula I, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R1 is C(O)N(R4R5).

[0012] In some cases, in a compound of formula I, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R1 is C(O)N(R4R5) and R5 is: heteroaryl, 2-pyridyl, 3-pyridyl or 4-pyridyl; or R5 is S(O)2Me.

[0013] In some cases, in a compound of formula I, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R7 is: C1-C 10 a straight-chain or branched alkyl, C1-C 10 a straight-chain or branched alkenyl or C1-C 10 a straight-chain or branched alkynyl, any of which may bear an alkyl ring or an alkyl ether ring containing the C1-C 10 a straight-chain or branched alkyl, the C1-C 10 a straight-chain or branched alkenyl or the C1-C 10 a straight-chain or branched alkynyl of one carbon; wherein any of the foregoing may be independently substituted by one or more of the substituents, which may be: deuterium, C1-C 10 a straight-chain alkyl, methyl, ethyl, C1-C10 branched alkyl, halogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxylic acid or a pharmaceutically acceptable salt thereof, amide, carbamate, urea, ester, alkoxy, methoxy, ethoxy, trifluoromethoxy, ether, cyclic ether, C1-C7 alkyl ether, C1-C7 cycloalkyl ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, fused aryl, biaryl, fused aryl-heteroaryl, fused diaryl, fused aryl-heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic group, tricyclic aliphatic group, adamantyl, cyano, acetal; ketal; or any combination thereof; wherein the C1-C 10 linear alkyl substituent, methyl substituent, ethyl substituent, C1-C 10 branched alkyl substituent, hydroxyl substituent, amino substituent, carboxylic acid or a pharmaceutically acceptable salt thereof substituent, amide substituent, carbamate substituent, urea substituent, ester substituent, alkoxy substituent, methoxy substituent, ethoxy substituent, ether substituent, cyclic ether substituent, C1-C7 alkyl ether substituent, C1-C7 cycloalkyl ether substituent, aryl substituent, heteroaryl substituent, fused aryl substituent, biaryl substituent, fused aryl-heteroaryl substituent, fused diaryl substituent, fused aryl-heteroaryl substituent, 5-membered heteroaryl substituent, 6-membered heteroaryl substituent, naphthyl substituent, cycloalkyl substituent, cyclopropyl substituent, cyclobutyl substituent, cyclopentyl substituent, cyclohexyl substituent, cycloheptyl substituent, tert-butyl substituent, bicyclic aliphatic group substituent, tricyclic aliphatic group substituent, adamantyl substituent, or any combination thereof may be independently and optionally substituted by one or more of the following: deuterium, C1-C 10 linear alkyl, methyl, ethyl, C1-C 10 branched alkyl, halogen, fluorine, chlorine, bromine, iodine, hydroxyl, alkoxy, methoxy, ethoxy, carbamate, urea, amide, ester, amine, trifluoromethoxy, ether, C1-C7 linear or branched alkyl ether, C1-C7 cyclic ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic group, tricyclic aliphatic group, adamantyl, cyano, acetal, ketal or any combination thereof.

[0014] In some cases, in the compound of formula I, its diastereomer or enantiomer, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R1 is:

[0015] In some cases, in the compound of formula I, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R1 is an ester or COOH.

[0016] In some cases, in the compound of formula I, the foregoing diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R2 is NH2.

[0017] In some cases, in the compound of formula I, the foregoing diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R6 is H.

[0018] In some cases, in the compound of formula I, the foregoing diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R7 is:

[0019] The present invention further provides diastereomers or enantiomers of the compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from

[0020] The present invention further provides a compound, diastereomers or enantiomers of the compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from:

[0021] The present invention further provides a compound of formula II The diastereomers or enantiomers of the compound of formula II, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein in the compound of formula II, R is C1, C2, C3, C4, C5, C6, C7, C8, C9 or C 10 a straight-chain or branched-chain alkyl group, which is optionally and independently substituted with substituents selected from: deuterium, halogen, fluorine, chlorine, C1-C 10 a straight-chain or branched-chain alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and any combination thereof.

[0022] The present invention further provides a pharmaceutical composition comprising a compound of formula I, a compound of formula II, a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, and a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical composition may be in unit dose form. Additionally, the pharmaceutical composition may comprise an additional active agent or a pharmaceutically acceptable salt thereof or a prodrug thereof. In some embodiments, the prodrug is an ester. In some embodiments, the ester is an ethyl ester or a tert-butyl ester. Furthermore, the pharmaceutical composition may be in the form of a powder, tablet, capsule, liquid or gel. In some embodiments, in the pharmaceutical composition, the compound of formula I, the compound of formula II, the compound, or a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing is present in the pharmaceutical composition in an amount in the range of about 0.001 mg to about 25,000 mg. In some embodiments, the additional active agent or a pharmaceutically acceptable salt thereof or a prodrug thereof may independently be present in the pharmaceutical composition in an amount in the range of about 0.001 mg to about 25,000 mg.

[0023] The present invention further provides a pharmaceutical composition, which comprises a compound of formula XVIII, a compound of formula XIX, a compound of formula XX, a diastereomer or enantiomer of any one of the foregoing, or a pharmaceutically acceptable salt of any one of the foregoing, or a deuterated derivative of any one of the foregoing; and a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical composition may be in unit dosage form. Additionally, the pharmaceutical composition may comprise an additional active agent or a pharmaceutically acceptable salt thereof or a prodrug thereof. In some embodiments, the prodrug is an ester. In some embodiments, the ester is an ethyl ester or a tert-butyl ester. Furthermore, the pharmaceutical composition may be in the form of a powder, tablet, capsule, liquid or gel. In some embodiments, in the pharmaceutical composition, the compound of formula I, the compound of formula II, the compound, or an enantiomer or diastereomer of any one of the foregoing, or a pharmaceutically acceptable salt of any one of the foregoing, or a deuterated derivative of any one of the foregoing is present in an amount in the range of about 0.001 mg to about 25,000 mg. In some embodiments, the additional active agent or a pharmaceutically acceptable salt thereof or a prodrug thereof may independently be present in the pharmaceutical composition in an amount in the range of about 0.001 mg to about 25,000 mg.

[0024] In some embodiments, a kit is provided, which comprises a compound of the present invention, its diastereomer, its enantiomer, its pharmaceutically acceptable salt, or its deuterated derivative, or a pharmaceutical composition of the present invention, and a container. In some embodiments, it is the pharmaceutical composition and container described herein. In some embodiments, the container is a syringe. In some embodiments, the container is an intravenous (IV) bag. In some embodiments, the container is disposable. In some embodiments, the container is recyclable. In some embodiments, the container is a disposable container. In some embodiments, the container is resealable.

[0025] In some embodiments, methods of treating a disease or disorder in a subject are provided. In some embodiments, the disease or disorder is cancer. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition herein, wherein the subject can be a subject in need thereof, thereby treating the disease or disorder, which can be cancer. In some embodiments, methods of treating a disease or disorder in a subject, wherein the subject can be a subject in need thereof, are provided, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, a compound of Formula II, a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing to treat the disease or disorder, which can be cancer. In some embodiments, the administration is selected from: oral, injection; subcutaneous, intratumoral; systemic, topical, intravenous, intraperitoneal, intramuscular and any combination thereof. In some embodiments, the subject can be a mammal. In some embodiments, the subject can be a human. In some embodiments, the subject can be male. In some embodiments, the subject can be female.

[0026] In some embodiments, methods of modulating ferroptosis in a tissue, which can be in a subject in need thereof, are provided, the method comprising contacting the tissue, directly or indirectly, optionally in a sustained manner, with the pharmaceutical composition herein in an amount effective to modulate ferroptosis in the tissue. In some embodiments, the subject can be a human. In some embodiments, the subject can be male. In some embodiments, the subject can be female.

[0027] In some embodiments, in the methods herein, the administration or the contacting can be: once daily, twice daily, three times daily, once weekly, once every two weeks, once every three weeks, once monthly, once every six months, once annually, or for life, as needed. In some embodiments, the effective or therapeutically effective amount can range from about 0.001 mg to about 25,000 mg of a compound herein, its enantiomer or diastereomer, a pharmaceutically acceptable salt of any of these, or a deuterated derivative of any of these, or the pharmaceutical composition herein, which can optionally be in unit dosage form.

[0028] In some embodiments, methods of preparing and testing a compound of Formula I and a compound of Formula II, enantiomers and diastereomers of any of these, salts and pharmaceutically acceptable salts of any of these, and deuterated derivatives of any of these are further provided.

[0029] In some embodiments, it is a compound, a diastereomer or enantiomer of the compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from:

[0030] In some embodiments, it is a compound, a diastereomer or enantiomer of the compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from:

[0031] In some embodiments, it is a compound, a diastereomer or enantiomer of the compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from:

[0032] In some embodiments, described herein is a compound of Formula XVIII: A diastereomer or enantiomer of the compound of Formula XVIII, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein in the compound of Formula XVIII: Each R1, R2 or R3 is independently: H, C1-C 10 Straight-chain or branched-chain alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C3-C 10 Heteroaryl, biphenyl, halogenated biphenyl, indole, triazole, isothiazole, oxazoline, C1-C6 straight-chain or branched-chain alkyl ether, -CH3, phenyl, -C(O)OR5, -C(O)NH2, -O-, -S-, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, -Cl, -Br, -I; Or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, and wherein the C3-C6 cycloalkyl may optionally be substituted by C1-C6 straight-chain or branched-chain alkyl, C1-C6 cycloalkyl, halogen, -CF3 or -F, Or R1 and R2 and R3 together form a C3-C6 cycloheteroaryl; and Wherein each R1, R2 or R3 is independently and optionally substituted by a substituent selected from: deuterium, halogen, fluorine, -CF3, chlorine, C1-C10 A straight-chain or branched-chain alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, a C3-C6 cycloalkyl group, phenyl, halogenated phenyl, biphenyl, halogenated biphenyl, isothiazole, triazole, furan, oxazoline, a C3-C6 heteroaryl group, urea, acid anhydride, and any combination thereof; wherein R4 is H or a C1-C6 straight-chain or branched-chain alkyl group; and wherein R5 is C1-C 10 A straight-chain or branched-chain alkyl group, which is optionally substituted by at least one heteroatom, halogen, or C1-C3 alkyl ether.

[0033] In some embodiments, it is a compound of formula XIX: A diastereomer or enantiomer of the compound of formula XIX, or a pharmaceutically acceptable salt of any one of the foregoing, or a deuterated derivative of any one of the foregoing; wherein in the compound of formula XIX: Each R1, R2, or R3 is independently: H, C1-C 10 A straight-chain or branched-chain alkyl group, a C3-C6 cycloalkyl group, a C6-C 10 An aryl group, a C3-C 10 A heteroaryl group, biphenyl, halogenated biphenyl, indole, triazole, isothiazole, oxazoline, a C1-C6 straight-chain or branched-chain alkyl ether, -C(O)OR5, -C(O)NH2, -O-, -S-, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, -Cl, -Br, -I, or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl group, and wherein the C3-C6 cycloalkyl group may optionally be substituted by a C1-C6 straight-chain or branched-chain alkyl group, a C1-C6 cycloalkyl group, halogen, -CF3, or -F, or R1 and R2 and R3 together form a C3-C6 cycloheteroaryl group; and wherein each R1, R2, or R3 is independently and optionally substituted by a substituent selected from: deuterium, halogen, fluorine, -CF3, chlorine, a C1-C 10 A straight-chain or branched-chain alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, a C3-C6 cycloalkyl group, phenyl, halogenated phenyl, biphenyl, halogenated biphenyl, isothiazole, triazole, furan, oxazoline, a C3-C6 heteroaryl group, urea, acid anhydride, and any combination thereof; wherein R4 is H or a C1-C6 straight-chain or branched-chain alkyl group; and wherein R5 is C1-C 10 A straight-chain or branched-chain alkyl group, which is optionally substituted by at least one heteroatom, halogen, or C1-C3 alkyl ether.

[0034] In some embodiments, it is a compound of formula XX: a diastereomer or enantiomer of the compound of formula XX, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein in the compound of formula XX: each R1, R2 or R3 is independently: H, C1-C4 straight-chain or branched-chain alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C5-C6 heteroaryl, biphenyl, halogenated biphenyl, triazole, isothiazole, oxazoline, C1-C6 straight-chain or branched-chain alkyl ether, -C(O)OR5, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, and wherein the C3-C6 cycloalkyl may optionally be substituted by C1-C6 straight-chain or branched-chain alkyl, C1-C6 cycloalkyl, halogen, -CF3 or -F; and wherein each R1, R2 or R3 is independently and optionally substituted by a substituent selected from: deuterium, halogen, fluorine, -CF3, chlorine, C1-C 10 straight-chain or branched-chain alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, C3-C6 cycloalkyl, phenyl, halogenated phenyl, biphenyl, halogenated biphenyl, isothiazole, triazole, oxazoline, C3-C6 heteroaryl and any combination thereof; wherein R4 is H or C1-C6 straight-chain or branched-chain alkyl; and wherein R5 is C1-C 10 straight-chain or branched-chain alkyl, which is optionally substituted by at least one heteroatom, halogen or C1-C3 alkyl ether.

[0035] In some embodiments, it is a pharmaceutical composition comprising a compound of Formula XVIII, XIX, XX or a compound described herein, a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; and a pharmaceutically acceptable excipient, diluent or carrier. In some embodiments, the pharmaceutical composition is in unit dosage form. In some embodiments, the pharmaceutical composition further comprises an additional active agent or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is in the form of a powder, tablet, capsule, liquid or gel. In some embodiments, the pharmaceutical composition is present in the pharmaceutical composition in an amount in the range of about 0.001 mg to about 25,000 mg. In some embodiments, it is a kit comprising the pharmaceutical composition described herein and a container. In some embodiments, the container is a syringe. In some embodiments, the container is an IV bag. In some embodiments, the container is disposable. In some embodiments, the container is a disposable container. In some embodiments, the container is a resealable container.

[0036] Also described herein is a method of treating cancer in a subject. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein, thereby treating the cancer. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of Formula XVIII, Formula XIX, Formula XX or a compound described herein; a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, thereby treating the cancer. In some embodiments, the cancer is carcinoma, sarcoma or melanoma. In some embodiments, the carcinoma is liver cancer. In some embodiments, the cancer is clear cell renal carcinoma or non-clear cell renal carcinoma. In some embodiments, the cancer is a cancer lacking the SWI / SNF complex. In some embodiments, the administration is selected from: oral, injection; subcutaneous, intratumoral; systemic, topical, intravenous, intraperitoneal, intramuscular and any combination thereof.

[0037] The present invention also describes methods of modulating ferroptosis in a tissue, the methods comprising contacting the tissue with a pharmaceutical composition described herein in an amount effective to modulate ferroptosis in the tissue. In some embodiments, the tissue is comprised in a subject. In some embodiments, the subject is a subject in need thereof. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the administration or the contacting is: once daily, twice daily, three times daily, once weekly, once every two weeks, once every three weeks, once monthly, once every six months, once annually, or for life, as needed. In some embodiments, the therapeutically effective amount or the effective amount ranges from about 0.001 mg to about 25,000 mg.

[0038] The present invention also describes methods of treating a disease or disorder in a subject, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein, thereby treating the disease or disorder. The present invention also describes methods of treating a disease or disorder in a subject, the methods comprising administering, in a therapeutically effective amount, a pharmaceutical composition described herein, a diastereomer or an enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, thereby treating the disease or disorder. In some embodiments, the disease or disorder is fibrosis or a kidney disease. Brief Description of the Drawings

[0039] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that illustrates exemplary embodiments, in which the principles of the present disclosure are utilized, and to the accompanying drawings, in which:

[0040] Figure 1 is a schematic diagram of the ferroptosis pathway.

[0041] Figures 2A - 2B Shows the tumor response after exposure to (1) BSO or (2) BSO + lip-1 or fer-1 for a period of time. Figure 2A Shows cleaved caspase-3 staining. Figure 2B Shows a graph depicting the fractional survival rate (y-axis) of cells exhibiting BSO and BSO + fer-1 over time (x-axis).

[0042] Figure 3 Shows the tumor response after exposure to (1) ML-210 or (2) ML-210 + lip-1 for 24 hours. The drugs were loaded to a concentration of 1-10 μM for both ML-210 and lip-1. Staining shows cleaved caspase-3. The dashed line indicates the drug exposure area. Scale bar: 100 micrometers (μm).

[0043] Figure 4 Shows the dose - response curves of BSO and RSL3 on the fractional cell viability (y - axis) normalized to DMSO. The x - axis shows the drug concentration.

[0044] Figures 5A - 5B Shows the tumor response after 24 - hour exposure to (1) RSL3 or (2) RSL3 + lip - 1. The drugs were loaded to achieve a concentration of 1 - 10 μM for both RSL3 and lip - 1. Figure 5A Shows tumor sections stained for cleaved caspase - 3. The dashed line indicates the drug - exposed area. Scale bar: 100 micrometers (μm). Figure 5B Shows representative H&E images 18 hours after treatment with (1) RSL3 or (2) RSL3 + lip - 1, as shown.

[0045] Figures 6A - 6B Is a schematic structure diagram of compound 322 analyzed by X - ray crystallography. Figure 6A Shows the absolute configuration of compound 322. Figure 6B Shows the ORTEP structure of compound 322.

[0046] Figures 7A - 7B Is a schematic structure diagram of compound 324 analyzed by X - ray crystallography. Figure 7A Shows the absolute configuration of compound 324. Figure 7B Shows the ORTEP structure of compound 324.

[0047] Figures 8A - 8B Is a schematic structure diagram of the hydrate of compound 328 analyzed by X - ray crystallography. Figure 8A Shows the absolute configuration of the hydrate of compound 328. Figure 8B Shows the ORTEP structure of the hydrate of compound 328.

[0048] Figures 9A - 9B Is a schematic structure diagram of compound 348 analyzed by X - ray crystallography. Figure 9A Shows the absolute configuration of compound 348. Figure 9B Shows the ORTEP structure of compound 348. Detailed description of the disclosure

[0049] The following description and examples detail embodiments of the present disclosure. It should be understood that the present disclosure is not limited to the specific embodiments described herein and can thus vary. There are various variations and modifications that are included within the scope of the present disclosure. Definitions

[0050] Throughout this disclosure, various embodiments may 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 embodiment. Thus, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual values down to one-tenth of the lower limit unit of the range, unless the context clearly dictates otherwise. For example, a description of a range such as 1 to 6 should be considered to have specifically disclosed sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual values within the range, such as 1.1, 2, 2.3, 5, or 5.9. This applies regardless of how large the range is. The upper and lower limits of these intermediate ranges may be independently included in a smaller range and are also covered within this disclosure, subject to any specific exclusions of the range. When the range includes one or both of the limits, ranges excluding one or both of the included limits are also included in this disclosure, unless the context clearly dictates otherwise.

[0051] Unless specifically stated or obvious from the context, as used herein, the term “about” should be understood to be within the normal tolerances in the art, for example within 2 standard deviations of the mean. “About” can be understood as within plus or minus of the stated value: 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%. All numerical values provided herein are modified by the term “about” unless the context clearly dictates otherwise. When a particular value is described in the application and claims, the term “about” is implicit and means within the acceptable error range of the particular value, unless otherwise stated.

[0052] Unless otherwise stated, the structures described herein are also intended to include all isomers of the structure (e.g., enantiomers, diastereomers, geometric (or conformational) forms; e.g., L and D nomenclature for each asymmetric center, R and S configurations for each asymmetric center, each asymmetric center, (Z) and (E) carbon-carbon double bond isomers, R and S configurations for each sulfoximine sulfur atom center, and (Z) and (E) conformational isomers. Thus, single stereochemical (enantiomeric, diastereomeric) isomers (enantiomers, diastereomers) of the compounds of the invention, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures are within the scope of this disclosure. Unless specifically defined, each independent stereocenter may include a mixture of its stereoisomers or a pure stereoisomer.

[0053] Unless otherwise indicated, compounds having one or more asymmetric centers as referred to herein include enantiomerically pure, diastereomeric, diastereomerically pure, enantiomerically enriched, diastereomerically enriched, and racemic mixtures thereof.

[0054] As used herein, the term "adjacent" and its grammatical equivalents refer to being immediately adjacent to a reference subject. For example, in the context of a cell or tissue, the term "adjacent" can mean that there are no other cells or tissues therebetween.

[0055] The following structural aspects: Bonds used in the structural formulas herein to denote attachment points as moieties or substituents to a core or backbone structure.

[0056] As used herein, the term "analogue" and its grammatical equivalents refer to molecules that are not identical but have similar structural features. An analogue of a drug or agent is a drug or agent related to a reference agent, but which may have a different chemical structure. The analogue exhibits activity similar to that of the reference drug or formulation, but the activity may be increased or decreased or otherwise modified. An analogue form of a compound or drug can mean that the backbone core of the structure is modified or altered compared to the reference drug.

[0057] As used herein, the term "prodrug" is a first molecule that undergoes a chemical change after administration to a subject to form a second molecule, where the second molecule is a bioactive agent.

[0058] As used herein, the term "anticancer agent" or "chemotherapeutic agent" and its grammatical equivalents refer to an agent capable of killing rapidly dividing cells (e.g., cancer cells), preventing rapidly dividing cells from further dividing, or slowing the division of rapidly dividing cells. Exemplary anticancer agents provided herein may include ferroptosis inducers, may be used in combination with one or more additional ferroptosis inducers, may be used in combination with iron-dependent cell death inducers, and / or may be used in combination with a second therapeutic agent or second active agent. The second therapeutic agent or second active agent may be in the form of a prodrug. The second therapeutic agent or second active agent may be in the form of a pharmaceutically acceptable salt. The second therapeutic agent or second active agent may be an alkylating agent, such as nitrogen mustard, may be chlorambucil, cyclophosphamide, ifosfamide, melphalan, or bisulfan; a nitrosourea, which may be, for example, streptozocin, carmustine, or lomustine; an alkyl sulfonate, such as busulfan; a triazine, such as dacarbazine or temozolomide; or an ethyleneimine, such as thiotepa or altretamine. The second therapeutic agent or second active agent may be an antimetabolite, which may be a purine antagonist, a pyrimidine antagonist, or a folic acid antagonist, such as 5-fluorouracil, 6-mercaptopurine, capecitabine, cladribine, or clofarabine. The second therapeutic agent or second active agent may be an antitumor antibiotic. The second therapeutic agent or second active agent may be a mitotic inhibitor. The second therapeutic agent or second active agent may be a corticosteroid. The second therapeutic agent or second active agent may be a plant alkaloid, such as actinomycin D, doxorubicin, or mitomycin, such as mitomycin C. The second therapeutic agent or second active agent may be an antitumor antibiotic, such as, doxorubicin, mitoxantrone, or bleomycin. The second therapeutic agent or second active agent may be, for example, nitrogen mustard, leucovorin, methotrexate, mercaptopurine, busulfan, chlorambucil, cyclophosphamide, vincristine, actinomycin, 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, topotecan, idarubicin, capecitabine, daunorubicin, valrubicin, temozolomide, cytarabine, epirubicin, arsenic trioxide, mitomycin, oxaliplatin, pemetrexed disodium, clofarabine, nelarabine, ixabepilone, bendamustine hydrochloride, methotrexate, cabazitaxel, erbulin mesylate, asparagine, omacetaxine mepesuccinate, radium dichloride 223, fluoxymesterone, methyltestosterone, tamoxifen, tamoxifen citrate, estramustine, interferon alpha 2b (recombinant), goserelin, flutamide, altiratinib, bicalutamide, anastrozole, porphyrin, nilutamide, imiquimod, letrozole, rituximab.Tamoxifen, thalidomide, trastuzumab emtansine, alitretinoin, bexarotene, denileukin diftitox, exemestane, gemtuzumab ozogamicin, exemestane, gemtuzumab ozogamicin, triptorelin, alendronate, imatinib, imatinib mesylate, peginterferon alfa-2b, fulvestrant, iron, iron-containing nanoparticles, ibritumomab tiuxetan, leuprorelin, leuprorelin acetate, abarelix, bortezomib, gefitinib, tositumomab and iodine I 131, tositumomab, bevacizumab, cetuximab, erlotinib, erlotinib hydrochloride, lenalidomide, sorafenib, sorafenib tosylate, dasatinib, decitabine, panitumumab, sunitinib, sunitinib malate, vorinostat, lapatinib, lapatinib ditosylate, nilotinib, temsirolimus, degarelix, everolimus, ofatumumab, pazopanib, pazopanib hydrochloride, romidepsin, denosumab, hydroxyurea, spuleucel-T, abiraterone, abiraterone acetate, brentuximab vedotin, crizotinib, ipilimumab, ruxolitinib, ruxolitinib phosphate, vandetanib, vemurafenib, pertuzumab, axitinib, bosutinib, cabozantinib, carfilzomib, enzalutamide, ponatinib, ponatinib hydrochloride, regorafenib, vismodegir, ziv-aflibercept, dabrafenib, trametinib, obinutuzumab, ado-trastuzumab emtansine, afatinib, ibrutinib, pomalidomide, idelalisib, belinostat, ceritinib, pembrolizumab, ramucirumab, lanreotide, blinatumomab, nivolumab, olaparib, checkpoint inhibitors, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, 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, ciltacabtagene autoleucel, the compounds of Table 1, their enantiomers or diastereomers, pharmaceutically acceptable salts of any of the foregoing, or deuterated derivatives of any of the foregoing, or any combination of the foregoing.

[0059] As used herein, the term "cancer" and its grammatical equivalents refer to the excessive proliferation of cells, the unique feature of which - loss of normal control - leads to uncontrolled growth, lack of differentiation, local tissue invasion, and metastasis. For the methods provided herein, cancer can be any cancer, including but not limited to any of the following: acute lymphocytic carcinoma, acute myeloid leukemia, alveolar rhabdomyosarcoma, bladder cancer, bone cancer, brain cancer, breast cancer, anal cancer, anal canal cancer, rectal cancer, eye cancer, intrahepatic bile duct cancer, joint cancer, cervical cancer, gallbladder cancer, or pleural cancer, nasal cancer, nasal cavity cancer, or middle ear cancer, oral cancer, vulvar cancer, chronic lymphocytic leukemia, chronic myeloid carcinoma, colon cancer, esophageal cancer, cervical cancer, fibrosarcoma, gastrointestinal cancer, Hodgkin lymphoma, hypopharyngeal cancer, kidney cancer, laryngeal cancer, leukemia, liquid tumor, liver cancer, lung cancer, lymphoma, malignant mesothelioma, mast cell tumor, melanoma, dedifferentiated melanoma, multiple myeloma, nasopharyngeal cancer, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, peritoneal cancer, omental cancer, mesenteric cancer, pharyngeal cancer, prostate cancer, colorectal cancer, kidney cancer, kidney cancer, non-clear cell renal cell carcinoma, clear cell renal cell carcinoma, skin cancer, small intestine cancer, soft tissue cancer, solid tumor, stomach cancer, testicular cancer, thyroid cancer, ureteral cancer, and / or bladder cancer. As used herein, the term "tumor" refers to the abnormal growth of cells or tissues, such as of the malignant type or the benign type. Any cancer or tumor condition, tumor, or population of cancer cells can be SWI / SNF-deficient. In some cases, any cancer or tumor condition, tumor, or population of cancer cells is not SWI / SNF-deficient.

[0060] As used herein, the term "chemoresistant cancer" and its grammatical equivalents refer to a cancer that does not respond or exhibits a reduced response to one or more chemotherapeutic agents.

[0061] The term "effective amount" or "therapeutically effective amount" and its grammatical equivalents refer to an amount sufficient to achieve or at least partially achieve the desired effect.

[0062] As used herein, the term "expression" and its grammatical equivalents refer to the biosynthesis of a gene product. For example, in the case of a structural gene, expression involves the transcription of the structural gene into mRNA and the translation of the mRNA into one or more polypeptides.

[0063] The term "ferroptosis" refers to a form of cell death that involves the production of iron-mediated reactive oxygen species and is characterized in part by lipid peroxidation. The term "ferroptosis inducer" or "ferroptosis activator" or "ferroptosis inducer" or "ferroptosis-inducing compound" or "ferroptosis regulator" refers to an agent that promotes or activates or regulates ferroptosis in cells.

[0064] In some embodiments, the compound or its salt may include an enantiomerically pure form. In some instances, the compounds or salts thereof disclosed herein may have an enantiomeric excess of greater than or equal to about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99%. The compound or its salt may be administered in its enantiomerically or diastereomerically pure form. In certain cases, the percent enantiomeric excess may be defined as: % ee = (|F R - F S | × 100), where F R is the mole fraction of the compound having the R stereocenter and F S is the mole fraction of the compound having the S stereocenter, and the two vertical lines denote taking the absolute value of the difference.

[0065] The diastereomeric excess or de (diastereomeric excess) value may indicate the excess of diastereomers in a diastereomeric mixture. It may be defined as: where m1 is the mass of the excess diastereomer and m2 is the mass of the deficient diastereomer. In some instances, the compound as a diastereomer or its salt or its pharmaceutically acceptable salt or its deuterated derivative may have a diastereomeric excess of greater than or equal to about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95% or 99%. For a 1:1 mixture of two diastereomers, de = 0%, and for a diastereomerically pure compound de = 100%.

[0066] As used herein, the term "hyperproliferative cell" and its grammatical equivalents refer to cells characterized by unwanted cell proliferation or an abnormally high rate or continuous cell division, which is independent or uncoordinated with the cell division of the surrounding normal tissue.

[0067] As used herein, the term "in vitro" and its grammatical equivalents refer to events that occur in an artificial environment, such as in a test tube or reaction vessel, in cell culture, etc., rather than events that occur in a multicellular organism.

[0068] As used herein, the term "in vivo" and its grammatical equivalents refer to events that occur in a multicellular organism (such as a non-human animal).

[0069] As used herein, the term "iron-dependent cell death agent" and its grammatical equivalents refer to an agent that induces, promotes, or activates iron-mediated cell death. In some cases, in the present disclosure, the term "iron-dependent cell death agent" is used interchangeably with ferroptosis inducer.

[0070] As used herein, the term "normal cell" and its grammatical equivalents refer to a cell that undergoes controlled cell division, a cell with controlled activation, or a quiescent cell.

[0071] The compounds herein are intended to include all isotopes of the atoms that occur in the compounds herein. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example but not limited thereto, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon may include 13 C, 14 C, 15 N, 31 P or 32 P. Isotopically labeled compounds can generally be prepared using an appropriate isotopically labeled reagent in place of the unlabeled reagent. For example, methyl also includes deuterated methyl, such as -CD3.

[0072] The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit any embodiment. As used herein, the singular forms "a", "an", and "the" are also intended to include the plural forms unless the context clearly dictates otherwise. It should also be understood that when the terms "comprises" and / or "comprising" are used in this specification, the presence of the specified features, integers, steps, operations, elements, and / or components is indicated, but one or more other features, integers, steps, operations, elements, components, and / or groups thereof are not excluded. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0073] The compounds described herein can be described as showing stereochemistry using a wedged dashed bond or a wedged solid bond, as shown below. For compounds having a stereogenic atom, when only one substituent is represented by a wedged dashed bond or a wedged solid bond, the fourth substituent can be interpreted as having an opposite orientation in space. Thus, the two exemplary structures shown below can be interpreted interchangeably.

[0074] For compounds having a stereogenic sulfoximine sulfur atom, when both substituents are represented by a wedged dashed bond or both are represented by a wedged solid bond, the third and fourth substituents can be interpreted as having an opposite orientation in space. Thus, the two exemplary structures shown below can be interpreted interchangeably. The left structure contains an oxo group in the plane, a double-bonded NH group in the plane, an R group out of the plane, and a saturated carbon substituent out of the plane. Overview

[0075] The present disclosure provides compounds, compositions comprising the compounds, and pharmaceutical compositions comprising the compounds, as well as methods of using these compositions to treat a disease or disorder in a subject. The compounds can be or include one or more compounds of Formula I, one or more compounds of Formula II, enantiomers of any of these, diastereomers of any of these, pharmaceutically acceptable salts of any of these, or deuterated derivatives of any of these, optionally in combination with a second therapeutic agent or second active agent. The composition or pharmaceutical composition can comprise any one or more of these. The disease or disorder can be cancer, e.g., in a tissue of a subject. The cancer can be in a mammal, or in a tissue of a mammal, which can be a human, and the mammal can be male or female. The disease or disorder can be an inflammatory disease or fibrosis, and the subject can be in need thereof and can be a mammal, a human, female or male.

[0076] The present disclosure further provides compounds, compositions comprising the compounds, and pharmaceutical compositions comprising the compounds, as well as methods of using these to modulate, inhibit or partially inhibit a target comprising glutamate-cysteine ligase (GCL), e.g., in a subject, optionally in a tissue. The compounds can be or include one or more compounds of Formula I, one or more compounds of Formula II, enantiomers of any of these, diastereomers of any of these, pharmaceutically acceptable salts of any of these, or deuterated derivatives of any of these, optionally in combination with a second therapeutic agent or second active agent. The subject can be in need thereof and can be a mammal, a human, female or male.

[0077] The present disclosure further provides compounds, compositions comprising the compounds, and pharmaceutical compositions comprising the compounds, as well as methods of preparing the compounds and the compositions comprising the compounds, and methods of using these to modulate or induce ferroptosis, optionally in a subject, optionally in a tissue. The compounds can be or include one or more compounds of Formula I, one or more compounds of Formula II, their enantiomers, their diastereomers, pharmaceutically acceptable salts of any of these, or deuterated derivatives of any of these, optionally in combination with a second therapeutic agent or second active agent. The subject can be in need thereof and can be a mammal, a human, female or male.

[0078] The present disclosure further provides treatment regimens for treating various diseases or disorders in a subject, such as cancer, inflammatory diseases, or fibrosis, or for modulating, inhibiting, or partially inhibiting GCL, or for modulating or inducing ferroptosis. The treatment regimens may include administering a compound of Formula I, a compound of Formula II, an enantiomer of any of these, a diastereomer of any of these, a pharmaceutically acceptable salt of any of these, or a deuterated derivative of any of these, optionally in combination with a second therapeutic agent or second active agent. Briefly, further described herein are (1) methods of characterizing ferroptosis-sensitive cells; (2) cell death inducers, including ferroptosis inducers and chemotherapeutic agents; (3) pharmaceutical compositions; (4) dosages; (5) methods of administration; (6) efficacy; (7) therapeutic applications; and (8) systems.

[0079] The compound, its enantiomer, its diastereomer, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing may be a sulfoximine. In some cases, the sulfoximine may not include BSO.

[0080] The subject herein may be a subject in need thereof, may be a mammal, may be a human, and may be male or female. The subject herein may be diagnosed with a disease or disorder prior to being treated, administered, or exposed to a compound of Formula I, a compound of Formula II, an enantiomer or diastereomer of any of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, a deuterated derivative of any of the foregoing, or a composition or pharmaceutical composition comprising any of the foregoing. The diagnosis may be from an in vitro diagnosis, or an in vitro diagnosis, which may be a companion diagnosis.

[0081] When two or more compounds of Formula I, Formula II, an enantiomer of any of the foregoing, a diastereomer of any of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing are included in a composition or pharmaceutical composition, the composition may be a fixed-dose combination drug.

[0082] When two, three, four, five, six, seven, eight, nine, or ten compounds, therapeutic agents, second therapeutic agents, or second active agents herein are administered to a cell, tissue, or subject, the compounds may be administered simultaneously or sequentially. When administered simultaneously, the administration may be as a single composition or pharmaceutical composition, which may be a fixed-dose combination drug.

[0083] Compounds such as those of formula I and formula II, medicaments, therapeutic agents, enantiomers or diastereomers of any of these, salts and pharmaceutically acceptable salts of any of these, and deuterated derivatives of any of these may be administered independently either continuously or discontinuously. Compounds such as those of formula XVIII, formula XIX and formula XX, medicaments, therapeutic agents, enantiomers or diastereomers of any of these, salts and pharmaceutically acceptable salts of any of these, and deuterated derivatives of any of these may be administered independently either continuously or discontinuously. When administered discontinuously, they may be administered at regular or irregular time intervals. Continuous and discontinuous administration may result in a baseline level of the compound or medicament that is continuously present in the cells, tissues, organs or systems. For example, the baseline level may be achieved for about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 or more hours. The administration may be independently by any route of administration and may be, for example, oral, intravenous, subcutaneous, intramuscular, intraperitoneal, intratumoral, intertumoral, administration to the brain or central nervous system, bladder, organ or part thereof, tissue or part thereof, or any combination of these. When administered as a solution, compounds such as those of formula I and formula II, medicaments, therapeutic agents, enantiomers or diastereomers of any of these, salts and pharmaceutically acceptable salts of any of these, and deuterated derivatives of any of these may independently have, for example, a concentration of about: 0.01 μM, 0.1 μM, 1.0 μM, 2.0 μM, 3.0 μM, 4.0 μM, 5.0 μM, 6.0 μM, 7.0 μM, 8.0 μM, 9.0 μM, 10 μM, 20 μM, 30 μM, 40 μM, 50 μM, 60 μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, 500 μM or higher.

[0084] In some embodiments, a compound of Formula I, a compound of Formula II, any compound or agent or therapeutic agent herein, an enantiomer of any of the foregoing, a diastereomer of any of the foregoing, a salt or pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing may be included as a ligand in a proteolysis targeting chimera (PROTAC) protein degrader. In some cases, a bifunctional PROTAC molecule may comprise a ligand of a target protein (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). In some cases, the POI may be any protein herein. In some cases, the POI may be cystine-glutamate antiporter (system Xc), glutathione peroxidase 4 (GPX4), p53, cargo receptor NCOA4, glutathione synthetase (GSH), or glutamate-cysteine ligase (GCL). Inactivation or inhibition of some of these molecules, such as system Xc, GPX4, or glutathione synthetase PROTAC protein degraders, may act by recruiting a selected E3 ligase into close proximity with a particular pathogenic protein so that it can be tagged with ubiquitin and sent for degradation by the proteasome. After protein degradation, the PROTAC may be released to continue to effect further degradation.

[0085] In some embodiments, the compounds described herein may be part of an antibody-drug conjugate (ADC), wherein the compound is optionally linked to the antibody via a linker.

[0086] In some cases, a compound of Formula I, a compound of Formula II, any compound or agent or therapeutic agent herein, an enantiomer of any of the foregoing, a diastereomer of any of the foregoing, a salt or pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing may be delivered directly to a tissue, tumor, or cell using a system comprising, for example, a pump, such as a micropump or an infusion pump, and at least one needle, hollow tube, and any combination thereof.

[0087] When the sulfoximine is described as a chemical structure, such as in the case of a compound of Formula I: Unless otherwise expressly stated, R6 denotes the presence of the substituent R6, and the imines containing R6 encompass (E), (Z), and mixtures of (E) and (Z) configurations. Ferroptosis

[0088] Cell death is a cellular process involved in development, cellular homeostasis, and the prevention of proliferative diseases such as cancer. Programmed cell death can take different forms, such as apoptosis, mitotic catastrophe, necrosis, senescence, and autophagy. Although each of these processes ultimately leads to cell death, the pathways and mechanisms appear to be unique at the molecular and cellular levels.

[0089] Ferroptosis is a non-apoptotic, oxidative form of regulated cell death involving the accumulation of lipid hydroperoxides and lipid peroxides on the cytoplasmic membrane. Cells undergoing ferroptosis do not exhibit cellular features or functions associated with apoptosis (the typical form of cell death). Examples of apoptotic cell features include, for example, mitochondrial cytochrome c release, caspase activation, and chromatin fragmentation. Another characteristic of ferroptosis is an elevated level of intracellular reactive oxygen species (ROS), which can be prevented by iron chelation and genetic inhibition of cellular iron uptake. The addition of iron (but not other divalent transition metal ions) can enhance ferroptosis signaling in cells.

[0090] Cellular components involved in and regulating ferroptosis include the cystine-glutamate antiporter (system Xc-), glutathione peroxidase 4 (GPX4), p53, the cargo receptor NCOA4, glutathione synthetase (GSH), and glutamate-cysteine ligase (GCL). Inactivation or inhibition of some of these molecules (such as system Xc-, GPX4, or glutathione synthetase) leads to iron-dependent cell death or ferroptosis.

[0091] Hyperproliferative cells in a drug-resistant state, such as drug-resistant cancer cells, have been found to exhibit dysregulation of the apoptotic cell pathway. Surprisingly, the resistance of hyperproliferative cells to apoptotic agents can enhance the ability to undergo ferroptosis. Due to their "flammable" ferroptosis-sensitive state, anti-apoptotic cells can be killed by ferroptosis induction. Methods for characterizing ferroptosis-sensitive cells

[0092] The present disclosure provides methods for identifying and characterizing ferroptosis-sensitive cells in a subject. In some embodiments, the characterization is performed prior to treating the subject with a ferroptosis inducer provided herein. Ferroptosis-sensitive cells can be identified by the following characteristics provided herein: (1) a selenium concentration that is higher than the selenium concentration in the corresponding normal cells; (2) an iron concentration that is higher than the iron concentration in the corresponding normal cells; (3) a polyunsaturated fatty acid (PUFA) concentration that is higher than the PUFA concentration in the corresponding normal cells; (4) a peroxidation index (PI) that is greater than the PI in the corresponding normal tissue; and / or (5) the expression of one or more markers indicative of a mesenchymal state in addition to other morphological and histological features. Methods for measuring the analyte concentrations of selenium, iron, and PUFA include, for example, mass spectrometry, chromatography, immunoassay, immunosorbent assay, absorbance and colorimetric assays, and microwave plasma-atomic emission spectrometry. Methods for measuring markers of mesenchymal cell state include, for example, immunoassay, polymerase chain reaction (PCR) assay, and sequencing assay. (1) Selenium (Se) concentration and selenoproteins

[0093] Selenium (Se) is a micronutrient that promotes the synthesis of selenoproteins in cells. Dietary selenium is present in meat, nuts, grains, mushrooms, and vegetables. The selenium content in the human body is about 13 milligrams (mg) to 20 mg. Selenium is involved in the cellular processes of selenoprotein synthesis and ferroptosis. Selenoproteins are rare proteins that contain a selenocysteine (Sec) residue at the position of cysteine. Non-limiting examples of selenoproteins include GPX1, GPX2, GPX3, GPX4, GPX6, TXNRD1, TXNRD2 (TXRD2), TXNRD3, DIO1, DIO2, DIO3, SEPHS2, SEPS1, SEPP1, SEP15, SEPN1 (SELENON), SEPX1, SEPW1 (SELENOW), SEPT1, SELH, SELI, SELK, SELM (SELENOM), SELO, and SELV. Selenoproteins exhibit biochemical activities such as redox, selenocysteine synthesis, and / or selenium transport. GPX4 is a phospholipid hydroperoxidase that catalyzes the reduction of hydrogen peroxide and organic peroxides, thereby protecting cells from membrane lipid peroxidation and oxidative stress. GPX4 is a regulator of the ferroptosis pathway, and inhibition of GPX4 induces ferroptotic cell death.

[0094] The present invention provides a method for identifying ferroptosis-sensitive cells in mammalian tissues by the concentration of selenium. In some embodiments, the method provided herein includes measuring the concentration of selenium (Se) in a cell, a plurality of cells, or a mammalian tissue. In some embodiments, the Se concentration in one or more cells of a mammalian tissue is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% higher than the Se concentration in the cells of healthy tissue. In some embodiments, the Se concentration in a plurality of cells of the mammalian tissue is 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100% higher than the Se concentration in the cells of healthy tissue. In some embodiments, the method provided herein includes administering to a mammal an effective amount of a ferroptosis inducer, wherein the selenium concentration in a plurality of cells of the mammalian tissue is higher than the selenium concentration in the cells of normal or healthy tissue; and inducing ferroptosis in the plurality of cells. (2) Iron concentration

[0095] Ferroptosis is an iron-dependent cellular process, and the intracellular iron concentration is increased in ferroptosis-sensitive cells compared to normal cells. Treatment of cells with deferoxamine (DFO), an iron chelator used to treat iron overload and reported to be an agent that blocks ferroptosis, can inhibit cell death. Alternatively, loading iron into cells by treatment with ferric ammonium citrate (FAC) is sufficient to mimic particle treatment and induce ferroptosis in amino acid-starved cells. Increased iron uptake in cells can lead to depletion of glutathione, which may be due to increased ROS generation leading to ferroptosis induction.

[0096] The present disclosure provides methods for identifying ferroptosis-sensitive cells in mammalian tissues by iron concentration. In some embodiments, the methods provided herein include measuring the concentration of iron or iron oxide in a cell, a plurality of cells, or a mammalian tissue. In some embodiments, ferroptosis-sensitive cells have an increased intracellular iron concentration that is at least about 7 parts per billion (ppb) or higher, about 8 ppb or higher, about 9 ppb or higher, about 10 ppb or higher, about 20 ppb or higher, about 30 ppb or higher, about 40 ppb or higher, about 50 ppb or higher, about 60 ppb or higher, about 70 ppb or higher, about 80 ppb or higher, about 90 ppb or higher, about 100 ppb or higher, about 110 ppb or higher, about 120 ppb or higher, about 130 ppb or higher, about 140 ppb or higher, about 150 ppb or higher, about 160 ppb or higher, up to 170 ppb. In some embodiments, ferroptosis-sensitive cells have an increased intracellular iron concentration that is at least about 2 micromolar (μM) or higher, 2.5 μM or higher, 3.0 μM or higher, 4.0 μM or higher, 5.0 μM or higher, up to 10 μM higher than that of normal cells. In some embodiments, the iron concentration in one or more cells of a mammalian tissue is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% higher than the iron concentration in cells of healthy tissue. In some embodiments, the iron concentration in a plurality of cells of the mammalian tissue is 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100% higher than the iron concentration in cells of healthy tissue. In some embodiments, the methods provided herein include administering to a mammal an effective amount of a ferroptosis inducer, wherein the iron concentration in a plurality of cells of the mammalian tissue is higher than the iron concentration in cells of normal or healthy tissue; and inducing ferroptosis in the plurality of cells. (3) PUFA status

[0097] Anti-apoptotic cells gain an advantage by being in a ferroptosis-sensitive state and having a high level of polyunsaturated fatty acids (PUFAs). Due to their "flammable" high-PUFA state, anti-apoptotic cells can be killed by ferroptosis induction. The flammable state is defined by a high membrane abundance of PUFAs (relative to MUFAs, monounsaturated fatty acids), which are prone to uncontrolled lipid peroxidation—a free radical chain reaction of polyunsaturated fatty acids—that leads to ferroptotic cell death.

[0098] PUFAs are classified as ω-3 (n-3) or ω-6 (n-6) according to the position of the last double bond relative to the terminal methyl group of the molecule. Non-limiting examples of PUFAs include: hexadecatrienoic acid (HTA), α-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA, eicosapentaenoic acid), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA, clupanodonic acid), docosahexaenoic acid (DHA, docosahexaenoic acid), tetracosahexaenoic acid (nisinic acid), tetracosapentaenoic acid, linoleic acid (LA), γ-linolenic acid (GLA), eicosadienoic acid, dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), docosadienoic acid, adrenic acid (AdA), docosapentaenoic acid (Osbond acid), tetracosatetraenoic acid, and tetracosapentaenoic acid. Humans can synthesize all fatty acids utilized by the human body except linoleic acid (LA, C18:2n-6) and α-linolenic acid (ALA, C18:3n-3).

[0099] The present disclosure provides methods for identifying ferroptosis-sensitive cells in mammalian tissues by the concentration of PUFAs. In some embodiments, the methods provided herein include administering to a mammal an effective amount of a ferroptosis inducer, wherein the concentration of polyunsaturated fatty acids (PUFAs) in a plurality of cells of the mammalian tissue is higher than the concentration of PUFAs in cells of normal or healthy tissue; and inducing ferroptosis in the plurality of cells. In some embodiments, the concentration of PUFAs in the plurality of cells of the mammalian tissue is greater than the concentration of PUFAs in cells of healthy or non-malignant tissue of the mammal. In some embodiments, the concentration of PUFAs in the plurality of cells of the mammalian tissue is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% higher than the concentration of PUFAs in cells of healthy tissue. In some embodiments, the concentration of PUFAs in the plurality of cells of the mammalian tissue is 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90% or 90%-100% higher than the concentration of PUFAs in cells of healthy tissue. In some embodiments, the concentration of PUFAs in the plurality of cells of the mammalian tissue is greater than a predetermined concentration of PUFAs. In some embodiments, the predetermined concentration of PUFAs is about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90 mole % of total lipids. In some embodiments, the predetermined concentration of PUFAs is about 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80 or 80-90 mole % of total lipids. In some embodiments, the predetermined concentration of PUFAs is about 20 mole % of total lipids. (4) PI index

[0100] The cell membrane composition must contain a sufficient threshold of polyunsaturated fatty acyl chains to support enzymatic and / or non-enzymatic lipid peroxidation. The peroxidability of polyunsaturated fatty acids (PUFAs) is linearly correlated with the number of bis-allylic positions present in the molecule. The sensitivity of cell membranes to lipid peroxidation can be estimated using the peroxidation index (PI), which is calculated based on the measured fatty acid composition (%, w / w) as follows: PI = (% dienoic acid × 1) + (% trienoic acid × 2) + (% tetraenoic acid × 3) + (% pentaenoic acid × 4) + (% hexaenoic acid × 5). Alternatively, PI can be calculated as: PI = (% monoenoic acid × 0.025) + (% dienoic acid × 1) + (% trienoic acid × 2) + (% tetraenoic acid × 4) + (pentaenoic acid × 6) + (hexaenoic acid × 8). Lipidomic measurements of cell membrane composition are used to determine the peroxidation index. Cell lines with low PI values (<50) are less sensitive to ferroptosis-inducing perturbations (such as GPX4 inhibition, GSH depletion, addition of pro-oxidant compounds). As the membrane PI value increases, cells are more prone to ferroptosis.

[0101] Cells grown in vitro have a different fatty acid profile from cells in vivo and have lower PI levels. Vertebrate cells cannot synthesize polyunsaturated fatty acids de novo and rely on dietary sources for such molecules. Typical cell culture methods use media supplemented with serum (usually 10%, v / v), which is the sole source of exogenous lipids and contains 1% of the PUFAs available to cells in vivo. Thus, the PUFA levels of cells grown in culture are half those of cells in vivo, and the content of monounsaturated fatty acids (MUFAs) is twice that of cells in vivo.

[0102] The ferroptosis sensitivity of cell lines can be regulated by including fatty acids in the culture medium. Saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and deuterated PUFAs can protect cells from ferroptosis, while the addition of PUFAs can increase the sensitivity of cells to ferroptosis-inducing perturbations. Supplementation of exogenous PUFAs in cell culture medium can mimic in vivo PUFA concentrations and induce membrane compositions with higher PI values. Regulatory analysis assays using fatty acid supplementation and ferroptosis inducers allow for the experimental determination of the specific membrane PUFA content or PI value sufficient to cause ferroptosis in a given cell line. For example, due to the preferential uptake of PUFAs, the peroxidation index (PI) of sarcomas and other cancer cells is higher than that of non-malignant tissues. Many sarcomas preferentially uptake PUFAs and incorporate polyunsaturated fatty acyl chains into membrane lipids, resulting in higher membrane peroxidation index values (PI > 100) compared to non-malignant tissues (average PI = 91). The difference in membrane peroxidability provides a therapeutic window for inducing ferroptosis to selectively target sarcoma cells rather than non-malignant tissues. The more peroxidizable membrane state is consistent with the observation of higher levels of lipid peroxidation stress in primary bone and soft tissue sarcomas. The addition of exogenous PUFAs can increase oxidative stress in osteosarcoma cells and exhibit selective cytotoxic effects.

[0103] The present disclosure provides methods for identifying ferroptosis-sensitive cells in mammalian tissues by the peroxidation index (PI). In some embodiments, the methods provided herein include administering to a mammal an effective amount of a ferroptosis inducer, wherein the PI of a plurality of cells of the mammalian tissue is greater than the PI in cells of a normal or healthy tissue; and inducing ferroptosis in the plurality of cells. In some embodiments, the PI in the plurality of cells of the mammalian tissue is greater than a predetermined PI. In some embodiments, the predetermined PI is about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150. In some embodiments, the predetermined PI is about 90. In some embodiments, the PI in the plurality of cells of the mammalian tissue is about 1% - 10%, 10% - 20%, 20% - 30%, 30% - 40%, 40% - 50%, 50% - 60%, 60% - 70%, 70% - 80%, 80% - 90%, or 90% - 100% greater than the PI in cells of a healthy or non-malignant tissue. (5) Mesenchymal cell state

[0104] Treatment-resistant cells are characterized by a high mesenchymal state of three cell and patient origins. The first cell characteristic is the expression of mesenchymal cell markers. Ferroptosis-sensitive cells exhibit one or more markers of the mesenchymal cell state. Mesenchymal cell state markers that can be used to identify ferroptosis-sensitive cells include, but are not limited to, ZEB1, ACSL4, FADS2, PPARγ, Fsp1, SLC7A11, SLC3A2, and LPCAT3. The second cell characteristic of ferroptosis-sensitive cells is the reduced expression of endothelial cell markers compared to normal cells. Non-limiting examples of endothelial cell markers include: vimentin, E-cadherin, and β(β)-actin. The third cell characteristic of ferroptosis-sensitive cells is sensitivity to GPX4 knockdown, resulting in cell death. GPX4 dependence is more pronounced in cancer cells adopting a treatment-resistant mesenchymal state compared to normal mesenchymal cell lines. Methods for reducing or silencing GPX4 expression can be achieved by, for example, CRISPR / Cas9, siRNA, or shRNA, etc.

[0105] The present disclosure provides methods for identifying ferroptosis-sensitive cells in mammalian tissues by the expression of one or more mesenchymal cell state markers. In some embodiments, the methods provided herein include administering to a mammal an effective amount of a ferroptosis inducer, wherein a plurality of cells of the mammalian tissue express one or more markers of the mesenchymal cell state; and inducing ferroptosis in the plurality of cells. In some embodiments, the expression of mesenchymal cell markers in the plurality of cells of the mammalian tissue is about 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100% higher than the expression of mesenchymal cell markers in cells of healthy or non-malignant tissues. (6) Additional morphological features of ferroptosis

[0106] The morphological characteristics of cells undergoing ferroptosis are the presence of mitochondria smaller than normal, with condensed mitochondrial membrane density, reduced or absent mitochondrial cristae, and rupture of the outer mitochondrial membrane. Histology and immunoassays can be used to determine whether a tissue is cancerous, whether it exhibits hyperplasia or fibrosis, and to identify ferroptosis-sensitive cells within mammalian tissues. The cell membrane of cells in a ferroptotic state lacks the rupture and blebbing of the plasma membrane typically associated with apoptosis. The nuclei of ferroptotic cells are of normal size and lack chromatin condensation.

[0107] In some embodiments, the methods provided herein include the step of obtaining a biological sample (e.g., a blood sample or a tissue biopsy) from a subject. In some embodiments, the methods provided herein further include fixing, processing, embedding, sectioning, and staining the biological sample for histological analysis. In some embodiments, the tissue comprises a histological abnormality. In some embodiments, the histological abnormality is determined by performing a tissue biopsy before or during the targeted, persistent administration of an ferroptosis inducer to the tissue. In some embodiments, the histological abnormality is hyperplasia, angiogenesis / vasculogenesis, or fibrosis. Hyperplasia is identified by an increase in the number of cells in the tissue compared to normal healthy tissue. Angiogenesis and vasculogenesis in a tissue sample are identified by immunoassays for vascular markers such as vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2). Fibrosis is characterized by abnormal collagen deposition between the cells identified in the tissue sample, e.g., by Masson's trichrome, Sirius red, or collagen staining. Cell Death and Ferroptosis Inducers

[0108] The present disclosure provides methods of inducing or modulating ferroptosis in vitro or in a subject's tissue, wherein the methods comprise: (a) continuously administering a therapeutically effective amount of a ferroptosis inducer, which can be a compound of Formula I, a compound of Formula II, any diastereomer or enantiomer thereof, a pharmaceutically acceptable salt thereof, a deuterated derivative thereof, a composition containing any of these, or a pharmaceutical composition containing any of these, optionally in combination with a second therapeutic agent; (b) optionally contacting the tissue in vivo with an effective amount of an iron-dependent cell death agent for a period of time; and / or (c) optionally contacting mammalian tissue with a priming agent and then contacting the mammalian tissue in vivo with an effective amount of a ferroptosis inducer for a period of time, thereby inducing or modulating ferroptosis in the subject's tissue. Figure 1 Exemplary targets in the ferroptosis pathway are provided and can include glutamate-cysteine ligase GCL or the glutamate-cysteine ligase catalytic (GCLC) subunit.

[0109] In some cases, the compounds of the present disclosure may need to be administered and / or contacted with cells or tissue substantially continuously or continuously at a threshold level or above to induce or modulate ferroptosis, or to modulate or inhibit or partially inhibit glutamate-cysteine ligase GCL or the glutamate-cysteine ligase catalytic (GCLC) subunit, or to treat a disease or disorder such as cancer, fibrosis, or an inflammatory disease.

[0110] Reference to a compound or agent or therapeutic agent, etc. may include one or more of these, and may include or be a first compound or agent or therapeutic agent, a second compound or agent or therapeutic agent, a third compound or agent or therapeutic agent, a fourth compound or agent or therapeutic agent, or more. (1) Ferroptosis-inducing compounds, agents, and iron-dependent cell death inducers

[0111] In some embodiments, the present disclosure provides compounds of Formula I: Their diastereomers or enantiomers, or pharmaceutically acceptable salts of any of the foregoing, or deuterated derivatives of any of the foregoing, Wherein: R1 is: C(O)OH; or C(O)OX, wherein X is an organic cation, an inorganic cation, Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ or Mn 2+ ; or C(O)OR3, wherein R3 is a straight-chain or branched-chain alkyl, cycloalkyl, cycloether, or straight-chain or branched-chain alkyl ether, any of which is optionally and independently substituted; or R3 is or R3 is or C(O)N(R4R5) wherein R4 is H; or R4 is a straight-chain or branched-chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; any of which is optionally and independently substituted; and R5 is H; or R5 is a straight-chain or branched-chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; any of which is optionally and independently substituted; or R5 is S(O)2alkyl; or R5 is S(O)2CF3; or R5 is S(O)2NH2; or R5 is S(O)2cycloalkyl, S(O)2cyclopropyl, S(O)2cyclobutyl, S(O)2cyclopentyl, S(O)2cyclohexyl, or S(O)2cycloheptyl; or R5 is or R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or R5 is pyrrolidinyl; or R5 is 2-tetrahydropyranyl, 3-tetrahydropyranyl; or 4-tetrahydropyranyl; or R5 is or R5 is alkylaryl or benzyl; or R5 is or R5 is 2-pyridyl, 3-pyridyl; or 4-pyridyl; or R5 is or R5 is or R5 is or R5 is or R5 is or CN; or and wherein R2 is: NH2, NHC(O)OMe or NHMe; and R6 is: H, C(O)Me or P(O)(OH)2; and R7 is: C1-C3 or C5-C 10 a straight or branched chain alkyl, C1-C 10 a straight or branched chain alkenyl or C1-C 10 a straight or branched chain alkynyl, any of which may be optionally substituted with an alkyl ring or an alkyl ether ring containing the C1-C3 or C5-C 10 a straight or branched chain alkyl, the C1-C 10 a straight or branched chain alkenyl or the C1-C 10 a straight or branched chain alkynyl of one carbon, any of the foregoing may be independently and optionally substituted, wherein when the straight chain C3-alkyl is substituted with a methyl group on the terminal carbon atom, the straight chain C3-alkyl substituted with a methyl group on the terminal carbon atom contains a further substitution; wherein when the C2-alkyl is substituted with an ethyl group on the terminal carbon atom, the C2-alkyl substituted with an ethyl group on the terminal carbon atom contains a further substitution; wherein when the C1-alkyl is substituted with a n-propyl group on the terminal carbon atom, the C1-alkyl substituted with a n-propyl group on the terminal carbon atom contains a further substitution; or R7 is:

[0112] In some cases, in a compound of formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R1 is: C(O)OH; or C(O)OR3, wherein R3 is a straight-chain or branched-chain alkyl, C1-C 10 straight-chain or branched-chain alkyl, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, cycloalkyl, C1-C 10 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, alkylcycloalkyl, alkylcyclohexyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl, alkyl ether, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypropyl, cycloalkyl ether, tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, tetrahydrofuranyl, 2-tetrahydrofuranyl, 2-tetrahydrofuranyl, alkylaryl, benzyl; and any of these is optionally and independently substituted by one or more C1-C 10 alkyl, one or more halogens, one or more fluorines, one or more chlorines, one or more deuteriums, bromine, one or more iodines, aryl, C6 aryl, C 10 aryl, heteroaryl, C1-C7 alkylcycloalkyl, unsubstituted tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl or any combination thereof.

[0113] In some cases, in a compound of formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing R1 is C(O)N(R4R5) wherein R5 is: C1-C 10 straight-chain or branched-chain alkyl, methyl, ethyl, propyl or butyl; any of them is optionally or independently substituted by one or more deuteriums, C1-C 10 straight-chain or branched-chain alkyl, one or more halogens, one or more fluorines, one or more chlorines, one or more iodines, one or more or any combination thereof.

[0114] In some cases, in a compound of formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, R1 is C(O)N(R4R5) and wherein R5 is: heteroaryl, 2-pyridyl, 3-pyridyl or 4-pyridyl; or R5 is S(O)2Me.

[0115] In some cases, in the compound of formula I, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing R7 is: C1-C3 or C5-C 10 a straight-chain or branched alkyl, C1-C 10 a straight-chain or branched alkenyl or C1-C 10 a straight-chain or branched alkynyl, any of which may be substituted with an alkyl ring or an alkyl ether ring, said alkyl ring or alkyl ether ring containing the C1-C3 or C5-C 10 a straight-chain or branched alkyl, the C1-C 10 a straight-chain or branched alkenyl or the C1-C 10 a straight-chain or branched alkynyl of one carbon; wherein any of the foregoing may be independently and optionally substituted with one or more of the substituents, which may be: deuterium, C1-C 10 a straight-chain alkyl, methyl, ethyl, C1-C 10 a branched alkyl, halogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, carboxylic acid or a pharmaceutically acceptable salt thereof, amide, carbamate, urea, ester, alkoxy, methoxy, ethoxy, trifluoromethoxy, ether, cyclic ether, C1-C7 alkyl ether, C1-C7 cycloalkyl ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, fused aryl, biaryl, fused aryl-heteroaryl, fused diaryl, fused aryl-heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic group, tricyclic aliphatic group, adamantyl, cyano, acetal; ketal; or any combination thereof; wherein: When a straight-chain C3-alkyl is substituted with a methyl substituent at the terminal carbon atom, the straight-chain C3-alkyl substituted with a methyl substituent at the terminal carbon atom contains a further substitution; When a C2-alkyl is substituted with an ethyl substituent at the terminal carbon atom, the C2-alkyl substituted with an ethyl substituent at the terminal carbon atom contains a further substitution; When a C1-alkyl is substituted with a n-propyl substituent at the terminal carbon atom, the C1-alkyl substituted with a n-propyl substituent at the terminal carbon atom contains a further substitution; and wherein the C1-C 10 a straight-chain alkyl substituent, a methyl substituent, an ethyl substituent, C1-C 10A branched alkyl substituent, a hydroxy substituent, an amino substituent, a carboxylic acid or a pharmaceutically acceptable salt thereof substituent, an amide substituent, a carbamate substituent, a urea substituent, an ester substituent, an alkoxy substituent, a methoxy substituent, an ethoxy substituent, an ether substituent, a cyclic ether substituent, a C1-C7 alkyl ether substituent, a C1-C7 cyclic ether substituent, an aryl substituent, a heteroaryl substituent, a fused aryl substituent, a biaryl substituent, a fused aryl-heteroaryl substituent, a fused diaryl substituent, a fused aryl-heteroaryl substituent, a 5-membered heteroaryl substituent, a 6-membered heteroaryl substituent, a naphthyl substituent, a cycloalkyl substituent, a cyclopropyl substituent, a cyclobutyl substituent, a cyclopentyl substituent, a cyclohexyl substituent, a cycloheptyl substituent, a tert-butyl substituent, a bicyclic aliphatic substituent, a tricyclic aliphatic substituent, an adamantyl substituent, or any combination thereof may be independently and optionally substituted by one or more of the following: C1-C 10 a straight-chain alkyl, a methyl, an ethyl, a C1-C 10 a branched alkyl, a halogen, a fluorine, a chlorine, a bromine, an iodine, a hydroxy, an alkoxy, a methoxy, an ethoxy, a carbamate, a urea, an amide, an ester, an amine, a trifluoromethoxy, an ether, a C1-C7 alkyl ether, a C1-C7 cyclic ether, a trihalomethyl, a trifluoromethyl, an aryl, a heteroaryl, a 5-membered heteroaryl, a 6-membered heteroaryl, a naphthyl, a cycloalkyl, a cyclopropyl, a cyclobutyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, a tert-butyl, a bicyclic aliphatic, a tricyclic aliphatic, an adamantyl, a cyano, an acetal, a ketal or any combination thereof.

[0116] There is also provided a compound of formula I: its diastereomers or enantiomers, or a pharmaceutically acceptable salt of any one of the foregoing, or a deuterated derivative of any one of the foregoing, wherein: R1 is: C(O)OH; or C(O)OX, wherein X is an organic cation, an inorganic cation, Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ or Mn 2+ ; or C(O)OR3, wherein R3 is a straight-chain or branched alkyl, a cycloalkyl, a cyclic ether, or a straight-chain or branched alkyl ether, wherein any of these is optionally and independently substituted; or R3 is or R3 is or C(O)N(R4R5) wherein R4 is H; or R4 is a straight-chain or branched-chain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein any of these is optionally and independently substituted; and R5 is H; or R5 is a straight-chain or branched-chain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein any of these is optionally and independently substituted; or R5 is S(O)2alkyl; or R5 is S(O)2CF3; or R5 is S(O)2NH2; or R5 is S(O)2cycloalkyl, S(O)2cyclopropyl, S(O)2cyclobutyl, S(O)2cyclopentyl, S(O)2cyclohexyl or S(O)2cycloheptyl; or R5 is or R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or R5 is pyrrolidinyl; or R5 is 2-tetrahydropyranyl, 3-tetrahydropyranyl; or 4-tetrahydropyranyl; or R5 is or R5 is alkylaryl or benzyl; or R5 is or R5 is 2-pyridyl, 3-pyridyl; or 4-pyridyl; or R5 is or R5 is or R5 is or R5 is or R5 is or CN; or or or or and R2 is: NH2, NHC(O)OMe or NHMe; and R6 is: H, C(O)Me or P(O)(OH)2; and R7 is: a straight-chain or branched-chain alkyl, alkenyl or alkynyl, any of which may be optionally and independently substituted; or R7 is: and wherein the compound of formula I is not buthionine sulfoximine (BSO) or a salt of BSO.

[0117] The present invention further provides a compound of formula II a diastereomer or enantiomer of the compound of formula II, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein in the compound of formula II, R is C1, C2, C3, C4, C5, C6, C7, C8, C9 or C 10 a straight-chain or branched-chain alkyl group, which is optionally and independently substituted with a substituent selected from: deuterium, halogen, fluorine, chlorine, C1-C 10 a straight-chain or branched-chain alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and any combination thereof.

[0118] The present invention further provides a pharmaceutical composition comprising a compound of formula I, a compound of formula II, a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, and a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical composition may be in unit dosage form. In addition, the pharmaceutical composition may comprise an additional active agent or a pharmaceutically acceptable salt thereof or a prodrug thereof. In addition, the pharmaceutical composition may be in the form of a powder, tablet, capsule, liquid or gel. In some embodiments, in the pharmaceutical composition, the compound of formula I, the compound of formula II, the compound, or a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing is present in the pharmaceutical composition in an amount in the range of about 0.001 mg to about 25,000 mg. In some embodiments, the additional active agent or a pharmaceutically acceptable salt thereof or a prodrug thereof may independently be present in the pharmaceutical composition in an amount in the range of about 0.001 mg to about 25,000 mg.

[0119] In some embodiments, a kit is provided that comprises a compound of the present invention, its diastereomers, its enantiomers, its pharmaceutically acceptable salts, or its deuterated derivatives, or a pharmaceutical composition of the present invention, and a container. In some embodiments, it is the pharmaceutical composition and container described herein. In some embodiments, the container is a syringe. In some embodiments, the container is an intravenous (IV) bag. In some embodiments, the container is disposable. In some embodiments, the container is recyclable. In some embodiments, the container is a disposable container. In some embodiments, the container is resealable.

[0120] In some embodiments, a method of treating a disease or disorder in a subject is provided. In some embodiments, the disease or disorder is cancer. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present invention, where the subject may be a subject in need thereof, thereby treating the disease or disorder, which may be cancer. In some embodiments, a method of treating a disease or disorder in a subject, where the subject may be a subject in need thereof, is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, a compound of Formula II, a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, thereby treating the disease or disorder, which may be cancer. In some embodiments, the administration is selected from: oral, injection; subcutaneous, intratumoral; systemic, topical, intravenous, intraperitoneal, intramuscular, and any combination thereof. In some embodiments, the subject may be a mammal. In some embodiments, the subject may be a human. In some embodiments, the subject may be male. In some embodiments, the subject may be female. In some embodiments, a method of treating a disease or disorder in a subject, where the subject may be a subject in need thereof, is provided, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula XVIII, a compound of Formula XIX, a compound of Formula XX, a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, thereby treating the disease or disorder, which may be cancer. In some embodiments, the administration is selected from: oral, injection; subcutaneous, intratumoral; systemic, topical, intravenous, intraperitoneal, intramuscular, and any combination thereof. In some embodiments, the subject may be a mammal. In some embodiments, the subject may be a human. In some embodiments, the subject may be male. In some embodiments, the subject may be female.

[0121] In some embodiments, methods of modulating ferroptosis in a tissue, which can be in a subject in need thereof, are provided, the methods comprising, for example, contacting the tissue, directly or indirectly, optionally in a sustained manner, with a pharmaceutical composition herein that can effectively modulate the amount of ferroptosis in the tissue. In some embodiments, the subject can be human. In some embodiments, the subject can be male. In some embodiments, the subject can be female.

[0122] In some embodiments, in the methods herein, the administration or the contacting can be: once daily, twice daily, three times daily, once weekly, once every two weeks, once every three weeks, once monthly, once every six months, once annually, or for life, as needed. In some embodiments, the effective or therapeutically effective amount can range from about 0.001 mg to about 25,000 mg of a compound herein, its enantiomer or diastereomer, a pharmaceutically acceptable salt thereof, or a deuterated derivative of any of these, or a pharmaceutical composition herein, which can optionally be in unit dosage form.

[0123] In some embodiments, methods of preparing and testing compounds of Formula I and compounds of Formula II, enantiomers and diastereomers of any of these, salts and pharmaceutically acceptable salts thereof, and deuterated derivatives of any of these are also provided. In some embodiments, methods of preparing and testing compounds of Formula XVIII, compounds of Formula XIX, compounds of Formula XX, enantiomers and diastereomers of any of these, salts and pharmaceutically acceptable salts thereof, and deuterated derivatives of any of these are also provided.

[0124] The methods provided herein include administering an agent, compound, or therapeutic agent that modulates cell death to a cell, tissue, or subject. In some embodiments, the administration induces cell death. In some embodiments, the administration inhibits cell death or rescues cells from cell death. In some embodiments, the administration modulates ferroptosis. In some embodiments, the administration induces ferroptosis in vivo. In some embodiments, the administration inhibits ferroptosis in vivo. In some embodiments, the agent is a ferroptosis inducer. In some embodiments, the agent is an iron-dependent cell death inducer. Agents that can be used to induce ferroptosis in vivo and treat a disease or disorder are discussed in further detail below.

[0125] In some embodiments, the agent is an inhibitor of glutamate-cysteine ligase (GCL). Glutamate-cysteine ligase (GCL) is a central node in the ferroptosis pathway, but it has been overlooked as a target. Loss of GCL activity induces ferroptosis in sensitive cells and only kills cells that are most sensitive to ferroptosis. Representative human GCL cDNA and human GCL protein sequences are publicly available from the National Center for Biotechnology Information (NCBI). Compared to variant 1, the human glutamate-cysteine ligase catalytic subunit isoform b (NM_001197115.2 and NP_001184044.1, which lack an in-frame exon in its 5' coding region. Compared to isoform a), this results in a shorter protein (isoform b), the glutamate-cysteine ligase catalytic subunit isoform a (NM_001498.4 and NP_001489.1, which represent longer transcripts and encode a longer isoform (a)).

[0126] In some embodiments, the agent is an inhibitor of the glutamate-cysteine ligase catalytic subunit (GCLC).

[0127] In some embodiments, the molecules, enantiomers, diastereomers, mixtures herein, their hydrates, their deuterated analogs, their salts, their pharmaceutically acceptable salts, compositions containing any of these, or pharmaceutical compositions containing any of these can be used to treat cancer or tumor disorders. In some embodiments, the cancer or tumor disorder can be skin cancer, sarcoma, melanoma, carcinoma, mesenchymal carcinoma, breast cancer, prostate cancer, cervical cancer or ovarian cancer, kidney cancer, renal cancer, liver cancer, hepatocarcinoma, renal carcinoma, non-clear cell renal carcinoma or clear cell renal carcinoma. In some embodiments, the molecules, enantiomers, diastereomers, mixtures herein, their hydrates, their deuterated analogs, their salts, their pharmaceutically acceptable salts, compositions containing any of these, or pharmaceutical compositions containing any of these can be used to treat cancers lacking the SWI / SNF complex. In some embodiments, the cancers lacking the SWI / SNF complex can be skin cancer, sarcoma, melanoma, mesenchymal carcinoma, breast cancer, prostate cancer, cervical cancer or ovarian cancer, kidney cancer, renal cancer, liver cancer, carcinoma, hepatocarcinoma, clear cell renal carcinoma or non-clear cell renal carcinoma.

[0128] In some embodiments, the agent is a statin. Exemplary statins include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0129] In some embodiments, the agent that induces ferroptosis in tissues is selected from Table 1. Exemplary ferroptosis inducers and their molecular formulas, chemical identifiers, and respective targets and / or mechanisms of action are provided in Table 1. Table 1. Ferroptosis inducers

[0130] In some embodiments, the ferroptosis inducer, which can be a second active agent or a second therapeutic agent, can be: (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jakacidin, buthionine sulfoximine (BSO), trigonelline, glutamic acid, sulfasalazine, auranofin, bruceollin, sorafenib, sorafenib-d3, sorafenib tosylate, trigonelline, FIN56, FINO2, CIL56, dihydrotanshinone I, GPX4-IN-3, its analogs, salts or derivatives. In some embodiments, the agents in Table 1 are in the form of pharmaceutically acceptable salts of small molecules.

[0131] In some cases, the therapeutic agent, contact agent, inhibitor, partial inhibitor or modulator or compound can be one or more of the following compounds in Table 2 or Table 3, an enantiomer or diastereomer of any of the foregoing, a mixture of more than one enantiomer or diastereomer, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of these.

[0132] In some embodiments, the biological activity of the compounds described herein can be measured as IC 50 value. The IC 50 value can be 0.0001 to 0.01, 0.01 to 0.1, 0.1 to 1, or 1 to 10 mM. In some embodiments, the IC 50 value can be at least 0.0001, at least 0.001, at least 0.01, at least 0.1, at least 1.0 or at least 10 mM. In some embodiments, the biological activity of the compounds described herein can be measured as EC 50 value or EC50 value. The EC 50 value can be.0001 to.01,.01 to.1,.1 to 1, 1 to 10 mM. In some embodiments, the EC 50 value can be at least.0001, at least.001, at least.01, at least.1, at least 1.0 or at least 10 mM. In Table 2, the following meanings are included: +++ is GCLIC 50 range less than or equal to 0.02 mM ++ is GCLIC 50 range greater than 0.02 mM to 2 mM + is GCLIC 50 range greater than 2 mM “nd” is no data collected @ is cell killing EC 50 greater than or equal to 1 mM ! is cell killing EC 50Less than 1 mM "nd" indicates that data was not collected The test protocol for the bioactivity data is described in Example 2. Table 2: Bioactivity Data Table 3: Bioactivity Data (continued) (2) Initiator

[0133] The present invention provides a method for inducing targeted cell death in mammalian tissues in vivo, the method comprising: (a) contacting a mammalian tissue with an initiator; (b) contacting the mammalian tissue in vivo with an effective amount of an iron death inducer for a duration of at least 4 hours, wherein it is determined by detection in the mammalian tissue that a plurality of cells in the mammalian tissue respond to the initiator: (i) the plurality of cells have a selenium concentration higher than the selenium concentration in the mammalian tissue before contact with the initiator; (ii) the plurality of cells have an iron concentration higher than the iron concentration in the mammalian tissue before contact with the initiator; (iii) the plurality of cells have a PUFA concentration higher than the PUFA concentration in the mammalian tissue before contact with the initiator; (iv) the plurality of cells express one or more markers indicative of a mesenchymal state; (v) the plurality of cells have a peroxidation index (PI) greater than the PI in the mammalian tissue before contact with the initiator; and / or (vi) hyperproliferation of cells in the mammalian tissue, wherein the iron death inducer induces targeted cell death in the mammalian tissue in vivo. In some embodiments, a primer is administered before administering the ferroptosis inducer provided herein. In some embodiments, the primer is administered in vivo, in vitro, or ex vivo. A primer is an agent that prepares a subject or tissue for administering a therapeutically effective dose of the ferroptosis inducer provided herein. In some embodiments, the primer is a ferroptosis inhibitor. In some embodiments, the primer renders cells within a tissue sensitive to ferroptosis. In some embodiments, the primer is a lipophilic antioxidant or a free radical scavenger. In some embodiments, the primer is a polyunsaturated fatty acid. In some embodiments, the primer is an iron chelator. In some embodiments, the primer is a lipid peroxidation inhibitor. In some embodiments, the primer modulates blood oxygen levels. In some embodiments, the primer is a hydroperoxide. In some embodiments, the primer is selected from: liproxstatin-1, ferrostatin-1, deferoxamine (DFO), iron, selenium, vitamin E, erythropoietin, polyunsaturated fatty acids, N-acetylcysteine, pyrethrosin-α-HBr, and methylnaphthalene-4-propionate endoperoxide (MNPE). In some embodiments, the polyunsaturated fatty acids are selected from: hexadecatrienoic acid (HTA), α-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA, eicosapentaenoic acid), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA, clupanodonic acid), docosahexaenoic acid (DHA, docosahexaenoic acid), tetracosahexaenoic acid (nisinic acid), tetracosapentaenoic acid, linoleic acid (LA), γ-linolenic acid (GLA), eicosadienoic acid, dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), docosadienoic acid, adrenic acid (AdA), docosapentaenoic acid (Osbond acid), tetracosatetraenoic acid, and tetracosapentaenoic acid. Non-limiting examples of primers are provided in Table 4. Table 4. Primers.

[0134] In some embodiments, the methods provided herein include administering any one of the agents listed in Table 1, Table 2, Table 3, or Table 4, or any compound, agent, or therapeutic agent herein, enantiomers of any of these, diastereomers of any of these, pharmaceutically acceptable salts of any of these, or deuterated derivatives of any of these. The present invention further provides pharmaceutical compositions, wherein the compositions comprise an ferroptosis inducer or compound and an initiator, or enantiomers or diastereomers of any of the foregoing, pharmaceutically acceptable salts of any of the foregoing, or deuterated derivatives of any of the foregoing. In some embodiments, the pharmaceutical composition further comprises a chemotherapeutic agent. (3) Additional Treatments and Cell Death Inducers

[0135] In some embodiments, the methods provided herein include administering to a subject at least one additional treatment. In some embodiments, the additional treatment is surgery. In some embodiments, the additional treatment is radiotherapy. In some embodiments, the additional treatment is a dietary supplement. Non-limiting examples of dietary supplements include: probiotics, selenium, iron, vitamins (such as vitamin A, vitamin C, vitamin E), curcumin, fish oil, β-carotene, hydrogen sulfide, fatty acids, methionine, cysteine, homocysteine, taurine, cystine or di-cysteine. In some embodiments, the dietary supplement is a high selenium nutritional supplement.

[0136] In some embodiments, the additional treatment is an additional therapeutic agent. In some embodiments, the methods provided herein include administering an additional agent in combination with the ferroptosis inducer, iron-dependent cell death inducer, and / or initiator provided herein. In some embodiments, the additional agent is a cell death inducer. 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 for treating cancer. Cancer chemotherapeutic agents that can be used in combination with the ferroptosis inducer or iron-dependent cell death agent provided herein include, but are not limited to, mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine, vindesine or Navelbine TM (vinorelbine, 5'-demethylanhydrovinblastine). In other cases, cancer chemotherapeutic agents include topoisomerase I inhibitors, such as camptothecin compounds. As used herein, "camptothecin compounds" include Camptosar TM (irinotecan HCL), Hycamtin TM(Topotecan HCL) and other compounds derived from camptothecin and its analogs. Another class of cancer chemotherapeutic agents that can be used in the methods and compositions disclosed herein are podophyllotoxin derivatives such as etoposide, teniposide, and mitopodozide. The present disclosure also encompasses other cancer chemotherapeutic agents known as alkylating agents that alkylate the genetic material in tumor cells. These include, but are not limited to, cisplatin, cyclophosphamide, mechlorethamine, thiotepa, carmustine, busulfan, chlorambucil, belomycin, uracil mustard, chlorambucil, and dacarbazine. The present disclosure encompasses antimetabolites as cancer chemotherapeutic agents. Examples of these types of agents include cytarabine, fluorouracil, methotrexate, mercaptopurine, azathioprine, and procarbazine. Another class of cancer chemotherapeutic agents that can be used in the methods and compositions disclosed herein include antibiotics. Examples include, but are not limited to, doxorubicin, bleomycin, actinomycin, daunorubicin, mithramycin, mitomycin, mitomycin C, and daunomycin. These compounds are available in a variety of commercially available liposomal formulations. The present disclosure also includes other cancer chemotherapeutic agents including, but not limited to, anti-tumor antibodies, dacarbazine, azacitidine, amsacrine, melphalan, ifosfamide, and mitoxantrone.

[0137] The disclosed agents provided herein can be administered in combination with other anti-tumor agents, including cytotoxic / anti-tumor agents and anti-angiogenic agents. Cytotoxic / anti-tumor agents can be defined as agents that attack and kill cancer cells. Some cytotoxic / anti-tumor agents can be alkylating agents that alkylate the genetic material in tumor cells such as cisplatin, cyclophosphamide, mechlorethamine, thiotepa, carmustine, busulfan, chlorambucil, berubicin, uracil mustard, chlorambucil, and dacarbazine. Other cytotoxic / anti-tumor agents can be antimetabolites of tumor cells such as cytarabine, fluorouracil, methotrexate, mercaptopurine, azathioprine, and procarbazine. Other cytotoxic / anti-tumor agents can be antibiotics such as doxorubicin, bleomycin, actinomycin, daunorubicin, mithramycin, mitomycin, mitomycin C, and daunomycin. These compounds are available in a variety of commercially available liposomal formulations. Still other cytotoxic / anti-tumor agents can be mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine, and etoposide. Various cytotoxic / anti-tumor agents include paclitaxel and its derivatives, asparaginase, anti-tumor antibodies, dacarbazine, azacitidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

[0138] Angiogenesis inhibitors can also be used. Suitable angiogenesis inhibitors for use in the disclosed methods and compositions include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers, and antisense oligonucleotides. Other inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukins 1 (including α and β), interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinases -1 and -2 (TIMP-1 or -2). Small molecules can also be used, including topoisomerases, such as razoxane, a topoisomerase II inhibitor with anti-angiogenic activity.

[0139] Other anti-cancer agents that can be used in combination with the ferroptosis inducer provided in this article may include, but are not limited to, acevine; aclarubicin; acodazole hydrochloride; acronine; adozenecin; aldesleukin; altretamine; ametycin; amitanadrine acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; aspirin; avastin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bevacizumab; bicalutamide; bisantrene hydrochloride; binaphthol dimethanesulfonate; bizelesin; bleomycin sulfate; brequinar sodium; bromopyramine; busulfan; actinomycin; cardisterone; caracemide; carboquone; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cinerubin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexmafoxane; denopterin; denopterin guanine methanesulfonate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; epipropidine; epirubicin hydrochloride; epuzolol; erythromycin estolate; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flucytosine; folinic acid; fosquidone; fosversine sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II or rIL2), interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3; interferon β-Ia; interferon γ-Ib; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprorelin acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; medroxyprogesterone acetate; melengestrol acetate; melphalan; methenolone; mercaptopurine; methotrexate; methotrexate sodium; metopterin; meturedepa; midostaurin; mitocarcin; mitomycin; mitomycin; mitomycin; mitomycin; mitosis; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; omapatrilat; oxisuran; paclitaxel; pegaspargase; peplomycin; pentostatin; peplomycin sulfate; pericyclophosphamide; pipobroman; piposulfan; pirarubicin hydrochloride; plicamycin; promestriene; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; ribonucleic acid; rogletimide; safingol; salfinol hydrochloride; semustine; sintrazole; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spirostatin; spiroplatin; streptozocin; streptozotocin; sulfofenur; tasomomycin; tegafur sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone;Thiomidazine; Thioguanine; Thiotepa; Thiazofurin; Tirapazamine; Toremifene Citrate; Triamcinolone Acetonide; Trimetrexate Phosphate; Trimetrexate Glucuronate; Triptorelin; Blomoprazole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinpocetine Sulfate; Vinylglycine Ester Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Catharanthine Sulfate; Vinylzolidine Sulfate; Vorozole; Zeniplatin; Zenocastat; Zorubicin Hydrochloride. Other anticancer agents include but are not limited to 20-epi-1,25-dihydroxyvitamin D3; 5-Ethynyluracil; Abiraterone; Aclarubicin; Acylfulvene; Decenyl Alcohol; Adozelesin; Aldesleukin; ALL-TK Antagonist; Altretamine; Amustine; Amine Oxidase; Amifostine; Aminolevulinic Acid; Amrubicin; Amsacrine; Anagrelide; Anastrozole; Andrographolide; Angiogenesis Inhibitor; Antagonist D; Antagonist G; Antarex; Anti-dorsalizing Morphogenetic Protein-1; Antiandrogen, Prostate Cancer; Antiestrogen; Antitumor Protein; Antisense Oligonucleotide; Glycine Aphidicolin; Apoptosis Gene Regulator; Apoptosis Regulator; Purine Acid; ara-CDP-DL-PTBA; Arginine Deiminase; Asulacrine; Atamestane; Atromentin; Acronastatin 1; Acronastatin 2; Acristatin 3; Azasetron; Azatoxin; Azatyrosine; Berryllin III Derivative; Benprotal; Batimastat; BCR / ABL Antagonist; Benzchlorin; Benzoyl Starry Cephalosporin; β-Lactam Derivative; β-Ethynyl; Betamycin B; Betulinic Acid; bFGF Inhibitor; Bicalutamide; Bisantrene; Bisaziridin Spermine; Bifonazole; Dienestrol; Bizelesin; Breflate; Bromopyramine; Budotitane; Buthionine Sulfoximine; Calcipotriol; Calciprotein C; Camptothecin Derivative; Canarypox IL-2; Capecitabine; Formamide-Amino-Triazole; Carboxyamidotriazole; CaRest M3; CARN 700; Cartilage-Derived Inhibitor; Carzelesin; Casein Kinase Inhibitor (ICOS); Castanospermine; Cecropin B; Cetrorelix; Chlorin; Chlorokine Sulfonamide; Cicaprost; Cis-Porphyrin; Cladribine; Clomifene Analogue; Clotrimazole; Colistin A; Colistin B; Combretastatin A4; Combretastatin Analogue; Concanavalin; Clancycidin 816; Cristatox; Cryptophycin 8; Cryptophycin A Derivative; Cucurbitacin A; Cyclopentanthraquinone; Cycloplatin; Cypemycin; Cytarabine Phosphate; Cytolytic Factor; Cytostatin; Daclizumab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Dexcyclophosphamide; Dexrazoxane; Dextroverapamil; Diazine Quinone; Dedeminin B; Didox; Diethylnorspermine; Dihydro-5-Azacytidine; 9-Dihydrotaxol; Dioxamycin; Diphenylspirostatin; Docetaxel; Docosanol; Dolasetron; Doxifluridine; Droloxifene; Dronabinol; Doxacurium SA; Ebselen;Ifosfamide; Edelfosine; Idecocolomab; Eflornithine; Elemen; Emitefur; Epirubicin; Epristeride; Estramustine analogues; Estrogen agonists; Estrogen antagonists; Etazolate; Etoposide phosphate; Exemestane; Fadrozole; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavoxate; Fluocysteine; Fluasterone; Fludarabine; Fluradrabine hydrochloride; Fofenimex; Formestane; Fosfomycin; Fotemustine; Gadolinium texaphyrin; Gallium nitrate; Gemcitabine; Ganirelix; Gelatinase inhibitors; Gemcitabine; Glutathione inhibitors; Heptesulfam; Herregulin; Hexamethyl bisacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifene; Itramadone; Ifosfamide; Ilomastat; Imidazoacridones; Imiquimod; Immunostimulatory peptides; Insulin-like growth factor-1 receptor inhibitors; Interferon agonists; Interferon; Interleukin; Iobenguane; Iodoxorubicin; 4-Piperitol; Iloprost; Irsogladine; Isoxazole; Isohalohydroxybenzoate B; Itasert; Jasmonolide; Kahalalide F; Laminin-N triacetate; Lanreotide; Lenvamycin; Lenograstim; Lentinan sulfate; Letastatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprorelin + estrogen + progesterone; Leuprorelin; Levamisole; Liazo; Linear polyamine analogues; Lipophilic disaccharide peptides; Lipophilic platinum compounds; Lysolinamide 7; Lobaplatin; Lombrutin; Lomtriptorelin; Lonidamine; Losoxantrone; Lovastatin; Losoxoribine; Lutotecan; Lutetium texaphyrin; Theophylline lysate; Lytic peptides; Maytansine; Mannastatin A; Marimastat; Masoprocol; Maxipime; Matrix metalloproteinase inhibitors; Mepronalil; Mebaral; Mitrin; Methioninase; Metoclopramide; MIF inhibitors; Mifepristone; Miltefosine; Mimosine; Mismatched double-stranded RNA; Mitoguazone; Mitolactol; Mitomycin analogues; Mitophide; Mitotoxin fibroblast growth factor-saporin; Mitoxantrone; Mofarotene; Mogamulizumab; Monoclonal antibody, human chorionic gonadotropin; Monophosphoryl lipid A + Mycobacterium cell wall sk; Mopidamol; Multidrug resistance gene inhibitors; Treatment based on multiple tumor suppressor 1; Mustard anticancer agents; Mycaperoxide B; Mycobacterium cell wall extract; Doparon; N-acetyl denaline; N-substituted benzamides; Nafarelin; Naglelestip; Naloxone; +Pentazocine; Narpavin; Naphine; Nartograstim; Nedaplatin; Neomycin; Neridronic Acid; Neutral Endopeptidase; Nilutamide; Nishamycin; Nitric Oxide Modulator; Nitroxide Antioxidant; Nitroline; O6-Benzylguanine; Octreotide; Oxycodone; Oligonucleotide; Onapristone; Ondansetron; Ondansetron; Metaraminol; Oral Cytokine Inducer; Ormaplatin; Oxazolone; Oxaliplatin; Oxanosomycin; Paclitaxel; Paclitaxel Analog; Paclitaxel Derivative; Palomid; Palmitoyl Nodulin; Pamidronic Acid; Panaxatriol; Panomifene; Pellimycin; Pazelliptine; Pegaspargase; Peldesine; Pentosan Polysulfate Sodium; Pentostatin; Pentrozole; Perfluoron; Pericylophosphamide; Perillyl Alcohol; Phenazineomycin; Phenylacetate; Phosphatase Inhibitor; Picibanil; Pilocarpine Hydrochloride; Pirarubicin; Picotixin; Placenta A; Placenta B; Plasminogen Activator Inhibitor; Platinum Complex; Platinum Compound; Platinum Triamine Complex; Porphyrin Sodium; Porphyrimycin; Prednisone; Propylbisacridine; Prostaglandin J2; Proteasome Inhibitor; Protein A-Based Immunomodulator; Protein Kinase C Inhibitor; Protein Kinase C Inhibitor, Microalgae; Protein Tyrosine Phosphatase Inhibitor; Purine Nucleoside Phosphorylase Inhibitor; Rhodoporphyrin; Pyrazoloacridine; Pyridine Oxidized Hemoglobin Polyoxyethylene Conjugate; RAF Antagonist; Raltitrexed; Ramosetron; Ras Farnesyl Protein Transferase Inhibitor; Ras Inhibitor; Ras-GAP Inhibitor; Demethyl Retilidine; Rhenium R e186 Etidronic acid; Nodulin; Ribozyme; RII Retinamide; Rogletimide; Rhodictin; Romidepsin; Roquinimex; Rubidone B1; Rubroacyloyl; Safingol; Santopin; SarCNU; Pulvomycin A; Sargramostim; Sdi 1 Mimetic; Semustine; Senescence-derived Inhibitor 1; Sense Oligonucleotide; Signal Transduction Inhibitor; Signal Transduction Modulator; Single-chain Antigen-binding Protein; Sizofiran; Sobuzoxane; Sodium Borocaptate; Sodium Phenylacetate; Solvent Alcohol; Somatomedin-binding Protein; Sonermin; Sparfosic Acid; Spicamycin D; Spiroxatrine; Splenin; Spongistatin 1; Squalamine; Stem Cell Inhibitor; Stem Cell Division Inhibitor; Stipiamide; Stromelysin Inhibitor; Sulfaguanidine; Superactive Vasoactive Intestinal Peptide Antagonist; Surastatin; Suramin; Swainsonine; Synthetic Glycosaminoglycan; Talimustine; Tamoxifen Methiodide; Uromustine; Tazarotene; Tebuthiuron Sodium; Tegafur; Telluropyridinium; Telomerase Inhibitor; Temoporfin; Temozolomide; Teniposide; Tetrachloro Decoxide; Tetrazomine; Thalidostine; Thiocolchicine; Thrombopoietin; Thrombopoietin Mimetic; Thymalfasin; Thymopoietin Receptor Agonist; Thymostimulin; Thyroid Stimulating Hormone; Ethyl Etopurpurin; Tirapazamine; Titanium Dichloride Ferrocene; Topsentin; Toremifene; Pluripotent Stem Cell Factor; Translation Inhibitor; Tretinoin; Triacetyluridine; Trabectedin; Trimetrexate; Triptorelin; Tropisetron; Turbosterol; Tyrosine Kinase Inhibitor; Tyrosine Phosphatase; UBC Inhibitor; Ubenimex; Urogenital Sinus-derived Growth Inhibitory Factor; Urokinase Receptor Antagonist; Vapreotide; Verorabine B; Erythroid Gene Therapy; Villanol; Villamine; Verdine; Verteporfin; Vinorelbine; Vincosatin; Vitamin A; Vorozole; Zarnotrine; Zeniplatin; Zilascorb; and Zinostatin Stimalamer. Any of the foregoing chemotherapeutic agents may be administered at a clinically effective dose. The chemotherapeutic agent may also be administered about -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 days or up to about 14 days after administration of the agent provided herein. In some cases, the subject may have a refractory cancer that is unresponsive to chemotherapy. General Methods for Preparing Pharmaceutical Compounds

[0140] The compounds described herein can be provided as amorphous solids or crystalline solids. The compounds of formula (I) can be provided as amorphous solids or crystalline solids. In some embodiments, the crystalline solid is a pure crystalline solid. In some embodiments, the crystalline solid is a polymorph. A particular polymorph can have different pharmaceutically relevant physical properties compared to another polymorph. In some embodiments, the polymorphs described herein can be characterized by a single X-ray diffraction method. The crystalline forms of the compounds described herein can be anhydrous, hydrates or solvates. Lyophilization can be employed to provide the compounds in amorphous solid form. It should also be understood that solvates (e.g., hydrates) of the compounds are also contemplated herein. The term "solvate" can refer to the physical association of a compound with one or more organic or inorganic solvent molecules. Such physical associations include hydrogen bonds. In certain cases, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be capable of being isolated. "Solvate" includes solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates and ethyl acetate solvates. Additionally, the compounds can be isolated and purified after their preparation to obtain a composition ("substantially pure") containing an amount of the compound of formula (I) equal to or greater than 99% by weight, which is then used or formulated as described herein. Such "substantially pure" compounds are also contemplated herein. The compounds can be prepared in a variety of ways and can be synthesized using the methods described herein. The reactions and techniques described herein are carried out in solvents suitable for the reagents and materials used and are suitable for the transformations effected. Additionally, in the description of the synthetic methods below, it should be understood that the reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work-up procedures, can be selected as the standard conditions for that reaction. Those skilled in the art of organic synthesis should understand that the functional groups present on the various parts of the molecule must be compatible with the proposed reagents and reactions.

[0141] In some embodiments, the embodiments included herein contain structures having protecting groups designated as "P", "P 1 ", "P 2 ", "P 3 ", etc. The protecting groups herein can be, for example, Boc, methanesulfonyl (Ms), toluenesulfonyl (Ts), p-nitrobenzenesulfonyl (Ns), benzyl (Bn), benzoyl (Bz), SEM, TMS, TIPS, Cbz or FMOC. These include conventional protecting groups used in organic synthesis. In some embodiments, the embodiments included herein include structures having alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, heteroalkenyl or heteroalkynyl groups designated as "R" groups, their halogenated derivatives, or combinations thereof. In some cases, R can be, for example: H, C1-C 10Straight-chain or branched alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C3-C 10 heteroaryl, biphenyl, halobiphenyl, indole, triazole, isothiazole, oxazoline, C1-C6 straight-chain or branched alkyl ether, -C(O)OR5, -C(O)NH2, -O-, -S-, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, -Cl, -Br, -I, or R1 and R2, R2 and R3, or R1 and R3 together form C3-C6 cycloalkyl, and wherein said C3-C6 cycloalkyl may optionally be substituted by C1-C6 straight-chain or branched alkyl, C1-C6 cycloalkyl, halogen, -CF3 or -F.

[0142] In some embodiments, the compounds described in the exemplary embodiments herein have the following stereochemical configurations: The compound is presented in the same manner as the following compound:

[0143] In some embodiments, the embodiments included herein include structures representative of the compounds described herein.

[0144] Scheme 1

[0145] Compound 521 can be prepared according to the synthetic route outlined in Scheme 1. For example, a suitably substituted alkyl (517) having an electrophilic center, such as an alkyl halide or sulfonate ester, can be reacted with a protected cysteine derivative such as 518 in the presence of a base to give a thioalkylation product 519. Compound 519 can be reacted with various oxidants such as PhI(OAc)2 and ammonium carbamate to give a sulfoximine derivative 520, which may or may not have additional substitution on the sulfoximine nitrogen as a protecting group. Compound 520 can be reacted with reagents such as NaOH or TFA to convert the ester to a carboxylic acid and remove the nitrogen protecting group (P2) to provide compound 521.

[0146] Scheme 2

[0147] Additional compounds described herein can be prepared according to the general route outlined in Scheme 2. Treatment of a compound such as 522 with a reagent such as a strong base or strong acid can provide a free carboxylic acid 523. Reaction of 523 with a variety of amines in the presence of a suitable amide bond-forming reagent such as PyBOP can provide an amide 524. Sulfur can be reacted under oxidative conditions to provide a sulfoximine 525, which can be further reacted with an amine protecting group removal reagent such as HCl in dioxane to provide a compound such as compound 526.

[0148] Scheme 3

[0149] Scheme 3 shows an additional scheme outlining the route to compound 532. Reacting compound 527 with 528 can provide compounds such as 529. Treating 529 with a suitable transesterification reagent such as methanol and HCl can provide compounds such as 530. Alternatively, the P in compound 529 3 can be removed to give P 3 = hydrogen, which is alkylated with various alkyl halides in the presence of a base and then sulfonated to give 528. Compound 528 can be reacted with a variety of oxidants to give the sulfoximine derivative 531, which can be further treated with reagents such as TFA or HCl to remove the amine protecting group and provide compound 532.

[0150] Scheme 4

[0151] Scheme 4 provides an alternative route to compound 536. Reacting compound 533 directly with compounds such as 534 in the presence of a radical generator such as AIBN can provide the coupled intermediate 535. Compound 535 can be similarly subjected to the sulfur oxidation step and amine deprotection outlined in Schemes 1 - 3 above.

[0152] Scheme 5

[0153] Scheme 5 shows a method for preparing the heterocyclic - substituted analogue 542. Reacting the nitrile - containing compound 357 with a suitably protected sulfur nucleophile 358 can provide the alkylated analogue 539. Treating 539 with a reagent such as TMS - azide can provide the tetrazole - substituted intermediate 540. Oxidizing the sulfur to a sulfoximine gives 541, which can be deprotected to give the final analogue 542.

[0154] Scheme 6

[0155] Intermediates containing a free carboxylic acid, such as 543 in Scheme 6, can be esterified under acidic conditions (e.g., methanol in HCl) to provide compound 544. Alternatively, the carboxylic acid can be directly alkylated with a suitable electrophile (e.g., butyl bromide) and a base (e.g., K2CO3) and then further converted to (I) by deprotecting the amine group under the conditions described previously.

[0156] Scheme 7

[0157] Scheme 7 provides a route for the preparation of compound 549. Treatment of ester 545 with a direct amide-forming reagent (e.g., NH3 in methanol) gives 546. Compound 546 can be further reacted with a dehydrating reagent such as trifluoroacetic anhydride to afford a compound such as 547. Reaction of 547 with an oxidizing agent such as PhI(OAc)2 and ammonium carbamate provides sulfoximine 548. Further treatment of 548 with a reagent that removes the amine protecting group gives compound 549.

[0158] Scheme 8

[0159] Compound 552 can be prepared from the aforementioned intermediate 547. Reaction of 547 with a reagent that converts a nitrile to a tetrazole such as NaN3 and ZnBr2 affords a compound such as 550. Oxidation of sulfur to a sulfoximine with PhI(OAc)2 and ammonium carbamate provides 551, which can be further reacted with an anhydrous acid (e.g., HCl in dioxane) to give 552.

[0160] Scheme 9 An alternative for compound 556 is shown in Scheme 9. A properly protected primary amide 553 can be reacted with DMF-DMA to form an amidine 554. Reaction with a diheteroatom nucleophile such as hydroxylamine gives a compound such as 555. Treatment of 555 with an acid such as TFA or HCl to remove the amine protecting group provides compound 556.

[0161] Scheme 10 Scheme 10 outlines another possible route to compound 560. Intermediate 553 can be converted to a nitrile 557 under dehydrating conditions and further reacted with hydroxylamine to afford an intermediate such as 558. Reaction of 558 with a methylene equivalent such as trimethoxymethane in the presence of an acid gives a compound such as 559. Further reaction with an amine deprotecting reagent such as TFA or HCl provides compound 560.

[0162] Scheme 11

[0163] The stereoselective synthesis of compound 566 is shown in Scheme 11. Chiral sulfinamide 561 can be alkylated on sulfur to afford intermediate 562. The reaction of 562 with an acid such as TFA can provide sulfinamide 563. Subsequent alkylation of 563 with a functionalized reagent such as 564 can provide the fully substituted intermediate 565. The reaction of 565 with an acid such as TFA or HCl can provide optically pure 566. By reacting 565 with a selective deprotection reagent, 567 is first obtained, and intermediate 565 or a compound with a similar structure can be further converted to 571. Protecting the free primary amine (567) gives 568, and then by reaction with a reagent such as dibenzyl phosphate, the sulfinimine nitrogen is phosphorylated to give 569. Removal of the various protecting groups provides the phosphorylated form consistent with compound 571.

[0164] Scheme 12

[0165] Additional general methods for preparing the compounds of interest in this application are shown in Scheme 12. Substituted alkenes such as 572 can react with various nucleophiles such as alkyl cuprates or arylboronic acids to provide poly-substituted esters such as 573. Treatment of 573 with a standard reducing agent such as LAH or NaBH4 can provide alcohol 574. The conversion of 574 to an alkylating agent (as an alkyl halide or alkyl sulfonate) can be achieved under standard conditions. For example, treatment of 574 with MsCl in a suitable solvent such as DCM in the presence of a base such as DIPEA can provide a compound such as 575. Compound 575 can react with a sulfur-containing reagent 576 in the presence of a base such as K2CO3 to provide 577. Compound 12e can be treated with an oxidizing agent such as PhI(OAc)2 and ammonium carbamate to provide a compound such as 578, which can be further treated with an anhydrous acid such as HCl in dioxane to provide compound 579.

[0166] Scheme 13

[0167] Alternative variants of compound 582 can be prepared using the methods outlined in Scheme 13. Starting from a compound such as 580, the aryl (or heteroaryl) can optionally be substituted with a group such as an iodide that promotes a cross-coupling reaction with a reagent such as an arylboronic acid to form a compound of formula 581. Compound 581 can react with a reagent such as NaOH or TFA to convert the ester to a carboxylic acid and remove the nitrogen protecting group (P2), giving compound 582.

[0168] Scheme 14

[0169] An alternative synthetic method for variants of compound 590 can be seen in Scheme 14. The reaction of a suitably substituted unsaturated ester such as 583 with a nucleophile such as triazole can form a substituted ester product 584. The further reaction of 584 with a reducing agent such as LAH can form a primary alcohol 585, which can be further reacted with an activator such as MsCl in the presence of an amine to form a compound such as 586. A compound such as 586 can be reacted with a doubly protected thiol 587 to form a dialkyl sulfide product 588. Compound 588 can be reacted with a variety of oxidizing agents to provide a sulfoximine derivative 589, which can be further treated with reagents such as TFA or HCl to remove the amine protecting group and provide compound 590.

[0170] Scheme 15

[0171] An additional synthetic method for variants of compound 598 can be seen in Scheme 15. The reaction of a suitably substituted unsaturated ester such as 591 with a coupling partner such as an aryl boronate ester in the presence of a transition metal catalyst such as rhodium can form a substituted ester product 592. The further reaction of 592 with a reducing agent such as LAH can form a primary alcohol 593, which can be further reacted with an activator such as MsCl in the presence of an amine to form a compound such as 594, where X = mesylate. A compound such as 594 can be reacted with a doubly protected thiol 595 to form a dialkyl sulfide product 596. Compound 596 can be reacted with a variety of oxidizing agents to provide a sulfoximine derivative 597, which can be further treated with reagents, for example, treated with NaOH to remove the acid protecting group (P 3 ) and treated with TFA or HCl to remove the amine protecting group (P 2 ) and provide compound 598.

[0172] A similar synthetic method starting from a cyclobutyl-substituted conjugated ester 599 can provide an intermediate 600 by reaction with a boron-containing coupling partner or an alkyl or aryl halide under appropriate coupling conditions (such as iridium / blue light catalysis). Similar to the method already outlined in Scheme 15, further transformations can be utilized to provide additional compound 601.

[0173] Scheme 16

[0174] Scheme 16 shows that those skilled in the art can prepare additional compounds by reacting an aryl or heteroaryl olefin with a thiol 603 in a suitable solvent such as methanol to form an adduct such as 604. Compound 604 can be reacted with a variety of oxidizing agents to provide a sulfoximine derivative 605, which can be further treated with reagents, for example, treated with NaOH to remove the acid protecting group (P 3 ) and treated with TFA or HCl to remove the amine protecting group (P2 ), and provides compound 606.

[0175] Scheme 17

[0176] Another method for preparing compound 612 is outlined in Scheme 17. Reacting compound 607 with compound 608 in a suitable solvent in the presence of a base such as TEA can afford intermediate 609. Reaction of 609 with various alkyl or aryl Grignard reagents or lithium species can provide the tertiary alcohol derivative 610. Alternatively, 609 can be reacted with a trifluoromethylating reagent such as trimethylsilyl trifluoromethane in the presence of TBAF to provide analogs such as 611, where R 1 = CF3. Compound 610 can be reacted with a variety of oxidizing agents to provide the sulfoximine derivative 611, which can be further treated with reagents, such as treatment with NaOH to remove the acid protecting group (P 3 ), treatment with TFA or HCl to remove the amine protecting group (P 2 ), and provides compound 612.

[0177] In the case where R or R 1 is an aryl or heteroaryl that can be substituted with one or more halogens or an alternative functional group compatible with cross-coupling reactions, further reaction with a cross-coupling reagent such as a substituted boronic acid can further generate additional compound 612. It should be understood that these types of reactions can be combined at various stages of the synthesis and can depend on cross-reactivity or protecting group modification.

[0178] Scheme 18

[0179] Additional analogs can be prepared starting from compound 613 by reacting with vinylmagnesium bromide in a suitable solvent such as THF to provide 614. Reaction of 614 with 615 in the presence of AIBN can afford compounds such as 616. Compound 616 can be reacted with a variety of oxidizing agents to generate an intermediate sulfoximine, which can be further treated with reagents, such as treatment with NaOH to remove the acid protecting group (P 3 ), treatment with TFA or HCl to remove the amine protecting group (P 2 ), and provides compound 617.

[0180] In the case where R is an aryl or heteroaryl that can be substituted with a halogen or an alternative functional group compatible with cross-coupling reactions, further reaction with a cross-coupling reagent such as a substituted boronic acid can further generate additional compound 617. It should be understood that these types of reactions can be combined at various stages of the synthesis and can depend on cross-reactivity or protecting group modification.

[0181] Scheme 19

[0182] Additional analogs can be prepared starting from compound 618 by reacting the alcohol group with a thiocarbonate - forming reagent such as phenyl chloroformate to give 619. Compound 619 can be further treated with a radical - initiating reagent such as AIBN to afford the deoxygenated analog 620. Compound 620 can be reacted with a variety of oxidizing agents to produce an intermediate sulfoximine, which can be further treated with reagents, for example, treated with NaOH to remove the acid - protecting group (P 3 ), treated with TFA or HCl to remove the amine - protecting group (P 2 ), and provide compound 621. In cases where R is an aryl or heteroaryl group that can be substituted by halogen or an alternative functional group compatible with cross - coupling reactions, further reaction with a cross - coupling reagent such as a substituted boronic acid can further yield additional compound 621. It should be understood that these types of reactions can be combined at various stages of the synthesis and can depend on cross - reactivity or protecting - group modification.

[0183] Scheme 20

[0184] Additional substituted analogs can be prepared via the route outlined in Scheme 20. Starting from carboxylic acid derivative 622, reaction with an amine in the presence of an amide - bond - forming reagent such as HATU can provide 623. Removal of the protecting group with TFA and / or a strong base can provide the amide - derived analog 624.

[0185] Scheme 21

[0186] Additional amide - substituted analogs can be prepared via the route outlined in Scheme 21. The cyclobutyl ester derivative 625 can be treated with a hydrolyzing reagent or an enzyme such as porcine liver esterase to give acid 626. Acid 626 can be reacted with an amine in the presence of an amide - bond - forming reagent such as HATU to give 627. Compound 627 can be reacted with a variety of oxidizing agents to produce an intermediate sulfoximine 628, which can be further treated with reagents, for example, treated with NaOH to remove the acid - protecting group (P 3 ), treated with TFA or HCl to remove the amine - protecting group (P 2 ), and provide compound 629.

[0187] Scheme 22

[0188] Analogs derived from sulfones can be prepared according to the method outlined in Scheme 22. Starting from readily available intermediates such as dialkyl sulfide 630, treatment with an oxidizing agent such as mCPBA gives sulfone intermediate 631. Treatment of 631 with an acid-base deprotecting reagent such as HCl in dioxane provides compound 632. It should also be understood that the R 1 ,R 2 and R 3 groups can be functionalized and derivatized at various stages of the method. For example, if R 1 is bromophenyl, it can be reacted with an arylboronic acid in the presence of a catalyst such as palladium to provide a biaryl-substituted analog.

[0189] Scheme 23

[0190] Sulfonamide-derived analogs can be prepared according to the method outlined in Scheme 23. Starting from readily available intermediates such as substituted amine 633, reaction with a sulfonyl chloride such as 634 in the presence of a base provides a compound such as 635. Treatment of 635 with an acid-base deprotecting reagent such as HCl in dioxane provides compound 636. It should also be understood that the R 1 ,R 2 and R 3 groups can be functionalized and derivatized at various stages of the method. For example, if R 1 is bromophenyl, it can be reacted with an arylboronic acid in the presence of a catalyst such as palladium to provide a biaryl-substituted analog. Pharmaceutical Compositions

[0191] The present invention provides pharmaceutical compositions, wherein the pharmaceutical compositions comprise an agent selected from Table 1 or a combination of agents selected from Table 1 and / or Table 2 and / or Table 3 and / or Table 4, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises a cell death inducer. In some embodiments, the pharmaceutical composition further comprises a chemotherapeutic agent. In some embodiments, the pharmaceutical compositions provided herein are in suspension, optionally in a homogeneous suspension. In some embodiments, the pharmaceutical compositions provided herein are in the form of an emulsion. In some embodiments, the pharmaceutical compositions provided herein comprise a salt form of any of the agents provided herein. In some embodiments, the salt is mesylate.

[0192] The present disclosure further provides a pharmaceutical composition comprising the ferroptosis inducer or iron-dependent cell death agent provided herein. In some embodiments, the agent provided herein is combined with a pharmaceutically acceptable salt, excipient, and / or carrier to form a pharmaceutical composition. The pharmaceutically acceptable salts, excipients, and carriers can be selected according to the route of administration, the location of the target tissue, and the time course of drug delivery. Pharmaceutically acceptable carriers or excipients can include solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents compatible with drug administration, etc.

[0193] In some embodiments, the pharmaceutical composition is in the form of a solid, semi-solid, liquid, or gas (aerosol). Injectable formulations can be prepared using suitable dispersing or wetting agents and suspending agents according to known techniques, such as sterile injectable aqueous or oily suspensions. The sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in a non-toxic parenterally acceptable diluent or solvent. Acceptable media and solvents that can be used include water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, a sterile fixed oil is used as a solvent or suspending medium. For this purpose, any mild fixed oil can be used, including synthetic mono- or di-glycerides of fatty acids. In addition, fatty acids such as oleic acid are also used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0194] Exemplary carriers and excipients can include glucose, sodium chloride, sucrose, lactose, cellulose, xylitol, sorbitol, maltitol, gelatin, polymers, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and any combination thereof. In some embodiments, the percentage of an excipient such as glucose or sodium chloride can be about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, or up to about 15%.

[0195] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the conjugated compounds, whether encapsulated or not, are admixed with at least one inert pharmaceutically acceptable excipient or carrier or diluent such as sodium citrate or calcium phosphate dibasic and / or (a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarders such as paraffin, (f) absorption promoters such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite, or (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents.

[0196] Tablets may be film-coated or enteric-coated by methods known in the art. Liquid dosage forms for oral administration may be in the form of, for example, solutions, syrups, or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid dosage forms may be prepared by conventional methods with pharmaceutically acceptable carriers and additives such as suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethanol, or fractionated vegetable oils; and preservatives, for example, methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid. The preparations may also suitably contain buffering salts, flavoring agents, coloring agents, and / or sweetening agents. If desired, the preparations for oral administration may be suitably formulated to provide controlled release of the active compound.

[0197] Preparations suitable for oral (sublingual) administration include, for example, lozenges containing the active compound in a flavored base, usually sucrose and acacia or tragacanth; and lozenges containing the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

[0198] The ferroptosis inducer provided herein may be formulated as a rectal composition, such as a suppository or a retention enema, for example, containing a conventional suppository base, such as cocoa butter or other glycerides, or a gelling agent, such as carbomer.

[0199] The pharmaceutical compositions may also be administered by controlled release formulations and / or delivery devices (see, for example, U.S. Patent No. 5,733,566).

[0200] A variety of delivery vehicles are known and can be used to administer the ferroptosis inducers provided herein, such as, but not limited to, encapsulated in liposomes, microparticles, microcapsules, nanoparticles, carriers, and recombinant cells. Liposomes and / or nanoparticles can also be used in conjunction with the administration of the compositions herein. Liposomes are formed from phospholipids dispersed in an aqueous medium and spontaneously form multilamellar concentric bilayer vesicles (also known as multilamellar vesicles (MLV)). The diameter of MLV is typically 25 nm to 4 μm. Sonication of MLV forms small unilamellar vesicles (SUV) with diameters in the range of 200 to 500 angstroms, which have an aqueous solution in their core.

[0201] When phospholipids are dispersed in water, depending on the molar ratio of lipid to water, phospholipids can form a variety of structures other than liposomes. At low ratios, liposomes are formed. The physical properties of liposomes depend on the pH value, ionic strength, and the presence of divalent cations. Liposomes have low permeability to ions and polar substances, but undergo a phase transition at high temperatures, which significantly changes their permeability. The phase transition involves a change from a closely packed ordered structure (called the gel state) to a loosely packed, less ordered structure (called the fluid state). This occurs at a characteristic phase transition temperature, resulting in increased permeability to ions, sugars, and drugs.

[0202] Liposomes interact with cells through different mechanisms: endocytosis by phagocytic cells of the reticuloendothelial system (such as macrophages and neutrophils); adsorption to the cell surface through non-specific weak hydrophobic or electrostatic forces, or through specific interactions with cell surface components; fusion with the plasma membrane by inserting the lipid bilayer of the liposome into the plasma membrane while releasing the liposome contents into the cytoplasm; and transfer of liposome lipids to the cell or subcellular membrane, or vice versa, without any association with the liposome contents. Altering the liposome formulation can change the mechanism(s) at work, although multiple mechanisms can act simultaneously. Nanocapsules can generally encapsulate compounds in a stable and reproducible manner. To avoid side effects due to intracellular polymer overload, such ultrafine particles (sized approximately 0.1 μm) should be designed using polymers that can degrade in vivo. Biodegradable polyalkylcyanoacrylate nanoparticles can also be used as delivery vehicles.

[0203] The tissue-specific targeting nanoparticle carriers provided herein can also be used as pharmaceutically acceptable carriers. In some embodiments, the nanoparticles are gold nanoparticles, platinum nanoparticles, iron oxide nanoparticles, lipid nanoparticles, selenium nanoparticles, tumor-targeting glycol chitosan nanoparticles (CNP), cathepsin B-sensitive nanoparticles, hyaluronic acid nanoparticles, paramagnetic nanoparticles, or polymer nanoparticles.

[0204] Suitable pharmaceutical formulations of ferroptosis inducers for transdermal applications include an effective amount of the agent and a carrier. The carrier includes an absorbable pharmacologically acceptable solvent to assist passage through the skin of a subject. For example, the transdermal device is in the form of a bandage or patch and includes a backing member, a reservoir containing the compound (optionally containing a carrier), optionally a rate control barrier for delivering the compound to the skin of the host at a controlled predetermined rate over an extended period of time, and means for securing the device to the skin. Matrix transdermal formulations can also be used. Suitable formulations for topical application (e.g., to the skin and eyes) are preferably aqueous solutions, ointments, creams or gels well known in the art. The formulations can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0205] In certain embodiments, the ferroptosis inducers provided herein are formulated as depot compositions. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. The ferroptosis inducers can be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil), an ion exchange resin, a biodegradable polymer, or as a slightly soluble derivative, e.g., as a slightly soluble salt.

[0206] In some embodiments, one or more of the agents provided herein are formulated as a medicated food composition (also referred to as a medical food). The food composition can be consumed by a mammal such as a human or a non-human mammal. The agents provided herein can be formulated as a dietary supplement or a medical food. In some embodiments, the agents provided herein are administered with a food ingredient. A food ingredient is any product, composition or food component known to have or disclosed as having a nutritional effect. The food can include a variety of meats (e.g., beef, pork, poultry, fish, etc.), dairy products (e.g., milk, cheese, eggs), fruits, vegetables, grains, breads, etc. and their components. The food can be fresh or preserved by methods such as canning, dehydration, freezing or smoking. The food can be provided in a raw, unprepared and / or natural state or in a cooked, prepared and / or combined state. In some embodiments, the food ingredient is selected from: fats, carbohydrates, proteins, fibers, nutritional balancers and mixtures thereof. In some embodiments, the medicated food composition provided herein further comprises one or more of proteins or amino acids. In some embodiments of any aspect, the medicated food composition further comprises adenine, one or more vitamins (e.g., vitamin E), potassium, fatty acids and / or calcium carbonate. Methods of administering the agent

[0207] The present disclosure provides methods for administering a treatment regimen to a subject having a disease or disorder (e.g., cancer, an autoimmune disease, or fibrosis). In some embodiments, the administering is a continuous administration of a therapeutically effective amount of an inducer of ferroptosis. In some embodiments, the continuous administration of the inducer of ferroptosis comprises providing to a tissue an amount of the inducer of ferroptosis sufficient to achieve a distribution of at least about 10 ng / mm 2 within the tissue for at least 4 hours, thereby inducing ferroptosis in the tissue. In some embodiments, the continuous administration further forms a sub-therapeutic amount gradient of the inducer of ferroptosis adjacent to the site of administration within the tissue. In some embodiments, the continuous administration of the inducer of ferroptosis comprises additional administration steps. In some embodiments, the inducer of ferroptosis is administered more than once. In some embodiments, the administering is performed by the systems provided herein. In some embodiments, the administering is a local administration within a tissue. In some embodiments, the tissue is contacted in vivo with an effective amount of an iron-dependent cell death agent for a duration of at least 4 hours. In some embodiments, the administering comprises contacting a mammalian tissue with a priming agent and contacting the mammalian tissue with an effective amount of the inducer of ferroptosis provided herein, wherein the inducer of ferroptosis induces targeted cell death in the mammalian tissue in vivo. In some embodiments, the administering is a local or systemic administration. In some embodiments, the administering or the contacting step is by intratumoral injection, oral administration, percutaneous injection, inhalation, nasal administration, topical administration, vaginal administration, ocular administration, intracerebral administration, rectal administration.

[0208] In some cases, the agents or combinations of agents provided herein are administered as unit dosage forms. Many agents can be administered orally as liquids, capsules, tablets, or chewable tablets. Since the oral route is the most convenient, generally the safest, and the cheapest route, it is one of the most commonly used. However, it also has limitations due to the way drugs typically move through the digestive tract. For drugs administered orally, absorption may begin in the mouth and stomach. However, most drugs are typically absorbed from the small intestine. The drug passes through the intestinal wall and reaches the liver, and then is transported to the target site via the bloodstream. The intestinal wall and the liver chemically alter (metabolize) many substances, thereby reducing the amount of drug reaching the blood. Thus, these drugs typically require a smaller dose when administered intravenously to produce the same effect.

[0209] In some embodiments, the agents provided herein are formulated for oral administration. In some embodiments, the agents provided herein are formulated for administration via subcutaneous, intradermal, intramuscular, inhalation, intravenous, intraperitoneal, intracranial, intrathecal, intratumoral, or oral routes. For the subcutaneous route, a needle is inserted into the fatty tissue beneath the skin. After injecting the drug, the drug enters small blood vessels (capillaries) and is carried away by the bloodstream. Alternatively, the drug reaches the bloodstream via lymphatic vessels. When a larger volume of the drug product is needed, the intramuscular route is preferred over the subcutaneous route. Since the muscle lies beneath the skin and fatty tissue, a longer needle is used. The agent is usually injected into the muscle of the upper arm, thigh, or buttocks. The rate at which the drug is absorbed into the blood depends in part on the blood supply to the muscle: the less the blood supply, the longer it takes for the drug to be absorbed. For the intravenous injection route, the needle is inserted directly into a vein. The solution containing the drug can be administered as a single dose or as a continuous infusion. For an infusion, the solution moves by gravity (from a collapsible plastic bag), or more commonly, through an infusion pump through a thin flexible tube to a tube (catheter) inserted into a vein (usually in the forearm). In some cases, the agent or treatment regimen is administered as an infusion. The infusion can last for a period of time. For example, the infusion can be the administration of the agent or treatment regimen over a period of about 5 minutes to about 5 hours. The infusion can be carried out over a time period of about 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, or up to about 5 hours.

[0210] In some embodiments, intravenous administration is used to deliver precise doses quickly and in a well-controlled manner throughout the body. It is also used for irritating solutions that would cause pain and damage tissue if administered subcutaneously or intramuscularly. Intravenous injection can be more difficult to administer than subcutaneous or intramuscular injection because it can be difficult to insert the needle or catheter into a vein, especially if the person is obese. When administered intravenously, the drug is delivered immediately into the bloodstream and tends to take effect more quickly than when administered by any other route. Therefore, healthcare practitioners closely monitor patients receiving intravenous injections for signs that the drug is working or causing adverse side effects. Also, the effects of drugs given by this route tend to last for a shorter period of time. Therefore, some drugs must be administered by continuous infusion to maintain a constant effect. For the intrathecal route, a needle is inserted between two vertebrae in the lower spine and into the space around the spinal cord. The drug is then injected into the spinal canal. A small amount of local anesthetic is usually used to numb the injection site. This route can be used when a rapid or local effect of the drug on the brain, spinal cord, or the tissue layers (meninges) covering them is needed, such as for treating infections of these structures.

[0211] For administration by inhalation, the ferroptosis inducers provided herein can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer, using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be determined by delivering a metered amount through the provision of a valve. Capsules and cartridges, such as gelatin, containing a powder mixture of the compound and a suitable powder matrix such as lactose or starch can be formulated for use in an inhaler or insufflator. Compared with nasal administration, the medicament administered by oral inhalation can be atomized into smaller droplets, so that the medicament can enter the lungs through the trachea (windpipe). The depth at which the medicament enters the lungs depends on the size of the droplets. Smaller droplets enter deeper positions, thereby increasing the amount of drug absorbed. Inside the lungs, they are absorbed into the blood.

[0212] Agents applied to the skin are generally used for their local effects and are thus most commonly used to treat superficial skin diseases such as psoriasis, eczema, skin infections (viral, bacterial, and fungal), pruritus, and dry skin. The drug is mixed with an inactive substance. Depending on the consistency of the inactive substance, the formulation can be an ointment, cream, lotion, solution, powder, or gel.

[0213] In some cases, the dosage of the treatment regimen can be determined based on the weight of the subject. For subjects determined to be obese (BMI > 35), the actual weight may need to be used. The formula for calculating BMI is: BMI = weight (kg) / [height (m)] 2 。

[0214] In some cases, the treatment regimen can be administered with a carrier or excipient. The ferroptosis inducers provided herein can be administered sequentially or simultaneously with one or more second agents via the same route or via different administration routes. When administered sequentially, the time between administrations is selected to favor the therapeutic efficacy and / or safety of the combination therapy, etc. In certain embodiments, the agent provided herein can be administered first, followed by the second agent, or, the second agent can be administered first, followed by the agent of the present disclosure (e.g., the ferroptosis inducer of Table 1). By way of example, but not limited to, the time between administrations is about 1 h, about 2 h, about 4 h, about 6 h, about 12 h, about 16 h, or about 20 h. In certain embodiments, the time between administrations is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or more than about 7 days. In some embodiments, the time between administrations is about 1 week, 2 weeks, 3 weeks, or 4 weeks or longer. In some embodiments, the time between administrations is about 1 month or 2 months or longer.

[0215] In some embodiments, the ferroptosis inducer provided herein contacts mammalian tissue for at least about 4 h, at least about 6 h, at least about 10 h, at least about 12 h, at least about 14 h, at least about 16 h, at least about 18 h, at least about 20 h, at least about 22 h, at least about 24 h, at least about 26 h, at least about 28 h, at least about 30 h, at least about 36 h, at least about 48 h, up to 72 h. In some embodiments, the ferroptosis inducer provided herein contacts mammalian tissue for about 4 h. In some embodiments, the ferroptosis inducer provided herein contacts mammalian tissue for about 6 h. In some embodiments, the ferroptosis inducer provided herein contacts mammalian tissue for about 10 h. In some embodiments, the ferroptosis inducer provided herein contacts mammalian tissue for about 12 h. In some embodiments, the ferroptosis inducer provided herein contacts mammalian tissue for about 24 h. In some embodiments, the ferroptosis inducer provided herein contacts mammalian tissue for about 48 h. In some embodiments, the ferroptosis inducer provided herein contacts mammalian tissue for about 72 h.

[0216] When administered concomitantly, the agent can be administered separately by the same or different routes simultaneously with a second agent, or administered as a single pharmaceutical composition by the same route. In certain embodiments, the dosage and frequency of administration of the second agent can use standard dosages and standard frequencies of administration for a particular compound. Dose and Tissue Distribution

[0217] The methods provided herein include administering to a subject an agent or pharmaceutical composition provided herein in an amount effective to induce ferroptosis in a tissue in vivo. The agents and pharmaceutical compositions for administration to a subject in need thereof can be formulated in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form is a physically discrete unit of the composition provided herein that is suitable for the subject to be treated. However, it will be understood that the total usage of the compositions provided herein will be determined by the attending physician within the scope of reasonable medical judgment. For any of the compositions provided herein, the therapeutically effective dose can initially be estimated in cell culture assays or in animal models such as mice, rabbits, dogs, pigs, or non-human primates. Animal models can also be used to achieve the desired concentration range and route of administration. Then, this information can be used to determine useful dosages and routes of administration for humans. The therapeutic efficacy and toxicity of the compositions provided herein can be determined in cell cultures or experimental animals by standard pharmaceutical procedures, such as ED 50 (which dose is therapeutically effective in 50% of the population) and LD 50 (which dose is lethal to 50% of the population). The dose ratio of toxicity to therapeutic effect is the therapeutic index and can be expressed as LD 50 / ED 50The ratio indicates. Pharmaceutical compositions exhibiting a large therapeutic index may be useful in some embodiments. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for human use.

[0218] A typical human dose of the agents provided herein (e.g., ferroptosis inducers) can be from about 10 μg / kg body weight / day to 10,000 mg / kg / day. In some embodiments, the dose of the agents provided herein is from about 0.1 mg / kg to about 1000 mg / kg, 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, a suitable dose 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 the agents provided herein is from about 100 mg / kg / day to about 6,400 mg / kg / day, four times a day. In some embodiments, the dose of the agents provided herein is from about 50 mg / kg / day to about 25 mg / kg / day. In some embodiments, the dose of the agents provided herein is from about 400 mg / kg / day to about 800 mg / kg / day. In certain embodiments, the dose of the agent can be administered once a day or divided into sub-doses and administered in multiple doses, such as two, three, or four times a day.

[0219] In some embodiments, the agents 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 agents are administered in an amount of at least about 1 microgram (μg) or more, about 5 μg or more, about 10 μg or more, about 20 μg or more, about 30 μg or more, about 40 μg or more, about 50 μg or more, about 60 μg or more, about 70 μg or more, about 80 μg or more, about 90 μg or more, up to 100 μg.

[0220] In some embodiments, the agents provided herein are administered at a concentration of at least about 0.1 micromoles per liter (μM) or higher, about 1 μM or higher, about 2 μM or higher, about 3 μM or higher, about 4 μM or higher, about 5 μM or higher, about 6 μM or higher, about 7 μM or higher, about 8 μM or higher, about 9 μM or higher, about 10 μM or higher, about 15 μM or higher, about 20 μM or higher, about 25 μM or higher, about 30 μM or higher, about 35 μM or higher, about 40 μM or higher, about 45 μM or higher, about 50 μM or higher, about 55 μM or higher, about 60 μM or higher, about 65 μM or higher, about 70 μM or higher, about 75 μM or higher, about 80 μM or higher, about 85 μM or higher, about 90 μM or higher, about 95 μM or higher, about 100 μM or higher, about 110 μM or higher, about 120 μM or higher, about 130 μM or higher, about 140 μM or higher, about 150 μM or higher, about 160 μM or higher, about 170 μM or higher, about 180 μM or higher, about 190 μM or higher, about 200 μM or higher, about 300 μM or higher, about 400 μM or higher, about 500 μM or higher, up to 1 mM. In some embodiments, the agents provided herein are administered at a concentration of at least about 0.1 μM to up to about 500 μM. In some embodiments, the agents provided herein are administered at a concentration of at least about 1 μM to up to 500 μM. In some embodiments, the agents provided herein are administered at a concentration of at least about 0.1 μM to up to 10 μM. In some embodiments, the agents provided herein are administered at a concentration of at least about 1 μM to up to 10 μM.

[0221] In some embodiments, the ferroptosis inducer provided herein is administered intravenously. In some embodiments, the ferroptosis inducer provided herein is administered 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, the ferroptosis inducer provided herein is administered intravenously once daily at a concentration of about 25 mg / kg. In some embodiments, the ferroptosis inducer provided herein is administered intravenously twice daily at a concentration of about 25 mg / kg. In some embodiments, the ferroptosis inducer provided herein is administered intravenously at a concentration of about 450 mg / kg / day. In some embodiments, the ferroptosis inducer provided herein is administered intravenously at a concentration of about 650 mg / kg / day. In some embodiments, the ferroptosis inducer provided herein is administered intravenously at a concentration of about 650 mg / kg / day for 3 consecutive days. In some embodiments, the ferroptosis inducer provided herein is administered intravenously at a concentration of about 1300 mg / kg / day. In some embodiments, the ferroptosis inducer provided herein is administered intravenously at a concentration of about 2400 mg / kg / day.

[0222] In some embodiments, the ferroptosis inducer provided herein is administered orally. In some embodiments, the ferroptosis inducer provided herein is administered 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, the ferroptosis inducer provided herein is administered orally once a day at a concentration of about 25 mg / kg. In some embodiments, the ferroptosis inducer provided herein is administered orally twice a day at a concentration of about 25 mg / kg. In some embodiments, the ferroptosis inducer provided herein is administered orally at a concentration of about 1300 mg / kg / day. In some embodiments, the ferroptosis inducer provided herein is administered orally at a concentration of about 2400 mg / kg / day.

[0223] The methods provided herein are characterized by or further include measuring the distribution of the agent in the target tissue. The distribution of the agent provided herein can be determined by the amount or concentration of the agent per square millimeter (mm 2 ) or cubic millimeter (mm 3 ) of tissue. For example, for local administration of the agent to a tumor, the tissue can be about 6 to 7 mm in diameter, 36 to 42 mm 2 , or 216 to 294 mm 3 . Data obtained from animal studies can be used to establish a range of drug distributions in mammalian tissues. Methods for determining the tissue distribution of a drug or agent include, for example, mass spectrometry, chromatography, imaging techniques, and immunoassays. The distribution of the agent provided herein can be determined using the systems provided herein.

[0224] In some embodiments, a therapeutically effective amount of an iron death inducer, a compound, an enantiomer of any of the foregoing, a diastereomer of any of the foregoing, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing is administered to a tissue, wherein the administration comprises providing to the tissue an amount of the iron death inducer sufficient to achieve a desired drug distribution. In some embodiments, the agent, compound, enantiomer of any of the foregoing, diastereomer of any of the foregoing, pharmaceutically acceptable salt of any of the foregoing, or deuterated derivative of any of the foregoing provided herein achieves the following distribution within the tissue: at least about 1 ng / mm 2 or more, about 5 ng / mm 2 or more, about 10 ng / mm 2 or more, about 15 ng / mm 2 or more, about 20 ng / mm 2 or more, about 25 ng / mm 2 or more, about 30 ng / mm 2 or more, about 35 ng / mm 2 or more, about 40 ng / mm 2 or more, about 45 ng / mm 2 or more, about 50 ng / mm 2 or more, about 55 ng / mm 2 or more, about 60 ng / mm 2 or more, about 65 ng / mm 2 or more, about 70 ng / mm 2 or more, about 75 ng / mm 2 or more, about 80 ng / mm 2 or more, about 85 ng / mm 2 or more, about 90 ng / mm 2 or more, about 95 ng / mm 2 or more, about 100 ng / mm 2 or more, about 110 ng / mm 2 or more, about 120 ng / mm 2 or more, about 130 ng / mm 2 or more, about 140 ng / mm 2 or more, about 150 ng / mm 2 or more, about 160 ng / mm 2 or more, about 170 ng / mm 2 or more, about 180 ng / mm 2 or more, about 190 ng / mm 2 or more, about 200 ng / mm 2or more, about 300 ng / mm 2 or more, about 400 ng / mm 2 or more, up to 500 ng / mm 2 In some embodiments, the agents, compounds, enantiomers of any of the foregoing, diastereomers of any of the foregoing, pharmaceutically acceptable salts of any of the foregoing, or deuterated derivatives of any of the foregoing provided herein achieve the following distribution in tissue: at least about 1 ng / mm 3 or more, about 5 ng / mm 3 or more, about 10 ng / mm 3 or more, about 15 ng / mm 3 or more, about 20 ng / mm 3 or more, about 25 ng / mm 3 or more, about 30 ng / mm 3 or more, about 35 ng / mm 3 or more, about 40 ng / mm 3 or more, about 45 ng / mm 3 or more, about 50 ng / mm 3 or more, about 55 ng / mm 3 or more, about 60 ng / mm 3 or more, about 65 ng / mm 3 or more, about 70 ng / mm 3 or more, about 75 ng / mm 3 or more, about 80 ng / mm 3 or more, about 85 ng / mm 3 or more, about 90 ng / mm 3 or more, about 95 ng / mm 3 or more, about 100 ng / mm 3 or more, about 110 ng / mm 3 or more, about 120 ng / mm 3 or more, about 130 ng / mm 3 or more, about 140 ng / mm 3 or more, about 150 ng / mm 3 or more, about 160 ng / mm 3 or more, about 170 ng / mm 3 or more, about 180 ng / mm 3 or more, about 190 ng / mm 3 or more, about 200 ng / mm 3 or more, about 300 ng / mm 3 or more, about 400 ng / mm3 or higher, up to 500 ng / mm 3 .

[0225] In some embodiments, the agents, compounds, enantiomers of any of the foregoing, diastereomers of any of the foregoing, pharmaceutically acceptable salts of any of the foregoing, or deuterated derivatives of any of the foregoing provided herein are administered at least about once, twice, three times, four times, or five times daily. In some embodiments of any aspect, the ferroptosis inducer is administered at least about weekly, at least about every 2 weeks, or at least about every 3 weeks. The amount of drug administered depends on the size of the tissue, the type of disease being treated, and the type of administration (e.g., topical administration to an internal tissue using the system provided herein). The effective dose will vary depending on the type of disease being treated, the route of administration, the use of excipients, and the likelihood of co - use with other therapeutic methods. Efficacy

[0226] The therapeutic efficacy of the agents and / or pharmaceutical compositions provided herein can be determined by evaluating and comparing the symptoms and quality of life of the patient before and after administration. Such methods are applicable regardless of the mode of administration. In some embodiments, before administration refers to the assessment of the patient's symptoms and quality of life before the start of treatment, and after administration refers to the assessment of the patient's symptoms and quality of life at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks after the start of treatment. In some embodiments, before administration refers to the assessment of the patient's symptoms and quality of life before the start of treatment, and after administration refers to the assessment of the patient's symptoms and quality of life at most 52 weeks after the start of treatment. In a specific embodiment, the post - administration assessment is performed about 2 - 8, 2 - 6, 4 - 6, or 4 weeks after the start of treatment. In one specific embodiment, the patient's symptoms (e.g., symptoms related to cancer, fibrosis, or autoimmune diseases) and quality of life are evaluated clinically and by questionnaire assessment before and after administration.

[0227] The agents and methods provided herein can be used to reduce cancer cell proliferation or survival in vivo or in vitro. Methods for evaluating tumor progression or cell proliferation are known in the art. In some embodiments, the overall response is evaluated according to the time - point response assessment (based on tumor burden) as follows: · Complete response (CR): All target lesions disappear. The short axis of any pathological lymph node (whether target or non - target) must be reduced to <10 mm. · Partial response (PR): The sum of the diameters of the target lesions is reduced by at least 30% with reference to the sum of the baseline diameters. · Progressive Disease (PD): The sum of the diameters of target lesions increases by at least 20% in total, with the smallest sum in the study as the reference (if the smallest sum in the study includes the baseline sum). In addition to the 20% relative increase, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered progression). · Stable Disease (SD): Using the smallest sum of diameters at the time of the study as the reference, there is neither sufficient shrinkage to meet the criteria for PR nor sufficient increase to meet the criteria for PD.

[0228] In some embodiments, an in vitro cell proliferation assay is used to evaluate the efficacy of one or more ferroptosis inducers provided herein. The compositions and methods provided herein result in a reduction in the proliferation or survival of multiple cells. For example, after treatment with one or more agents provided herein, cell proliferation or survival is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to cell proliferation or survival prior to treatment.

[0229] In some embodiments, an animal model is used to evaluate the in vivo efficacy of one or more ferroptosis inducers provided herein. The ferroptosis inducers and methods provided herein can result in a reduction in the size or volume of hyperproliferative tissue (e.g., a tumor). For example, after treatment, the tissue size is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) relative to its size prior to treatment. The size of the tissue (e.g., a tumor) can be measured by any reproducible measurement method. The size of the tissue can be measured as the diameter of the tumor or by any reproducible measurement method. A ferroptosis inhibitor (e.g., an agent in Table 2 or Table 3) can be used to determine the efficacy of a specific test agent (also referred to herein as an active agent) for inducing ferroptosis in a tissue. For example, a combination of a ferroptosis inducer paired with a ferroptosis inhibitor (e.g., lipastatin-1) can be used to determine whether the test agent targets a protein or nucleic acid involved in the ferroptosis pathway (see Figure 1)。The present disclosure further provides a method for rescuing one or more cells from cell death and / or ferroptosis in vivo, the method comprising: administering a ferroptosis inhibitor to a subject. In some embodiments, the method further comprises administering a ferroptosis inducer. The present disclosure further provides a method for screening the ferroptosis sensitivity of multiple cells in a tissue, the method comprising: contacting the tissue with a ferroptosis inducer and a ferroptosis inhibitor; and measuring one or more parameters indicative of ferroptosis. In some embodiments, the ferroptosis inducer is an agent in Table 1 or a test agent. In some embodiments, the ferroptosis inhibitor is any agent listed in Table 2 or Table 3. In some embodiments, the ferroptosis inhibitor is any agent listed in Table 4. In some embodiments, the ferroptosis inducer is any agent listed in Table 2 or Table 3. In some embodiments, the ferroptosis inhibitor is lipastatin-1. In some embodiments, the one or more parameters indicative of ferroptosis are PUFA concentration, PI index, regulation of the expression of mesenchymal cell state markers, or regulation of iron or selenium concentration. The screening method provided herein can be readily extended for high-throughput analysis, which allows the evaluation or prediction of the ferroptosis-inducing activity of test agents. Similarly, the screening method can be performed in the animal models described above in the presence and absence of a ferroptosis inhibitor.

[0230] Treatment of a disease or disorder (such as cancer) can further result in a reduction in the number of hyperproliferative tissues (such as tumors). For example, relative to the number before treatment, the number of hyperproliferative tissues or tumors is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) after treatment. The number of tumors can be measured by any reproducible measurement method. The number of tumors can be measured by counting tumors visible to the naked eye or tumors visible at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x or 50x). In some embodiments, the methods and ferroptosis inducers provided herein increase the number or activity of white blood cells in the tumor microenvironment. In some embodiments, the white blood cells specifically target cancer cells having a high PUFA concentration compared to normal cells.

[0231] Treatment of cancer can reduce the number of metastatic nodules in other tissues or organs away from the primary tumor site. For example, relative to the number before treatment, the number of metastatic nodules is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) after treatment. The number of metastatic nodules can be measured by any reproducible measurement method. The number of metastatic nodules can be measured by counting metastatic nodules visible to the naked eye or visible at a specified magnification (e.g., 2x, 10x or 50x).

[0232] Treating a disease or disorder (e.g., cancer) can result in an increase in the average survival time of a population of subjects treated according to the present disclosure compared to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, 120 days or longer). The increase in the population average survival time can be measured by any reproducible method. The increase in the population average survival time can be measured, for example, by calculating the average survival length of the population after starting treatment with a compound of the present disclosure. The increase in the average survival time of the population can also be measured, for example, by calculating the average survival length of the population after completing the first round of treatment with a compound of the present disclosure.

[0233] Treating a disease or disorder (e.g., cancer) can also result in a decrease in the mortality rate of a population of treated subjects compared to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, 25% or higher). The decrease in the mortality rate of the treated population can be measured by any reproducible means, for example, by calculating the average number of disease-related deaths per unit time in the population after starting treatment with a compound of the present disclosure. The decrease in the population mortality rate can also be measured, for example, by calculating the average number of disease-related deaths per unit time in the population after completing the first round of treatment with an ferroptosis inducer.

[0234] Treating a disease or disorder can also result in a reduction in at least one symptom associated with the disease, disorder or condition. In some embodiments, the methods provided herein reduce at least one symptom of the disease or disorder by at least 10%, 20%, 30%, 40%, 50%, 70%, 80%, 90% or more relative to a previous amount. In some embodiments, cell death can be detected at a time point when or after the mammalian tissue is contacted with an ferroptosis inducer, after contacting or administering the ferroptosis inducer to the mammalian tissue. In some embodiments, the methods provided herein increase cell death by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more relative to a previous amount. Therapeutic applications

[0235] Methods for treating a disease or disorder in a subject are provided herein. In some embodiments, the subject has, is suspected of having, or is at risk of developing a hyperproliferative disease or disorder. In some embodiments, the methods provided herein further comprise the step of obtaining a tissue biopsy for histological analysis. In some embodiments, the tissue comprises histological abnormalities, wherein the histological abnormalities are hyperplasia or fibrosis.

[0236] In some embodiments, the subject has, is suspected of having, or is at risk of developing a disease or disorder associated with abnormal angiogenesis or vasculogenesis. Diseases or disorders associated with abnormal angiogenesis or vasculogenesis can include, but are not limited to, ocular neovascularization, macular degeneration, retinopathy, sarcoma, polycystic kidney disease, benign hyperplasia, leiomyoma, adenoma, lipoma, hemangioma, fibroma, vascular occlusion, restenosis, atherosclerosis, pre-neoplastic lesions, carcinoma in situ, and cancer. In some embodiments, the subject has, is suspected of having, an autoimmune disease 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 subject has, is suspected of having, fibrosis or is at risk of developing fibrosis. Non-limiting examples of diseases and disorders associated with fibrosis include: keloid, hypertrophic scar, systemic sclerosis, pulmonary hypertension, cardiac fibrosis, hypertrophic cardiomyopathy, valvular disease, myelofibrosis, myelodysplastic syndrome, chronic myelogenous leukemia, portal hypertension, hepatocellular carcinoma, retroperitoneal fibrosis, intestinal fibrosis, enteropathy, subretinal fibrosis, preretinal fibrosis, cystic fibrosis, emphysema, pancreatic fibrosis, chronic pancreatitis, ductal obstruction, joint fibrosis, renal fibrosis, nephrogenic systemic fibrosis, renal anemia, chronic kidney disease, Dupuytren's contracture, Ledderhose disease (plantar fibromatosis), primary biliary cholangitis (PBC), non-alcoholic steatohepatitis (NASH), scleroderma, diabetic neuropathy, hypertensive nephrosclerosis, allograft nephropathy, cirrhosis, and pulmonary fibrosis.

[0237] In some embodiments, the subject has, is suspected of having, or is at risk of developing cancer. In some embodiments, the subject has a benign tumor. In some embodiments, the subject has a pre-cancerous lesion. In some embodiments, the subject has basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). In some embodiments, the subject has a metastatic tumor. In some embodiments, the cancer is a solid cancer or a blood cancer. In some embodiments, the blood cancer is leukemia or lymphoma. In some embodiments, the subject has a solid tumor. In some embodiments, the solid tumor is a carcinoma, melanoma, or sarcoma. In some embodiments, the melanoma is a dedifferentiated melanoma or an amelanotic melanoma. In some embodiments, the subject has a melanoma with a mutation in the B-Raf proto-oncogene, serine / threonine kinase (BRAF). In some embodiments, the subject 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 a leiomyosarcoma. In some embodiments, the carcinoma is colon adenocarcinoma. In some embodiments, the carcinoma is liver cancer. In some embodiments, the carcinoma is kidney cancer. In some embodiments, the carcinoma is clear cell renal carcinoma. In some embodiments, the carcinoma is non-clear cell renal carcinoma.

[0238] Non-limiting examples of cancers that can be treated with the agents provided herein include: acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, angiosarcoma); appendiceal cancer; benign monoclonal gammopathy; bile duct cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast carcinoma, breast medullary carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; connective tissue cancer; epithelial cancer; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric 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), laryngeal cancer (e.g., laryngeal carcinoma, pharyngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma)); hematopoietic system cancers (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CIVIL, T-cell CML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell 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 lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., Waldenström's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; or 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, Sézary 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 of the leukemias / lymphomas as described above; and multiple myeloma (MM)), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immunocyte amyloidosis; kidney cancer (e.g., Wilms' tumor also known as nephroblastoma, renal cell carcinoma, clear cell renal carcinoma, non-clear cell renal carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer); lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative diseases (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), agnogenic myeloid metaplasia (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CIVIL), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinoma (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 tumor); penile cancer (e.g., penile Paget's disease or scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell tumor; paraneoplastic syndrome; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); colorectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (e.g., appendiceal 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 thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., vulvar Paget's disease).;

[0239] The present invention provides methods of administering ferroptosis inducers to a tissue, wherein the tissue comprises different cell types. In some embodiments, the tissue comprises a heterogeneous cell population, wherein the heterogeneous cell population comprises at least one of precancerous cells and non-cancerous cells. In some embodiments, the tissue comprises a heterogeneous cell population, wherein the heterogeneous cell population comprises an immune cell population.

[0240] The present disclosure provides methods for inducing the recruitment of immune cells to a tumor, the methods comprising: administering to a subject a ferroptosis inducer provided herein by any method provided herein. In some embodiments, the administration is a continuous administration for at least about 10 hours to recruit the immune cells to the tumor site. In some embodiments, the immune cells are white blood cells. In some embodiments, immune cell recruitment can be detected at the time or after the time of contact of the mammalian tissue with the ferroptosis inducer, after contact or administration of the ferroptosis inducer to the mammalian tissue. In some embodiments, the administration reduces the size of the tumor and / or increases the number of white blood cells within the tumor. System

[0241] The present disclosure further provides a system for delivering a ferroptosis inducer or an iron-dependent cell death inducer provided herein. The present disclosure further provides a system for inducing ferroptosis in vivo, the system comprising: an implantable microdevice configured for local administration to a tissue, comprising: (a) a cylindrical support structure having at least one micropore formed on a surface of the support structure or within the support structure; (b) a microdose of a ferroptosis inducer in the at least one micropore; and (c) a compound release mechanism for continuous administration to control the release of the ferroptosis inducer from the micropore, wherein the microdose of the ferroptosis inducer forms a sub-therapeutic dose gradient of the ferroptosis inducer at the administration site within the tissue for a duration of at least 4 hours, wherein the microdevice is configured to be implanted into the tissue using a catheter, cannula, or biopsy needle, and wherein the microdevice is further configured to release the ferroptosis inducer from the at least one micropore to an administration site within an anti-apoptotic tissue adjacent to the at least one micropore.

[0242] The present disclosure further provides a system for identifying ferroptosis induction in an animal model, the system comprising: (a) an animal model comprising a target tissue of interest; (b) a microdevice configured to be implanted into the tissue of the animal model using a catheter, cannula, or biopsy needle, comprising: (i) at least one micropore containing one or more active agents; (ii) a microdose of the one or more active agents in the at least one micropore; (iii) a compound release mechanism comprising a polymeric matrix for controlling the release of the one or more active agents from the micropore into the tissue; wherein the system measures the results of ferroptosis induction in the animal model after administering the one or more active agents to the tissue and identifies one or more active agents that induce ferroptosis in the tissue, relative to a baseline tissue to which the one or more active agents have not been administered.

[0243] The present invention further provides a system for screening ferroptosis-induced cell death in vivo, the system comprising: (a) an animal model comprising a target tissue of interest; (b) a microdevice configured to be implanted into the tissue of the animal model using a catheter, cannula or biopsy needle, the microdevice comprising: (i) at least one micropore containing one or more active agents; (ii) at least one micropore containing one or more ferroptosis inhibitors; (ii) a microdose of the one or more active agents; and / or one or more ferroptosis inhibitors in the at least one micropore; (iii) a compound release mechanism comprising a polymer matrix for controlling the release of the one or more active agents from the micropores into the tissue; wherein the system measures the results of ferroptosis induction in the animal model after administration of the one or more active agents to the tissue, relative to a baseline tissue to which the one or more active agents have not been administered, and wherein the system measures the results of ferroptosis induction in the animal model after administration of the one or more active agents to the tissue, relative to administration of the one or more active agents and one or more ferroptosis inhibitors, and identifies one or more active agents that induce ferroptosis in the tissue.

[0244] The system provided herein generally includes a plurality of micropores disposed on or within a support structure. The micropores contain one or more active agents, alone or in combination, in one or more doses and / or release pharmacokinetics. Preferably, the device is configured to deliver a microdose amount so as to substantially eliminate overlap of the active agents released from different micropores in the tissue. In some embodiments, the device is configured to facilitate implantation and removal in the target tissue. In an exemplary embodiment, the device has a cylindrical shape with symmetric holes on the outer side of the device, each hole containing one or more drugs at one or more concentrations. The size of the device is suitable for placement using a catheter, cannula or stylet. In a preferred embodiment, the device has a guide wire to assist in placement and retrieval. The device may also include features that help maintain the spatial stability of the tissue excised with the device, such as fins or stabilizers that can be deployed from the device before or at the time of removal. Optionally, the device has optical fibers, sensors, and / or interactive features, such as remote access (e.g., Wi-Fi), to provide in-situ retrieval of information and modification of the device release characteristics. In a most preferred embodiment, the optical fibers and / or sensors can be individually accessed to discrete holes.

[0245] In some embodiments, the systems provided herein are formed of biocompatible silicon, metal, ceramic, or polymer. They may include materials such as radiopaque materials or materials that can be imaged using ultrasound or MRI. They can be fabricated using techniques such as deep ion etching, nanoimprint lithography, micromachining, laser etching, three-dimensional printing, or stereolithography. Drugs can be loaded by injecting a solution or suspension into the pores and then removing the solvent by drying, evaporation, or lyophilization, or by placing the drug in tablet or granule form into the pores. In a preferred embodiment, the drug is loaded on top of a hydrogel pad within the micropores. The hydrogel pad swells during implantation, delivering the drug to the surrounding tissue. The drug release pharmacokinetics is a function of the drug solubility, excipients, pore size, and the tissue of the implant device (higher release rates occur in more highly vascularized tissues compared to less vascularized tissues).

[0246] In some embodiments, the systems provided herein are directly implanted into solid tumors or tissue to be biopsied. After implantation, the systems provided herein locally release an array of microdoses of active agents. Subsequent analysis of the tumor's response to the array of active agents can be used to identify specific drugs, drug combinations, and / or doses that are effective in treating the patient's solid tumor. By locally delivering an array of microdoses of drugs, the microassay device can be used to rapidly test the patient's response to multiple treatment regimens under actual physiological conditions without causing systemic toxicity. This data can be selectively combined with genomic data to accurately predict the systemic drug response.

[0247] Without limitation, the systems provided herein can administer the agents provided herein according to any of the methods provided herein. For example, the systems provided herein can be used to deliver a microdose of an agent to a tissue in the body. The systems described herein can provide a sustained administration of a therapeutically effective amount of a ferroptosis inducer to a tissue, wherein the sustained administration of the therapeutically effective amount includes providing to the tissue an amount of the ferroptosis inducer sufficient to achieve a distribution of at least about 10 ng / mm 2 for at least 4 hours, thereby inducing ferroptosis in the tissue. In some embodiments, the sustained administration further forms a gradient of a sub-therapeutically effective amount of the ferroptosis inducer near the site of use within the tissue. In some embodiments, the sustained administration of the therapeutically effective amount of the ferroptosis inducer is at least 10 hours. In some embodiments, the therapeutically effective amount of the ferroptosis inducer is a concentration of at least about 1 μM up to 10 μM. In some embodiments, the systems provided herein are implanted into a tumor. In some embodiments, the system delivers one or more ferroptosis inducers to the tumor. Exemplary embodiments

[0248] The present disclosure provides methods for inducing ferroptosis in a tissue of a subject, the methods comprising: continuously administering a therapeutically effective amount of a ferroptosis inducer to the tissue, wherein the continuous administration of the therapeutically effective amount comprises providing to the tissue an amount sufficient to achieve at least about 10 ng / mm 2An amount of a ferroptosis inducer that is distributed for at least 4 hours to induce ferroptosis in the tissue. The present disclosure further provides methods wherein the continuous administration further forms a gradient of a sub-therapeutic amount of the ferroptosis inducer near the site of administration within the tissue. The present disclosure further provides methods wherein the continuous administration of the ferroptosis inducer includes additional administration steps. The present disclosure further provides methods wherein the tissue comprises a heterogeneous cell population, wherein the heterogeneous cell population comprises at least one of precancerous cells and non-cancerous cells. The present disclosure further provides methods wherein the tissue comprises a heterogeneous cell population, wherein the heterogeneous cell population comprises an immune cell population. The present disclosure further provides methods wherein the tissue comprises a heterogeneous cell population, wherein the heterogeneous cell population comprises a first cell population that comprises a higher concentration of selenium or iron compared to a predetermined level of selenium or iron; and a second cell population that comprises a normal concentration of selenium or iron compared to the predetermined level of selenium or iron. The present disclosure further provides methods wherein the tissue comprises a homogeneous cell population. The present disclosure further provides methods wherein the tissue comprises a plurality of cancer cells. The present disclosure further provides methods wherein the tissue comprises a plurality of cells that express one or more markers indicative of a mesenchymal state. The present disclosure further provides methods wherein the one or more markers are selected from: ZEB1, ACSL4, FADS2, PPARγ, Fsp1, SLC7A11, SLC3A2, and LPCAT3. The present disclosure further provides methods wherein the tissue comprises a plurality of cells with reduced expression of one or more endothelial cell markers. The present disclosure further provides methods wherein the endothelial cell marker is vimentin, E-cadherin, or β(β)-actin. The present disclosure further provides methods wherein the tissue comprises histological abnormalities. The present disclosure further provides methods wherein histological abnormalities are determined by a tissue biopsy before or during targeted, continuous administration of a ferroptosis inducer to the tissue. The present disclosure further provides methods wherein the histological abnormality is hyperplasia or fibrosis. The present disclosure further provides methods wherein the tissue comprises a plurality of cells with a polyunsaturated fatty acid (PUFA) concentration greater than the PUFA concentration in normal tissue cells. The present disclosure further provides methods wherein the PUFA concentration in the plurality of cells is greater than a predetermined PUFA concentration. The present disclosure further provides methods wherein the tissue comprises a plurality of cells with a peroxidation index (PI) greater than the PI in cells of normal or healthy tissue; and ferroptosis is induced in the plurality of cells. The present disclosure further provides methods wherein the PI in the plurality of cells is greater than a predetermined PI. The present disclosure further provides methods wherein the ferroptosis inducer is glutathione peroxidase 4 (GPX4), glutathione synthetase, glutamate-cysteine ligase, phosphoserine-TRNA kinase (PSTK), eukaryotic elongation factor selenocysteine-TRNA specific (EEFSEC), selenophosphate synthetase 2 (SEPHS2),Inhibitors of Sep(O-phosphoserine)tRNA:Sec(selenocysteine)tRNA synthase(SEPSECS)or SECIS-binding protein 2(SECISBP2). Further provided herein are methods, wherein the inhibitor is a small molecule, a peptide or a nucleic acid. Further provided herein are methods, wherein the ferroptosis inducer is any one or more of the agents in Table 1. Further provided herein are methods, wherein the ferroptosis inducer is any one or more of the agents in Table 2 or Table 3. Further provided herein are methods, wherein the ferroptosis inducer is selected from Table 1, for example selected from: (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jacareic acid, buthionine sulfoximine(BSO), trigonelline, glutamic acid, sulfasalazine, auranofin, bruceolide, sorafenib, sorafenib-d3, sorafenib tosylate, trigonelline, FIN56, FINO2, CIL56, dihydrotanshinone I, GPX4-IN-3, its analogs or derivatives. Further provided herein are methods, wherein the ferroptosis inducer contacts the tissue at the local site for about 6 hours. Further provided herein are methods, wherein the ferroptosis inducer contacts the tissue at the local site for about 10 hours. Further provided herein are methods, wherein the ferroptosis inducer contacts the tissue at the local site for about 24 hours. Further provided herein are methods, wherein the ferroptosis inducer contacts the tissue at the local site for about 48 hours. Further provided herein are methods, wherein the ferroptosis inducer contacts the tissue at the local site for about 72 hours. Further provided herein are methods, wherein the ferroptosis inducer is administered at a concentration of at least about 1 μM to 10 μM. Further provided herein are methods, wherein the tissue is resistant to treatment with an anti-apoptotic agent. Further provided herein are methods, wherein the tissue is a tumor or a tissue containing multiple cancer cells. Further provided herein are methods, wherein the cancer is a solid tumor or a blood cancer. Further provided herein are methods, wherein the blood cancer is leukemia or lymphoma. Further provided herein are methods, wherein the solid tumor is carcinoma, melanoma or sarcoma. Further provided herein are methods, wherein the melanoma is dedifferentiated melanoma or amelanotic melanoma. Further provided herein are methods, wherein the subject has cancer or is at risk of developing cancer. Further provided herein are methods, wherein the cancer is acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, angiosarcoma); appendiceal cancer; benign monoclonal gammopathy; cholangiocarcinoma (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, breast medullary carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma),Medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; connective tissue carcinoma; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell carcinoma; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic system cancer (e.g., leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell 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 lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., Waldenström macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; 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, Sézary 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 of the leukemias / lymphomas as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immunocyte amyloidosis; kidney cancer (e.g., Wilms' tumor also known as nephroblastoma, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer, liver cancer); lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC),Lung adenocarcinoma); Leiomyosarcoma (LMS); Mastocytosis (e.g., systemic mastocytosis); Muscle cancer; Myelodysplastic syndrome (MDS); Mesothelioma; Myeloproliferative disease (MPD) (e.g., Polycythemia vera (PV), Essential thrombocythemia (ET), Angiogenic myeloid metaplasia (AMM) also known as Myelofibrosis (MF), Chronic idiopathic myelofibrosis, Chronic myelogenous leukemia (CIVIL), Chronic neutrophilic leukemia (CNL), Hypereosinophilic syndrome (HES); Neuroblastoma; Neurofibroma (e.g., Neurofibromatosis (NF) type 1 or 2, Schwannomatosis); Neuroendocrine carcinoma (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 tumor); Penile cancer (e.g., Penile Paget's disease or Scrotum); Pinealoma; Primitive neuroectodermal tumor (PNT); Plasma cell tumor; Paraneoplastic syndrome; Intraepithelial neoplasia; 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 intestine cancer (e.g., Appendiceal 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 cancer; Synovioma; Testicular cancer (e.g., Seminoma, Testicular embryonal carcinoma); Thyroid cancer (e.g., Papillary thyroid carcinoma, Papillary thyroid carcinoma (PTC), Medullary thyroid carcinoma); Urethral cancer; Vaginal cancer; or Vulvar cancer (e.g., Vulvar Paget's disease).

[0249] The present disclosure further provides a method of inducing iron-dependent cell death in a tissue of a subject, the method comprising: contacting the tissue in vivo with an effective amount of an iron-dependent cell death agent for a duration of at least 4 hours, wherein the tissue comprises one or more of the following: (a) a plurality of cells having a selenium concentration higher than the selenium concentration in the corresponding normal tissue; (b) a plurality of cells having an iron concentration higher than the iron concentration in the corresponding normal tissue; (c) a plurality of cells having a PUFA concentration higher than the PUFA concentration in the corresponding normal tissue; (d) a plurality of cells expressing one or more markers indicative of a mesenchymal state; and / or (e) a plurality of cells having a peroxidation index (PI) greater than the PI in the corresponding normal tissue, wherein the effective amount of the iron-dependent cell death agent is a concentration of at least about 0.1 μM to at most 500 μM in the tissue over the duration. The present disclosure further provides a method, wherein the iron-dependent cell death agent is any one of the agents listed in Table 1. The present disclosure further provides a method, wherein the iron-dependent cell death agent is any one of the agents listed in Table 2 or Table 3. The present disclosure further provides a method, wherein the ferroptosis inducer is selected from Table 1, such as selected from: (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jacaric acid, buthionine sulfoximine (BSO), trigonelline, glutamate, sulfasalazine, auranofin, bruceatol, sorafenib, sorafenib-d3, sorafenib tosylate, trigonelline, FIN56, FINO2, CIL56, dihydrotanshinone I, GPX4-IN-3, an analogue or derivative thereof. The present disclosure further provides a method, wherein the iron-dependent cell death agent contacts the tissue at a local site for about 6 hours. The present disclosure further provides a method, wherein the iron-dependent cell death agent contacts the tissue at a local site for about 10 hours. The present disclosure further provides a method, wherein the iron-dependent cell death agent contacts a site on the tumor for about 24 hours. The present disclosure further provides a method, wherein the iron-dependent cell death agent contacts a site on the tumor for about 48 hours. The present disclosure further provides a method, wherein the iron-dependent cell death agent contacts a site on the tumor for about 72 h. The present disclosure further provides a method, wherein the tissue is a tumor or a pre-cancerous lesion. The present disclosure further provides a method, wherein the tumor is resistant to one or more anti-apoptotic agents. The present disclosure further provides a method, wherein the tumor is a carcinoma, melanoma or sarcoma. The present disclosure further provides a method, wherein the melanoma is a dedifferentiated melanoma or an amelanotic melanoma. The present disclosure further provides a method, wherein the method further comprises the step of obtaining a tissue biopsy for histological analysis. The present disclosure further provides a method, wherein the tissue comprises histological abnormalities, wherein the histological abnormalities are hyperplasia or fibrosis.The present invention further provides a method, wherein the one or more markers indicating a mesenchymal state are selected from: ZEB1, ACSL4, FADS2, PPARγ, Fsp1, SLC7A11, SLC3A2, and LPCAT3. The present invention further provides a method, wherein the tissue comprises a plurality of cells with reduced expression of one or more endothelial cell markers. The present invention further provides a method, wherein the endothelial cell marker is vimentin, E-cadherin, or β(β)-actin. The present invention further provides a method, wherein the agent reduces the tissue size or tissue volume by at least 5%. The present invention further provides a method, wherein the agent is administered together with another agent. The present invention further provides a method, wherein the other agent is a cell death inducer or a dietary supplement.

[0250] The present invention further provides a method for inducing targeted cell death in mammalian tissues in vivo, wherein the method comprises: (a) contacting a mammalian tissue with an initiator; (b) contacting the mammalian tissue in vivo with an effective amount of an iron death inducer for a duration of at least 4 hours, at which time it is determined by detection in the mammalian tissue that a plurality of cells in the mammalian tissue respond to the initiator: (i) the plurality of cells contain a selenium concentration higher than the selenium concentration in the mammalian tissue before contacting with the initiator; (ii) the plurality of cells contain an iron concentration higher than the iron concentration in the mammalian tissue before contacting with the initiator; (iii) the plurality of cells contain a PUFA concentration higher than the PUFA concentration in the mammalian tissue before contacting with the initiator; (iv) the plurality of cells express one or more markers indicating a mesenchymal state; (v) the plurality of cells contain a peroxidation index (PI) greater than the PI in the mammalian tissue before contacting with the initiator; and / or (vi) hyperproliferation of cells in the mammalian tissue, wherein the iron death inducer induces targeted cell death in the mammalian tissue in vivo. The present invention further provides a method, wherein step (a) is carried out in vivo, in vitro or ex vivo. The present invention further provides a method, wherein the method further comprises the step of obtaining a biopsy of the mammalian tissue for histological analysis. The present invention further provides a method, wherein the method further comprises the step of detecting a plurality of cells in the mammalian tissue that respond to the initiator. The present invention further provides a method, wherein the detection is carried out by histological determination or immunohistochemical determination. The present invention further provides a method, wherein the initiator is any one of the agents listed in Table 4. The present invention further provides a method, wherein the initiator is lipastatin-1, ferrostatin-1, deferoxamine (DFO), iron, vitamin E, polyunsaturated fatty acid or selenium. The present invention further provides a method, wherein the method further comprises administering a cell death inducer. The present invention further provides a method, wherein the cell death inducer is a chemotherapeutic agent. The present invention further provides a method, wherein the iron death inducer is any one of the agents listed in Table 1. The present invention further provides a method, wherein the iron death inducer is selected from Table 1, for example selected from: (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jakacid, buthionine sulfoximine (BSO), trigonelline, glutamate, sulfasalazine, auranofin, bruceantin, sorafenib, sorafenib-d3, sorafenib tosylate, trigonelline, FIN56, FINO2, CIL56, dihydrotanshinone I, GPX4-IN-3, its analogs or derivatives. The present invention further provides a method, wherein the iron death inducer contacts the mammalian tissue for about 6 hours. The present invention further provides a method, wherein the iron death inducer contacts the mammalian tissue for about 10 hours.The present invention further provides methods, wherein the ferroptosis inducer contacts the mammalian tissue for about 24 hours. The present invention further provides methods, wherein the ferroptosis inducer contacts the mammalian tissue for about 48 hours. The present invention further provides methods, wherein the ferroptosis inducer contacts the mammalian tissue for about 72 hours. The present invention further provides methods, wherein the effective amount of the ferroptosis inducer is a concentration of at least about 1 μM to 10 μM. The present invention further provides methods, wherein after contacting with the ferroptosis inducer, cell death can be detected at the time point when the mammalian tissue contacts the ferroptosis inducer or at a later time point. The present invention further provides methods, wherein after contacting with the ferroptosis inducer, immune cell recruitment can be detected at the time point when the mammalian tissue contacts the ferroptosis inducer or at a later time point. The present invention further provides methods, wherein the tissue is human tissue. The present invention further provides methods, wherein the administration or the contacting step is by intratumoral injection, oral administration, percutaneous injection, inhalation, nasal administration, topical administration, vaginal administration, ocular administration, intracerebral administration, rectal administration. The present invention further provides methods, wherein the administration or the contacting step is by intravenous administration, intra-arterial administration, intramuscular administration or subcutaneous administration.

[0251] The present invention further provides a system, wherein the system comprises: an implantable microdevice configured for local administration to a tissue, comprising: (a) a cylindrical support structure having at least one micropore formed on the surface of or within the support structure; (b) a microdose of a ferroptosis inducer in at least one of the micropores; and (c) a compound release mechanism for continuous administration to control the release of the ferroptosis inducer from the micropores, wherein the microdose of the ferroptosis inducer forms a sub-therapeutic dose gradient of the ferroptosis inducer at the administration site within the tissue for a duration of at least 4 hours, wherein the microdevice is configured to allow implantation into the tissue using a catheter, cannula or biopsy needle, and wherein the microdevice is further configured to release the ferroptosis inducer from the at least one micropore to the administration site within the anti-apoptotic tissue adjacent to the at least one micropore.

[0252] The present invention further provides a system for screening ferroptosis-induced cell death in vivo, the system comprising: (a) an animal model comprising a target tissue of interest; (b) a microdevice configured to be implanted into the tissue of the animal model using a catheter, cannula or biopsy needle, the microdevice comprising: (i) at least one micropore containing one or more active agents; (ii) at least one micropore containing one or more ferroptosis inhibitors; (ii) a microdose of the one or more active agents; and / or one or more ferroptosis inhibitors in the at least one micropore; (iii) a compound release mechanism comprising a polymer matrix for controlling the release of the one or more active agents from the micropore into the tissue; wherein the system measures the results of ferroptosis induction in the animal model after administration of the one or more active agents to the tissue relative to a baseline tissue to which the one or more active agents have not been administered, and wherein the system measures the results of ferroptosis induction in the animal model after administration of the one or more active agents to the tissue relative to administration of the one or more active agents and one or more ferroptosis inhibitors, and identifies one or more active agents that induce ferroptosis in the tissue.

[0253] The present invention further provides a system for screening ferroptosis-induced cell death in vivo, the system comprising: (a) an animal model comprising a target tissue of interest; (b) a microdevice configured to be implanted into the tissue of the animal model using a catheter, cannula or biopsy needle, the microdevice comprising: (i) at least one micropore containing one or more active agents; (ii) at least one micropore containing one or more ferroptosis inhibitors; (ii) a microdose of the one or more active agents; and / or one or more ferroptosis inhibitors in the at least one micropore; (iii) a compound release mechanism comprising a polymer matrix for controlling the release of the one or more active agents from the micropore into the tissue; wherein the system measures the results of ferroptosis induction in the animal model after administration of the one or more active agents to the tissue relative to a baseline tissue to which the one or more active agents have not been administered, and wherein the system measures the results of ferroptosis induction in the animal model after administration of the one or more active agents to the tissue relative to administration of the one or more active agents and one or more ferroptosis inhibitors, and identifies one or more active agents that induce ferroptosis in the tissue. The present invention further provides a system, wherein the ferroptosis inhibitor is lipastatin-1 or ferrostatin-1.

[0254] The present invention further provides a method for regulating ferroptosis in vivo, the method comprising: (a) contacting mammalian tissue in vivo with an effective amount of a ferroptosis inducer for a duration of at least 4 hours, wherein the ferroptosis inducer induces targeted cell death in mammalian tissue in vivo; and (b) contacting mammalian tissue in vivo with an effective amount of a ferroptosis inducer and a ferroptosis inhibitor, thereby regulating ferroptosis in vivo. The present invention further provides a method, wherein the ferroptosis inhibitor is lipastatin-1, ferrostatin-1, deferoxamine (DFO), iron, vitamin E, polyunsaturated fatty acid or selenium. The present invention further provides a method, wherein the ferroptosis inducer is an inhibitor of glutathione peroxidase 4 (GPX4), glutathione synthetase, glutamate-cysteine ligase, phosphoserine-TRNA kinase (PSTK), eukaryotic elongation factor selenocysteine-TRNA specific (EEFSEC), selenophosphate synthetase 2 (SEPHS2), Sep(O-phosphoserine)TRNA:Sec (selenocysteine)TRNA synthetase (SEPSECS) or SECIS binding protein 2 (SECISBP2). The present invention further provides a method, wherein the ferroptosis inducer is selected from (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jacaric acid, buthionine sulfoximine (BSO), trigonelline, glutamate, sulfasalazine, auranofin, bruceine D, sorafenin, sorafenin-d3, sorafenib tosylate, trigonelline, FIN56, FINO2, CIL56, dihydrotanshinone I, GPX4-IN-3, its analogs or derivatives. The present invention further provides a method, wherein the ferroptosis inducer contacts the mammalian tissue for about 6 hours. The present invention further provides a method, wherein the ferroptosis inducer contacts the mammalian tissue for about 10 hours. The present invention further provides a method, wherein the ferroptosis inducer contacts the mammalian tissue for about 24 hours. The present invention further provides a method, wherein the ferroptosis inducer contacts the mammalian tissue for about 48 hours. The present invention further provides a method, wherein the ferroptosis inducer contacts the mammalian tissue for about 72 hours. The present invention further provides a method, wherein the effective amount of the ferroptosis inducer is a concentration of at least about 1 μM to 10 μM. The present invention further provides a method, wherein after contacting with the ferroptosis inducer, cell death can be detected at the time point when or after the mammalian tissue contacts with the ferroptosis inducer. The present invention further provides a method, wherein after contacting with the ferroptosis inducer, immune cell recruitment can be detected at the time point when or after the mammalian tissue contacts with the ferroptosis inducer. The present invention further provides a method, wherein the tissue is human tissue.The present disclosure further provides methods, wherein the administering or contacting step is by intratumoral injection, oral administration, transdermal injection, inhalation, nasal administration, topical administration, vaginal administration, ocular administration, intracerebral administration, or rectal administration. The present disclosure further provides methods, wherein the administering or contacting step is via intravenous administration, intraarterial administration, intramuscular administration, or subcutaneous administration. The present disclosure further provides methods, wherein the methods further comprise measuring one or more parameters indicative of ferroptosis in mammalian tissue, wherein the one or more parameters are selected from: the concentration of selenium; the concentration of iron; the PUFA concentration; the expression of one or more markers indicative of a mesenchymal state; the peroxidation index (PI); and / or cell proliferation.

[0255] The present disclosure further provides a composition for treating a disease or disorder, wherein the composition comprises any one of the agents or a combination of agents in Table 1; and the system provided herein.

[0256] The present disclosure further provides a pharmaceutical composition for treating a disease or disorder, wherein the pharmaceutical composition comprises any one of the agents or a combination of agents in Table 1; and a pharmaceutically acceptable excipient. The present disclosure further provides a pharmaceutical composition for treating a disease or disorder, wherein the pharmaceutical composition comprises any one of the agents or a combination of agents in Table 1 or Table 2; and a pharmaceutically acceptable excipient.

[0257] In some embodiments, it is a compound, a diastereomer or enantiomer of the compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from:

[0258] In some embodiments, it is a compound, a diastereomer or enantiomer of the compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from:

[0259] In some embodiments, it is a compound, a diastereomer or enantiomer of the compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from:

[0260] In some embodiments, described herein is a compound of Formula XVIII: The diastereomers or enantiomers of the compound of formula XVIII, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein in the compound of formula XVIII: Each R1, R2 or R3 is independently: H, C1-C 10 Straight-chain or branched-chain alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C3-C 10 Heteroaryl, biphenyl, halogenated biphenyl, indole, triazole, isothiazole, oxazoline, C1-C6 straight-chain or branched-chain alkyl ether, -CH3, phenyl, -C(O)OR5, -C(O)NH2, -O-, -S-, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, -Cl, -Br, -I; Or R1 and R2, R2 and R3, or R1 and R3 together form C3-C6 cycloalkyl, and wherein the C3-C6 cycloalkyl may optionally be substituted by C1-C6 straight-chain or branched-chain alkyl, C1-C6 cycloalkyl, halogen, -CF3 or -F, or R1 and R2 and R3 together form C3-C6 cycloheteroaryl; and wherein each R1, R2 or R3 is independently and optionally substituted by a substituent selected from: deuterium, halogen, fluorine, -CF3, chlorine, C1-C 10 Straight-chain or branched-chain alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, C3-C6 cycloalkyl, phenyl, halogenated phenyl, biphenyl, halogenated biphenyl, isothiazole, triazole, furan, oxazoline, C3-C6 heteroaryl, urea, acid anhydride and any combination thereof; wherein R4 is H or C1-C6 straight-chain or branched-chain alkyl; and Wherein R5 is C1-C 10 Straight-chain or branched-chain alkyl, which is optionally substituted by at least one heteroatom, halogen or C1-C3 alkyl ether.

[0261] In some embodiments, it is a compound of formula XIX: The diastereomers or enantiomers of the compound of formula XIX, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein in the compound of formula XIX: Each R1, R2 or R3 is independently: H, C1-C 10 Straight-chain or branched-chain alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C3-C 10heteroaryl, biphenyl, halobiphenyl, indole, triazole, isothiazole, oxazoline, C1-C6 straight or branched alkyl ether, -C(O)OR5, -C(O)NH2, -O-, -S-, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, -Cl, -Br, -I, or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, and wherein said C3-C6 cycloalkyl may optionally be substituted by C1-C6 straight or branched alkyl, C1-C6 cycloalkyl, halogen, -CF3 or -F; or R1 and R2 and R3 together form a C3-C6 cycloheteroaryl; and wherein each of R1, R2 or R3 is independently and optionally substituted by a substituent selected from: deuterium, halogen, fluorine, -CF3, chlorine, C1-C 10 straight or branched alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, C3-C6 cycloalkyl, phenyl, halophenyl, biphenyl, halobiphenyl, isothiazole, triazole, furan, oxazoline, C3-C6 heteroaryl, urea, acid anhydride and any combination thereof; wherein R4 is H or C1-C6 straight or branched alkyl; and wherein R5 is C1-C 10 straight or branched alkyl, which is optionally substituted by at least one heteroatom, halogen or C1-C3 alkyl ether.

[0262] In some embodiments, it is a compound of formula XX: a diastereomer or enantiomer of said compound of formula XX, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein in the compound of formula XX: each of R1, R2 or R3 is independently: H, C1-C4 straight or branched alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C5-C6 heteroaryl, biphenyl, halobiphenyl, triazole, isothiazole, oxazoline, C1-C6 straight or branched alkyl ether, -C(O)OR5, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, and wherein said C3-C6 cycloalkyl may optionally be substituted by C1-C6 straight or branched alkyl, C1-C6 cycloalkyl, halogen, -CF3 or -F; and wherein each of R1, R2 or R3 is independently and optionally substituted by a substituent selected from: deuterium, halogen, fluorine, -CF3, chlorine, C1-C 10A straight-chain or branched-chain alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, a C3-C6 cycloalkyl group, phenyl, halophenyl, biphenyl, halobiphenyl, isothiazole, triazole, oxazoline, a C3-C6 heteroaryl group, and any combination thereof; wherein R4 is H or a C1-C6 straight-chain or branched-chain alkyl group; and wherein R5 is a C1-C 10 straight-chain or branched-chain alkyl group, which is optionally substituted by at least one heteroatom, halogen, or a C1-C3 alkyl ether.

[0263] In some embodiments, it is a pharmaceutical composition comprising a compound of formula XVIII, XIX, XX, or a compound described herein, a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, and a pharmaceutically acceptable excipient, diluent, or carrier. In some embodiments, the pharmaceutical composition is in unit dose form. In some embodiments, the pharmaceutical composition further comprises an additional active agent or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is in the form of a powder, tablet, capsule, liquid, or gel. In some embodiments, the pharmaceutical composition is present in the pharmaceutical composition in an amount in the range of about 0.001 mg to about 25,000 mg. In some embodiments, a kit comprises the pharmaceutical composition described herein and a container. In some embodiments, the container is a syringe. In some embodiments, the container is an IV bag. In some embodiments, the container is disposable. In some embodiments, the container is a disposable container. In some embodiments, the container is a resealable container.

[0264] Also described herein is a method of treating cancer in a subject. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein, thereby treating the cancer. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of formula XVIII, a compound of formula XIX, a compound of formula XX, or a compound described herein, a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, thereby treating the cancer. In some embodiments, the cancer is carcinoma, sarcoma, or melanoma. In some embodiments, the carcinoma is liver cancer. In some embodiments, the cancer is clear cell renal carcinoma or non-clear cell renal carcinoma. In some embodiments, the cancer is a cancer lacking the SWI / SNF complex. In some embodiments, the administration is selected from: oral, injection; subcutaneous, intratumoral; systemic, topical, intravenous, intraperitoneal, intramuscular, and any combination thereof.

[0265] The present invention also describes methods of modulating ferroptosis in a tissue, the methods comprising contacting the tissue with a pharmaceutical composition described herein in an amount effective to modulate ferroptosis in the tissue. In some embodiments, the tissue is comprised in a subject. In some embodiments, the subject is a subject in need thereof. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the administration or the contacting is: once daily, twice daily, three times daily, once weekly, once every two weeks, once every three weeks, once monthly, once every six months, once annually, or for life, as needed. In some embodiments, the therapeutically effective amount or the effective amount ranges from about 0.001 mg to about 25,000 mg.

[0266] The present invention also describes methods of treating a disease or disorder in a subject, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein, thereby treating the disease or disorder. The present invention also describes methods of treating a disease or disorder in a subject, the methods comprising administering a therapeutically effective amount of a pharmaceutical composition described herein, a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, thereby treating the disease or disorder. In some embodiments, the disease or disorder is fibrosis or a kidney disease.

[0267] The present invention also describes crystalline forms of the compounds described herein.

[0268] The following examples are set forth to more clearly illustrate the principles and practice of the embodiments disclosed herein and should not be construed as limiting the scope of any claimed embodiment. Unless otherwise indicated, all parts and percentages are by weight. Examples Example 1: Compound Synthesis, Purification, and Characterization

[0269] The compounds of the present disclosure and the intermediates for preparing the compounds of the present disclosure can be prepared using the procedures shown in the following examples and related procedures. The methods and conditions used in these examples and the actual compounds prepared in these examples are not meant to be limiting, but rather to demonstrate how the compounds of the present disclosure can be prepared. The starting materials and reagents used in these examples, when not prepared by the procedures described herein, are generally commercially available, reported in the chemical literature, or can be prepared by using the procedures described in the chemical literature. Column chromatography is carried out using a pre-packed silica gel column or a manually loaded column chromatography system. Preparative high performance liquid chromatography (HPLC) is carried out using a reverse phase column sized appropriately for the amount of material to be separated, typically eluted with a gradient of increasing concentration of methanol or acetonitrile in water, also containing 0.05% or 0.1% trifluoroacetic acid or 10 mM ammonium acetate, at an elution rate appropriate for the column size and the separation to be achieved. In some cases, chiral chromatography is carried out to separate stereoisomers. Chemical names are determined using ChemDraw Ultra, version 20.1 (CambridgeSoft). The following abbreviations are used: angstrom AIBN 2,2’-azobis(2-methylpropionitrile) aq. aqueous Ac2O acetic anhydride brine saturated aqueous sodium chloride solution Boc tert-butoxycarbonyl BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate bpy 2,2’-bipyridine Bn benzyl Bz benzoyl Cbz benzyloxycarbonyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMFDMA N,N-dimethylformamide dimethyl acetal DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol Et3SiH triethylsilane FA formic acid FMOC 9-fluorenylmethyloxycarbonyl g gram h hours HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High Performance Liquid Chromatography i-PrOH Isopropyl alcohol KHMDS Potassium bis(trimethylsilyl)amide LAH Lithium aluminum hydride LCMS Liquid Chromatography - Mass Spectrometry m-CPBA m-Chloroperbenzoic acid MeCN Acetonitrile MeOH Methanol MHz Megahertz MS Molecular sieve MsCl Methanesulfonyl chloride MTBE tert-Butyl methyl ether NaOAc Sodium acetate NH4OAc Ammonium acetate NIS N-Iodosuccinimide NMO N-Methylmorpholine N-oxide NMR Nuclear Magnetic Resonance Ns p-Nitrobenzenesulfonyl Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 Dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) Pd(OAc)2 Palladium(II) acetate Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)2Cl2 Dichlorobis(triphenylphosphine)palladium(II) pet ether Petroleum ether PIDA (Diacetoxyiodo)benzene PhI(OAc)2 (Diacetoxyiodo)benzene PPTS Pyridinium p-toluenesulfonate p-TsOH p-Toluenesulfonic acid Ts p-Toluenesulfonyl TsCl p-Toluenesulfonyl chloride [Rh(COD)CI]2 Chloro(1,5-cyclooctadiene)rhodium(I) dimer SEM 2-(Trimethylsilyl)ethoxymethyl t-BuOH tert-Butanol TBAF Tetra-N-butylammonium fluoride TEA Triethylamine TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran TIPS Triisopropylsilyl ether TLC Thin layer chromatography TMS Trimethylsilyl TMSCF3 Trimethyl(trifluoromethyl)silane TPAP Ammonium tetrapropylammonium perruthenate HPLC conditions: A. Phenomnex Luna C18, 2×50mm, 5μm, column temperature 40°C, 0 - 30% B for 3 min, then 100% B for 1 min. Solvent A: 0.04% TFA in water, solvent B: 0.02% TFA in MeCN. 1 mL / min. B. XBridge C18, 2.1×50mm, 5μm, column temperature 40°C, 0 - 95% B for 3.85 min. Solvent A: 10 mM NH4CO3 in water, solvent B: MeCN, 1 mL / min or preferably 0.8 mL / min. C. Phenomnex Luna C18, 2×50mm, 5μm, column temperature 40°C, 5 - 95% B for 3 min, then 95% B for 1 min. Solvent A: 0.04% TFA in water, solvent B: 0.02% TFA in MeCN. 1 mL / min. D. Phenomnex Luna C18, 2×50mm, 5μm, column temperature 40°C, 0 - 60% B for 5 min, then increased to 100% B for 1.5 min. Solvent A: 0.04% TFA in water, solvent B: 0.02% TFA in MeCN. 0.8 mL / min. E. Phenomnex Luna C18, 2×50mm, 5μm, column temperature 40°C, 0 - 30% B for 3 min, then 30% B for 1 min. Solvent A: 0.04% TFA in water, solvent B: 0.02% TFA in MeCN. 1 mL / min. F. Kinetix C18, 2.1×50mm, 5μm, column temperature 40°C, 5 - 95% B for 3 min, then 95% B for 1 min. Solvent A: 0.04% TFA in water, solvent B: 0.02% TFA in MeCN. 1 mL / min. G. XBridge C18, 2.1×50 mm, 5 µm, column temperature 40 °C, 0 - 30% B for 3.4 min, then 100% B for 0.45 min. Solvent A: 10 mM NH4CO3 in water, solvent B: MeCN, 0.6 mL / min. H. Kinetix C18, 2×50 mm, 5 µm, column temperature 40 °C, 0 - 30% B for 3 min, then 100% B for 1 min. Solvent A: 0.04% TFA in water, solvent B: 0.02% TFA in MeCN. 1 mL / min. I. XBridge C18, 2.1×50 mm, 5 µm, column temperature 40 °C, 0 - 60% B for 4 min, then 60% B for 2 min. Solvent A: 10 mM NH4CO3 in water, solvent B: MeCN, 0.6 mL / min. J. Kinetix EVOC18, 2×30 mm, 5 µm, column temperature 40 °C, 5 - 95% B for 0.7 min, then 95% B for 0.46 min. Solvent A: 0.04% TFA in water, solvent B: 0.02% TFA in MeCN. 1.5 mL / min. K. XBridge C18, 2.1×50 mm, 5 µm, column temperature 40 °C, 0 - 60% B for 4 min, then 60% B for 2 min. Solvent A: 10 mM NH4CO3 in water, solvent B: MeCN, 0.6 mL / min. L. Chomolith Flash RB - 18e C18, 2×25 mm, column temperature: 40 °C, 0 - 30% B for 3.5 min, then 30% B for 0.3 min. Solvent A: 0.04% TFA in water, solvent B: 0.02% TFA in MeCN, flow rate 0.8 mL / min. M. Merck Chomolith Flash RP - 18e, column temperature: 40 °C, 0 - 30% B for 1.2 min, then 30% B for 0.4 min. Solvent A: 0.04% TFA in water, solvent B: 0.02% TFA in MeCN, flow rate 1.5 mL / min. N. Agilent poroshell 120 EC - C18 3.0×50 mm, 2.7 µm, column temperature: 45 °C, 5 - 99% B for 3 min, then 99% B for 1 min. Solvent A: 0.04% TFA in water, solvent B: 0.02% TFA in MeCN, flow rate 1 mL / min. O. Waters XSelect HSS T3 4.6×50 mm, 3.5 µm, column temperature: 40 °C, 0 - 30% B for 3 min, then 100% B for 1 min. Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN, flow rate 1 mL / min. P. Agilent ZORBAX SB - Aq, 2.1×50 mm, 5 µm, column temperature: 45 °C, 0 - 80% B for 3.4 min, then 100% B for 0.5 min. Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN, flow rate 0.6 mL / min. Q. EVOC18 2.1×30 mm 5 µm, column temperature: 45 °C, 0 - 60% B for 3.6 min, then 60% B for 0.25 min. Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN, flow rate 0.6 mL / min. R. Waters XSelect HSS T3 4.6×50 mm, 3.5 µm, column temperature: 40 °C, 0 - 60% B for 3 min, then 100% B for 1 min. Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN, flow rate 1 mL / min. S. Agilent ZORBAX RX - SIL, 4.6×150 mm, 5 µm, column temperature: 40 °C, 0 - 85% B for 7 min. Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN, 1 mL / min. T. Agilent XBridge C18, 2.1×50 mm, 5 µm, column temperature: 40 °C, 0 - 60% B for 4 min, then 60% B for 2 min. Solvent A: 10 mM NH4HCO3 in water, Solvent B: MeCN, flow rate 0.8 mL / min. U. Halo C18, 3.0×30 mm, 5 µm, column temperature: 40 °C, 10 - 100% B for 0.5 min, then 100% B for 0.4 min. Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN, flow rate 2 mL / min.

[0270] Exemplary Embodiment 1a (2S)-2 - Amino - 4-(2-(4 - chlorophenyl)ethylsulfonylimino)butyric acid

[0271] At 0 °C, methanesulfonyl chloride (MsCl, 19.2 mmol, 1.48 mL) was added to a mixture of (4-chlorophenyl)ethan-1-ol (100 mg, 6.39 mmol) and triethylamine (TEA, 19.2 mmol, 2.67 mL) in DCM (10 mL). The mixture was stirred at 0 - 25 °C for 16 h. The mixture was quenched with water and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1, 1 / 1) to give ethyl 4-chlorobenzenemethanesulfonate (1 g, 66.7% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3) δ 7.34 - 7.28 (m, 2H), 7.18 (d, J = 8.44 Hz, 2H), 4.40 (t, J = 6.79 Hz, 2H), 3.04 (t, J = 6.79 Hz, 2H), 2.90 (s, 3H).

[0272] Under Ar, potassium iodide (KI, 2.4 mmol) and potassium carbonate (K2CO3, 4.8 mmol) were added to a mixture of ethyl 4-chlorobenzenemethanesulfonate (375 mg, 1.6 mmol) and tert-butyl (tert-butoxycarbonyl)-L-homocysteinate (400 mg, 1.6 mmol) in DMF. The mixture was stirred at 25 - 70 °C for 16 h, quenched with water, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1, R f = 0.50) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((4-chlorophenethyl)thio)butanoate (0.37 g, 60% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3-d) δ 7.29 - 7.25 (m, 3H), 7.14 (d, J = 8.44 Hz, 2H), 5.10 (brd, J = 6.97 Hz, 1H), 4.42 (br d, J = 4.65 Hz, 1H), 3.75 (s, 3H), 2.90 - 2.81 (m, 2H), 2.80 - 2.71 (m, 2H), 2.61 - 2.51 (m, 2H), 2.18 - 2.06 (m, 1H), 1.98 - 1.85 (m, 1H), 1.45 (s, 9H).

[0273] A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((4-chlorophenethyl)thio)butyrate (170 mg, 0.44 mmol), PhI(OAc)2 (1.1 mmol) and ammonium carbamate (2.2 mmol) in i-PrOH (3 mL) was stirred at 25 °C for 16 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, silica gel 100 - 200 mesh, petroleum ether / ethyl acetate = 5 / 1, 0 / 1) to give methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-(4-chlorophenyl)ethylsulfinyl)butyrate (0.1 g, 56% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3-d) δ 7.31 (d, J = 8.33 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.19 (d, J = 8.33 Hz, 2H), 5.31 (s, 1H), 4.49 (s, 1H), 4.42 (br s, 1H), 3.78 (s, 3H), 3.47 - 3.28 (m, 2H), 3.17 (br d, J = 7.89 Hz, 4H), 2.51 - 2.34 (m, 1H), 2.31 - 2.13 (m, 1H), 1.45 (s, 9H).

[0274] A mixture of methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-(4-chlorophenyl)ethylsulfinyl)butyrate (40.0 mg, 95.5 mmol) in HCl (6 M, 1 mL) was stirred at 50 °C for 16 h. The mixture was dried by lyophilization to give (2S)-2-amino-4-(2-(4-chlorophenyl)ethylsulfinyl)butyric acid (28.8 mg, 80% yield, HCl) as a yellow oil. LCMS: Rt = 2.445 min, (ES + ) m / z (M + H) + = 305.0, HPLC conditions: A; 1 1H NMR (400 MHz, D2O) δ 7.38 - 7.32 (m, 2H), 7.31 - 7.24 (m, 2H), 4.09 (br s, 1H), 4.07 - 3.98 (m, 2H), 3.91 - 3.66 (m, 2H), 3.21 (br t, J = 7.15 Hz, 2H), 2.38 (br d, J = 6.72 Hz, 2H).

[0275] Exemplary embodiment 1b (2S)-2-Amino-4-(2-phenylethylsulfinyl)butyric acid

[0276] To a solution of (2S)-2-((tert-butoxycarbonyl)amino)-4-sulfanylbutyric acid benzyl ester (0.800 g, 2.46 mmol) and 2-bromoethylbenzene (500 mg, 365 mL, 2.7 mmol) in DMF (10 mL) was added K2CO3 (1.02 g, 7.38 mmol). The mixture was stirred at 20 °C for 1 h. Water (30 mL) was added, and the product was extracted with MTBE (30 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 9:1 to 7:3) to give (S)-2-((tert-butoxycarbonyl)amino)-4-(phenylethylthio)butyric acid benzyl ester (1.1 g, crude), as a colorless oil. 1 1H NMR (400 MHz, CDCl3-d) δ 7.41 - 7.27 (m, 7H), 7.26 - 7.12 (m, 3H), 5.18 (q, J = 12.5 Hz, 3H), 4.50 - 4.36 (m, 1H), 2.89 - 2.79 (m, 2H), 2.77 - 2.67 (m, 2H), 2.57 - 2.45 (m, 2H), 2.17 - 2.06 (m, 1H), 1.99 - 1.83 (m, 1H), 1.44 (s, 9H).

[0277] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-(phenylethylthio)butyric acid benzyl ester (1.00 g, 2.33 mmol) in DCM (10 mL) was added m-CPBA (473 mg, 2.33 mmol, 85% purity). The mixture was stirred at 20 °C for 1 h. The reaction was quenched with NaHCO3 (20 mL), and then extracted with DCM (20 mL × 2). The combined organic phases were washed with Na2SO3 (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:1 to 1:2) to give (2S)-2-((tert-butoxycarbonyl)amino)-4-(phenylethylsulfinyl)butyric acid benzyl ester (910 mg, 88% yield), as a colorless oil. 11H NMR (400 MHz, CDCl3-d) δ 7.39 - 7.29 (m, 7H), 7.26 - 7.19 (m, 3H), 5.35 - 5.10 (m, 3H), 4.45 (br d, J = 4.3 Hz, 1H), 3.18 - 2.99 (m, 2H), 2.99 - 2.79 (m, 2H), 2.77 - 2.59 (m, 2H), 2.45 - 2.26 (m, 1H), 2.23 - 2.07 (m, 1H), 1.43 (s, 9H).

[0278] To a solution of benzyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(phenylethanesulfinyl)butyrate (910 mg, 2.04 mmol) in MeOH (10 mL) was added ammonium carbamate (797 mg, 10.2 mmol) and PhI(OAc)2 (1.97 g, 6.13 mmol). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated to give the crude product. Water (20 mL) was added to the residue and the product was extracted with ethyl acetate (20 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:1 to 1:2) to give benzyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-phenylethanesulfinimido)butyrate (620 mg, 66% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3-d) δ 7.42 - 7.27 (m, 8H), 7.26 - 7.19 (m, 2H), 5.37 - 5.12 (m, 3H), 4.50 - 4.33 (m, 1H), 3.38 - 2.90 (m, 6H), 2.48 - 2.32 (m, 1H), 2.23 - 2.11 (m, 1H), 1.43 (s, 9H).

[0279] To a solution of benzyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-phenylethylsulfonimidoyl)butyrate (0.40 g, 868 mmol) in THF (5 mL) and H2O (1 mL) was added LiOH.H2O (72.9 mg, 1.74 mmol). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated to give a residue. Water (10 mL) was added and the aqueous layer was extracted with DCM (10 mL). The aqueous phase was adjusted to pH ~4 with 2N HCl and extracted with DCM (10 mL × 3). The combined organic extracts were concentrated to give (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-phenylethylsulfonimidoyl)butyric acid (274 mg, 85% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3-d) δ 7.39 - 7.27 (m, 3H), 7.25 (br s, 2H), 5.60 (br d, J = 6.4 Hz, 1H), 4.57 - 4.27 (m, 1H), 3.58 - 3.39 (m, 2H), 3.33 - 3.02 (m, 4H), 2.45 - 2.14 (m, 2H), 1.45 (s, 9H).

[0280] A solution of (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-phenylethylsulfonimidoyl)butyric acid (80.0 mg, 216 mmol) in HCl / dioxane (4M, 3 mL) was stirred at 20 °C for 4 h. The mixture was concentrated, water was added and the mixture was washed with DCM (2 mL × 3). The aqueous phase was concentrated to give (2S)-2-amino-4-(2-phenylethylsulfonimidoyl)butyric acid (76.31 mg, crude, HCl) as a white solid. LCMS: Rt = 1.672 min., (ES + ) m / z (M + H) + = 271.1, HPLC conditions: A; 1 1H NMR (400 MHz, D2O) δ 7.55 - 7.17 (m, 5H), 4.17 - 3.94 (m, 3H), 3.86 - 3.67 (m, 2H), 3.32 - 3.20 (m, 2H), 2.48 - 2.29 (m, 2H).

[0281] The compounds described in Table 5 were prepared using the above method. Table 5. Characterization of Compounds 3 - 48

[0282] Exemplary Embodiment 1c (2S)-2-Amino-4-(3-methyl-3-phenylbutylsulfonylimino)butyric acid

[0283] To a solution of 3-methyl-3-phenylbutyric acid (1.00 g, 5.61 mmol) in THF (12 mL) at 0 °C was added LiAlH4 (213 mg, 5.61 mmol). The mixture was stirred at 20 °C under N2 for 2 h. The mixture was diluted with ethyl acetate (10 mL) and quenched with water (0.2 mL), 15% NaOH (0.2 mL) and water (0.6 mL). The mixture was dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to give 3-methyl-3-phenylbutan-1-ol (640 mg, 69% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3-d) δ 7.40 - 7.29 (m, 4H), 7.23 - 7.17 (m, 1H), 3.57 - 3.46 (m, 2H), 2.02 - 1.93 (m, 2H), 1.36 (s, 6H).

[0284] To a solution of 3-methyl-3-phenylbutan-1-ol (640 mg, 3.90 mmol) and TEA (592 mg, 5.84 mmol, 813 μL) in DCM (6 mL) at 0 °C was added MsCl (536 mg, 4.68 mmol, 362 μL). The mixture was stirred at 20 °C for 1 h. The mixture was poured into water (10 mL) and extracted with EtOAc (15 mL × 2). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 92:8) to give 3-methyl-3-phenylbutyl methanesulfonate (880 mg, 93% yield) as a colorless oil. 11H NMR (400 MHz, CDCl3-d) δ 7.37 - 7.31 (m, 4H), 7.25 - 7.18 (m, 1H), 4.09 - 3.98 (m, 2H), 2.89 - 2.81 (m, 3H), 2.21 - 2.07 (m, 2H), 1.39 (s, 6H).

[0285] To a solution of (S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-4-mercaptobutanoate (880 mg, 3.02 mmol) in DMF (8 mL) was added 3-methyl-3-phenylbutyl methanesulfonate (879 mg, 3.62 mmol), K2CO3 (1.25 g, 9.06 mmol) and KI (1.0 g, 6.04 mmol). The mixture was stirred at 25 °C under Ar for 16 h. The mixture was poured into water (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1) to give (S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-4-((3-methyl-3-phenylbutyl)thio)butanoate (700 mg, 53% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3-d) δ 7.32 (d, J = 4.4 Hz, 4H), 7.23 - 7.16 (m, 1H), 5.05 (br d, J = 7.2 Hz, 1H), 4.22 (br d, J = 5.3 Hz, 1H), 2.53 - 2.39 (m, 2H), 2.28 - 2.17 (m, 2H), 1.98 (br s, 1H), 1.94 - 1.86 (m, 2H), 1.82 - 1.70 (m, 1H), 1.50 - 1.42 (m, 18H), 1.33 (s, 6H).

[0286] To a solution of tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-((3-methyl-3-phenylbutyl)thio)butanoate (500 mg, 1.14 mmol) in i-PrOH (5 mL) was added PhI(OAc)2 (1.47 g, 4.57 mmol) and ammonium carbamate (714 mg, 9.14 mmol). The mixture was stirred at 20 °C for 16 h. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 70:30) to give tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3-methyl-3-phenylbutylsulfinyl)butanoate (400 mg, 75% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3-d) δ 7.38 - 7.30 (m, 4H), 7.25 - 7.19 (m, 1H), 5.19 (br s, 1H), 4.23 (br s, 1H), 3.16 - 2.90 (m, 2H), 2.89 - 2.66 (m, 2H), 2.36 - 2.22 (m, 1H), 2.20 - 2.09 (m, 2H), 2.05 - 1.92 (m, 1H), 1.46 (d, J = 7.5 Hz, 18H), 1.39 (s, 6H).

[0287] A solution of tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3-methyl-3-phenylbutylsulfinyl)butanoate (70.0 mg, 149 mmol) in HCl / dioxane (2 mL, 4 M) was stirred at 25 °C for 2 h. The reaction mixture was concentrated and the residue was dissolved in water (2 mL) and extracted with DCM (1 mL × 2). The aqueous layer was lyophilized to give (2S)-2-amino-4-(3-methyl-3-phenylbutylsulfinyl)butanoic acid (36.0 mg, 69% yield, HCl salt) as a yellow solid. LCMS: Rt = 2.776 min, (ES + ) m / z (M + H) + = 313.1, HPLC conditions: A; 1 1H NMR (400 MHz, D2O) δ 7.51 - 7.37 (m, 4H), 7.34 - 7.25 (m, 1H), 4.10 - 3.97 (m, 1H), 3.96 - 3.73 (m, 2H), 3.43 (br d, J = 7.6 Hz, 2H), 2.35 (br d, J = 6.7 Hz, 2H), 2.27 - 2.15 (m, 2H), 1.38 (s, 6H).

[0288] Exemplary Embodiment 1d (2S)-4-(3-(1H-pyrazol-4-yl)propylsulfonylimino)-2-aminobutyric acid

[0289] To a solution of (S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-4-mercaptobutyrate (500 mg, 1.72 mmol) and 4-(3-chloropropyl)-1H-pyrazole (372 mg, 2.06 mmol, HCl) in DMF (5 mL) were added K2CO3 (711 mg, 5.15 mmol) and KI (569 mg, 3.43 mmol). The mixture was stirred at 20 °C for 16 h under Ar. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 75:25 to 60:40) to give (S)-tert-butyl 4-((3-(1H-pyrazol-4-yl)propyl)thio)-2-((tert-butoxycarbonyl)amino)butyrate (600 mg, 88% yield) as a yellow oil. 1 HNMR (400 MHz, CDCl3-d) δ 7.50 - 7.40 (m, 3H), 5.11 (br d, J = 6.7 Hz, 1H), 4.28 (br s, 1H), 2.63 (t, J = 7.4 Hz, 2H), 2.58 - 2.48 (m, 4H), 2.07 - 2.00 (m, 1H), 1.93 - 1.82 (m, 3H), 1.46 (d, J = 8.3 Hz, 18H).

[0290] To a solution of tert-butyl (S)-4-((3-(1H-pyrazol-4-yl)propyl)thio)-2-((tert-butoxycarbonyl)amino)butanoate (200 mg, 0.5 mmol) in i-PrOH (2 mL) was added PhI(OAc)2 (644 mg, 2.0 mmol) and ammonium carbamate (312 mg, 4.0 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated. The mixture was poured into water (1 mL) and extracted with EtOAc (2 mL × 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase: [water (0.2% FA)-MeCN]; B%: 10%-40%, 12 min) to give tert-butyl (2S)-4-(3-(1H-pyrazol-4-yl)propylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoate (70 mg, 33% yield) as a white solid. 1 1H NMR (400 MHz, CDCl3-d) δ 7.43 (s, 2H), 5.39 (br d, J = 6.8 Hz, 1H), 4.26 (br s, 1H), 3.23 - 2.96 (m, 4H), 2.68 (t, J = 7.3 Hz, 2H), 2.46 - 2.28 (m, 1H), 2.21 - 1.99 (m, 3H), 1.45 (d, J = 12.5 Hz, 18H).

[0291] A solution of tert-butyl (2S)-4-(3-(1H-pyrazol-4-yl)propylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoate (30 mg, 70 mmol) in HCl / dioxane (1 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give (2S)-4-(3-(1H-pyrazol-4-yl)propylsulfonimidoyl)-2-aminobutanoic acid (19 mg, 87% yield, HCl) as a colorless solid. LCMS: Rt = 0.398 min., (ES + ) m / z (M + H) + = 275.0, HPLC conditions: A; 1 1H NMR (400 MHz, D2O) δ 7.94 (s, 2H), 4.11 - 3.96 (m, 1H), 3.93 - 3.55 (m, 4H), 2.87 - 2.67 (m, 2H), 2.50 - 2.35 (m, 2H), 2.17 (q, J = 7.8 Hz, 2H).

[0292] Prepare the compounds described in Table 6 using the above method. "HPLC rt" represents the retention time in the HPLC analysis experiment consistent with the above purification method. Table 6. Characterization data of Compounds 51 - 66

[0293] Exemplary Embodiment 1e

[0294] Step 1: (2S)-Methyl 2-amino-4-(2-(pyrazin-2-yl)ethylsulfonimidoyl)butanoate

[0295] A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-mercaptobutanoate (200 mg, 0.8 mmol) and 2-vinylpyrazine (170 mg, 1.6 mmol) in MeOH (2 mL) was stirred under Ar at 15 °C for 16 h. The mixture was concentrated and the residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1, R f = 0.12), to give methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((2-(pyrazin-2-yl)ethyl)thio)butanoate (0.25 g, 83% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3-d) δ 8.51 (br d, J = 9.04 Hz, 2H), 8.45 (d, J = 1.98 Hz, 1H), 5.13 (br d, J = 7.06 Hz, 1H), 4.41 (br d, J = 3.97 Hz, 1H), 3.75 (s, 3H), 3.16 - 3.05 (m, 2H), 3.02 - 2.92 (m, 2H), 2.65 - 2.52 (m, 2H), 2.20 - 2.07 (m, 1H), 1.96 - 1.85 (m, 1H), 1.45 (s, 9H).

[0296] A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((2-(pyrazin-2-yl)ethyl)thio)butyrate (200 mg, 563 μmol) in MeOH (5 mL) was added with PhI(OAc)2 (453 mg, 1.41 mmol) and ammonium carbamate (220 mg, 2.81 mmol). The mixture was stirred at 25 °C for 2 h, concentrated, and the residue was purified by preparative TLC (ethyl acetate:methanol = 10:1, R f = 0.28) to give methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-(pyrazin-2-yl)ethylsulfonimidoyl)butyrate (0.2 g, 92% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3-d) δ 8.58 (s, 1H), 8.54 - 8.51 (m, 1H), 8.49 (d, J = 2.41 Hz, 1H), 5.34 (br s, 1H), 5.31 (s, 1H), 4.43 (br s, 1H), 3.78 (s, 3H), 3.68 - 3.59 (m, 2H), 3.50 - 3.36 (m, 2H), 3.29 - 3.14 (m, 2H), 2.53 - 2.41 (m, 1H), 2.29 - 2.15 (m, 1H), 1.45 (s, 9H).

[0297] To a mixture of methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-(pyrazin-2-yl)ethylsulfonimidoyl)butyrate (50 mg, 129 mmol) in DCM (5 mL) at 15 °C was added TFA (1.54 g, 13.5 mmol, 1 mL) and the mixture was stirred for 1 h. Toluene (50 mL) was added to the mixture and concentrated to give a residue. H2O (20 mL) was added to the residue and the mixture was extracted with DCM (20 mL × 2). The aqueous phase was lyophilized to give methyl (2S)-2-amino-4-(2-(pyrazin-2-yl)ethylsulfonimidoyl)butyrate (26.44 mg, 44% yield, TFA) as a pale yellow oil. LCMS: Rt = 0.916 min., (ES + ) m / z (M + H) + = 287.1; HPLC conditions: A; 11H NMR (400 MHz, D2O) δ 8.63 - 8.59 (m, 2H), 8.54 - 8.49 (m, 1H), 2.65 - 2.44 (m, 2H), 4.40 - 4.29 (m, 1H), 4.20 - 4.07 (m, 2H), 4.00 - 3.86 (m, 2H), 3.84 (s, 2H), 3.81 (br s, 1H), 3.51 (br t, J = 7.27 Hz, 2H).

[0298] Exemplary Embodiment 1f (2S)-Methyl 2-amino-4-(2-phenylethylsulfonimidoyl)butanoate

[0299] A solution of (2S)-2-(tert-Butoxycarbonylamino)-4-(2-phenylethylsulfonimidoyl)butanoic acid (140 mg, 378 mmol) in HCl / MeOH (4M, 3 mL) was stirred at 20 °C for 16 h. The mixture was concentrated, water (5 mL) was added, and the mixture was extracted with DCM (5 mL × 3). The aqueous phase was concentrated to give (2S)-methyl 2-amino-4-(2-phenylethylsulfonimidoyl)butanoate (110 mg, 84% yield, HCl) as a white solid. LCMS: Rt = 2.049 min., (ES + ) m / z (M + H) + = 285.2; HPLC conditions: A; 1 1H NMR (400 MHz, D2O) δ 7.46 - 7.29 (m, 5H), 4.26 - 4.16 (m, 1H), 4.02 - 3.91 (m, 2H), 3.83 (s, 3H), 3.71 - 3.56 (m, 2H), 3.25 (br t, J = 7.8 Hz, 2H), 2.52 - 2.31 (m, 2H).

[0300] Exemplary Embodiment 1g (2S)-Methyl 4-(2-(1H-tetrazol-5-yl)ethylsulfonimidoyl)-2-aminobutanoate

[0301] To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-mercaptobutyrate (300 mg, 1.2 mmol) and 3-bromopropionitrile (192 mg, 1.44 mmol, 118 mL) in DMF (3 mL) was added KI (398 mg, 2.4 mmol) and K2CO3 (497 mg, 3.6 mmol). The mixture was stirred at 20 °C under Ar for 16 h. The mixture was poured into water (20 mL) and extracted with EtOAc (10 mL × 2). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 1:1, R f = 0.62) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((2-cyanoethyl)thio)butyrate (330 mg, 91% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3-d) δ 5.12 (brs, 1H), 4.45 (br s, 1H), 3.88 - 3.69 (m, 3H), 2.90 - 2.75 (m, 2H), 2.66 (q, J = 7.2 Hz, 4H), 2.13 (br s, 1H), 1.95 (td, J = 7.2, 14.3 Hz, 1H), 1.51 - 1.41 (m, 9H).

[0302] To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((2-cyanoethyl)thio)butyrate (200 mg, 661 mmol) in dioxane (2 mL) was added dibutyl(oxo)tin (32.9 mg, 132 mmol) and TMSN3 (228 mg, 1.98 mmol, 261 mL). The mixture was stirred at 120 °C for 5 h. The reaction was quenched with aqueous KF (2 mL), and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75×30 mm, 3 μm; mobile phase: [water (0.2% formic acid)-MeCN]; B%: 20% - 50%, 12 min) to give methyl (S)-4-((2-(1H-tetrazol-5-yl)ethyl)thio)-2-((tert-butoxycarbonyl)amino)butyrate (145 mg, 64% yield) as a yellow oil. 11H NMR (400 MHz, CDCl3-d) δ 14.34 (br s, 1H), 5.42 (br d, J = 8.6 Hz, 1H), 4.68 (br d, J = 4.2 Hz, 1H), 3.79 (s, 3H), 3.48 - 3.34 (m, 1H), 3.22 - 3.09 (m, 1H), 3.02 - 2.91 (m, 2H), 2.80 (br d, J = 4.4 Hz, 1H), 2.73 - 2.61 (m, 1H), 2.13 - 1.88 (m, 2H), 1.48 (s, 9H).

[0303] To a solution of methyl (S)-4-((2-(1H-tetrazol-5-yl)ethyl)thio)-2-((tert-butoxycarbonyl)amino)butanoate (145 mg, 420 mmol) in MeOH (2 mL) was added PhI(OAc)2 (270 mg, 840 mmol) and ammonium carbamate (163 mg, 2.10 mmol). The mixture was stirred at 20 °C for 3 h. The mixture was poured into water (10 mL) and extracted with EtOAc (15 mL × 3). The aqueous phase was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30 mm, 5 μm; mobile phase: [water (0.2% formic acid)-MeCN]; B%: 1% - 30%, 10 min), to give methyl (2S)-4-(2-(1H-tetrazol-5-yl)ethylsulfinyl)-2-((tert-butoxycarbonyl)amino)butanoate (43 mg, 27% yield) as a white solid. 1 1H NMR (400 MHz, D2O) δ 4.33 (br s, 1H), 3.88 - 3.73 (m, 5H), 3.62 - 3.49 (m, 2H), 3.44 - 3.28 (m, 2H), 2.41 (br dd, J = 5.5, 14.1 Hz, 1H), 2.29 - 2.10 (m, 1H), 1.44 (s, 9H).

[0304] A mixture of methyl (2S)-4-(2-(1H-tetrazol-5-yl)ethylsulfinyl)-2-((tert-butoxycarbonyl)amino)butanoate (10 mg, 26.5 mmol) in HCl / MeOH (1 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give methyl (2S)-4-(2-(1H-tetrazol-5-yl)ethylsulfinyl)-2-aminobutanoate (8.17 mg, 98% yield, HCl) as a yellow oil. LCMS: Rt = 0.358 min., (ES + ) m / z (M + H) += 277.0; HPLC condition: A; 1 H NMR (400 MHz, D2O) δ 4.33 (br t, J = 6.5 Hz, 1H), 3.96 - 3.78 (m, 5H), 3.64 - 3.44 (m, 4H), 2.55 - 2.40 (m, 2H).

[0305] Exemplary Embodiment 1h (2S)-Methyl 2-amino-4-(3-phenylpropylsulfonylimino)butanoate

[0306] Under argon, to a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-mercaptobutanoate (200 mg, 0.8 mmol) in DMF (2 mL) was added K2CO3 (277 mg, 2.01 mmol) and 3-bromopropylbenzene (160 mg, 0.8 mmol, 121 mL). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into water (6 mL) and extracted with EtOAc (4 mL × 2). The combined organic extracts were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:1) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((3-phenylpropyl)thio)butanoate (240 mg, 81% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3-d) δ 7.32 - 7.27 (m, 2H), 7.23 - 7.21 (m, 3H), 5.10 (br d, J = 6.4 Hz, 1H), 4.41 (br s, 1H), 3.75 (s, 3H), 2.72 (t, J = 7.6 Hz, 2H), 2.61 - 2.47 (m, 4H), 2.17 - 2.03 (m, 1H), 1.97 - 1.81 (m, 3H), 1.45 (s, 9H).

[0307] A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((3-phenylpropyl)thio)butanoate (120 mg, 327 mmol), PhI(OAc)2 (316 mg, 980 mmol) and ammonium carbamate (127 mg, 1.63 mmol) in MeOH (2 mL) was degassed and purged with N2 three times. The mixture was stirred at 30 °C for 16 h under a N2 atmosphere. The reaction mixture was concentrated, and the residue was diluted with water (2 mL) and extracted with EtOAc (2 mL × 2). The combined organic extracts were washed with brine (2 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 30:1) to give methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3-phenylpropylsulfinyl)butanoate (40 mg, 31% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3-d) δ 7.35 - 7.29 (m, 2H), 7.27 - 7.16 (m, 3H), 5.31 (br s, 1H), 4.41 (br s, 1H), 3.77 (s, 3H), 3.28 - 2.99 (m, 4H), 2.79 (br t, J = 7.2 Hz, 2H), 2.38 (br d, J = 10.0 Hz, 1H), 2.18 (br dd, J = 7.2, 15.6 Hz, 3H), 1.45 (s, 9H).

[0308] A mixture of methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3-phenylpropylsulfinyl)butanoate (40 mg, 100 mmol) in HCl / MeOH (1.5 mL, 4 M) was stirred at 17 °C for 1 h. The reaction mixture was concentrated to give a residue. The residue was diluted with water (1 mL) and extracted with DCM (0.5 mL × 5). The aqueous phase was concentrated to give methyl (2S)-2-amino-4-(3-phenylpropylsulfinyl)butanoate (29 mg, 94% yield) as a yellow oil. LCMS: Rt = 1.561 min, (ES + ) m / z (M + H) + = 299.1; HPLC conditions: F; 1 1H NMR (400 MHz, D2O) δ 7.44 - 7.38 (m, 2H), 7.35 - 7.30 (m, 3H), 4.34 (dd, J = 7.6, 5.6 Hz, 1H), 3.87 (s, 3H), 3.81 - 3.65 (m, 2H), 3.62 - 3.47 (m, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2.58 - 2.37 (m, 2H), 2.28 - 2.17 (m, 2H).

[0309] Exemplary Embodiment 1i (2S)-Methyl 2-amino-4-(3-cyclopropylpropylsulfonimidoyl)butanoate

[0310] At 15 °C, MsCl (172 mg, 1.5 mmol, 116 μL) and TEA (303 mg, 3 mmol, 417 μL) were added to a mixture of 3-cyclopropylpropan-1-ol (100 mg, 998 mmol) in DCM (2 mL). The mixture was stirred at 15 °C for 1 h and the mixture was quenched with saturated NaHCO3 (20 mL) and extracted with DCM (20 mL × 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The mixture was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1, R f = 0.38), to give 3-cyclopropylpropyl methanesulfonate (80 mg, 45% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3-d) δ 4.28 (t, J = 6.58 Hz, 2H), 3.05 - 2.97 (m, 3H), 1.87 (quin, J = 7.02 Hz, 2H), 1.33 (q, J = 7.23 Hz, 2H), 0.75 - 0.63 (m, 1H), 0.53 - 0.40 (m, 2H), 0.09 - 0.00 (m, 2H).

[0311] At 25 °C, K2CO3 (163 mg, 1.18 mmol) was added to a mixture of 3-cyclopropylpropyl methanesulfonate (70 mg, 393 mmol) and (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-mercaptobutanoate (97.9 mg, 393 mmol) in DMF (1 mL). The mixture was stirred at 25 °C under Ar for 16 h. The mixture was added to H2O (50 mL) and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100 - 200 mesh silica gel, petroleum ether / ethyl acetate = 10 / 1, 5 / 1), to give (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-((3-cyclopropylpropyl)thio)butanoate (0.1 g, 77% yield) as a colorless oil. 11H NMR (400 MHz, CDCl3-d) δ 5.11 (br s, 1H), 4.42 (br s, 1H), 3.76 (s, 3H), 2.56 (t, J = 7.45 Hz, 4H), 2.13 (br d, J = 8.33 Hz, 1H), 1.90 (qd, J = 14.03, 7.23 Hz, 2H), 1.69 (quin, J = 7.45 Hz, 2H), 1.46 (s, 9H), 1.38 - 1.25 (m, 3H), 0.73 - 0.61 (m, 1H), 0.47 - 0.41 (m, 2H), 0.07 - 0.01 (m, 2H).

[0312] To a mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-((3-cyclopropylpropyl)thio)butyrate (100 mg, 302 mmol) in MeOH (2 mL) at 25 °C was added PhI(OAc)2 (243 mg, 754 mmol), ammonium carbamate (118 mg, 1.51 mmol). The mixture was stirred at 25 °C for 16 h, concentrated, and the residue was purified by preparative TLC (petroleum ether:ethyl acetate = 0:1, R f = 0.13), to give methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3-cyclopropylpropylsulfinyl)butyrate (0.04 g, 37% yield) as a colorless oil. 1 1H NMR (400 MHz, CDCl3-d) δ 5.35 (brd, J = 19.95 Hz, 1H), 4.45 (br s, 1H), 3.79 (s, 2H), 3.34 - 3.11 (m, 1H),, 3.59 - 3.09 (m, 1H), 3.35 - 3.06 (m, 1H), 2.58 - 2.39 (m, 1H), 2.29 - 2.15 (m, 1H), 2.07 - 1.92 (m, 2H), 1.46 (s, 9H), 1.38 (q, J = 7.31 Hz, 2H), 0.77 - 0.61 (m, 1H), 0.52 - 0.43 (m, 2H), 0.10 - 0.04 (m, 2H), 0.09 - 0.04 (m, 1H).

[0313] To a mixture of methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3-cyclopropylpropylsulfonimidoyl)butyrate (40 mg, 110 mmol) in DCM (1 mL) at 15 °C was added TFA (1.23 g, 10.8 mmol, 0.8 mL) and the mixture was stirred at 15 °C for 1 h. The mixture was concentrated and H2O (30 mL) was added to the residue and the mixture was extracted with DCM (30 mL × 2). The aqueous phase was lyophilized to give methyl (2S)-2-amino-4-(3-cyclopropylpropylsulfonimidoyl)butyrate (31 mg, 73% yield, TFA) as a colorless oil. LCMS: Rt = 2.076 min., (ES + ) m / z (M+H) + = 263.1; HPLC conditions: A; 1 H NMR (400 MHz, D2O) δ 4.35 (dd, J = 7.76, 5.69 Hz, 1H), 3.94 - 3.81 (m, 5H), 3.78 - 3.65 (m, 2H), 2.64 - 2.43 (m, 2H), 1.98 (quin, J = 7.64 Hz, 2H), 1.46 - 1.33 (m, 2H), 0.74 - 0.64 (m, 1H), 0.48 - 0.39 (m, 2H), 0.07 - 0.02 (m, 2H).

[0314] Exemplary embodiment 1j (2S)-2-Amino-4-(3,3-dimethylbutylsulfonimidoyl)butyric acid butyl ester

[0315] To a solution of (tert-butoxycarbonyl)-L-homocysteine butyl ester (3.00 g, 10.3 mmol) in DMF was added K2CO3 (20.6 mmol), KI (10.3 mmol) and 1-bromo-3,3-dimethyl-butane (2.55 g, 15.4 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 98:2 to 1:1) to give (S)-2-((tert-butoxycarbonyl)amino)-4-((3,3-dimethylbutyl)thio)butyric acid butyl ester (3.74 g, 97% yield) as a colorless oil. 11H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J = 7.9 Hz, 1H), 4.09 - 3.90 (m, 3H), 2.55 - 2.49 (m, 1H), 2.43 - 2.36 (m, 2H), 1.85 - 1.75 (m, 2H), 1.57 - 1.45 (m, 2H), 1.39 - 1.25 (m, 13H), 0.89 - 0.81 (m, 12H).

[0316] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-((3,3-dimethylbutyl)thio)butanoic acid butyl ester (1.8 g, 4.79 mmol) in MeOH was added PhI(OAc)2 (4 eq) and ammonium carbamate (5 eq). The mixture was stirred at 20 °C for 6 h. The reaction mixture was concentrated, and the residue was diluted with water and extracted with DCM. The combined organic extracts were concentrated and purified by column chromatography to give (2S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfinyl)butanoic acid butyl ester (1.57 g, 81% yield) as a colorless oil. 1 1H NMR (400 MHz, MeOD-d4) δ 4.27 (br dd, J = 4.6, 8.2 Hz, 3H), 3.30 (br s, 1H), 3.29 - 3.06 (m, 4H), 2.39 - 2.27 (m, 1H), 2.21 - 2.08 (m, 1H), 1.78 - 1.63 (m, 5H), 1.50 - 1.39 (m, 11H), 1.04 - 0.94 (m, 12H).

[0317] To a solution of (2S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfinyl)butanoic acid butyl ester (60 mg, 147 mmol) in HCl / dioxane (4N, 3 mL). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated and dried by lyophilization to give (2S)-2-amino-4-(3,3-dimethylbutylsulfinyl)butanoic acid butyl ester (30 mg, 59% yield) as a white solid. LCMS: Rt = 1.930 min., (ES + ) m / z (M + H) + = 307.1; HPLC conditions: C; 11H NMR (400 MHz, D2O) δ 4.36 - 4.31 (m, 1H), 4.29 (t, J = 6.5 Hz, 2H), 3.76 - 3.60 (m, 2H), 3.58 - 3.39 (m, 2H), 2.59 - 2.41 (m, 2H), 1.76 - 1.61 (m, 4H), 1.31 (s, 2H), 0.97 - 0.92 (m, 9H), 0.91 - 0.86 (m, 3H).

[0318] Exemplary Embodiment 1k (2S)-2-Amino-4-(butylsulfonylimino)butyric acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester

[0319] To a solution of (2S)-2-((tert-butoxycarbonyl)amino)-4-(butylsulfonylimino)butyric acid (0.1 g, 310 mmol) and 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (120 mg, 620 mmol) in DMF (2 mL) was added K2CO3 (85.7 mg, 620 mmol) and the mixture was stirred at 20 °C for 3 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (15 mL × 2). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f = 0.25), to give (2S)-2-((tert-butoxycarbonyl)amino)-4-(butylsulfonylimino)butyric acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester (50 mg, 37% yield) as a yellow oil. 1 1H NMR (400 MHz, CDCl3-d) δ 5.50 - 5.28 (m, 1H), 4.94 (s, 2H), 4.44 (br dd, J = 2.3, 6.7 Hz, 1H), 3.28 - 3.04 (m, 4H), 2.53 - 2.40 (m, 2H), 2.30 - 2.18 (m, 4H), 1.91 - 1.76 (m, 2H), 1.54 - 1.43 (m, 12H), 1.03 - 0.95 (m, 3H).

[0320] A solution of (2S)-2-((tert-butoxycarbonyl)amino)-4-(butylsulfonylimino)butanoic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (50 mg, 115 mmol) in DCM (2 mL) and TFA (0.2 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated at 35 °C. Water (10 mL) was added and the mixture was extracted with DCM (10 mL × 3). The aqueous phase was lyophilized to give (2S)-2-amino-4-(butylsulfonylimino)butanoic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (37 mg, 67% yield, TFA) as a yellow solid. LCMS: Rt = 2.075 min., (ES + ) m / z (M+H) + = 335.0; HPLC conditions: A; 1 H NMR (400 MHz, D2O) δ 5.22 - 5.12 (m, 2H), 4.43 - 4.33 (m, 1H), 3.77 (br t, J = 7.9 Hz, 2H), 3.67 - 3.50 (m, 2H), 2.60 - 2.43 (m, 2H), 2.17 (s, 3H), 1.83 (quin, J = 7.7 Hz, 2H), 1.48 (sxt, J = 7.4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0321] The compounds described in Table 7 were prepared using the general method outlined above. Table 7. Characterization data for compounds 74 - 99

[0322] Exemplary embodiment 1l (2S)-2-Amino-N-butyl-4-(3,3-dimethylbutylsulfonylimino)butanamide

[0323] To a solution of N-(tert-butoxycarbonyl)-S-(3,3-dimethylbutyl)-L-homocysteine methyl ester (3 g, 9 mmol) in MeOH (24 mL) was added PhI(OAc)2 (11.9 g, 36.0 mmol) and ammonium carbamate (5.62 g, 71.9 mmol). The mixture was stirred at 20 °C for 16 h and then concentrated. Water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (45 mL × 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:1) to give methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfinyl)butyrate (1.6 g, 49% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3-d) δ 5.39 - 5.23 (m, 1H), 4.44 (br s, 1H), 3.79 (s, 3H), 3.23 - 2.94 (m, 4H), 2.50 - 2.36 (m, 1H), 2.24 - 2.10 (m, 1H), 1.78 - 1.67 (m, 2H), 1.46 (s, 9H), 0.96 (s, 9H).

[0324] To a solution of methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfinyl)butyrate (1.60 g, 4.39 mmol) in THF (12 mL) and H2O (4 mL) was added LiOH·H2O (368 mg, 8.78 mmol). The mixture was stirred at 25 °C for 2 h. The solution was adjusted to pH ~5 with citric acid and extracted with ethyl acetate (20 mL × 4). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfinyl)butyrate (1.30 g, 85% yield) as a white solid. 1 H NMR (400 MHz, CDCl3-d) δ 5.69 (br d, J = 6.5 Hz, 1H), 4.55 - 4.37 (m, 1H), 3.53 - 3.17 (m, 4H), 2.47 - 2.21 (m, 2H), 1.82 - 1.65 (m, 2H), 1.44 (s, 9H), 0.96 (d, J = 3.4 Hz, 9H).

[0325] To a mixture of methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfonylimino)butanoate (300 mg, 855 mmol), butan-1-amine (313 mg, 4.28 mmol) and DIEA (331 mg, 2.57 mmol) in DMF (5 mL) was added HATU (488 mg, 1.28 mmol). The mixture was stirred at 20 °C for 2 h, then poured into water (10 ml) and extracted with ethyl acetate (5 mL×3). The combined organic extracts were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Phenomenex Luna C18 100×30 mm×5um; mobile phase: [water (0.2% FA)-MeCN]; B%: 30%-50%, 12 min) to give tert-butyl ((2S)-1-(butylamino)-4-(3,3-dimethylbutylsulfonylimino)-1-oxobutan-2-yl)carbamate (80.0 mg, 23% yield) as a white solid. 1 H NMR (400 MHz, MeOD-d4) δ 4.26 - 4.18 (m, 1H), 3.70 - 3.47 (m, 4H), 3.23 (brt, J = 6.9 Hz, 2H), 2.33 (br s, 1H), 2.22 - 2.08 (m, 1H), 1.84 - 1.74 (m, 2H), 1.57 - 1.46 (m, 11H), 1.43 - 1.29 (m, 3H), 1.03 (s, 9H), 0.96 (t, J = 7.3 Hz, 3H)

[0326] A solution of tert-butyl ((2S)-1-(butylamino)-4-(3,3-dimethylbutylsulfonylimino)-1-oxobutan-2-yl)carbamate (40 mg, 98.6 mmol) in HCl / dioxane (4 M, 4.0 mL) was stirred at 20 °C for 1 h. The reaction mixture was concentrated. The residue was dissolved in water (1 mL) and extracted with DCM (1 mL×2). The aqueous phase was lyophilized to give (2S)-2-amino-N-butyl-4-(3,3-dimethylbutylsulfonylimino)butanamide (25 mg, 74% yield) as a white solid. LCMS: Rt = 1.852 min, (ES + ) m / z (M + H) + = 306.1; HPLC conditions: C; 11H NMR (400 MHz, D2O) δ 4.10 (br d, J = 1.6 Hz, 1H), 3.61 - 3.49 (m, 4H), 3.30 - 3.15 (m, 2H), 2.45 - 2.37 (m, 2H), 1.72 - 1.65 (m, 2H), 1.47 (quin, J = 7.2 Hz, 2H), 1.28 (d, J = 7.6 Hz, 2H), 0.91 (s, 9H), 0.88 - 0.82 (m, 3H).

[0327] Exemplary Embodiment 1m (2S)-2-Amino-4-(3,3-dimethylbutanesulfinyl)-N-(pyridin-3-yl)butanamide

[0328] To a solution of N-(tert-butoxycarbonyl)-S-(3,3-dimethylbutyl)-L-homocysteine methyl ester (4.7 g, 14.1 mmol) in THF (35 mL) and H2O (7 mL) was added LiOH·H2O (1.18 g, 28.9 mmol). The mixture was stirred at 25 °C for 2 h. The solution was adjusted to pH = 5 with citric acid and extract...

Claims

1. Compound of formula I: Its diastereomers or enantiomers, or pharmaceutically acceptable salts of any of the foregoing, or deuterated derivatives of any of the foregoing, wherein: R1 is: C(O)OH; or C(O)OX, where X is an organic cation, an inorganic cation, Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ or Mn 2+ ; or or C(O)OR3, where R3 is a straight-chain or branched-chain alkyl, cycloalkyl, cycloether or straight-chain or branched-chain alkyl ether, any of which is optionally and independently substituted; or R3 is or R3 is or C(O)N(R4R5) where R4 is H; or R4 is a straight-chain or branched-chain alkyl, C1-C 10 straight-chain or branched-chain alkynyl, CH2-CCH alkyne, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein any one of these is optionally and independently substituted; and R5 is absent; or R5 is H; or R5 is a straight-chain or branched-chain alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; any of which is optionally and independently substituted; or R5 is S(O)2alkyl; or R5 is S(O)2CF3; or R5 is S(O)2NH2; or R5 is S(O)2cycloalkyl, S(O)2cyclopropyl, S(O)2cyclobutyl, S(O)2cyclopentyl, S(O)2cyclohexyl or S(O)2cycloheptyl; or R5 is or R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or R5 is pyrrolidinyl; or R5 is 2-tetrahydropyranyl, 3-tetrahydropyranyl; or 4-tetrahydropyranyl; or R5 is or R5 is alkylaryl or benzyl; or R5 is or R5 is 2-pyridyl, 3-pyridyl; or 4-pyridyl; or R5 is or R5 is or R5 is or R5 is or R5 is or CN; or or or or and R2 is: NH2, NHC(O)OMe or NHMe; and R6 is: H, C(O)Me or P(O)(OH)2; and R7 is: C1-C3 or C5-C 10 a straight-chain or branched-chain alkyl group, C1-C 10 a straight-chain or branched-chain alkenyl group or C1-C 10 a straight-chain or branched-chain alkynyl group, any one of them may be optionally substituted with an alkyl ring or an alkyl ether ring, and the alkyl ring or the alkyl ether ring contains the C1-C3 or C5-C 10 a straight-chain or branched-chain alkyl group, the C1-C 10 a straight-chain or branched-chain alkenyl group or the C1-C 10 a carbon atom of a straight-chain or branched-chain alkynyl group, any one of the foregoing may be independently and optionally substituted, provided that when a straight-chain C3-alkyl group is substituted with a methyl group at the terminal carbon atom, the straight-chain C3-alkyl group substituted with a methyl group at the terminal carbon atom contains a further substitution; provided that when a C2-alkyl group is substituted with an ethyl group at the terminal carbon atom, the C2-alkyl group substituted with an ethyl group at the terminal carbon atom contains a further substitution; provided that when a C1-alkyl group is substituted with a n-propyl group at the terminal carbon atom, the C1-alkyl group substituted with a n-propyl group at the terminal carbon atom contains a further substitution; or R7 is:

2. The compound of formula I according to claim 1, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein R1 is: C(O)OH; or C(O)OR3, wherein R3 is a straight-chain or branched-chain alkyl, C1-C 10 straight-chain or branched-chain alkyl, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, cycloalkyl, C1-C 10 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, alkylcycloalkyl, alkylcyclohexyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl, alkyl ether, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypropyl, cycloalkyl ether, tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, tetrahydrofuranyl, 2-tetrahydrofuranyl, 2-tetrahydrofuranyl, alkylaryl, benzyl; wherein any of these is optionally and independently substituted with one or more C1-C 10 alkyl, one or more halogens, one or more fluorines, one or more chlorines, one or more deuteriums, bromine, one or more iodines, aryl, C6 aryl, C 10substituted with aryl, heteroaryl, C1-C7 alkyl cycloalkyl, unsubstituted tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl, or any combination thereof.

3. The compound of formula I according to claim 1, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein R1 is C(O)N(R4R5) and wherein R5 is: C1-C 10 a straight-chain or branched-chain alkyl, methyl, ethyl, propyl or butyl; any one of them is optionally or independently substituted with one or more deuteriums, C1-C 10 a straight-chain or branched-chain alkyl, one or more halogens, one or more fluorines, one or more chlorines, one or more iodines, one or more or any combination thereof.

4. The compound of formula I according to claim 1, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein R1 is C(O)N(R4R5) and wherein R5 is: heteroaryl, 2-pyridyl, 3-pyridyl or 4-pyridyl; or R5 is S(O)2Me.

5. The compound of formula I according to claim 1, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein R7 is: C1-C3 or C5-C 10 a straight-chain or branched-chain alkyl, C1-C 10 a straight-chain or branched-chain alkenyl or C1-C 10 a straight-chain or branched-chain alkynyl, any of which may be attached with an alkyl ring or an alkyl ether ring, and the alkyl ring or alkyl ether ring contains the C1-C3 or C5-C 10 a straight-chain or branched-chain alkyl, the C1-C 10 a straight-chain or branched-chain alkenyl or the C1-C 10 a straight-chain or branched-chain alkynyl of one carbon; any of the foregoing may be independently and optionally substituted with one or more of the substituents, and the substituents may be: deuterium, C1-C 10 a straight-chain alkyl, methyl, ethyl, C1-C 10Branched alkyl, halogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxylic acid or a pharmaceutically acceptable salt thereof, amide, carbamate, urea, ester, alkoxy, methoxy, ethoxy, trifluoromethoxy, ether, cyclic ether, C1-C7 alkyl ether, C1-C7 cycloalkyl ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, fused aryl, biaryl, fused aryl-heteroaryl, fused diaryl, fused aryl-heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic group, tricyclic aliphatic group, adamantyl, cyano, acetal; ketal; or any combination thereof; wherein when the straight-chain C3-alkyl is substituted with a methyl substituent at the terminal carbon atom, the straight-chain C3-alkyl substituted with a methyl substituent at the terminal carbon atom contains a further substitution; wherein when the C2-alkyl is substituted with an ethyl substituent at the terminal carbon atom, the C2-alkyl substituted with an ethyl substituent at the terminal carbon atom contains a further substitution; wherein when the C1-alkyl is substituted with a n-propyl substituent at the terminal carbon atom, the C1-alkyl substituted with a n-propyl substituent at the terminal carbon atom contains a further substitution; and wherein said C1-C 10 Straight-chain alkyl substituent, methyl substituent, ethyl substituent, C1-C 10 Branched alkyl substituent, hydroxyl substituent, amino substituent, carboxylic acid or a pharmaceutically acceptable salt thereof substituent, amide substituent, carbamate substituent, urea substituent, ester substituent, alkoxy substituent, methoxy substituent, ethoxy substituent, ether substituent, cyclic ether substituent, C1-C7 alkyl ether substituent, C1-C7 cycloalkyl ether substituent, aryl substituent, heteroaryl substituent, fused aryl substituent, biaryl substituent, fused aryl-heteroaryl substituent, fused diaryl substituent, fused aryl-heteroaryl substituent, 5-membered heteroaryl substituent, 6-membered heteroaryl substituent, naphthyl substituent, cycloalkyl substituent, cyclopropyl substituent, cyclobutyl substituent, cyclopentyl substituent, cyclohexyl substituent, cycloheptyl substituent, tert-butyl substituent, bicyclic aliphatic group substituent, tricyclic aliphatic group substituent, adamantyl substituent, or any combination thereof may be independently and optionally substituted with one or more of the following: C1-C 10 Straight-chain alkyl, methyl, ethyl, C1-C 10Branched alkyl, halogen, fluorine, chlorine, bromine, iodine, hydroxyl, alkoxy, methoxy, ethoxy, carbamate, urea, amide, ester, amine, trifluoromethoxy, ether, C1-C7 alkyl ether, C1-C7 cyclic ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic group, tricyclic aliphatic group, adamantyl, cyano, acetal, ketal or any combination thereof.

6. Compound of formula I: Its diastereomers or enantiomers, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein R1 is: C(O)OH, or C(O)OX, where X is an organic cation, an inorganic cation, Na + , K + , Mg 2+ , Ca 2+ , Zn 2+ or Mn 2+ ; or or C(O)OR3, where R3 is a straight-chain or branched alkyl, cycloalkyl, cyclic ether or straight-chain or branched alkyl ether, any of which is optionally and independently substituted; or R3 is or R3 is or C(O)N(R4R5) where R4 is H; or R4 is a straight-chain or branched alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; any of which is optionally and independently substituted; and R5 is H; or R5 is a straight-chain or branched alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; any of which is optionally and independently substituted; or R5 is S(O)2alkyl; or R5 is S(O)2CF3; or R5 is S(O)2NH2; or R5 is S(O)2 cycloalkyl, S(O)2 cyclopropyl, S(O)2 cyclobutyl, S(O)2 cyclopentyl, S(O)2 cyclohexyl or S(O)2 cycloheptyl; or R5 is or R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or R5 is pyrrolidinyl; or R5 is 2-tetrahydropyranyl, 3-tetrahydropyranyl; or 4-tetrahydropyranyl; or R5 is or R5 is alkylaryl or benzyl; or R5 is or R5 is 2-pyridyl, 3-pyridyl; or 4-pyridyl; or R5 is or R5 is or R5 is or R5 is or R5 is or CN; or and R2 is: NH2, NHC(O)OMe or NHMe; and R6 is: H, C(O)Me or P(O)(OH)2; and R7 is: a straight-chain or branched alkyl, alkenyl or alkynyl, any of which may be optionally and independently substituted; or R7 is: and wherein the compound of formula I is not buthionine sulfoximine (BSO) or a salt of BSO.

7. The compound of formula I according to claim 6, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein R1 is: C(O)OH; or C(O)OR3, where R3 is an alkyl group, C1-C 10 linear or branched alkyl, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, cycloalkyl, C1-C 10 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, alkylcyclohexyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl, alkyl ether, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypropyl, cycloalkyl ether, tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, tetrahydrofuranyl, 2-tetrahydrofuranyl, 2-tetrahydrofuranyl, alkylaryl, benzyl; where any one of these is optionally and independently substituted by one or more deuteriums, C1-C 10 linear or branched alkyl, one or more halogens, one or more fluorines, one or more chlorines, one or more bromines, one or more iodines, aryl, C6 aryl, C 10 aryl, heteroaryl,, C1-C7 alkyl cycloalkyl, unsubstituted tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl or any combination thereof.

8. The compound of formula I according to claim 6, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any one of the foregoing, or a deuterated derivative of any one of the foregoing, where R1 is C(O)N(R4R5) and where R5 is: C1-C 10 linear or branched alkyl, methyl, ethyl, propyl or butyl; any one of them is optionally or independently substituted by one or more deuteriums, C1-C 10 linear or branched alkyl, one or more halogens, one or more fluorines, one or more chlorines, one or more iodines, one or more or any combination thereof.

9. The compound of formula I according to claim 6, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any one of the foregoing, or a deuterated derivative of any one of the foregoing, where R1 is C(O)N(R4R5) and where R5 is: heteroaryl, 2-pyridyl, 3-pyridyl or 4-pyridyl; or R5 is S(O)2Me.

10. The compound of formula I according to claim 6, its diastereomers or enantiomers, a pharmaceutically acceptable salt of any one of the foregoing, or a deuterated derivative of any one of the foregoing, where R7 is: C1-C 10 a straight-chain or branched alkyl group, C1-C 10 a straight-chain or branched alkenyl group or C1-C 10 a straight-chain or branched alkynyl group, any of which may be substituted with an alkyl ring or an alkyl ether ring, said alkyl ring or alkyl ether ring containing the C1-C 10 a straight-chain or branched alkyl group, the C1-C 10 a straight-chain or branched alkenyl group or the C1-C 10 a straight-chain or branched alkynyl group at one carbon; wherein any of the foregoing may be independently substituted with one or more of the substituents, which may be: deuterium, C1-C 10 a straight-chain alkyl group, methyl, ethyl, C1-C 10 a branched alkyl group, halogen, fluorine, chlorine, bromine, iodine, hydroxyl, amino, carboxylic acid or a pharmaceutically acceptable salt thereof, amide, carbamate, urea, ester, alkoxy, methoxy, ethoxy, trifluoromethoxy, ether, cyclic ether, a C1-C7 straight-chain or branched alkyl ether, a C1-C7 cycloalkyl ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, fused aryl, biaryl, fused aryl-heteroaryl, fused diaryl, fused aryl-heteroaryl, a 5-membered heteroaryl, a 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic group, tricyclic aliphatic group, adamantyl, cyano, acetal; ketal; or any combination thereof; wherein the C1-C 10 a straight-chain alkyl substituent, a methyl substituent, an ethyl substituent, C1-C 10 a branched alkyl substituent, a hydroxyl substituent, an amino substituent, a carboxylic acid or a pharmaceutically acceptable salt thereof substituent, an amide substituent, a carbamate substituent, a urea substituent, an ester substituent, an alkoxy substituent, a methoxy substituent, an ethoxy substituent, an ether substituent, a cyclic ether substituent, a C1-C7 straight-chain or branched alkyl ether substituent, a C1-C7 cycloalkyl ether substituent, an aryl substituent, a heteroaryl substituent, a fused aryl substituent, a biaryl substituent, a fused aryl-heteroaryl substituent, a fused diaryl substituent, a fused aryl-heteroaryl substituent, a 5-membered heteroaryl substituent, a 6-membered heteroaryl substituent, a naphthyl substituent, a cycloalkyl substituent, a cyclopropyl substituent, a cyclobutyl substituent, a cyclopentyl substituent, a cyclohexyl substituent, a cycloheptyl substituent, a tert-butyl substituent, a bicyclic aliphatic group substituent, a tricyclic aliphatic group substituent, an adamantyl substituent, or any combination thereof may be independently and optionally substituted with one or more of the following: deuterium, C1-C 10 a straight-chain alkyl group, methyl, ethyl, C1-C 10Branched alkyl, halogen, fluorine, chlorine, bromine, iodine, hydroxyl, alkoxy, methoxy, ethoxy, carbamate, urea, amide, ester, amine, trifluoromethoxy, ether, C1-C7 straight-chain or branched alkyl ether, C1-C7 cyclic ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic group, tricyclic aliphatic group, adamantyl, cyano, acetal, ketal or any combination thereof.

11. The compound of formula I according to claim 1 or claim 6, its diastereomer or enantiomer, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein R1 is:

12. The compound of formula I according to claim 1 or claim 6, its diastereomer or enantiomer, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein R1 is 13. The compound of formula I according to claim 1 or claim 6, the foregoing diastereomer or enantiomer, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein R2 is NH2.

14. The compound of formula I according to claim 1 or claim 6, the foregoing diastereomer or enantiomer, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein R6 is H.

15. The compound of formula I according to claim 1 or claim 6, the foregoing diastereomer or enantiomer, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein R7 is:

16. A compound, a diastereomer or enantiomer of said compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein said compound is selected from:

17. A compound, a diastereomer or enantiomer of said compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from:

18. A compound of formula II A diastereomer or enantiomer of the compound of formula II, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein in the compound of formula II, R is C1, C2, C3, C4, C5, C6, C7, C8, C9 or C 10 a straight-chain or branched-chain alkyl group, optionally and independently substituted with substituents selected from the group consisting of: deuterium, halogen, fluorine, chlorine, C1-C 10 a straight-chain or branched-chain alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and any combination thereof.

19. A pharmaceutical composition comprising a compound of formula I, a compound of formula II, or a compound according to any one of claims 1-18; a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; and a pharmaceutically acceptable excipient, diluent or carrier.

20. The pharmaceutical composition according to claim 19, which is in unit dosage form.

21. The pharmaceutical composition according to any one of claims 19 - 20, which further comprises an additional active agent or a pharmaceutically acceptable salt thereof.

22. The pharmaceutical composition according to any one of claims 19 - 21, which is in the form of a powder, tablet, capsule, liquid or gel.

23. The pharmaceutical composition according to any one of claims 19 - 22, wherein the compound of formula I, the compound of formula II, the compound, or an enantiomer or diastereomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing is present in the pharmaceutical composition in an amount in the range of about 0.001 mg to about 25,000 mg.

24. A kit, comprising the pharmaceutical composition according to any one of claims 19 - 23 and a container.

25. The kit according to claim 24, wherein the container is a syringe.

26. The kit according to claim 24, wherein the container is an IV bag.

27. The kit according to claim 24, wherein the container is disposable.

28. The kit according to claim 24, wherein the container is a disposable container.

29. The kit according to claim 24, wherein the container is a resealable container.

30. A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 19 - 23, thereby treating the cancer.

31. A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I, a compound of formula II or a compound according to any one of claims 1 - 18; a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, thereby treating the cancer.

32. The method according to claim 30 or claim 31, wherein the administration is selected from: oral, injection; subcutaneous, intratumoral; systemic, topical, intravenous, intraperitoneal, intramuscular and any combination thereof.

33. A method of regulating ferroptosis in a tissue, the method comprising contacting the tissue with a pharmaceutical composition according to any one of claims 19 - 23 in an amount effective to regulate ferroptosis in the tissue.

34. The method according to claim 33, wherein the tissue is comprised in a subject.

35. A method according to any one of claims 30 - 32 or 34, wherein the subject is a subject in need thereof.

36. A method according to claim 34 or 35, wherein the subject is a mammal.

37. A method according to claim 36, wherein the subject is a human.

38. A method according to any one of claims 30 - 37, wherein the administration or the contact is: once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, once a month, once every six months, once a year, or for life, as needed.

39. A method according to any one of claims 30 - 38, wherein the therapeutically effective amount or the effective amount ranges from about 0.001 mg to about 25,000 mg.

40. A compound, a diastereomer or an enantiomer of the compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from:

41. A compound, a diastereomer or enantiomer of the compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from:

42. A compound, a diastereomer or enantiomer of the compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein the compound is selected from:

43. A compound of formula XVIII: A diastereomer or enantiomer of the compound of formula XVIII, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein in the compound of formula XVIII: Each R1, R2 or R3 is independently: H, C1-C 10 A straight-chain or branched-chain alkyl, a C3-C6 cycloalkyl, a C6-C 10 An aryl, a C3-C 10heteroaryl, biphenyl, halobiphenyl, indole, triazole, isothiazole, oxazoline, C1-C6 straight or branched alkyl ether, -CH3, phenyl, -C(O)OR5, -C(O)NH2, -O-, -S-, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, -Cl, -Br, -I, or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, and wherein said C3-C6 cycloalkyl may optionally be substituted with a C1-C6 straight or branched alkyl, C1-C6 cycloalkyl, halogen, -CF3 or -F; or R1 and R2 and R3 together form a C3-C6 cycloheteroaryl; and wherein each R1, R2 or R3 is independently and optionally substituted with a substituent selected from: deuterium, halogen, fluorine, -CF3, chlorine, C1-C 10 straight or branched alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, C3-C6 cycloalkyl, phenyl, halophenyl, biphenyl, halobiphenyl, isothiazole, triazole, furan, oxazoline, C3-C6 heteroaryl, urea, acid anhydride and any combination thereof; wherein R4 is H or a C1-C6 straight or branched alkyl; and wherein R5 is C1-C 10 straight or branched alkyl, which is optionally substituted with at least one heteroatom, halogen or C1-C3 alkyl ether.

44. Compound of formula XIX: the diastereomers or enantiomers of the compound of formula XIX, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein in the compound of formula XIX: each R1, R2 or R3 is independently: H, C1-C 10 straight or branched alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C3-C 10 heteroaryl, biphenyl, halobiphenyl, indole, triazole, isothiazole, oxazoline, C1-C6 straight or branched alkyl ether, -C(O)OR5, -C(O)NH2, -O-, -S-, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, -Cl, -Br, -I, or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, and wherein said C3-C6 cycloalkyl may optionally be substituted with a C1-C6 straight or branched alkyl, C1-C6 cycloalkyl, halogen, -CF3 or -F; or R1, R2, and R3 together form a C3-C6 cycloheteroaryl; and wherein each of R1, R2, or R3 is independently and optionally substituted with a substituent selected from: deuterium, halogen, fluorine, -CF3, chlorine, C1-C 10 a straight-chain or branched alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, C3-C6 cycloalkyl, phenyl, halophenyl, biphenyl, halobiphenyl, isothiazole, triazole, furan, oxazoline, C3-C6 heteroaryl, urea, acid anhydride, and any combination thereof; wherein R4 is H or a C1-C6 straight-chain or branched alkyl; and wherein R5 is C1-C 10 a straight-chain or branched alkyl, optionally substituted with at least one heteroatom, halogen, or C1-C3 alkyl ether.

45. Compound of formula XX: a diastereomer or enantiomer of the compound of formula XX, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; wherein in the compound of formula XX: each of R1, R2, or R3 is independently: H, a C1-C4 straight-chain or branched alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C5-C6 heteroaryl, biphenyl, halobiphenyl, triazole, isothiazole, oxazoline, C1-C6 straight-chain or branched alkyl ether, -C(O)OR5, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, and wherein the C3-C6 cycloalkyl may optionally be substituted with a C1-C6 straight-chain or branched alkyl, C1-C6 cycloalkyl, halogen, -CF3, or -F; and wherein each of R1, R2, or R3 is independently and optionally substituted with a substituent selected from: deuterium, halogen, fluorine, -CF3, chlorine, C1-C 10 a straight-chain or branched alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, C3-C6 cycloalkyl, phenyl, halophenyl, biphenyl, halobiphenyl, isothiazole, triazole, oxazoline, C3-C6 heteroaryl, and any combination thereof; wherein R4 is H or a C1-C6 straight-chain or branched alkyl; and wherein R5 is C1-C 10 a straight-chain or branched alkyl, optionally substituted with at least one heteroatom, halogen, or C1-C3 alkyl ether.

46. A pharmaceutical composition comprising a compound of formula XVIII, XIX, XX or a compound according to any one of claims 40 - 42; a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing; and a pharmaceutically acceptable excipient, diluent or carrier.

47. The pharmaceutical composition according to claim 46, which is in unit dosage form.

48. The pharmaceutical composition according to claim 46 or claim 47, which further comprises an additional active agent or a pharmaceutically acceptable salt thereof.

49. The pharmaceutical composition according to claims 46 - 48, which is in the form of a powder, tablet, capsule, liquid or gel.

50. The pharmaceutical composition according to any one of claims 46 - 49, wherein the compound of formula XVIII, XIX, XX or a compound according to any one of claims 40 - 42; or an enantiomer or diastereomer of any of the foregoing; or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing is present in the pharmaceutical composition in an amount in the range of about 0.001 mg to about 25,000 mg.

51. A kit comprising the pharmaceutical composition according to any one of claims 46 - 50 and a container.

52. The kit according to claim 51, wherein the container is a syringe.

53. The kit according to claim 51, wherein the container is an IV bag.

54. The kit according to claim 51, wherein the container is disposable.

55. The kit according to claim 51, wherein the container is a disposable container.

56. The kit according to claim 51, wherein the container is a resealable container.

57. A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of claims 46 - 50, thereby treating the cancer.

58. A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula XVIII, formula XIX, formula XX or a compound according to any one of claims 40 - 42; a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, thereby treating the cancer.

59. The method according to claim 58, wherein the cancer is carcinoma, sarcoma or melanoma.

60. The method according to claim 58, wherein the cancer is clear cell renal carcinoma or non-clear cell renal carcinoma.

61. The method according to claim 58, wherein the cancer is liver cancer.

62. The method according to claim 58, wherein the cancer is a cancer with SWI / SNF complex deletion.

63. The method according to any one of claims 58 to 62, wherein the administration is selected from: oral, injection; subcutaneous, intratumoral; systemic, local, intravenous, intraperitoneal, intramuscular, and any combination thereof.

64. A method of modulating ferroptosis in a tissue, the method comprising contacting the tissue with a pharmaceutical composition according to any one of claims 46 - 50 in an amount effective to modulate ferroptosis in the tissue.

65. The method according to claim 64, wherein the tissue is comprised in a subject.

66. The method according to any one of claims 57 - 63 or 65, wherein the subject is a subject in need thereof.

67. The method according to claim 57 or 58, wherein the subject is a mammal.

68. The method according to claim 67, wherein the subject is a human.

69. The method according to any one of claims 57 - 68, wherein the administration or the contacting is: as needed, once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, once a month, once every six months, once a year, or for life.

70. The method according to any one of claims 57 - 69, wherein the therapeutically effective amount or the effective amount ranges from about 0.001 mg to about 25,000 mg.

71. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any one of claims 46 - 50, thereby treating the disease or disorder.

72. A method of treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 46 - 50; a diastereomer or enantiomer of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, thereby treating the disease or disorder.

73. The method according to claim 71 or 72, wherein the disease or disorder is fibrosis or a kidney disease.

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