Compositions and methods for inducing ferroptosis

Abstract

Methods and systems, and compounds and agents for inducing or modulating ferroptosis in cells, tissues, or tumors of a subject are provided. Various agents and compounds are described. Various methods of administration are described for optimal modulation of ferroptosis, e.g., induction and killing of target cells. Methods for making, purifying, and characterizing various compounds are described. The present disclosure further encompasses other cancer chemotherapeutic agents, including, but not limited to, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, ifosfamide, and mitoxantrone.

Description

[Technical Field]

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

[0002] Incorporation by Reference of Sequence Listing This application contains a Sequence Listing, which has been submitted through the Patent Center. The entire Sequence Listing, entitled 203718-715601.xml, created on June 29, 2023, and having a size of 2,935 bytes, is incorporated herein by reference. [Background technology]

[0003] background 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 therapies induce cell death through a cellular process called apoptosis. The apoptotic pathway is involved in many common types of anti-cancer treatments and ionizing radiation, which contribute to tumor regression or the toxic side effects of treatment. Given the ability of hyperproliferative cells to resist cell death by current apoptosis-driven therapeutic agents, there is a need to develop new methods, compounds, and compositions that induce cell death in hyperproliferative cells. Summary of the Invention [Means for solving the problem]

[0004] summary Compounds of Formula I: [ka] or a diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, During the ceremony, R1 is C(O)OH, or C(O)OX (X is an organic cation, an inorganic cation, or Na + , K. + , Mg 2+ , Ca 2+ , Zn 2+ or Mn 2+ is), or [ka] ,or C(O)OR3, where R3 is a linear or branched alkyl, cycloaklyl, cyclic ether, or linear or branched alkyl ether, any of which is optionally independently substituted or or R3 is [ka] or R3 is [ka] ), or R1 is C(O)N(R4R5) wherein R4 is H, or R4 is a straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally independently substituted; R5 is H, or R5 is a straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally and independently substituted; or R5 is S(O)2 alkyl, 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 [ka] 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 [ka] or R5 is alkylaryl or benzyl, or R5 is [ka] or R5 is 2-pyridyl, 3-pyridyl or 4-pyridyl, or R5 is [ka] or R5 is [ka] or R5 is [ka] or R5 is [ka] or R5 is [ka] is), or CN, or [ka] and R2 is NH2, NHC(O)OMe or NHMe; R6 is H, C(O)Me or P(O)(OH)2; R7 is a linear or branched C1-C3 or C5-C 10 Alkyl, straight or branched chain C1-C 10 Alkenyl or straight or branched C1-C 10 alkynyl, any of which may have an alkyl ring or alkyl ether ring, which may be a straight or branched chain C1-C3 or C5-C 10 Alkyl, straight or branched chain C1-C 10 Alkenyl or straight or branched C1-C 10 containing one carbon of alkynyl, any of the foregoing being independently optionally substituted; if a linear C3-alkyl is substituted at the terminal carbon atom with a methyl group, then the linear C3-alkyl substituted at the terminal carbon atom with a methyl group contains further substitution; if a C2-alkyl is substituted at the terminal carbon atom with an ethyl group, then the C2-alkyl substituted at the terminal carbon atom with an ethyl group contains further substitution; if a C1-alkyl is substituted at the terminal carbon atom with an n-propyl group, then the C1-alkyl substituted at the terminal carbon atom with an n-propyl group contains further substitution; or R7 is [ka] [ka] [ka] Provided herein are compounds 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, wherein:

[0005] In some examples, in the 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 and R3 is linear or branched C1-C 10 Alkyl, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, C1-C 10 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, alkylcycloalkyl, alkylcyclohexyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl, linear or branched alkyl ether, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypropyl, cyclic alkyl ether, tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, tetrahydrofuranyl, 2-tetrahydrofuranyl, 2-tetrahydrofuranyl, alkylaryl, benzyl; Any of these may be one or more of C1 to C 10 alkyl, one or more halogens, one or more fluoro, one or more chloro, one or more deuteriums, bromo, one or more iodo, aryl, C aryl, C 10Optionally, independently substituted with aryl, heteroaryl, C1-C7 alkylcycloaklyl, unsubstituted tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, or 4-tetrahydropyranyl, or any combination thereof.

[0006] In some examples, in a compound of Formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R1 is C(O)N(R4R5), R5 is Straight or branched chain C1-C 10 alkyl, methyl, ethyl, propyl, or butyl, any of which may contain one or more deuterium atoms, straight or branched C1-C 10 Optionally and independently substituted with alkyl, one or more halo, one or more fluoro, one or more chloro, one or more iodo, one or more or any combination thereof.

[0007] In some examples, in a compound of Formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R1 is C(O)N(R4R5), R5 is heteroaryl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or R5 is S(O)2Me.

[0008] In some examples, in a compound of Formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R7 is a straight or branched chain C1-C3 or C5-C 10 Alkyl, straight or branched chain C1-C 10 Alkenyl or straight or branched C1-C 10alkynyl, any of which may have an alkyl ring or alkyl ether ring, which may be a straight or branched C1-C3 or C5-C 10 Alkyl, straight or branched chain C1-C 10 Alkenyl or straight or branched C1-C 10 Alkynyl contains one carbon, and any of the above can be deuterium, straight chain C1-C 10 Alkyl, methyl, ethyl, branched chain C1-C 10 optionally substituted independently and optionally with one or more substituents which may be alkyl, halogen, fluoro, chloro, bromo, iodo, 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, cyclic C1-C7 alkyl 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, tricyclic aliphatic, adamantyl, cyano, acetal, ketal, or any combination thereof; If a linear C3-alkyl is substituted at a terminal carbon atom with a methyl group substituent, then the linear C3-alkyl substituted at a terminal carbon atom with a methyl group substituent contains further substitutions, If the C2-alkyl is substituted at the terminal carbon atom by an ethyl group, the C2-alkyl substituted at the terminal carbon atom by an ethyl group contains further substitutions, If the C1-alkyl is substituted at the terminal carbon atom by an n-propyl group, the C1-alkyl substituted at the terminal carbon atom by an n-propyl group may further contain substitutions, Linear C1~C 10Alkyl substituent, methyl substituent, ethyl substituent, branched chain C1-C 10 alkyl substituents, hydroxyl substituents, amino substituents, substituents which are carboxylic acids or pharmaceutically acceptable salts thereof, amide substituents, carbamate substituents, urea substituents, ester substituents, alkoxy substituents, methoxy substituents, ethoxy substituents, ether substituents, cyclic ether substituents, C1-C7 alkyl ether substituents, cyclic C1-C7 ether substituents, aryl substituents, heteroaryl substituents, fused aryl substituents, biaryl substituents, fused aryl-heteroaryl substituents, fused diaryl substituents, fused aryl-heteroaryl substituents, 5-membered heteroaryl substituents, 6-membered heteroaryl substituents, naphthyl substituents, cycloalkyl substituents, cyclopropyl substituents, cyclobutyl substituents, cyclopentyl substituents, cyclohexyl substituents, cycloheptyl substituents, tert-butyl substituents, bicyclic aliphatic substituents, tricyclic aliphatic substituents, adamantly substituents, or any combination thereof; Straight chain C1~C 10 Alkyl, methyl, ethyl, branched chain C1-C 10 and optionally substituted independently with one or more of alkyl, halogen, fluoro, chloro, bromo, iodo, hydroxyl, alkoxy, methoxy, ethoxy, carbamate, urea, amide, ester, amine, trifluoromethoxy, ether, C1-C7 alkyl ether, cyclic C1-C7 ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, 5-membered hereroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic, tricyclic aliphatic, adamantyl, cyano, acetal, ketal, or any combination thereof.

[0009] Similarly, a compound of formula I: [ka] or a diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, During the ceremony, R1 is C(O)OH, or C(O)OX (X is an organic cation, an inorganic cation, or Na + , K. + , Mg 2+ , Ca 2+ , Zn 2+ or Mn 2+ is), or [ka] [ka] ,or C(O)OR3, where R3 is a linear or branched alkyl, cycloalkyl, cyclic ether, or linear or branched alkyl ether, any of which is optionally independently substituted or or R3 is [ka] or R3 is [ka] is), or C(O)N(R4R5) wherein R4 is H, or R4 is a straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally independently substituted; R5 is H or absent, or R5 is a straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally and independently substituted; or R5 is S(O)2 alkyl, 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 [ka] 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 [ka] or R5 is alkylaryl or benzyl, or R5 is [ka] or R5 is 2-pyridyl, 3-pyridyl or 4-pyridyl, or R5 is [ka] or R5 is [ka] or R5 is [ka] or R5 is [ka] or R5 is [ka] is), or CN, or [ka] and R2 is NH2, NHC(O)OMe or NHMe; R6 is H, C(O)Me or P(O)(OH)2; R7 is a straight or branched chain alkyl, alkenyl, or alkynyl, any of which may be optionally and independently substituted; or R7 is [ka] [ka] [ka] and The compound of Formula I is not buthionine sulfoximine (BSO) or a salt of BSO. Provided is 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.

[0010] In some examples, in a compound of Formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R1 is C(O)OH, or C(O)OR3 (R3 is alkyl, straight or branched C1-C 10Alkyl, 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, cyclic alkyl ether, tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, tetrahydrofuranyl, 2-tetrahydrofuranyl, 2-tetrahydrofuranyl, alkylaryl, benzyl, any of which may contain one or more deuterium atoms, a straight or branched C1-C 10 alkyl, one or more halogens, one or more fluoro, one or more chloro, one or more bromo, one or more iodo, aryl, C aryl, C 10 optionally independently substituted with aryl, heteroaryl, C1-C7 alkylcycloalkyl, unsubstituted tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, or 4-tetrahydropyranyl, or any combination thereof is.

[0011] In some examples, in a compound of Formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R1 is C(O)N(R4R5).

[0012] In some examples, in a compound of Formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R1 is C(O)N(R4R5), R5 is heteroaryl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or R5 is S(O)2Me.

[0013] In some examples, in a compound of Formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R7 is a straight or branched chain C1-C 10 Alkyl, straight or branched chain C1-C 10 Alkenyl or straight or branched C1-C 10 alkynyl, any of which may have an alkyl ring or alkyl ether ring, which may be linear or branched C1-C 10 Alkyl, straight or branched chain C1-C 10 Alkenyl or straight or branched C1-C 10 Alkynyl contains one carbon, and any of the above can be deuterium, straight chain C1-C 10 Alkyl, methyl, ethyl, branched chain C1-C 10 optionally substituted independently by one or more substituents which may be alkyl, halogen, fluoro, chloro, bromo, iodo, 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, cyclic C1-C7 alkyl 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, tricyclic aliphatic, adamantyl, cyano, acetal, ketal, or any combination thereof; Linear C1~C 10 Alkyl substituent, methyl substituent, ethyl substituent, branched chain C1-C 10alkyl substituents, hydroxyl substituents, amino substituents, carboxylic acid or pharmaceutically acceptable salt thereof substituents, amide substituents, carbamate substituents, urea substituents, ester substituents, alkoxy substituents, methoxy substituents, ethoxy substituents, ether substituents, cyclic ether substituents, C1-C7 alkyl ether substituents, cyclic C1-C7 ether substituents, aryl substituents, heteroaryl substituents, fused aryl substituents, biaryl substituents, fused aryl-heteroaryl substituents, fused diaryl substituents, fused aryl-heteroaryl substituents, 5-membered heteroaryl substituents, 6-membered heteroaryl substituents, naphthyl substituents, cycloalkyl substituents, cyclopropyl substituents, cyclobutyl substituents, cyclopentyl substituents, cyclohexyl substituents, cycloheptyl substituents, tert-butyl substituents, bicyclic aliphatic substituents, tricyclic aliphatic substituents, adamantyl substituents, or any combination thereof; Deuterium, straight chain C1-C 10 Alkyl, methyl, ethyl, branched chain C1-C 10 and optionally substituted independently with one or more of alkyl, halogen, fluoro, chloro, bromo, iodo, hydroxyl, alkoxy, methoxy, ethoxy, carbamate, urea, amide, ester, amine, trifluoromethoxy, ether, linear or branched C1-C7 alkyl ether, cyclic C1-C7 ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic, tricyclic aliphatic, adamantyl, cyano, acetal, ketal, or any combination thereof.

[0014] In some examples, in the 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 [ka] is.

[0015] In some examples, in the compound of formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R1 is an ester or COOH.

[0016] In some examples, in the compound of Formula I, the diastereomer or enantiomer described above, or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R2 is NH2.

[0017] In some examples, in the compound of formula I, the diastereomer or enantiomer described above, or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R6 is H.

[0018] In some examples, in the compound of Formula I, the diastereomer or enantiomer described above, or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R7 is [ka] [ka] [ka] is.

[0019] Similarly, provided herein are diastereomers or enantiomers of the compounds, or pharmaceutically acceptable salts of any of the foregoing, or deuterated derivatives of any of the foregoing, wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0020] Similarly provided herein is a compound, a diastereomer or enantiomer of a compound, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein the compound is [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0021] Similarly, a compound of formula II [ka] Provided herein is a diastereomer or enantiomer of a 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 deuterium, halogen, fluorine, chlorine, straight or branched chain C1-C 10straight or branched C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl, optionally independently substituted with substituents selected from the group consisting of alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and any combination thereof; 10 It is alkyl.

[0022] Also provided herein are pharmaceutical compositions comprising a compound of Formula I, a compound of Formula II, any of the diastereomers or enantiomers described above, or any of the pharmaceutically acceptable salts described above, or any of the deuterated derivatives described above, and a pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutical composition may be in unit dose form. Furthermore, the pharmaceutical composition may include 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, the compound of Formula I, the compound of Formula II, the compound, or any of the enantiomers or diastereomers described above, or any of the pharmaceutically acceptable salts described above, or any of the deuterated derivatives described above, is present in the pharmaceutical composition in an amount ranging from 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 be present independently in the pharmaceutical composition in an amount ranging from about 0.001 mg to about 25,000 mg.

[0023] Also provided herein are pharmaceutical compositions comprising a compound of Formula XVIII, a compound of Formula XIX, a compound of Formula XX, any diastereomer or enantiomer thereof, any pharmaceutically acceptable salt thereof, or any deuterated derivative thereof, and a pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutical composition may be in unit dose form. Furthermore, the pharmaceutical composition may include an additional active agent, 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, the compound of Formula I, the compound of Formula II, or any enantiomer or diastereomer thereof, or any pharmaceutically acceptable salt thereof, or any deuterated derivative thereof, is present in the pharmaceutical composition in an amount ranging from 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 be present independently in the pharmaceutical composition in an amount ranging from about 0.001 mg to about 25,000 mg.

[0024] In some embodiments, a kit is provided comprising a compound described herein, a diastereomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, or a pharmaceutical composition described herein, and a container. In some embodiments, a pharmaceutical composition described herein and a container. 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 reusable. In some embodiments, the container is a single-use container. In some embodiments, the container is resealable.

[0025] In some embodiments, methods of treating a disease or condition in a subject are provided. In some embodiments, the disease or condition is cancer. In some embodiments, the method comprises administering a therapeutically effective amount of a pharmaceutical composition herein to a subject, which may be a subject in need thereof, thereby treating the disease or condition, which may be cancer. In some embodiments, methods of treating a disease or condition in a subject, which may be a subject in need thereof, are provided, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, a compound of Formula II, any diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, thereby treating the disease or condition, which may be cancer. In some embodiments, the administering step is selected from the group consisting of 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 human. In some embodiments, the subject may be male. In some embodiments, the subject may be female.

[0026] In some embodiments, there is provided a method of modulating ferroptosis in a tissue that may be present in a subject that may be in need thereof, comprising contacting the tissue, for example, directly or indirectly, optionally continuously, with a pharmaceutical composition herein in an amount effective to modulate ferroptosis in the tissue. 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.

[0027] In some embodiments, the administering or contacting step in the methods herein can be once daily, twice daily, three times daily, weekly, once every two weeks, once every three weeks, once a month, once every six months, once a year, or lifelong, as needed. In some embodiments, the effective or therapeutically effective amount can be in the range of about 0.001 mg to about 25,000 mg of a compound herein, its enantiomer or diastereomer, a pharmaceutically acceptable salt of either of these, or a deuterated derivative of either of these, or a pharmaceutical composition herein, which can optionally be in unit dose form.

[0028] In some embodiments, methods of making and testing compounds of Formula I and Formula II, enantiomers and diastereomers of any of them, salts and pharmaceutically acceptable salts of any of them, and deuterated derivatives of any of them are also provided.

[0029] In some embodiments, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0030] In some embodiments, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt of any of the foregoing; or a deuterated derivative of any of the foregoing.

[0031] In some embodiments, [ka] or a pharmaceutically acceptable salt of any of the foregoing; or a deuterated derivative of any of the foregoing.

[0032] In some embodiments, the compound of Formula XVIII: [ka] , a diastereomer or enantiomer of a compound of formula XVIII, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, are described herein, wherein in the compound of formula XVIII: Each R1, R2 or R3 is independently H, linear or branched C1-C 10 Alkyl, C3-C6 cycloalkyl, C6-C 10Aryl, C3-C 10 heteroaryl, biphenyl, halogenated biphenyl, indole, triazole, isothiazole, oxazoline, linear or branched C1-C6 alkyl ether, -CH3, phenyl, -C(O)OR5, -C(O)NH2, -O-, -S-, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, -Cl, -Br, -I, or or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, which is optionally substituted with linear or branched C1-C6 alkyl, C1-C6 cycloalkyl, halogen, -CF3, or -F; or R1, R2 and R3 together form a C3-C6 cycloheteroaryl; Each R1, R2 or R3 is deuterium, halogen, fluorine, -CF3, chlorine, straight or branched chain C1-C 10 each independently and optionally substituted with substituents selected from the group consisting of 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, anhydride, and any combination thereof; R4 is H or linear or branched C1-C6 alkyl; R5 is a linear or branched C1-C alkyl group optionally substituted with at least one heteroatom, halogen, or C1-C3 alkyl ether. 10 It is alkyl.

[0033] In some embodiments, the compound of formula XIX: [ka] or a diastereomer or enantiomer of a 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, linear or branched C1-C 10 Alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C3-C 10 heteroaryl, biphenyl, halogenated biphenyl, indole, triazole, isothiazole, oxazoline, linear or branched C1-C6 alkyl ether, -C(O)OR5, -C(O)NH2, -O-, -S-, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, -Cl, -Br, -I, or or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, which is optionally substituted with linear or branched C1-C6 alkyl, C1-C6 cycloalkyl, halogen, -CF3, or -F; or R1, R2 and R3 together form a C3-C6 cycloheteroaryl; Each R1, R2 or R3 is deuterium, halogen, fluorine, -CF3, chlorine, straight or branched chain C1-C 10 each independently and optionally substituted with substituents selected from the group consisting of 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, anhydride, and any combination thereof; R4 is H or linear or branched C1-C6 alkyl; R5 is a linear or branched C1-C alkyl group optionally substituted with at least one heteroatom, halogen, or C1-C3 alkyl ether. 10 It is alkyl.

[0034] In some embodiments, the compound of formula XX: [ka] A diastereomer or enantiomer of a compound of formula XX, or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, wherein: Each R1, R2 or R3 is independently H, linear or branched C1-C4 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C5-C6 heteroaryl, biphenyl, halogenated biphenyl, triazole, isothiazole, oxazoline, linear or branched C1-C6 alkyl ether, -C(O)OR5, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, or or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, which is optionally substituted with linear or branched C1-C6 alkyl, C1-C6 cycloalkyl, halogen, -CF3, or -F; Each R1, R2 or R3 is deuterium, halogen, fluorine, -CF3, chlorine, straight or branched chain C1-C 10 each independently and optionally substituted with substituents selected from the group consisting of 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; R4 is H or linear or branched C1-C6 alkyl; R5 is a linear or branched C1-C alkyl group optionally substituted with at least one heteroatom, halogen, or C1-C3 alkyl ether. 10 It is alkyl.

[0035] In some embodiments, the present invention is a pharmaceutical composition comprising a compound of Formula XVIII, XIX, XX, or a compound described herein, any diastereomer or enantiomer thereof, any pharmaceutically acceptable salt thereof, or any deuterated derivative thereof, 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 ranging from about 0.001 mg to about 25,000 mg. In some embodiments, the present invention is a kit comprising a 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 single-use container. In some embodiments, the container is a resealable container.

[0036] Also described herein are methods for treating cancer in a subject. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a 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, any diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt thereof, or any deuterated derivative thereof, 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 SWI / SNF-deficient complex cancer. In some embodiments, the administering step is selected from the group consisting of oral, injection; subcutaneous, intratumoral; systemic, topical, intravenous, intraperitoneal, intramuscular, and any combination thereof.

[0037] Also described herein are methods of modulating ferroptosis in a tissue, 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 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 administering or contacting step 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 a year, or for life, as needed. In some embodiments, the therapeutically effective amount or effective amount is in the range of about 0.001 mg to about 25,000 mg.

[0038] Also described herein are methods of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein, thereby treating the disease or condition. Similarly, described herein are methods of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a composition described herein, any diastereomer or enantiomer described above, or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, thereby treating the disease or condition. In some embodiments, the disease or condition is fibrosis or kidney damage.

[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 sets forth illustrative embodiments, in which the principles of the present disclosure are utilized, and the accompanying drawings, in which: [Brief explanation of the drawings]

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

[0041] [Figure 2A] Figures 2A-2B demonstrate tumor response over time after exposure to (1) BSO or (2) BSO plus lip-1 or fer-1. Figure 2A shows cleaved caspase-3 staining. Figure 2B shows a graph demonstrating the percentage of viable cells (y-axis) over time (x-axis) for BSO and BSO plus fer-1. [Figure 2B] Figures 2A-2B demonstrate tumor response over time after exposure to (1) BSO or (2) BSO plus lip-1 or fer-1. Figure 2A shows cleaved caspase-3 staining. Figure 2B shows a graph demonstrating the percentage of viable cells (y-axis) over time (x-axis) for BSO and BSO plus fer-1.

[0042] [Figure 3] Figure 3 demonstrates tumor response 24 hours after exposure to (1) ML-210 or (2) ML-210 + lip-1. Drugs were loaded to achieve concentrations of 1-10 μM for both ML-210 and lip-1. Staining indicates cleaved caspase-3. Dashed lines indicate the area of drug exposure. Scale bar: 100 micrometers (μm).

[0043] [Figure 4] Figure 4 demonstrates dose-response curves of BSO and RSL3 against percentage cell viability (y-axis) normalized to DMSO. The x-axis indicates drug concentration.

[0044] [Figure 5A] Figures 5A-5B demonstrate tumor responses 24 hours after exposure to (1) RSL3 or (2) RSL3 + lip-1. Drugs were loaded to achieve concentrations of 1-10 μM for both RSL3 and lip-1. Figure 5A shows tumor sections stained for cleaved caspase-3. Dashed lines indicate the area of drug exposure. 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 indicated. [Figure 5B]Figures 5A-5B demonstrate tumor responses 24 hours after exposure to (1) RSL3 or (2) RSL3 + lip-1. Drugs were loaded to achieve concentrations of 1-10 μM for both RSL3 and lip-1. Figure 5A shows tumor sections stained for cleaved caspase-3. Dashed lines indicate the area of drug exposure. 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 indicated.

[0045] [Figure 6] 6A-6B are structural diagrams 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] [Figure 7] 7A-7B are structural diagrams 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] [Figure 8] 8A-8B are structural diagrams 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] [Figure 9] 9A-9B are structural diagrams 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 INVENTION

[0049] Detailed Description of the Disclosure The following description and examples illustrate the embodiments of the present disclosure in detail. It should be understood that the present disclosure is not limited to the specific embodiments described herein and may therefore vary. Numerous variations and modifications exist herein, and are encompassed within the scope of the present disclosure.

[0050] definition 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. Accordingly, the description of a range should be considered to specifically disclose all possible subranges and individual numerical values within that range, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise. For example, the description of a range such as 1 to 6 should be considered to specifically disclose subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual numbers within that range, for example, 1.1, 2, 2.3, 5, and 5.9. This applies regardless of the breadth of the range. The upper and lower limits of these intervening ranges may independently be included in the smaller ranges, which are also encompassed within the scope of the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, unless the context clearly dictates otherwise.

[0051] Unless specifically stated or clear from the context, the term "about" as used herein is understood to mean within the range of normal tolerance in the art, for example, within 2 standard deviations of the mean value. "About" can be understood as within plus or minus 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value. Unless otherwise clear from the context, all numerical values presented herein are modified by the term "about." When a specific value is described in this application and claims, unless otherwise specified, the term "about" is implicit and, in this context, means within an acceptable error range for the specific value.

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

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

[0054] The term "adjacent" and its grammatical equivalents, as used herein, refers to something immediately next to a reference. For example, in the context of cells or tissues, the term adjacent can mean that there are no other cells or tissues in between.

[0055] To illustrate the bond that is the point of attachment of a moiety or substituent to a core or backbone structure, the following structural context is used: [ka] is used in the structural formulas herein.

[0056] The term "analog" and its grammatical equivalents, as used herein, refer to molecules that are not identical but have similar structural features.A drug or drug analog is a drug or drug that is related to a reference drug, but its chemical structure may differ.An analog exhibits similar activity to the reference drug or drug, but the activity may be increased, decreased, or otherwise improved.An analog form of a compound or drug may mean that the main chain core of the structure is modified or changed compared to the reference drug.

[0057] The term "prodrug," as used herein, refers to 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] The term "anticancer agent" or "chemotherapeutic agent" and their grammatical equivalents, as used herein, refer to an agent that can kill rapidly dividing cells (e.g., cancer cells), prevent further division of rapidly dividing cells, or slow down the division of rapidly dividing cells. Exemplary anticancer agents provided herein can include a ferroptosis inducer, can be used in combination with one or more additional ferroptosis inducers, can be used in combination with an iron-dependent cell death inducer, and / or can be used in combination with a second therapeutic agent or second active agent. The second therapeutic agent or second active agent can be in the form of a prodrug. The second therapeutic agent or second active agent can be in the form of a pharmaceutically acceptable salt. The second therapeutic or active agent may be an alkylating agent such as a nitrogen mustard, chlorambucil, cyclophosphamide, ifosfamide, melphalan, or busulfan; a nitrosourea, such as streptozocin, carmustine, or lomustine; an alkylsulfonate, such as busulfan; a triazine, such as dacarbazine or temozolomide; or an ethyleneimine, such as thiotepa or altretamine. The second therapeutic or active agent may be an antimetabolite, which may be a purine antagonist, pyrimidine antagonist, or folate antagonist, such as 5-fluorouracil, 6-mercaptopurine, capecitabine, cladribine, or clofarabine. The second therapeutic or active agent may be an antitumor antibiotic. The second therapeutic or 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,Mechlorethamine, leucovorin, methotrexate, mercaptopurine, busulfan, chlorambucil, cyclophosphamide, vincristine, dactinomycin, vinblastine, thioguanine, procarbazine, floxuridine, fluorouracil, mitotane, bleomycin, doxorubicin, dacarbazine, lomustine, carmustine, cisplatin, asparaginase, streptozocin, etoposide, ifosfamide, carboplatin, altretamine, fludarabine, pentostatin, paclitaxel, melphalan, teniposide, cladribine, vinorelbine , pegaspargase, thiotepa, docetaxel, gemcitabine, irinotecan, topotecan, idarubicin, capecitabine, daunorubicin, valrubicin, temozolomide, cytarabine, epirubicin, arsenic trioxide, mitomycin, oxaliplatin, pemetrexed disodium, clofarabine, nelarabine, ixabepilone, bendamustine hydrochloride, pralatrexate, carbazitazel, eribulin mesylate, asparaginase derived from blackleg disease fungus chrsanthemi, omacetaxine mepesuccinate, radium-223 dichloride, fluoxymesterone, methyltestosterone, tamoxifen, tamoxifen citrate, estramustine, interferon alpha-2b (recombinant), goserelin, flutamide, aldesleukin, bicalutamide, anastrozole, porfimer, nilutamide, imiquimod, letrazole , rituximab, toremifene, thalidomide, trastuzumab, alitretinoin, bexarotene, denileukin diftitox, exemestane, gemtuzumab ozogamicin, exemestane, gemtuzumab ozogamicin, triptorelin, alemtuzumab, imatinib, imatinib mesylate, peginterferon alpha 2-B, fulvestrant, iron, iron-containing nanoparticles, ibritumomab tiuxetan, leuprolide, leuprolide 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, sipuleucel (sp uleucel-T, abiraterone, abiraterone acetate (abiratone), brentuximab vedotin, crizotinib, iprimumab, ruxolitinib, ruxolitinib phosphate, vandetanib, vemurafenib, pertuzumab, axitinib, bosutinib, cabozantinib (carbozantinib), carfilzomib, enzalutamide, ponatinib, ponatinib hydrochloride, regorafenib, vismodegrib, ziv-aflibercept, dabrafenib, trametinib, obinutuzumab, adotrastuzumab emtansine emtansine), afatinib, ibrutinib, pomalidomide, idelalisib, belinstat, ceritinib, pembrolizumab (perbrolizumab), 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, brexcabtagene autolucel, lisocabtagene maraleucel, idecabtagene biclucel, siltacabtagene autolucel, a compound of Table 1, an enantiomer or diastereomer thereof, a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, or any combination of the above.

[0059] The term "cancer" and its grammatical equivalents, as used herein, refers to the hyperproliferation of cells whose characteristic traits, i.e., loss of normal control, result in unregulated growth, lack of differentiation, local tissue invasion, and metastasis. In relation to the methods provided herein, cancer includes, but is not limited to, acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bladder cancer, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or rectum, eye cancer, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vulva, chronic lymphocytic leukemia, chronic myeloid carcinoma, colon cancer, esophageal cancer, cervical cancer, fibrosarcoma, gastrointestinal cancer, Hodgkin's lymphoma, hypopharyngeal cancer, kidney cancer. The tumor may be any cancer, including any one of: laryngeal cancer, leukemia, liquid tumors, liver cancer, lung cancer, lymphoma, malignant mesothelioma, mast cell tumor, melanoma, dedifferentiated melanoma, multiple myeloma, nasopharyngeal cancer, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, peritoneal, omental and mesenteric cancer, pharyngeal cancer, prostate cancer, colorectal cancer, renal cancer, carcinoma, renal cancer, non-clear cell renal carcinoma, clear cell renal 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, for example, an abnormal growth of cells or tissues, whether malignant or benign. Any cancer or neoplastic condition, tumor, or population of cancerous cells may be SWI / SNF-deficient. In some examples, any cancer or neoplastic condition, tumor, or population of cancerous cells is not SWI / SNF-deficient.

[0060] The term "drug-resistant cancer" and its grammatical equivalents, as used herein, refers to a cancer that does not respond to or shows a reduced response to one or more chemotherapeutic agents.

[0061] The terms "effective amount" or "therapeutically effective amount" and their grammatical equivalents refer to an amount sufficient to achieve or at least partially achieve a desired effect.

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

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

[0064] In some embodiments, the compound or its salt may comprise an enantiomerically pure form.In some examples, the compound or its salt disclosed herein may have an enantiomeric excess 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 some cases, the percent enantiomeric excess is as follows: %ee=(|F R -F S |×100)(in the formula, F R is the mole fraction of compounds with R stereocenters, and F S is the mole fraction of compounds with S stereocenters, and the two perpendicular lines indicate the absolute value of the difference).

[0065] The value of diastereomeric excess, or de (diastereomeric excess), can indicate the excess of one diastereomer in a diastereomeric mixture. It can be defined as:

number

[0066] The term "hyperproliferative cells" and grammatical equivalents, as used herein, refers to cells characterized by unwanted cell proliferation or abnormally rapid or sustained cell division that is unrelated to or uncoordinated with cell division in surrounding normal tissues.

[0067] The term "in vitro" and its grammatical equivalents, as used herein, refers to events that take place in an artificial environment, e.g., a test tube or reaction vessel, cell culture, etc., rather than within a multicellular organism.

[0068] The term "in vivo" and its grammatical equivalents, as used herein, refers to events that take place within a multicellular organism, such as a non-human animal.

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

[0070] The term "normal cell" and its grammatical equivalents, as used herein, refers to a cell undergoing controlled cell division, controlled activation, or a quiescent cell.

[0071] The compounds herein are intended to include all isotopes of atoms occurring in the compounds herein. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C. 14 C. 15 N, 31 P or 32 Isotopically labeled compounds can generally be prepared by substituting an appropriate isotopically labeled reagent for the non-labeled reagent that would otherwise be used. For example, methyl groups can also include deuterated methyl groups such as -CD3.

[0072] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit any embodiments. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. It is further understood that the terms "comprises" and / or "comprising," as used herein, specify the presence of the specified features, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. 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 may be depicted to indicate stereochemistry using dotted or wedge bonds, as shown below. For compounds with stereogenic atoms, if only one of the substituents is dotted or wedge, the fourth substituent can be interpreted as having the opposite orientation in space. Thus, the two exemplary structures shown below can be interpreted interchangeably. [ka]

[0074] For compounds with stereogenic sulfoximine sulfur atoms, if two substituents are both dotted or both wedges, the third and fourth substituents can be interpreted as having opposite orientations in space. Thus, the two exemplary structures shown below can be interpreted interchangeably. The structure on the left contains an oxo group on the inside of the plane, a double-bonded NH group on the inside of the plane, an R group on the outside of the plane, and a saturated carbon substituent on the outside of the plane. [ka]

[0075] Overview Provided herein are compounds, compositions containing the compounds, and pharmaceutical compositions containing the compounds, as well as methods of using them to treat diseases or conditions in subjects. The compounds may be or may include one or more compounds of Formula I, one or more compounds of Formula II, any enantiomers thereof, any diastereomers thereof, any pharmaceutically acceptable salts thereof, or any deuterated derivatives thereof, optionally in combination with a second therapeutic agent or second active agent. The composition or pharmaceutical composition may contain one or more of any of these. The disease or condition may be, for example, cancer in the tissue of a subject. The cancer may be contained in a mammal, which may be human, male or female, or may be contained in the tissue of a mammal. The disease or condition may be an inflammatory disease or fibrosis, and the subject may be in need thereof and may be a mammal, human, female or male.

[0076] Also provided herein are compounds, compositions containing compounds, pharmaceutical compositions containing compounds, and methods of using them to modulate, inhibit, or partially inhibit targets, including glutamate-cysteine ligase (GCL), for example, 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, any enantiomer thereof, any diastereomer thereof, any pharmaceutically acceptable salt thereof, or any deuterated derivative thereof, optionally in combination with a second therapeutic agent or second active agent.The subject may be in need thereof, and may be a mammal, a human, female or male.

[0077] Similarly, provided herein are compounds, compositions comprising compounds, pharmaceutical compositions comprising compounds, and methods for making compounds and compositions comprising compounds, and methods for using them to modulate or induce ferroptosis in subjects, and in tissues, if necessary.The compound can be or include one or more compounds of formula I, one or more compounds of formula II, their enantiomers, their diastereomers, the pharmaceutically acceptable salts of any of these, or the deuterated derivatives of any of these, optionally in combination with a second therapeutic agent or a second active agent.The subject in need thereof can be a mammal, a human, female or male.

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

[0079] The compound, its enantiomer, its diastereomer, any pharmaceutically acceptable salt of the foregoing, or any deuterated derivative of the foregoing may be a sulfoximine, which may, in some instances, be free of 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 condition before being treated with, administered with, or contacted with a compound of Formula I, a compound of Formula II, any of the enantiomers or diastereomers described above, any of the pharmaceutically acceptable salts described above, any of the deuterated derivatives described above, or a composition or pharmaceutical composition comprising any of the above. The diagnosis may be from an in vitro diagnosis or an in vitro diagnosis that may be a companion diagnosis.

[0081] When two or more compounds of Formula I, Formula II, any of the enantiomers described above, any of the diastereomers described above, any of the pharmaceutically acceptable salts described above, or any of the deuterated derivatives described above are contained in a composition or pharmaceutical composition, the composition may be a fixed-dose combination drug.

[0082] In this specification, when two, three, four, five, six, seven, eight, nine or ten compounds, therapeutic agents, second therapeutic agents or second activators are administered to a cell, tissue or subject, the compounds can be administered simultaneously or sequentially.When administered simultaneously, the administration can be a single composition or pharmaceutical composition, and these can be fixed dose combination drugs.

[0083] For example, the compounds of formula I and formula II, drugs, any of their therapeutic enantiomers or diastereomers, any of their salts and pharmaceutically acceptable salts, and any of their deuterated derivatives can be administered independently, continuously or discontinuously.For example, the compounds of formula XVIII and formula XIX and formula XX, drugs, any of their therapeutic enantiomers or diastereomers, any of their salts and pharmaceutically acceptable salts, and any of their deuterated derivatives can be administered independently, continuously or discontinuously.When administered discontinuously, administration can be at regular intervals or irregular intervals.Continuous and discontinuous administration can result in the sustained presence of a baseline level of the compound or drug in cells, tissues, organs, or systems. The baseline level can be reached, for example, 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 hours or longer. Administration can independently be by any route of administration, for example, oral, intravenous, subcutaneous, intramuscular, intraperitoneal, intratumor, intertumor, to the brain or central nervous system, to the bladder, to an organ or portion thereof, to a tissue or portion thereof, or any combination thereof. For example, the compounds of Formula I and Formula II, agents, therapeutic enantiomers or diastereomers of any of these, salts and pharmaceutically acceptable salts of any of these, and deuterated derivatives of any of these, when administered as a solution, can independently have a concentration of, for example, or 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 drug or therapeutic agent herein, any enantiomer thereof, any diastereomer thereof, any salt or pharmaceutically acceptable salt thereof, or any deuterated derivative thereof may be included as a ligand in a targeted proteolysis chimera (PROTAC) protein degrader. In some examples, a bifunctional PROTAC molecule may include a ligand of a protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). In some examples, the POI may be any protein referred to herein. In some examples, the POI may be cysteine-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 proteolytic agents, can act by recruiting selected E3 ligases to the vicinity of specific disease-causing proteins, which can then be tagged with ubiquitin and targeted for degradation by the proteasome. After the protein is degraded, the PROTAC can be released to continue causing further degradation.

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

[0086] In some examples, a compound of Formula I, a compound of Formula II, any compound or drug or therapeutic agent herein, any enantiomer of the foregoing, any diastereomer of the foregoing, any salt or pharmaceutically acceptable salt of the foregoing, or any deuterated derivative of the foregoing can be delivered directly to a tissue, tumor, or cell using, for example, a system comprising a pump, e.g., a minipump, or a syringe pump, and at least one or more needles, hollow tubes, and any combination thereof.

[0087] Unless expressly stated otherwise, the sulfoximine may be, for example, a compound of formula I: [ka] When depicted as a chemical structure, R6 illustrates the presence of the substituent R6, and imines containing R6 include (E), (Z), and mixtures of (E) and (Z) configurations.

[0088] Ferroptosis 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 cell death, necrosis, senescence, and autophagy. Each of these processes ultimately leads to cell death, but the pathways and mechanisms appear to be unique, both 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 in the plasma membrane of cells. Cells undergoing ferroptosis do not exhibit the cellular characteristics and functions associated with apoptosis, the standard form of cell death. Examples of apoptotic cellular features include, for example, the release of mitochondrial cytochrome c, caspase activation, and chromatin fragmentation. Ferroptosis is also characterized by increased levels of intracellular reactive oxygen species (ROS), which can be blocked by iron chelation and genetic inhibition of cellular iron uptake. The addition of iron, but not other divalent transition metal ions, can activate ferroptosis signaling in cells.

[0090] Cellular components involved in and regulating ferroptosis include, among others, cysteine-glutamate antiporter (system Xc), glutathione peroxidase 4 (GPX4), p53, cargo receptor NCOA4, glutathione synthetase (GSH), glutamate-cysteine ligase (GCL). 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] For example, hyperproliferative cells in a drug-resistant state, such as drug-resistant cancer cells, have been found to exhibit dysregulation in the apoptotic cellular pathway. Surprisingly, drug resistance to apoptotic agents by hyperproliferative cells can increase their ability to undergo ferroptosis. Apoptosis-resistant cells can be killed by ferroptosis induction due to their "excitable" ferroptosis-susceptible state.

[0092] Methods for characterizing ferroptosis-sensitive cells Provided herein is a method for identifying and characterizing ferroptosis-sensitive cells in a subject. In some embodiments, characterization is performed before treating the subject with the ferroptosis-inducing agent provided herein. Ferroptosis-sensitive cells can be identified by the following characteristics, among other morphological and histological characteristics, provided herein: (1) a selenium concentration higher than that of corresponding normal cells, (2) an iron concentration higher than that of corresponding normal cells, (3) a polyunsaturated fatty acid (PUFA) concentration higher than that of corresponding normal cells, (4) a peroxidizability index (PI) higher than that of corresponding normal tissues, and / or (5) the expression of one or more markers indicative of mesenchymal state. Methods for measuring the concentrations of analytes such as selenium, iron, and PUFA include, for example, mass spectrometry, chromatography, immunoassay, immunosorbent assay, absorbance and colorimetric assay, and microwave plasma atomic emission spectroscopy. Methods for measuring markers of mesenchymal cell state include, for example, immunoassay, polymerase chain reaction (PCR) assay, and sequencing assay.

[0093] (1) Selenium (Se) concentration and selenoproteins Selenium (Se) is a micronutrient that promotes cellular synthesis of selenoproteins. Dietary selenium is found in meat, nuts, grains, mushrooms, and vegetables. The selenium content in the human body ranges from approximately 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 instead of a 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 oxidation-reduction, 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 its inhibition induces ferroptotic cell death.

[0094] Provided herein is a method for identifying ferroptosis-susceptible cells in mammalian tissue by selenium concentration.In some embodiments, provided herein is a method comprising measuring the concentration of selenium (Se) in a cell, a plurality of cells or mammalian tissue.In some embodiments, the Se concentration in a cell or a plurality of cells of 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 cells of healthy tissue. In some embodiments, the Se concentration in the plurality of cells of the mammalian tissue is 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100% higher than the Se concentration in the cells of the healthy tissue. In some embodiments, the methods provided herein include administering to a mammal an effective amount of a ferroptosis-inducing agent, wherein the plurality of cells of the mammalian tissue have a selenium concentration higher than the selenium concentration in cells of the normal or healthy tissue, and ferroptosis is induced in the plurality of cells.

[0095] (2) Iron concentration Ferroptosis is an iron-dependent cellular process, and ferroptosis-susceptible cells have increased intracellular iron concentrations compared to normal cells. Cells treated with deferoxamine (DFO), an iron chelator used to treat iron overload and a drug reported to block ferroptosis, can inhibit cell death. Alternatively, loading cells with iron by treatment with ferric ammonium citrate (FAC) is sufficient to mimic particle treatment and induce ferroptosis in amino acid-starved cells. Increased intracellular iron uptake can potentially lead to glutathione depletion due to increased ROS generation, which leads to ferroptosis induction.

[0096] Provided herein is a method for identifying ferroptosis-susceptible cells in mammalian tissue by iron concentration.In some embodiments, provided herein is a method comprising measuring the iron or iron oxide concentration in a cell, a plurality of cells or mammalian tissue. In some embodiments, the ferroptosis-susceptible cells comprise an increased intracellular concentration of iron of at least about 7 parts per billion (ppb) or more, about 8 ppb or more, about 9 ppb or more, about 10 ppb or more, about 20 ppb or more, about 30 ppb or more, about 40 ppb or more, about 50 ppb or more, about 60 ppb or more, about 70 ppb or more, about 80 ppb or more, about 90 ppb or more, about 100 ppb or more, about 110 ppb or more, about 120 ppb or more, about 130 ppb or more, about 140 ppb or more, about 150 ppb or more, about 160 ppb or more, up to 170 ppb. In some embodiments, the ferroptosis-susceptible cells comprise an increased intracellular concentration of iron that is at least about 2 micromolar (μM) or more, 2.5 μM or more, 3.0 μM or more, 4.0 μM or more, 5.0 μM or more, or up to 10 μM higher than the intracellular concentration of iron in normal cells. In some embodiments, the iron concentration in a cell or 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 a healthy tissue. In some embodiments, the iron concentration in a plurality of cells of the mammalian tissue is 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100% higher than the iron concentration in cells of the healthy tissue.In some embodiments, the methods provided herein include administering to a mammal an effective amount of a ferroptosis-inducing agent, wherein a plurality of cells in a tissue of the mammal have an iron concentration that is higher than the iron concentration of cells in a normal or healthy tissue, and ferroptosis is induced in the plurality of cells.

[0097] (3) PUFA status Apoptosis-resistant cells benefit from a ferroptosis-susceptible state accompanied by high levels of polyunsaturated fatty acids (PUFAs). Apoptosis-resistant cells can be killed by ferroptosis induction due to their "excitable" high-PUFA state. The excitable state is defined by the high membrane abundance of PUFAs (relative to MUFAs, monounsaturated fatty acids), which makes PUFAs susceptible to uncontrolled lipid peroxidation, a radical chain reaction of polyunsaturated fatty acids, that leads to ferroptotic cell death.

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

[0099] Provided herein is a method for identifying ferroptosis-sensitive cells in mammalian tissue by the concentration of PUFA.In some embodiments, provided herein is a method comprising administering an effective amount of a ferroptosis inducer to a mammal, wherein a plurality of cells in the mammalian tissue have a polyunsaturated fatty acid (PUFA) concentration that is higher than the PUFA concentration of the cells in normal or healthy tissue, and ferroptosis is induced in the plurality of cells.In some embodiments, the PUFA concentration in the plurality of cells in the mammalian tissue is higher than the PUFA concentration in the cells in healthy or non-malignant tissue of mammal. In some embodiments, the PUFA concentration 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 PUFA concentration in the cells of the healthy tissue. In some embodiments, the PUFA concentration in the plurality of cells of the mammalian tissue is 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100% higher than the PUFA concentration in the cells of the healthy tissue. In some embodiments, the PUFA concentration in the plurality of cells of the mammalian tissue is greater than a predetermined PUFA concentration. In some embodiments, the predetermined PUFA concentration is about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 mole percent of total lipids. In some embodiments, the predetermined PUFA concentration is about 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, or 80-90 mole percent of total lipids. In some embodiments, the predetermined PUFA concentration is about 20 mole percent of total lipids.

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

[0101] Cells grown in vitro have a different fatty acid profile and lower PI levels than those of cells in vivo. Vertebrate cells cannot synthesize PUFAs de novo and rely on dietary sources of such molecules. Typical cell culture methods use serum-supplemented (usually 10%, v / v) media, which is the only exogenous lipid source and contains 1% of the PUFAs available to cells in the body. As a result, cells grown in culture have half the PUFA levels of cells in vivo and double the amount of monounsaturated fatty acids (MUFAs).

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

[0103] Provided herein is a method for identifying ferroptosis-susceptible cells in mammalian tissue by peroxidative potential index (PI).In some embodiments, provided herein is a method comprising administering an effective amount of a ferroptosis inducer to a mammal, wherein a plurality of cells in the mammalian tissue have a PI higher than the PI of cells in normal or healthy tissue, and ferroptosis is induced in the plurality of cells.In some embodiments, the PI in the plurality of cells in the mammalian tissue is higher 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 a plurality of cells of a 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 PI in cells of a healthy or non-malignant tissue.

[0104] (5) Mesenchymal cell state Therapy-resistant cells have three cell- and patient-derived signatures of a highly mesenchymal state. The first cell signature is the expression of mesenchymal cell markers. Ferroptosis-sensitive cells exhibit one or more markers of a mesenchymal state. Mesenchymal cell 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 signature of ferroptosis-sensitive cells is reduced expression of endothelial cell markers compared to normal cells. Non-limiting examples of endothelial cell markers include vimentin, E-cadherin, and beta (β)-actin. The third cell signature of ferroptosis-sensitive cells is sensitivity to GPX4 knockdown, which leads to cell death. GPX4 dependency is more pronounced in cancer cells that adopt a therapy-resistant mesenchymal state than in normal mesenchymal cell lines. Methods of reducing or silencing GPX4 expression can be achieved, for example, by CRISPR / Cas9, siRNA or shRNA, among others.

[0105] Provided herein are methods for identifying ferroptosis-susceptible cells in mammalian tissue by expression of one or more markers of a mesenchymal cell state. In some embodiments, the methods provided herein include administering an effective amount of a ferroptosis-inducing agent to a mammal, wherein a plurality of cells in the mammalian tissue express one or more markers of a mesenchymal cell state, and ferroptosis is induced in the plurality of cells. In some embodiments, the expression of the mesenchymal cell markers in the plurality of cells in the mammalian tissue is about 1% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100% higher than the expression of the mesenchymal cell markers in cells of healthy or non-malignant tissue.

[0106] (6) Additional morphological characteristics of ferroptosis Cells undergoing ferroptosis are morphologically characterized by the presence of smaller-than-normal mitochondria with condensed mitochondrial membrane density, reduced or absent mitochondrial crystallites, and rupture of the outer mitochondrial membrane. Histology and immunoassays can be used to determine whether tissue is cancerous, hyperplastic, or fibrotic, and to identify ferroptosis-susceptible cells within mammalian tissues. Cells undergoing ferroptosis lack plasma membrane rupture and blebbing, which is typically associated with apoptosis. The nuclei of ferroptotic cells are normal in size and lack chromatin condensation.

[0107] In some embodiments, the methods provided herein include obtaining a biological sample (e.g., a blood sample or 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 contains a histological abnormality. In some embodiments, the histological abnormality is determined by tissue biopsy before or during targeted, sustained administration of a ferroptosis-inducing agent to the tissue. In some embodiments, the histological abnormality is hyperplasia, angiogenesis / angiogenesis, or fibrosis. Hyperplasia is identified by an increased number of cells in the tissue compared to normal, healthy tissue. Angiogenesis and angiogenesis are identified in the tissue sample by immunoassays for vascular markers, such as vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2). Fibrosis is characterized by abnormal collagen deposition between cells, identified in the tissue sample, for example, by Masson's Trichrome, Sirius Red, or collagen staining.

[0108] Cell death and ferroptosis inducers Provided herein is a method for inducing or modulating ferroptosis in vitro or in a subject's tissue, comprising: (a) sustained administration of a therapeutic amount of a ferroptosis inducer, which may be a compound of Formula I, a compound of Formula II, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of these, a deuterated derivative of any of these, 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 the 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. Exemplary targets in the ferroptosis pathway are provided in Figure 1 and can include glutamate-cysteine ligase GCL or glutamate-cysteine ligase catalytic (GCLC) subunit.

[0109] In some examples, the compounds herein may require substantial or continuous administration and / or contact with cells or tissues at or above threshold levels to induce or modulate ferroptosis, or to modulate, inhibit or partially inhibit glutamate-cysteine ligase GCL or glutamate-cysteine ligase catalytic (GCLC) subunits, or to treat diseases or conditions such as cancer, fibrosis, or inflammatory diseases.

[0110] A reference to a compound, or agent, or therapeutic agent, etc. can include one or more of these and can 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.

[0111] (1) Ferroptosis-inducing compounds, drugs, and iron-dependent cell death inducers In some embodiments, the compound of formula I: [ka] or a diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, During the ceremony, R1 is C(O)OH, or C(O)OX (X is an organic cation, an inorganic cation, or Na + , K. + , Mg 2+ , Ca 2+ , Zn 2+ or Mn 2+ is), or [ka] ,or C(O)OR3, where R3 is a linear or branched alkyl, cycloalkyl, cyclic ether, or linear or branched alkyl ether, any of which is optionally independently substituted or or R3 is [ka] or R3 is [ka] is), or C(O)N(R4R5) wherein R4 is H, or R4 is a straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally independently substituted; R5 is H, or R5 is a straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally and independently substituted; or R5 is S(O)2 alkyl; 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 [ka] 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 [ka] or R5 is alkylaryl or benzyl, or R5 is [ka] or R5 is 2-pyridyl, 3-pyridyl or 4-pyridyl, or R5 is [ka] or R5 is [ka] or R5 is [ka] or R5 is [ka] or R5 is [ka] is), or CN, or [ka] and R2 is NH2, NHC(O)OMe or NHMe; R6 is H, C(O)Me or P(O)(OH)2; R7 is a straight or branched chain C1-C3 or C5-C 10 Alkyl, straight or branched chain C1-C 10 Alkenyl or straight or branched C1-C 10 alkynyl, any of which may have an alkyl ring or alkyl ether ring, which may be a straight or branched C1-C3 or C5-C 10 Alkyl, straight or branched chain C1-C 10 Alkenyl or straight or branched C1-C 10containing one carbon of alkynyl, any of the foregoing being independently optionally substituted; if a linear C3-alkyl is substituted at the terminal carbon atom with a methyl group, then the linear C3-alkyl substituted at the terminal carbon atom with a methyl group contains further substitution; if a C2-alkyl is substituted at the terminal carbon atom with an ethyl group, then the C2-alkyl substituted at the terminal carbon atom with an ethyl group contains further substitution; if a C1-alkyl is substituted at the terminal carbon atom with an n-propyl group, then the C1-alkyl substituted at the terminal carbon atom with an n-propyl group contains further substitution; or R7 is [ka] [ka] [ka] Provided herein are compounds of Formula I, a diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing,

[0112] In some examples, in the 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 and R3 is a straight or branched alkyl, straight or branched C1-C 10 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, alkylcycloalkyl, alkylcyclohexyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl, alkyl ether, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypropyl, cyclic alkyl ether, tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, tetrahydrofuranyl, 2-tetrahydrofuranyl, 2-tetrahydrofuranyl, alkylaryl, benzyl; Any of these may be one or more of C1 to C 10 alkyl, one or more halogens, one or more fluoro, one or more chloro, one or more deuteriums, bromo, one or more iodo, aryl, C aryl, C 10 Optionally, independently substituted with aryl, heteroaryl, C1-C7 alkylcycloalkyl, unsubstituted tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, or 4-tetrahydropyranyl, or any combination thereof.

[0113] In some examples, in a compound of Formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R1 is C(O)N(R4R5), R5 is Straight or branched chain C1-C 10 alkyl, methyl, ethyl, propyl, or butyl, any of which may contain one or more deuterium atoms, straight or branched C1-C 10 Optionally and independently substituted with alkyl, one or more halo, one or more fluoro, one or more chloro, one or more iodo, one or more or any combination thereof.

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

[0115] In some examples, in a compound of Formula I, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, R7 is a straight or branched chain C1-C3 or C5-C 10 Alkyl, straight or branched chain C1-C 10 Alkenyl or straight or branched C1-C 10 alkynyl, any of which may have an alkyl ring or alkyl ether ring, which may be a straight or branched C1-C3 or C5-C 10 Alkyl, straight or branched chain C1-C 10 Alkenyl or straight or branched C1-C 10 Alkynyl contains one carbon, and any of the above can be deuterium, straight chain C1-C 10 Alkyl, methyl, ethyl, branched chain C1-C 10optionally substituted independently and optionally with one or more substituents which may be alkyl, halogen, fluoro, chloro, bromo, iodo, 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, cyclic C1-C7 alkyl 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, tricyclic aliphatic, adamantyl, cyano, acetal, ketal, or any combination thereof; If a linear C3-alkyl is substituted at a terminal carbon atom with a methyl group substituent, then the linear C3-alkyl substituted at a terminal carbon atom with a methyl group substituent contains further substitutions, If the C2-alkyl is substituted at the terminal carbon atom by an ethyl group, the C2-alkyl substituted at the terminal carbon atom by an ethyl group contains further substitutions, If the C1-alkyl is substituted at the terminal carbon atom by an n-propyl group, the C1-alkyl substituted at the terminal carbon atom by an n-propyl group may further contain substitutions, Linear C1~C 10 Alkyl substituent, methyl substituent, ethyl substituent, branched chain C1-C 10alkyl substituents, hydroxyl substituents, amino substituents, carboxylic acid or pharmaceutically acceptable salt thereof substituents, amide substituents, carbamate substituents, urea substituents, ester substituents, alkoxy substituents, methoxy substituents, ethoxy substituents, ether substituents, cyclic ether substituents, C1-C7 alkyl ether substituents, cyclic C1-C7 ether substituents, aryl substituents, heteroaryl substituents, fused aryl substituents, biaryl substituents, fused aryl-heteroaryl substituents, fused diaryl substituents, fused aryl-heteroaryl substituents, 5-membered heteroaryl substituents, 6-membered heteroaryl substituents, naphthyl substituents, cycloalkyl substituents, cyclopropyl substituents, cyclobutyl substituents, cyclopentyl substituents, cyclohexyl substituents, cycloheptyl substituents, tert-butyl substituents, bicyclic aliphatic substituents, tricyclic aliphatic substituents, adamantyl substituents, or any combination thereof; Straight chain C1~C 10 Alkyl, methyl, ethyl, branched chain C1-C 10 and optionally substituted independently with one or more of alkyl, halogen, fluoro, chloro, bromo, iodo, hydroxyl, alkoxy, methoxy, ethoxy, carbamate, urea, amide, ester, amine, trifluoromethoxy, ether, C1-C7 alkyl ether, cyclic C1-C7 ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic, tricyclic aliphatic, adamantyl, cyano, acetal, ketal, or any combination thereof.

[0116] Similarly, a compound of formula I: [ka] or a diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, During the ceremony, R1 is C(O)OH, or C(O)OX (X is an organic cation, an inorganic cation, or Na + , K. + , Mg 2+ , Ca 2+ , Zn 2+ or Mn 2+ is), or [ka] ,or C(O)OR3, where R3 is a linear or branched alkyl, cycloalkyl, cyclic ether, or linear or branched alkyl ether, any of which is optionally independently substituted or or R3 is [ka] or R3 is [ka] is), or C(O)N(R4R5) wherein R4 is H, or R4 is a straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally independently substituted; R5 is H, or R5 is a straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally and independently substituted; or R5 is S(O)2 alkyl; 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 [ka] 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 [ka] or R5 is alkylaryl or benzyl, or R5 is [ka] or R5 is 2-pyridyl, 3-pyridyl or 4-pyridyl, or R5 is [ka] or R5 is [ka] or R5 is [ka] or R5 is [ka] or R5 is [ka] is), or CN, or [ka] and R2 is NH2, NHC(O)OMe or NHMe; R6 is H, C(O)Me or P(O)(OH)2; R7 is a straight or branched chain alkyl, alkenyl, or alkynyl, any of which may be optionally and independently substituted; or R7 is [ka] [ka] [ka] and The compound of Formula I is not buthionine sulfoximine (BSO) or a salt of BSO. Provided is a compound of Formula I, a diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing.

[0117] Similarly, a compound of formula II [ka] or a diastereomer or enantiomer of a 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 deuterium, halogen, fluorine, chlorine, straight or branched chain C1-C 10straight or branched C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl, optionally independently substituted with substituents selected from the group consisting of alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and any combination thereof; 10 It is alkyl.

[0118] Also provided herein are pharmaceutical compositions comprising a compound of Formula I, a compound of Formula II, any of the diastereomers or enantiomers described above, or any of the pharmaceutically acceptable salts described above, or any of the deuterated derivatives described above, and a pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutical composition may be in unit dose form. Furthermore, the pharmaceutical composition may include an additional active agent, a pharmaceutically acceptable salt thereof, or a prodrug thereof. Furthermore, the pharmaceutical composition may be in the form of a powder, tablet, capsule, liquid, or gel. In some embodiments, the compound of Formula I, the compound of Formula II, the compound, or any of the enantiomers or diastereomers described above, or any of the pharmaceutically acceptable salts described above, or any of the deuterated derivatives described above, is present in the pharmaceutical composition in an amount ranging from 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 be independently present in the pharmaceutical composition in an amount ranging from about 0.001 mg to about 25,000 mg.

[0119] In some embodiments, a kit is provided comprising a compound described herein, a diastereomer thereof, an enantiomer thereof, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, or a pharmaceutical composition described herein, and a container. In some embodiments, a pharmaceutical composition described herein and a container. 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 reusable. In some embodiments, the container is a single-use container. In some embodiments, the container is resealable.

[0120] In some embodiments, methods of treating a disease or condition in a subject are provided. In some embodiments, the disease or condition is cancer. In some embodiments, the method comprises administering a therapeutically effective amount of a pharmaceutical composition herein to a subject, which may be a subject in need thereof, thereby treating the disease or condition, which may be cancer. In some embodiments, methods of treating a disease or condition in a subject, which may be a subject in need thereof, are provided, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, a compound of Formula II, any diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, thereby treating the disease or condition, which may be cancer. In some embodiments, the administering step is selected from the group consisting of 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 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 condition in a subject, which may be a subject in need thereof, is provided, comprising administering to the subject a therapeutically effective amount of a compound of Formula XVIII, Formula XIX, Formula XX, any diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt thereof, or any deuterated derivative thereof, thereby treating the disease or condition, which may be cancer. In some embodiments, the administering step is selected from the group consisting of 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 human. In some embodiments, the subject may be male. In some embodiments, the subject may be female.

[0121] In some embodiments, there is provided a method of modulating ferroptosis in a tissue that may be present in a subject that may be in need thereof, comprising contacting the tissue, for example, directly or indirectly, optionally continuously, with a pharmaceutical composition herein in an amount effective to modulate ferroptosis in the tissue. 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.

[0122] In some embodiments, the administering or contacting step in the methods herein can be once daily, twice daily, three times daily, weekly, once every two weeks, once every three weeks, once a month, once every six months, once a year, or lifelong, as needed. In some embodiments, the effective or therapeutically effective amount can be in the range of about 0.001 mg to about 25,000 mg of a compound herein, its enantiomer or diastereomer, a pharmaceutically acceptable salt of either of these, or a deuterated derivative of either of these, or a pharmaceutical composition herein, which can optionally be in unit dose form.

[0123] Also provided in some embodiments are methods of making and testing compounds of Formula I and Formula II, any enantiomers and diastereomers thereof, salts and pharmaceutically acceptable salts of any of them, and deuterated derivatives of any of them. Also provided in some embodiments are methods of making and testing compounds of Formula XVIII, Formula XIX, Formula XX, any enantiomers and diastereomers thereof, salts and pharmaceutically acceptable salts of any of them, and deuterated derivatives of any of them.

[0124] The methods provided herein include administering to a cell, tissue, or subject an agent, compound, or therapeutic agent that modulates cell death. In some embodiments, the administering step induces cell death. In some embodiments, the administering step inhibits or rescues a cell from cell death. In some embodiments, the administering step modulates ferroptosis. In some embodiments, the administering step induces ferroptosis in vivo. In some embodiments, the administering step 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 useful for inducing ferroptosis in vivo and for treating diseases or disorders are discussed in further detail below.

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

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

[0127] In some embodiments, the molecules herein, the enantiomers, diastereomers herein, mixtures thereof, hydrates thereof, deuterated analogs thereof, salts thereof, pharmaceutically acceptable salts thereof, compositions comprising any of these, or pharmaceutical compositions comprising any of these, can be used to treat cancer or neoplastic conditions. In some embodiments, the cancer or neoplastic condition can be skin cancer, sarcoma, melanoma, carcinoma, mesenchymal cancer, breast cancer, prostate cancer, cervical cancer, or ovarian cancer, kidney cancer, renal cancer, liver cancer, renal cancer, non-clear cell renal cancer, or clear cell renal cancer. In some embodiments, the molecules herein, the enantiomers, diastereomers herein, mixtures thereof, hydrates thereof, deuterated analogs thereof, salts thereof, pharmaceutically acceptable salts thereof, compositions comprising any of these, or pharmaceutical compositions comprising any of these, can be used to treat SWI / SNF complex-deficient cancers. In some embodiments, the SWI / SNF complex deficient cancer may be skin cancer, sarcoma, melanoma, mesenchymal cancer, breast cancer, prostate cancer, cervical cancer or ovarian cancer, kidney cancer, renal cancer, liver cancer, carcinoma, liver cancer, 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 a tissue is selected from Table 1. Exemplary ferroptosis inducers are provided in Table 1 along with their formulas, chemical identifiers, and respective targets and / or mechanisms of action. [Table 1-1] [Table 1-2] [Table 1-3]

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

[0130] In some embodiments, the ferroptosis inducer, which may be a second active agent or second therapeutic agent, may be (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jacalic acid, buthionine sulfoximine (BSO), trigonelline, glutamate, sulfasalazine, auranofin, brusatol, sorafenib, sorafenib-d3, sorafenib tosylate, trigonelline, FIN56, FINO2, CIL56, dihydroisotanshinone I, GPX4-IN-3, or an analog, salt, or derivative thereof. In some embodiments, the agents in Table 1 are pharmaceutically acceptable salt forms of small molecules.

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

[0132] In some embodiments, the biological activity of the compounds described herein is measured by IC 50 It may be measured as an IC value. 50 The value can be between 0.0001 and 0.01, 0.01 and 0.1, 0.1 and 1, or 1 and 10 mM. In some embodiments, the IC 50 The EC 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 is measured by an EC 50 It may be measured as an EC value or an EC 50 The value can be between 0.0001 and 0.01, 0.01 and 0.1, 0.1 and 1, or 1 and 10 mM. 50 The 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 Table 2, the following meanings apply: +++ indicates an IC of GCL less than or equal to 0.02 mM 50 is in the range ++ indicates IC of GCL from >0.02mM to 2mM 50 is in the range + IC of GCL higher than 2 mM 50 is in the range "nd" means no data collected @ is a cell-killing EC50 greater than or equal to 1 mM 50 is ! indicates cell-killing EC<1mM 50 is "nd" indicates that data was not collected The testing protocol for bioactivity data is described in Example 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18] [Table 2-19] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10]

[0133] (2) Priming agent 1. A method of inducing targeted cell death in vivo in mammalian tissue, the method comprising: (a) contacting the mammalian tissue with a priming agent; (b) contacting the mammalian tissue with an in vivo effective amount of a ferroptosis-inducing agent for a duration of at least four hours, wherein the ferroptosis-inducing agent induces in vivo targeted cell death in mammalian tissue, if a plurality of cells in the mammalian tissue are responsive to the priming agent as determined by detecting: (i) a plurality of cells comprising a concentration of selenium that is higher than the concentration of selenium in the mammalian tissue prior to contact with the priming agent; (ii) a plurality of cells comprising a concentration of iron that is higher than the concentration of iron in the mammalian tissue prior to contact with the priming agent; (iii) a plurality of cells comprising a concentration of PUFAs that is higher than the concentration of PUFAs in the mammalian tissue prior to contact with the priming agent; (iv) a plurality of cells expressing one or more markers indicative of a mesenchymal state; (v) a plurality of cells comprising a peroxidative potential index (PI) that is higher than the PI in the mammalian tissue prior to contact with the priming agent; and / or (vi) hyperproliferation of cells in the mammalian tissue. Provided herein are methods for inducing targeted cell death in mammalian tissue in vivo. In some embodiments, a priming agent is administered prior to administration of a ferroptosis-inducing agent provided herein. In some embodiments, the priming agent is administered in vivo, in vitro, or ex vivo. A priming agent is an agent that prepares a subject or tissue for administration of a therapeutically effective dose of a ferroptosis-inducing agent provided herein. In some embodiments, the priming agent is a ferroptosis inhibitor. In some embodiments, the priming agent sensitizes cells in the tissue to ferroptosis. In some embodiments, the priming agent is a lipophilic antioxidant or a radical scavenger. In some embodiments, the priming agent is a polyunsaturated fatty acid. In some embodiments, the priming agent is an iron chelator. In some embodiments, the priming agent is a lipid peroxidation inhibitor. In some embodiments, the priming agent modulates blood oxygen levels. In some embodiments, the priming agent is a hydroperoxide.In some embodiments, the priming agent is selected from the group consisting of liproxstatin-1, ferrostatin-1, deferoxamine (DFO), iron, selenium, vitamin E, erythropoietin, polyunsaturated fatty acids, N-acetylcysteine, pifithrin-alpha-HBr, and methylnaphthalene-4-propionic acid endoperoxide (MNPE). In some embodiments, the polyunsaturated fatty acid is hexadecatrienoic acid (HTA), alpha-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA, timnodonic acid), heneicosapentaenoic acid (HPA), docosapentaenoic acid (DPA, clupanodonic acid), docosahexaenoic acid (DHA, selenoic acid), or selenoic acid. The priming agent may be selected from the group consisting of carboxylic acid, tetracosahexaenoic acid (nicosinic acid), tetracosapentaenoic acid, linoleic acid (LA), gamma-linolenic acid (GLA), eicosadienoic acid, dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA), docosadienoic acid, adrenic acid (AdA), docosapentaenoic acid (osbond acid), tetracosatetraenoic acid, and tetracosapentaenoic acid. Non-limiting examples of priming agents are provided in Table 4. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[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, drug, or therapeutic agent herein, any enantiomer thereof, any diastereomer thereof, any pharmaceutically acceptable salt thereof, or any deuterated derivative thereof. Further provided herein is a pharmaceutical composition comprising a ferroptosis-inducing agent or compound and a priming agent, or any enantiomer or diastereomer thereof, any pharmaceutically acceptable salt thereof, or any deuterated derivative thereof. In some embodiments, the pharmaceutical composition further comprises a chemotherapeutic agent.

[0135] (3) Additional treatments and cell death inducers In some embodiments, the methods provided herein include administering at least one additional treatment to the subject. In some embodiments, the additional treatment is surgery. In some embodiments, the additional treatment is radiation therapy. In some embodiments, the additional treatment is a nutritional supplement. Non-limiting examples of nutritional supplements include probiotics, selenium, iron, vitamins (e.g., vitamin A, vitamin C, vitamin E), curcumin, fish oil, beta-carotene, hydrogen sulfide, fatty acids, methionine, cysteine, homocysteine, taurine, cystine, or dicysteine. In some embodiments, the nutritional 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 priming agent 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. The chemotherapeutic agent or compound is any agent or compound useful in 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, and Navelbine™ (vinorelbine, 5'-noranhydroblastine). In still other cases, the cancer chemotherapeutic agent includes a topoisomerase I inhibitor, such as a camptothecin compound. As used herein, "camptothecin compounds" includes Camptosar™ (irinotecan HCl), Hycamtin™ (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 further encompasses other cancer chemotherapeutic agents known as alkylating agents that alkylate genetic material in tumor cells. These include, without limitation, cisplatin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, verstine, uracil mustard, chlornaphazin, and dacarbazine. The present disclosure encompasses antimetabolites as chemotherapeutic agents. Examples of these types of agents include cytosine arabinoside, fluorouracil, methotrexate, mercaptopurine, azathioprime, and procarbazine.Additional classes 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, dactinomycin, daunorubicin, mithramycin, mitomycin, mitomycin C, and daunomycin. Numerous liposomal formulations of these compounds are commercially available. The present disclosure further encompasses other cancer chemotherapeutic agents, including, but not limited to, antitumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, ifosfamide, and mitoxantrone.

[0137] The agents disclosed herein may be administered in combination with other anti-tumor agents, including cytotoxic / antineoplastic agents and anti-angiogenic agents. Cytotoxic / antineoplastic agents can be defined as agents that attack and kill cancer cells. Some cytotoxic / antineoplastic agents may be alkylating agents that alkylate genetic material in tumor cells, such as cisplatin, cyclophosphamide, nitrogen mustard, trimethylenethiophosphoramide, carmustine, busulfan, chlorambucil, verstine, uracil mustard, chlornaphazine, and dacarbazine. Other cytotoxic / antineoplastic agents may be antimetabolites for tumor cells, such as cytosine arabinoside, fluorouracil, methotrexate, mercaptopuririne, azathioprine, and procarbazine. Other cytotoxic / antineoplastic agents may be antibiotics, such as doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mitomycin C, and daunomycin. Numerous liposomal formulations of these compounds are commercially available. Still other cytotoxic / antineoplastic agents may be mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine, and etoposide. Miscellaneous cytotoxic / antineoplastic agents include taxol and its derivatives, L-asparaginase, antitumor antibodies, dacarbazine, azacitidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.

[0138] Antiangiogenic agents can also be used. Suitable antiangiogenic agents 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, interferon, interleukin 1 (including α and β), interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1 and -2). Small molecules containing topoisomerases, such as razoxane, a topoisomerase II inhibitor with antiangiogenic activity, can also be used.

[0139] Other anti-cancer agents that can be used in combination with the ferroptosis inducers provided herein include, but are not limited to, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; avastin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bevacizumab; bicalutamide; bilirubin; Santren hydrochloride; Visnafide dimesylate; Bizelesin; Bleomycin sulfate; Brequinar sodium; Bropirimine; Busulfan; Cactinomycin; Calsterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Crisnatol mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin hydrochloride; Decitabine Dexormaplatin; Dezaguanine; Dezaguanine mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin hydrochloride; Droloxifene; Droloxifene citrate; Dromostanolone propionate; Duazomycin; Edatrexate; Eflornithine hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropizin; Epirubicin hydrochloride; Elbrozole; Esorubicin hydrochloride; Estramustine; Estramustine phosphate sodium; Eta Nidazole; etoposide; etoposide phosphate; etopurine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; folinic acid; foskidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II or rIL2), interferon alfa-2a; interferon alfa-2b;Interferon alpha-n1; Interferon alpha-n3; Interferon beta-Ia; Interferon gamma-Ib; Iproplatin; Irinotecan hydrochloride; Lanreotide acetate; Letrozole; Leuprolide acetate; Liarozole hydrochloride; Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melengestrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocalcin; Mitochromin omin); mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisulan; paclitaxel; pegaspargase; periomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; promestane; porfimer sodium; porfiroma Isin;Prednimustine;Procarbazine hydrochloride;Puromycin;Puromycin hydrochloride;Pyrazofurin;Rivopurin;Rogletimide;Safingol;Safingol hydrochloride;Semustine;Simtrazene;Sparphosate sodium;Sparsomycin;Spirogermanium hydrochloride;Spiromustine;Spiroplatin;Streptonigrin;Streptozocin;Sulofenur;Tallysomycin;Tecogalan sodium;Tegafur;Teroxantrone hydrochloride;Temoporfin;Teniposin Do;Teroxylon;Testolactone;Thiamiprine;Thioguanine;Thiotepa;Tiazofurin;Tirapazamine;Toremifene citrate;Trestron acetate;Triciribine phosphate;Trimetrexate;Trimetrexate glucuronate;Triptorelin;Tubrozole hydrochloride;Uracil mustard;Uredep;Vapreotide;Verteporfin;Vinblastine sulfate;Vincristine sulfate;Vindesine;Vindesine sulfate;Binepidine sulfate;Vingrisinate sulfate;Vinleurosine sulfate;Vinorelbine tartrate;Other anticancer drugs include, but are not limited to, 20-epi-1,25-dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol, adzelesin, aldesleukin, ALL-TK antagonists, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, anti-dorsalizing morphogenetic protein-1 (anti-dorsalizing morphogenetic protein-1), and the like. protein-1); antiandrogens, prostate cancer; antiestrogens; antineoplastons; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atlimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxins; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists ;Benzochlorins;Benzoylstaurosporines;Beta-lactam derivatives;Beta-arretin;Betaclamycin B;Betulinic acid;bFGF inhibitors;Bicalutamide;Bisantrene;Bisaziridinylspermine;Bisnafide;Bistraten A;Bizelesin;Brefurate;Bropirimine;Budotitanium;Buthionine sulfoximine;Calcpotriol;Calphostin C;Camptothecin derivatives;Canarypox IL-2;Capecitabine;Carboxamido-amino-triazoles;Carboxamidotriazoles;CaRest M3;CARN700;Cartilage-derived inhibitors;Carzelesin;Casein kinase inhibitors (ICOS);Castanospermine;Cecropin B;Cetrorelix;Chlorin;Chloroquinoxaline sulfonamides;Cicaprost;cis-porphyrins;Cladribine;Clomiphene analogs;ClotrimazoleCollismycin A; Collismycin B; Combretastatin A4; Combretastatin analogs; Conagenin; Clambesidin 816; Crisnatol; Cryptophycin 8; Cryptophycin A derivatives; Curacin A; Cyclopentanthraquinone; Cycloplatam; Cypemycin; Cytarabine octophosphate; Cytolytic factors; Cytostatin; Dacliximab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Dexyphosph Amido;Dexrazoxane;Dexverapamil;Diazicon;Didemnin B;Didox;Diethylnorspermine;Dihydro-5-azacytidine;Dihydrotaxol, 9-;Dioxamycin;Diphenylspiromustine;Docetaxel;Docosanol;Dolasetron;Doxifluridine;Droloxifene;Dronabinol;Duocarmycin SA;Ebselen;Ecomustine;Edelfosine;Edrecolomab;Eflornithine;Elemene;Emiteflur;Epirubicin;Epristeride;Estramustine analogs;Estrogen agonists ;Estrogen antagonists;Etanidazole;Etoposide phosphate;Exemestane;Fadrozole;Fazarabine;Fenretinide;Filgrastim;Finasteride;Flavopiridol;Flezelastine;Fluasterone;Fludarabine;Fluorodaunornithine hydrochloride;Forfenimex;Formestane;Fostriecine;Fotemustine;Gadolinium texaphyrin;Gallium nitrate;Galocitabine;Ganirelix;Gelatinase inhibitors;Gemcitabine;Glutathione inhibitors;Hepsulfam;Heregulin;Hexamethylenebisacetate Amides; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridone; imiquimod; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; ilopract; irsogladine; isobengazole; isohomohalichondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate;Lanreotide; Leinamycin; Lenograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprolide + estrogen + progesterone; Leuprorelin; Levamisole; Liarozole; Linear polyamine analogs; Lipophilic disaccharide peptides; Lipophilic platinum compounds; Lissoclinamide 7; Lobaplatin; Lombricine; Lometerexol; Lonidamine; Losoxantrone; Lovastatin; Loxoribine; Lurtotecan; Lutetium texaphyrin; Rhizophylline; Lytic peptides; Maytansine; Mannostatin A; Marimastat ;Masoprocol;Maspin;Matrilysin inhibitors;Matrix metalloproteinase inhibitors;Menogaril;Melbarone;Meterelin;Methioninase;Metoclopramide;MIF inhibitors;Mifepristone;Miltefosine;Mirimostim;Mismatched double-stranded RNA;Mitoguazone;Mitolactol;Mitomycin analogs;Mitonafide;Mitotoxin fibroblast growth factor-saporin;Mitoxantrone;Mofalotene;Molgramostim;Monoclonal antibodies, human chorionic gonadotropin;Monophosphoryl lipid A+Mycobacterium cell wall sk;Mopidamol;Multidrug resistance gene inhibitors;Multiple tumor suppressors (multiple tumor suppressor)1-based therapy; mustard anticancer drugs; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagressip; naloxone + pentazocine; napavine; naphterpine; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidants; nitric Lurin; O6-benzylguanine; Octreotide; Oxenon; Oligonucleotides; Onapristone; Ondansetron; Ondansetron; Oracin; Oral cytokine inducers; Ormaplatin; Osateron; Oxaliplatin; Oxaunomycin; Paclitaxel; Paclitaxel analogs; Paclitaxel derivatives; Palauamine; Palmitoylrhizoxin; Pamidronate; Panaxytriol; Panomyphen; Parabactin; Pazeliptin;Pegaspargase; Perdecin; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubron; Perfosfamide; Perillyl alcohol; Phenazinomycin; Phenylacetate; Phosphatase inhibitors; Picibanil; Pilocarpine hydrochloride; Pirarubicin; Piritrexim; Prasetin A; Prasetin B; Plasminogen activator inhibitors; Platinum complexes; Platinum compounds; Platinum-triamine complexes; Porfimana; Tritium; Porfiromycin; Prednisone; Propylbis-acridone; Prostaglandin J2; Proteasome inhibitors; Protein A-based immunomodulators; Protein kinase C inhibitors; Protein kinase C inhibitors, microalgae; Protein tyrosine phosphatase inhibitors; Purine nucleoside phospholyase inhibitors; Purpurin; Pyrazoloacridine; Pyridoxylated hemoglobin polyoxyethylene conjugates; RAF antagonists; Raltitrexed; Ramosetron; Ras farnesyl protein transferase inhibitors; Ras inhibitors; Ras-GAP inhibitors; Demethylretiriptin; Rhenium Re186 etidronate; Rhizoxin; Ribozyme; RII retinamide; Rogletimide; Rohitukin; Romurtide; Roquinimex; Rubiginone B1; Ruboxil; Safingol; Saintopine; SarCNU; Sarcophytol A; Sargramostim; Sdi 1 mimetics; semustine; senescence-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction modulator; single-chain antigen-binding protein; sizofiran; sobuzoxane; borocaptate sodium; sodium phenylacetate; sorberol; somatomedin-binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; stromelysin inhibitor; sulfinosine; superactive vasoactive intestinal peptide antagonist antagonist); suradista; suramin; swainsonine; synthetic glycosaminoglycans; talimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; telapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetics; thymalfasin; thymopoietin receptor agonists; thymotrin; thyroid-stimulating hormone; ethyl etiopurinse; tirapazamine; titanocene dichloride; topsentin;These include toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, triciribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, erythrocyte gene therapy, veraresol, veramine, verdins, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoteron, zeniplatin, zilascorub, and zinostatin stimalamer. Any of the foregoing chemotherapeutic agents can be administered at a clinically effective dose. The chemotherapeutic agent can also be administered from about day -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or up to about day 14 after administration of an agent provided herein. In some cases, the subject may have a refractory cancer that does not respond to the chemotherapeutic agent;

[0140] General Methods for Making Pharmaceutical Compounds The compounds described herein can be obtained as amorphous or crystalline solids. The compounds of Formula (I) can be obtained as amorphous 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 may have distinct 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 form of the compounds described herein may be an anhydrate, a hydrate, or a solvate. Lyophilization can be used to obtain the compound as an amorphous solid. It should be further understood that solvates (e.g., hydrates) of the compounds are also contemplated herein. The term "solvate" can refer to a physical association of a compound with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In certain instances, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Furthermore, following their preparation, compounds can be isolated and purified to obtain compositions containing 99% or more by weight ("substantially pure") amounts of the compound of Formula (I), which can then be used or formulated as described herein. Such "substantially pure" compounds are also contemplated herein. Compounds can be prepared in a variety of ways and synthesized using the methods described herein. The reactions and techniques described herein are carried out in solvents appropriate to the reagents and materials employed and suitable for the transformations being performed. Similarly, in the description of synthetic methods set forth below, it should be understood that reaction conditions, including the selection of solvents, reaction atmospheres, reaction temperatures, experimental durations, and workup procedures, can be selected to be standard conditions for the reactions.It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed.

[0141] In some embodiments, the schemes contained herein are "P", "P 1 "," "P 2 "," "P 3 " and the like. Protecting groups herein may be, for example, Boc, mesyl (Ms), tosyl (Ts), nosyl (Ns), benzyl (Bn), benzoyl (Bz), SEM, TMS, TIPS, Cbz, or FMOC. These include conventional protecting groups utilized in organic synthesis. In some embodiments, the schemes included herein include structures containing alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, heteroalkenyl, or heteroalkynyl groups, halogenated derivatives thereof, or combinations thereof, designated as "R" groups. In some examples, R can be, for example, H, linear or branched C1-C 10 Alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C3-C 10 or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, which may be optionally substituted with a linear or branched C1-C6 alkyl, C1-C6 cycloalkyl, halogen, -CF3, or -F.

[0142] In some embodiments, the compounds depicted in the exemplary schemes herein have the following stereochemical configuration: [ka] This representation of the compound is: [ka] This is the same as the compound presented as

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

[0144] Scheme 1 [ka]

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

[0146] Scheme 2 [ka]

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

[0148] Scheme 3 [ka]

[0149] A further scheme outlining a route to compound 532 is shown in Scheme 3. Compound 527 can be reacted with 528 to give compounds such as 529. Treatment of 529 with methanol and a suitable transesterification reagent such as HCl can give compounds such as 530. Alternatively, P in compound 529 can be reacted with 532 to give compounds such as 530. 3 is removed and P 3 = hydrogen, whereupon alkylation of the compound with various alkyl halides in the presence of base, followed by a sulfonation reaction, affords 528. Compound 528 can be reacted with various oxidation reagents to afford the sulfoximine derivative 531, which upon further treatment with reagents such as TFA or HCl removes the amine protecting group to afford compound 532.

[0150] Scheme 4 [ka]

[0151] Scheme 4 provides an alternative route to compound 536. Compound 533 can be reacted directly with a compound such as 534 in the presence of a radical generating reagent such as AIBN to afford coupled intermediate 535. Compound 535 can similarly undergo a sulfur oxidation step and amine deprotection as previously outlined in Schemes 1-3.

[0152] Scheme 5 [ka]

[0153] Scheme 5 demonstrates a process for making heterocyclic-substituted analogs of 542. Reaction of the nitrile-containing compound 357 with an appropriately protected sulfur nucleophile 358 can provide the alkylated analog 539. Treatment of 539 with a reagent such as TMS-azide can provide the tetrazole-substituted intermediate 540. Oxidation of the sulfur to a sulfoximine affords 541, which can be deprotected to the final analog 542.

[0154] Scheme 6 [ka]

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

[0156] Scheme 7 [ka]

[0157] Scheme 7 provides a route for preparing compound 549. Ester 545 can be treated with a direct amide-forming reagent, such as NH in methanol, to give 546. Compound 546 can be further reacted with a dehydrating reagent, such as trifluoroacetic anhydride, to give compounds such as 547. Reaction of 547 with an oxidizing agent, such as PhI(OAc) and ammonium carbamate can give sulfoximine 548. Further treatment of 548 with a reagent capable of removing the amine protecting group can give compound 549.

[0158] Scheme 8 [ka]

[0159] Compound 552 can be prepared from the previously described intermediate 547. Reaction of 547 with reagents such as NaN and ZnBr, which convert the nitrile to a tetrazole, can provide compounds such as 550. Oxidation of the sulfur to a sulfoximine with PhI(OAc) and ammonium carbamate can provide 551, which can be further reacted with an anhydrous acid such as HCl in dioxane to provide 552.

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

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

[0162] Scheme 11 [ka]

[0163] The stereoselective synthesis of compound 566 is shown in Scheme 11. Chiral sulfinamide 561 can be alkylated at sulfur to give intermediate 562. Reaction of 562 with an acid such as TFA affords sulfinamide 563. Subsequent alkylation of 563 with a functionalizing reagent such as 564 affords the fully substituted intermediate 565. Reaction of 565 with an acid such as TFA or HCl affords optically pure 566. Intermediate 565 or a compound of similar structure can be further converted to 571 by first reacting 565 with a selective deprotection reagent to give 567. Protection of the free primary amine (567) to give 568 allows phosphorylation of the sulfoximine nitrogen by reaction with a reagent such as dibenzyl phosphate to give 569. Unmasking of various protecting groups affords the corresponding phosphorylated form of compound 571.

[0164] Scheme 12 [ka]

[0165] Additional methods for the general preparation of compounds of interest in this application are shown in Scheme 12. Reaction of substituted olefins such as 572 with various nucleophiles, such as alkyl cuprates or arylboronic acids, can provide multi-substituted esters such as 573. Treatment of 573 with standard reducing agents, such as LAH or NaBH, can provide alcohol 574. Conversion of 574 to alkylating agents, such as either alkyl halides or alkyl sulfonates, can be achieved under standard conditions. For example, treatment of 574 with MsCl in the presence of a base, such as DIPEA, in a suitable solvent, such as DCM, can provide compounds such as 575. Compound 575 can be reacted with a sulfur-containing reagent 576 in the presence of a base, such as KCO, to provide 577. Treatment of compound 12e with an oxidizing reagent, such as PhI(OAc) and ammonium carbamate, can provide compounds such as 578, which can be further treated with an anhydrous acid, such as HCl in dioxane, to provide compound 579.

[0166] Scheme 13 [ka]

[0167] An alternative variation of compound 582 can be prepared using the methods outlined in Scheme 13. Starting with a compound such as 580, the aryl (or heteroaryl) group can be optionally substituted with a group such as iodide, which facilitates cross-coupling reactions with reagents such as arylboronic acids, to form a compound of formula 581. Compound 581 can be reacted with a reagent such as NaOH or TFA to convert the ester to a carboxylic acid and remove the nitrogen protecting group (P2) to give compound 582.

[0168] Scheme 14 [ka]

[0169] Alternative synthetic methods for variations of compound 590 can be found in Scheme 14. Reaction of an appropriately substituted unsaturated ester such as 583 with a nucleophile such as triazole can form the substituted ester product 584. Further reaction of 584 with a reducing agent such as LAH can form primary alcohol 585, which can be further reacted with an activating agent such as MsCl in the presence of an amine to form a compound such as 586. Compounds such as 586 can be reacted with bis-protected thiol 587 to form dialkyl sulfide product 588. Compound 588 can be reacted with various oxidation reagents to give sulfoximine derivative 589, which can be further treated with reagents such as TFA or HCl to remove the amine protecting group and give compound 590.

[0170] Scheme 15 [ka]

[0171] Additional synthetic methods for variations of compound 598 can be found in Scheme 15. Reaction of an appropriately substituted unsaturated ester such as 591 with a coupling partner such as an arylboronic ester in the presence of a transition metal catalyst such as rhodium can form the substituted ester product 592. Further reaction of 592 with a reducing agent such as LAH can form a primary alcohol 593, which can be further reacted with an activating agent such as MsCl in the presence of an amine to form a compound such as 594 (X = mesylate). Compounds such as 594 can be reacted with a bis-protected thiol 595 to form the dialkyl sulfide product 596. Compound 596 can be reacted with various oxidation reagents to give the sulfoximine derivative 597, which can be further treated with a reagent such as NaOH to remove the acid protecting group (P 3 ) is removed and further treatment with reagents such as TFA or HCl results in the removal of the amine protecting group (P 2 ) can be removed to give compound 598.

[0172] A similar synthetic approach can be used starting from cyclobutyl-substituted conjugated ester 599, which can be reacted with either a boron-containing coupling partner or an alkyl or aryl halide under appropriate coupling conditions, such as iridium / blue light catalysis, to afford intermediate 600. Further transformations similar to those already outlined with respect to Scheme 15 can be used to afford additional compound 601.

[0173] Scheme 16 [ka]

[0174] Scheme 16 illustrates how one skilled in the art can prepare additional compounds by reacting an arylalkene or heteroarylalkene with a thiol 603 in a suitable solvent such as methanol to form an adduct such as 604. Compound 604 can be reacted with various oxidation reagents to provide the sulfoximine derivative 605, which upon further treatment with a reagent such as NaOH, can afford the acid protecting group (P 3 ) is removed and further treatment with reagents such as TFA or HCl results in the amine protecting group (P 2 ) can be removed to give compound 606.

[0175] Scheme 17 [ka]

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

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

[0178] Scheme 18 [ka]

[0179] Additional analogs can be prepared starting with compound 613 by reaction with vinylmagnesium bromide in a suitable solvent such as THF to give 614. Reaction of 614 with 615 in the presence of AIBN can give compounds such as 616. Compound 616 can be reacted with a variety of oxidation reagents to give sulfoximine intermediates which, upon further treatment with a reagent such as NaOH, can remove the acid protecting group (P 3 ) is removed and further treatment with TFA or HCl results in the amine protecting group (P 2 ) can be removed to give compound 617.

[0180] When R is an aryl or heteroaryl optionally substituted with a halogen or 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 compounds 617. It should be understood that these types of reactions can be incorporated at various stages of the synthesis and may depend on cross-reactivity or protecting group modifications.

[0181] Scheme 19 [ka]

[0182] Additional analogs can be prepared starting with compound 618 by reacting the alcohol group with a thiocarbonate-forming reagent such as phenyl chlorothionoformate to give 619. Compound 619 can be further treated with a radical initiator reagent such as AIBN to give the deoxygenated analog 620. Compound 620 can be reacted with various oxidizing reagents to produce sulfoximine intermediates, which can be further treated with a reagent such as NaOH to give the acid protecting group (P 3 ) is removed and further treatment with TFA or HCl results in the amine protecting group (P 2) is removed to afford compound 621. When R is an aryl or heteroaryl optionally substituted with a halogen or 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 621. It should be understood that these types of reactions can be incorporated at various stages of the synthesis and may depend on cross-reactivity or protecting group modification.

[0183] Scheme 20 [ka]

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

[0185] Scheme 21 [ka]

[0186] Additional amide-substituted analogs can be prepared by the routes outlined in Scheme 21. Cyclobutyl ester derivative 625 can be treated with a hydrolysis reagent or an enzyme such as pig 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 various oxidation reagents to generate sulfoximine intermediate 628, which can be further treated with a reagent such as NaOH to remove the acid protecting group (P 3 ) is removed and further treatment with TFA or HCl results in the amine protecting group (P 2 ) can be removed to give compound 629.

[0187] Scheme 22 [ka]

[0188] Sulfone-derived analogs can be prepared according to the methods outlined in Scheme 22. Starting with a readily available intermediate such as dialkyl sulfide 630, treatment with an oxidizing agent such as mCPBA can provide sulfone intermediate 631. Treatment of 631 with an acid-based deprotecting reagent such as HCl in dioxane can provide compound 632. R 1 , R 2 and R 3 It should also be understood that the group R may be functionalized and derivatized at various stages in the process. For example, 1 When is a bromophenyl group, reaction with an arylboronic acid in the presence of a catalyst such as palladium can provide biaryl-substituted analogs.

[0189] Scheme 23 [ka]

[0190] Sulfonamide-derived analogs can be prepared according to the methods outlined in Scheme 23. Starting with a readily available intermediate such as substituted amine 633, reaction with a sulfonyl chloride such as 634 in the presence of base can give compounds such as 635. Treatment of 635 with an acid-based deprotecting reagent such as HCl in dioxane can give compound 636. R 1 , R 2 and R 3 It should also be understood that the group R may be functionalized and derivatized at various stages in the process. For example, 1When is a bromophenyl group, reaction with an arylboronic acid in the presence of a catalyst such as palladium can provide biaryl-substituted analogs.

[0191] Pharmaceutical Composition Provided herein are pharmaceutical compositions comprising 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-inducing agent. In some embodiments, the pharmaceutical composition further comprises a chemotherapeutic agent. In some embodiments, the pharmaceutical compositions provided herein are in a suspension, optionally a uniform suspension. In some embodiments, the pharmaceutical compositions provided herein are in emulsion form. In some embodiments, the pharmaceutical compositions provided herein comprise a salt form of any one of the agents provided herein. In some embodiments, the salt is a methanesulfonate salt.

[0192] Similarly, provided herein is 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 pharmaceutically acceptable salt, additive and / or carrier to form a pharmaceutical composition.Pharmaceutical salt, additive and carrier can be selected based on the route of administration, the location of target tissue and the time course of drug delivery.Pharmaceutical acceptable carrier or additive can include solvent, dispersion medium, coating, antibacterial and antifungal agent, isotonic agent and absorption delaying agent, etc., that are compatible with pharmaceutical administration.

[0193] In some embodiments, the pharmaceutical composition is in solid, semisolid, liquid, or gas (aerosol) form. Suitable dispersing or wetting agents and suspending agents may be used to formulate injectable preparations, such as sterile injectable aqueous or oily suspensions, according to known techniques. Sterile injectable preparations may also be injectable sterile solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are used as solvents or suspending media. For this purpose, any non-irritating, fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable preparations. Injectable preparations 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 medium before use.

[0194] Exemplary carriers and additives can include dextrose, sodium chloride, sucrose, lactose, cellulose, xylitol, sorbitol, malitol, gelatin, polymers, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and any combination thereof. In some embodiments, the additive, such as dextrose or sodium chloride, can be present in a percentage of 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 encapsulated or unencapsulated conjugate may be mixed with at least one inert pharmaceutically acceptable excipient or carrier or diluent, such as sodium citrate or dicalcium phosphate, and / or (a) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) a binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; (c) a humectant, such as glycerol; (d) agar, carbonate, or the like. They are mixed with disintegrating agents such as calcium, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarders such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (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 can be either film-coated or enteric-coated according to methods known in the art.Liquid preparations for oral administration can be, for example, in the form of solution, syrup or suspension, or liquid preparations can be presented as a dry product for reconstitution with water or other suitable vehicle before use.Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable carriers and additives, for example, 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, ethyl alcohol or fractionated vegetable oils; and preservatives, for example, methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid.Preparation can also contain buffer salts, flavoring agents, coloring agents and / or sweeteners as appropriate.If desired, preparations for oral administration can be suitably formulated to cause controlled release of active compound.

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

[0198] The ferroptosis inducing agents provided herein can be formulated as rectal compositions, e.g., suppositories or retention enemas, e.g., containing a conventional suppository base, e.g., cocoa butter or other glycerides, or a gel-forming agent such as carbomer.

[0199] Pharmaceutical compositions can also be administered via controlled release formulations and / or delivery devices (see, eg, US Pat. No. 5,733,566).

[0200] Various delivery vehicles are known and can be used to administer the ferroptosis-inducing agents provided herein, including, but not limited to, liposomes, microparticles, microcapsules, nanoparticles, vectors, and encapsulation in recombinant cells. Liposomes and / or nanoparticles can also be used in conjunction with the administration of the compositions herein. Liposomes are formed from phospholipids that disperse in an aqueous medium and spontaneously form multilamellar concentric bilayer vesicles (also called multilamellar vesicles (MLVs)). MLVs generally have diameters of 25 nm to 4 μm. Sonication of MLVs results in the formation of small unilamellar vesicles (SUVs) with diameters ranging from 200 to 500 angstroms, containing aqueous solution within their cores.

[0201] When dispersed in water, phospholipids can form various structures other than liposomes, depending on the lipid to water molar ratio. At low ratios, liposomes form. The physical characteristics of liposomes depend on pH, ionic strength, and the presence of divalent cations. Liposomes exhibit low permeability to ionic and polar substances, but at elevated temperatures, they can undergo a phase transition that significantly alters their permeability. The phase transition involves a change from a tightly packed, ordered structure known as the gel state to a loosely packed, less ordered structure known as the fluid state. This occurs at a specific phase transition temperature and results in increased permeability to ions, sugars, and drugs.

[0202] Liposomes interact with cells through a variety of mechanisms: endocytosis by phagocytic cells of the reticuloendothelial system, such as macrophages and neutrophils; adsorption to cell surfaces through either nonspecific weak hydrophobic or electrostatic forces or specific interactions with cell-surface components; fusion with the plasma membrane by insertion of the liposome lipid bilayer into the plasma membrane, with concomitant release of the liposomal contents into the cytoplasm; and transfer of liposomal lipids to or from the plasma membrane or subcellular membrane without any association of the liposomal contents. Varying liposome formulations alter the mechanisms at work, but more than one mechanism may operate simultaneously. Nanocapsules can generally entrap compounds in a stable and reproducible manner. To avoid side effects due to intracellular polymer overload, such ultrafine particles (approximately 0.1 μm in size) should be designed using polymers that can be degraded in vivo. Biodegradable polyalkyl-cyanoacrylate nanoparticles can also be used as delivery vehicles.

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

[0204] Suitable pharmaceutical formulations of ferroptosis inducers for transdermal application include an effective amount of the agent and a carrier. The carrier comprises an absorbable pharmacologically acceptable solvent to support passage through the skin of a subject. For example, a transdermal device is in the form of a bandage or patch, comprising a backing member, a reservoir containing the compound, optionally with a carrier, a rate-controlling barrier for delivering the compound to the host's skin at a controlled, predetermined rate over a prolonged period of time, and a means for fixing the device to the skin. Matrix transdermal formulations may also be used. Suitable formulations for topical application, for example, to the skin and eyes, are preferably aqueous solutions, ointments, creams, or gels well known in the art. The formulation may contain a solubilizer, stabilizer, tonicity enhancer, buffer, and preservative.

[0205] In certain embodiments, provided herein is ferroptosis inducer formulated as depot composition.This long-acting formulation can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.Ferroptosis inducer can be formulated with suitable polymeric material or hydrophobic material (for example, as emulsion in acceptable oil), ion exchange resin, biodegradable polymer, or as poorly soluble derivative, for example, as poorly soluble salt.

[0206] In some embodiments, one or more agents provided herein are formulated as a pharmaceutical food composition (also referred to as a medical food). The food composition may be for consumption by a mammal, e.g., a human or non-human mammal. The agents provided herein may be formulated as a dietary supplement or a medical food. In some embodiments, the agents provided herein are administered with a food ingredient. The food ingredient is any product, composition, or component of food known to have or disclosed to have a nutritional effect. Food can include various meats (e.g., beef, pork, poultry, fish, etc.), dairy products (e.g., milk, cheese, eggs), fruits, vegetables, grains, bread, etc., and their components. Food can be fresh or preserved, for example, by canning, dehydrating, freezing, or smoking. Food can be provided raw, unprepared, and / or natural, or cooked, prepared, and / or combined. In some embodiments, the food ingredient is selected from the group consisting of fat, carbohydrate, protein, fiber, nutritional balancing agent, and mixtures thereof. In some embodiments, the pharmaceutical food compositions provided herein further comprise one or more of a protein or an amino acid. In some embodiments of any of the aspects, the pharmaceutical food compositions further comprise adenine, one or more vitamins (e.g., vitamin E), potassium, fatty acids, and / or calcium carbonate.

[0207] How the drug is administered Methods for administering a therapeutic regimen to a subject having a disease or disorder (e.g., cancer, autoimmune disease, or fibrosis) may be provided herein. In some embodiments, the administering step is sustained administration of a therapeutically effective amount of a ferroptosis-inducing agent. In some embodiments, the sustained administration of the ferroptosis-inducing agent is at least about 10 ng / mm in tissue for a period of at least 4 hours. 2the tissue in an amount sufficient to achieve a distribution of the ferroptosis-inducing agent in the tissue adjacent to the administration site, thereby inducing ferroptosis in the tissue. In some embodiments, the sustained administration further forms a gradient of a subtherapeutic amount of the ferroptosis-inducing agent within the tissue adjacent to the administration site. In some embodiments, the sustained administration of the ferroptosis-inducing agent comprises an additional administration step. In some embodiments, the ferroptosis-inducing agent is administered more than once. In some embodiments, the administering step is via a system provided herein. In some embodiments, the administering step is local administration within the 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 step comprises contacting the mammalian tissue with a priming agent and contacting the mammalian tissue with an effective amount of the ferroptosis-inducing agent provided herein, wherein the ferroptosis-inducing agent induces targeted cell death in the mammalian tissue in vivo. In some embodiments, the administering step is local administration or systemic administration. In some embodiments, 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.

[0208] In some cases, the drug or drug combination provided herein is administered as a unit dosage form. Many drugs can be orally administered as liquid, capsule, tablet or chewable tablet. The oral route is the most convenient, usually the safest and cheapest, and therefore the most commonly used route. However, because it is the way that drugs typically travel through the digestive tract, there are limitations. For orally administered drugs, absorption can begin in the mouth and stomach. However, most drugs are usually absorbed from the small intestine. Drugs pass through the intestinal wall and travel to the liver before being transported to their target site via the bloodstream. The intestinal wall and liver chemically modify (metabolize) many drugs, reducing the amount of drug that reaches the bloodstream. Therefore, these drugs are often given in smaller doses to produce the same effect when injected intravenously.

[0209] In some embodiments, the agents provided herein are formulated for oral administration. In some embodiments, the agents provided herein are formulated for administration / use in administration by subcutaneous, intradermal, intramuscular, inhalation, intravenous, intraperitoneal, intracranial, intrathecal, intratumoral, or oral routes. In the subcutaneous route, a needle is inserted into the fatty tissue just below the skin. After the drug is injected, it then moves to small blood vessels (capillaries) and is carried by the bloodstream. Alternatively, the drug can reach the bloodstream through lymphatic vessels. When a larger amount of drug product is needed, the intramuscular route is preferred over the subcutaneous route. Because the muscle is under the skin and fatty tissue, a longer needle is used. The drug is usually injected into the muscles of the upper arm, thigh, or buttocks. How quickly the drug is absorbed into the bloodstream depends in part on the blood supply to the muscle. The less blood supply there is, the longer it takes for the drug to be absorbed. For the intravenous route, a needle is inserted directly into a vein. The drug-containing solution may be given in a single dose or by continuous infusion. For infusion, the solution is moved by gravity (from a collapsible plastic bag) or, more commonly, by an infusion pump through thin, flexible tubing to a tube (catheter) inserted into a vein, usually in the forearm. In some cases, the drug or therapeutic regimen is administered as an infusion. The infusion can be carried out over a period of time. For example, the infusion can be for a period of about 5 minutes to about 5 hours, over a period of about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 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 rapidly and precisely deliver a dose throughout the body with sufficient control. Intravenous administration is also used for irritating solutions that would cause pain and damage tissue if administered via subcutaneous or intramuscular injection. Intravenous injections can be more difficult to administer than subcutaneous or intramuscular injections, especially if the person is obese, as it can be difficult to insert a needle or catheter into a vein. When administered intravenously, drugs are delivered immediately to the bloodstream and tend to take effect more quickly than when administered via any other route. Therefore, medical professionals closely monitor people who receive intravenous injections for signs that the drug is working or causing unwanted side effects. Similarly, the effects of drugs administered via this route tend to last for a shorter period of time. Therefore, some medications must be administered via continuous infusion to maintain consistent effects. In 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 often used to make the injection site painless. This route is used when a drug needs to have a rapid or local effect on the brain, spinal cord, or the layers of tissue that cover them (meninges), for example, to treat infections of these structures.

[0211] For administration by inhalation, the ferroptosis inducer provided herein can be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. For pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges, for example, gelatin, can be formulated to contain a powder mix of the compound and a suitable powder base, for example, lactose or starch, for use in an inhaler or insufflator. Medicaments administered by oral inhalation can be atomized into droplets smaller than those administered by nasal route, so that the drug can pass through the windpipe (trachea) and enter the lungs. How deep the drug enters the lungs depends on the size of the droplets. Smaller droplets penetrate deeper, thereby increasing the amount of drug absorbed. Within the lungs, the drug is absorbed into the bloodstream.

[0212] Drugs that are applied to the skin are usually used for their local effect, and therefore are most commonly used to treat superficial skin disorders such as psoriasis, eczema, skin infections (viral, bacterial and fungal), itching and dry skin.Drugs are mixed with inactive substances.Depending on the consistency of inactive substances, formulations can be ointments, creams, lotions, liquids, powders or gels.

[0213] In some cases, treatment regimens can be administered according to the subject's weight. For subjects who are determined to be obese (BMI>35), it may be necessary to use actual weight. BMI is calculated as follows: BMI = weight (kg) / [height (m)] 2 It is calculated by:

[0214] In some cases, the treatment regimen may be administered with a carrier or additive. The ferroptosis inducer provided herein may be administered sequentially or simultaneously with one or more of the second agents, either by the same administration route or by different administration routes. When administered sequentially, the time between administrations is selected to provide benefits, particularly to the therapeutic efficacy and / or safety of the combined treatment. In certain embodiments, the agent provided herein may be administered first, and then the second agent, or alternatively, the second agent may be administered first, and then the agent of the present disclosure (e.g., the ferroptosis inducer of Table 1) is administered. By way of example and not limitation, the time between administrations is about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 16 hours, or about 20 hours. In certain embodiments, the period between administrations is further about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days. In some embodiments, the period between administrations is about 1 week, 2 weeks, 3 weeks, or 4 weeks, or longer. In some embodiments, the period between doses is about one or two months, or longer.

[0215] In some embodiments, the ferroptosis inducing agent provided herein is contacted with mammalian tissue for at least about 4 hours, at least about 6 hours, at least about 10 hours, at least about 12 hours, at least about 14 hours, at least about 16 hours, at least about 18 hours, at least about 20 hours, at least about 22 hours, at least about 24 hours, at least about 26 hours, at least about 28 hours, at least about 30 hours, at least about 36 hours, at least about 48 hours, or up to 72 hours. In some embodiments, the ferroptosis inducing agent provided herein is contacted with mammalian tissue for about 4 hours. In some embodiments, the ferroptosis inducing agent provided herein is contacted with mammalian tissue for about 6 hours. In some embodiments, the ferroptosis inducing agent provided herein is contacted with mammalian tissue for about 10 hours. In some embodiments, the ferroptosis inducing agent provided herein is contacted with mammalian tissue for about 12 hours. In some embodiments, the ferroptosis inducing agent provided herein is contacted with mammalian tissue for about 24 hours. In some embodiments, the ferroptosis-inducing agent provided herein is contacted with the mammalian tissue for about 48 hours. In some embodiments, the ferroptosis-inducing agent provided herein is contacted with the mammalian tissue for about 72 hours.

[0216] When administered simultaneously, the agents can be administered separately and simultaneously with the second agent by the same or different route, or can be administered in a single pharmaceutical composition by the same route. In certain embodiments, the amount and frequency of administration of the second agent can be the standard dosage and frequency used for the particular compound.

[0217] Dosing and tissue distribution The methods provided herein include administering to a subject an effective amount of a drug or pharmaceutical composition provided herein to induce ferroptosis in a tissue in vivo. Drugs and pharmaceutical compositions for administration to a subject in need thereof may be formulated in dosage unit form for ease of administration and dosage uniformity. A dosage unit form is a physically discrete unit of a composition provided herein appropriate for the subject being treated. However, it will be understood that the total amount of a composition provided herein to be used will be determined by the attending physician within the scope of sound medical judgment. For any composition provided herein, a therapeutically effective dose can be initially estimated either 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 a desired concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. The therapeutic efficacy and toxicity of the compositions provided herein can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, for example, ED. 50 (the dose that is therapeutically effective in 50% of the population) and LD 50 (the dose that is lethal to 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, and the therapeutic index is defined as the LD 50 / ED 50 Therapeutic indices can be expressed as a ratio of 0 to 1. In some embodiments, pharmaceutical compositions that exhibit large therapeutic indices can be useful. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for human use.

[0218] A typical human dose of an agent provided herein (e.g., a ferroptosis inducer) may be about 10 μg / kg body weight / day to 10,000 mg / kg / day. In some embodiments, the dose of an agent provided herein is about 0.1 mg / kg to about 1000 mg / kg, 1 mg / kg to 1000 mg / kg, 1 mg / kg to 800 mg / kg, about 1 mg / kg to about 700 mg / kg, about 2 mg / kg to about 500 mg / kg, about 3 mg / kg to about 400 mg / kg, 4 mg / kg to about 300 mg / kg, or about 5 mg / kg to about 200 mg / kg. In certain embodiments, a suitable dosage of the agent is 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, 20 ... The dose may be 0 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, or up to 9,600 mg / kg. In some embodiments, the dose of an agent provided herein is about 100 mg / kg / day to about 6,400 mg / kg / day, administered four times daily. In some embodiments, the dose of an agent provided herein is about 50 mg / kg / day to about 25 mg / kg / day. In some embodiments, the dose of the agents provided herein is about 400 mg / kg / day to about 800 mg / kg / day. In certain embodiments, the dose of the agent can be administered once daily or can be divided into subdoses and administered in multiple doses, for example, two, three, or four times daily.

[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, or 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, or up to 100 μg.

[0220] In some embodiments, the agents provided herein are at least about 0.1 micromolar (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 In some embodiments, the agent provided herein is administered at a concentration of at least 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, or up to 1 mM. In some embodiments, the agent provided herein is administered at a concentration of at least about 0.1 μM to about 500 μM. In some embodiments, the agent provided herein is administered at a concentration of at least about 1 μM to 500 μM. In some embodiments, the agent provided herein is administered at a concentration of at least about 0.1 μM to 10 μM. In some embodiments, the agent provided herein is administered at a concentration of at least about 1 μM to 10 μM.

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

[0222] In some embodiments, the ferroptosis inducer provided herein is orally administered.In some embodiments, the ferroptosis inducer provided herein is at least about 20mg / kg, about 25mg / kg, about 30mg / kg, about 35mg / kg, about 40mg / kg, about 45mg / kg, about 50mg / kg, about 60mg / kg, about 70mg / kg, about 80mg / kg, about 90mg / kg, about 100mg / kg, about 200mg / kg, about 300mg / kg, about 400mg / kg The ferroptosis inducer provided herein is orally administered at a concentration of about 25 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, or up to about 2500 mg / kg. In some embodiments, the ferroptosis inducer provided herein is orally administered once a day at a concentration of about 25 mg / kg. In some embodiments, the ferroptosis inducer provided herein is orally administered twice a day at a concentration of about 25 mg / kg. In some embodiments, the ferroptosis inducer provided herein is orally administered at a concentration of about 1300 mg / kg / day. In some embodiments, the ferroptosis-inducing agents provided herein are orally administered at a concentration of about 2400 mg / kg / day.

[0223] The methods provided herein can further include characterizing or measuring the distribution of the agent in the target tissue. The distribution of the agent provided herein can be measured in millimeters per square millimeter (mm) of tissue. 2 ) or cubic millimeters (mm 3 For example, in the case of local administration of a drug to a tumor, the tissue is approximately 6-7 mm in diameter, 36-42 mm in diameter, and 2 or 216~294mm 3The data obtained from animal studies can be used to formulate the extent of drug distribution in mammalian tissues. Methods for determining the tissue distribution of drugs or agents include, for example, mass spectrometry, chromatography, imaging techniques and immunoassays. The distribution of the drugs provided herein can be determined using the system provided herein.

[0224] In some embodiments, the tissue is administered a therapeutic amount of a ferroptosis inducer, compound, any of the above enantiomers, any of the above diastereomers, any of the above pharmaceutically acceptable salts, or any of the above deuterated derivatives, wherein administering comprises providing the ferroptosis inducer to the tissue in an amount sufficient to achieve a desired drug distribution. In some embodiments, the agents, compounds, any of the above enantiomers, any of the above diastereomers, any of the above pharmaceutically acceptable salts, or any of the above deuterated derivatives provided herein have a concentration of 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 2or 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 2 or 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, any of the enantiomers, any of the diastereomers, any of the pharmaceutically acceptable salts, or any of the deuterated derivatives provided herein achieve tissue distribution of 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 3or 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 / mm 3 or more, up to 500 ng / mm 3 achieve tissue distribution of

[0225] In some embodiments, the agent, compound, any of the above-mentioned enantiomers, any of the above-mentioned diastereomers, any of the above-mentioned pharmaceutically acceptable salts, or any of the above-mentioned deuterated derivatives provided herein is administered at least about once a day, twice a day, three times a day, four times a day, or five times a day. In some embodiments of any of the aspects, the ferroptosis inducer is administered at least about every week, at least about every two weeks, or at least about every three 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., local administration to the tissue in vivo 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 additives, and the possibility of co-use with other therapeutic treatments.

[0226] efficacy The therapeutic efficacy of the agents and / or pharmaceutical compositions provided herein can be determined by assessing and comparing a patient's symptoms and quality of life before and after administration. Such methods are applicable regardless of the mode of administration. In some embodiments, pre-administration refers to assessing a patient's symptoms and quality of life before the start of treatment, and post-administration refers to assessing a 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, or 20 weeks after the start of treatment. In some embodiments, pre-administration refers to assessing a patient's symptoms and quality of life before the start of treatment, and post-administration refers to assessing a patient's symptoms and quality of life up to 52 weeks after the start of treatment. In certain embodiments, post-administration assessment is performed about 2-8, 2-6, 4-6, or 4 weeks after the start of treatment. In certain embodiments, the patient's symptoms (e.g., symptoms associated with cancer, fibrosis, or autoimmune disease) and quality of life before and after administration are assessed clinically and by questionnaire assessment.

[0227] The agents and methods provided herein can be used to reduce the proliferation or survival of cancer cells in vivo or in vitro.Methods for assessing tumor progression or cell proliferation are known in the art.In some embodiments, the overall response is assessed from the response assessment (based on tumor burden) at each time point as follows: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must have a short axis reduction to <10mm. Partial response (PR): At least a 30% reduction in the sum of the diameters of the target lesions, relative to the baseline sum diameter. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of the target lesions relative to the lowest sum at the time of study (this includes the baseline sum if it is the lowest at the time of study). 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 also constitutes progression.) Stable Disease (SD): Neither sufficient regression to qualify for PR nor sufficient growth to qualify for PD, based on the smallest total diameter during the study.

[0228] In some embodiments, in vitro cell proliferation assay is used to evaluate the efficacy of one or more ferroptosis inducers provided herein.Compositions and methods provided herein cause the proliferation or survival of multiple cells to decrease.For example, after treatment with one or more agents provided herein, cell proliferation or survival is reduced by 5% or more (for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) compared to the cell proliferation or survival before treatment.

[0229] In some embodiments, animal models are used to evaluate the efficacy of one or more ferroptosis inducers provided herein in vivo. The ferroptosis inducers and methods provided herein can cause a reduction in the size or volume of over-proliferating tissue (e.g., tumor). For example, the tissue size after treatment is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) compared to its size before treatment. The size of tissue (e.g., tumor) can be measured by any reproducible measurement means. The size of tissue may be measured as tumor diameter or by any reproducible measurement means. Ferroptosis inhibitors (e.g., agents in Table 2 or Table 3) may be used to determine the efficacy of a particular test agent (also referred to herein as an active agent) for inducing ferroptosis in tissue. For example, a combination of a ferroptosis inhibitor (e.g., liproxstatin-1) paired with a ferroptosis inducer can be used to determine whether a test agent targets a protein or nucleic acid involved in the ferroptosis pathway (see FIG. 1). Further provided herein is a method for rescuing one or more cells from cell death and / or ferroptosis in vivo, comprising administering a ferroptosis inhibitor to a subject. In some embodiments, the method further comprises administering a ferroptosis inducer. Further provided herein is a method for screening a plurality of cells in a tissue for ferroptosis susceptibility, 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 or test agent in Table 1. 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-inducing agent is any agent listed in Table 2 or Table 3.In some embodiments, the ferroptosis inhibitor is liproxstatin-1. In some embodiments, the one or more parameters that indicate ferroptosis are PUFA concentration, PI index, modulation of the expression of markers of mesenchymal cell state, or modulation of iron or selenium concentration. The screening method provided herein can be easily scaled up for high-throughput analysis, which allows evaluation or prediction of the ferroptosis-inducing activity of test agents. Similarly, the screening method can be carried out in the animal models discussed above in the presence and absence of ferroptosis inhibitors.

[0230] Treating disease or disorder (e.g., cancer) can also result in a reduction in the number of hyperproliferative tissues (e.g., tumors). For example, the number of hyperproliferative tissues or tumors after treatment is reduced by 5% or more (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) compared to the number before treatment. The number of tumors can be measured by any reproducible measurement means. The number of tumors can be measured by counting tumors visible to the naked eye or at a specific 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 leukocytes in tumor microenvironment. In some embodiments, leukocytes specifically target cancer cells with high PUFA concentration compared to normal cells.

[0231] Treating cancer can reduce the number of metastatic nodules in other tissues or organs away from the primary tumor site.For example, the number of metastatic nodules after treatment is reduced by 5% or more (for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) compared to the number before treatment.The number of metastatic nodules can be measured by any reproducible measuring means.The number of metastatic nodules can be measured by counting the metastatic nodules that are visible to the naked eye or at a specific magnification (for example, 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 with the present disclosure compared to a population of untreated subjects. For example, the average survival time is extended by more than 30 days (more than 60 days, more than 90 days, more than 120 days, or more). The increase in the average survival time of a population can be measured by any reproducible means. The increase in the average survival time of a population can be measured, for example, by calculating the average length of survival of a population after the start of treatment with a compound of the present disclosure. The increase in the average survival time of a population can also be measured, for example, by calculating the average length of survival of a population after the completion of the first round of treatment with a compound of the present disclosure.

[0233] Treating disease or disorder (for example, cancer) can also result in a reduction in the mortality rate of the treated population compared with the untreated population.For example, the mortality rate is reduced by more than 2% (for example, more than 5%, more than 10%, more than 25% or more).The reduction 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 of the population per unit time after the start of treatment with the compound of the present disclosure.The reduction in the mortality rate of the population can also be measured by, for example, calculating the average number of disease-related deaths of the population per unit time after the completion of the first round of treatment with 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 compared to the number before treatment. In some embodiments, after contact with mammalian tissue or administration of a ferroptosis inducer, cell death can be detected at the time of contacting or after contacting the mammalian tissue with the ferroptosis inducer. 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 compared to the number before treatment.

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

[0236] In some embodiments, the subject has, is suspected of having, or is at risk of developing a disease or condition associated with abnormal angiogenesis or vasculogenesis. Diseases or conditions associated with abnormal angiogenesis or vasculogenesis 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, preneoplastic lesions, intraepithelial carcinoma, and cancer. In some embodiments, the subject has, is suspected of having, or is at risk of developing an autoimmune disease. Non-limiting examples of related autoimmune diseases include rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, oral hairy leukoplakia, and psoriasis. In some embodiments, the subject has, is suspected of having, or is at risk of developing fibrosis. Non-limiting examples of diseases and conditions associated with fibrosis include keloid scars, hypertrophic scars, systemic sclerosis, pulmonary arterial hypertension, cardiac fibrosis, hypertrophic cardiomyopathy, valvular disease, myelofibrosis, myelodysplastic syndromes, chronic myeloid leukemia, portal hypertension, hepatocellular carcinoma, retroperitoneal fibrosis, intestinal fibrosis, intestinal disease, subretinal fibrosis, epiretinal fibrosis, cystic fibrosis, emphysema, pancreatic fibrosis, chronic pancreatitis, ductal obstruction, arthrofibrosis, renal fibrosis, nephrogenic systemic fibrosis, renal anemia, chronic kidney disease, Dupuytren's disease, Ledderhose disease (plantar fibromatosis), primary biliary cholangitis (PBC), non-alcoholic steatohepatitis (NASH), scleroderma, diabetic neuropathy, hypertensive nephrosclerosis, transplant nephropathy, liver 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 precancerous 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 a 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 B-Raf proto-oncogene, serine / threonine kinase (BRAF) mutation. 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 renal carcinoma. 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); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, adenocarcinoma of the breast, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; connective tissue cancer; epithelial carcinoma; ependymoma; endothelial cancer (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); familial 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), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancer (e.g., leukemias such as acute lymphocytic 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));Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., 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 longitudinal lymphoma lymphomas such as sarcoid B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, B-cell NHL such as precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma); and precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), T-cell NHL, such as angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma; a mixture of one or more of the above leukemias / lymphomas; and multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, Renal cell carcinoma, clear cell renal carcinoma, non-clear cell renal carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle carcinoma; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPDs) (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; neurofibromas (e.g., type 1 or type 2 neurofibromatosis (NF), schwannoma);Neuroendocrine cancers (e.g., gastrointestinal pancreatic neuroendocrine tumors (GEP NETs), carcinoid tumors); osteosarcomas (e.g., bone cancer); ovarian cancers (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancers (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet cell tumors); penile cancers (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumors (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); colorectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancers (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine bowel cancer (e.g., appendix cancer); soft tissue sarcomas (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., Paget's disease of the vulva);

[0239] Provided herein is a method for administering a ferroptosis inducer to tissue, wherein the tissue comprises various cell types.In some embodiments, the tissue comprises a heterogeneous population of cells, and the heterogeneous population of cells comprises at least one of precancerous cells and non-cancerous cells.In some embodiments, the tissue comprises a heterogeneous population of cells, and the heterogeneous population of cells comprises a population of immune cells.

[0240] Provided herein is a method for inducing immune cell recruitment to tumors, comprising administering a ferroptosis inducer provided herein to a subject by any of the methods provided herein. In some embodiments, the administering step is a sustained administration for at least about 10 hours, thereby recruiting immune cells to the tumor site. In some embodiments, the immune cells are leukocytes. In some embodiments, after contact with mammalian tissue or administration of the ferroptosis inducer, the recruitment of immune cells can be detected at or after contacting the mammalian tissue with the ferroptosis inducer. In some embodiments, the administering step reduces tumor size and / or increases the number of leukocytes in the tumor.

[0241] system

[0010] Provided herein is a system for delivering the ferroptosis inducer or iron-dependent cell death inducer provided herein.

[0011] Further provided herein is a system for inducing ferroptosis in vivo, the system comprising: (a) a cylindrical support structure having at least one microwell formed on or within the support structure; (b) a microdose of a ferroptosis inducer in the at least one microwell; and (c) an implantable microdevice configured for localized administration to tissue, the microdose comprising a compound release mechanism for sustained administration to control the release of the ferroptosis inducer from the microwell, wherein the microdose of the ferroptosis inducer forms a gradient of a subtherapeutic dose of the ferroptosis inducer at the administration site within the tissue for a duration of at least 4 hours; the microdevice is configured to be implanted into the tissue using a catheter, cannula, or biopsy needle; and the microdevice is further configured to release the ferroptosis inducer from the at least one microwell to the administration site within the apoptosis-resistant tissue adjacent to the at least one microwell.

[0242] Further provided herein is a system for identifying ferroptosis induction in an animal model, comprising: (a) an animal model containing a target tissue of interest; (b) a microdevice configured to allow implantation into the tissue in the animal model using a catheter, cannula, or biopsy needle, the microdevice comprising: (i) at least one microwell containing one or more active agents; (ii) a microdose of the one or more active agents in the at least one microwell; and (iii) a compound release mechanism comprising a polymer matrix for controlling the release of the one or more active agents from the microwell into the tissue, wherein the system measures the outcome of ferroptosis induction after administration of the one or more active agents to the tissue in the animal model compared to baseline tissue not administered the one or more active agents, and identifies that the one or more active agents induce ferroptosis in the tissue.

[0243] 1. A system for screening for ferroptosis-induced cell death in vivo, the system comprising: (a) an animal model containing a target tissue of interest; (b) a microdevice configured to allow implantation into the tissue in the animal model using a catheter, cannula, or biopsy needle, the microdevice comprising: (i) at least one microwell containing one or more active agents; (ii) at least one microwell containing one or more ferroptosis inhibitors; (ii) a microdose of the one or more active agents and / or the one or more ferroptosis inhibitors in the at least one microwell; and (iii) a microwell Further provided herein is a system comprising a microdevice comprising a compound release mechanism comprising a polymer matrix for controlling the release of one or more active agents from the microdevice into the tissue, wherein the system measures the outcome of ferroptosis induction in an animal model after administration of the one or more active agents to the tissue compared to baseline tissue not administered the one or more active agents, and the system measures the outcome of ferroptosis induction in an animal model after administration of the one or more active agents to the tissue compared to administration of the one or more active agents and one or more ferroptosis inhibitors, and identifies that the one or more active agents induce ferroptosis in the tissue.

[0244] The systems provided herein generally include multiple microwells disposed on or within a support structure. The microwells contain one or more active agents, alone or in combination, at one or more dosages and / or release pharmacokinetics. Preferably, the device is configured to deliver microdoses to substantially eliminate overlap in tissue of active agents released from different microwells. In some embodiments, the device is configured for easy implantation and retrieval in the target tissue. In an exemplary embodiment, the device has a cylindrical shape with symmetrical wells on the exterior of the device, each containing one or more drugs at one or more concentrations. The device is sized to allow placement using a catheter, cannula, or stylet. In a preferred embodiment, the device has a guidewire to aid in placement and retrieval. The device may also include features to help maintain spatial stability of tissue ablated by the device, such as fins or stabilizers that can be extended from the device before or during removal. Optionally, the device has fiber optics, sensors, and / or bidirectional features, such as remote accessibility (e.g., Wi-Fi) to provide in situ retrieval of information and modification of device release characteristics. In the most preferred embodiment, the optical fibers and / or sensors have individual access to different wells.

[0245] In some embodiments, the systems provided herein are formed from biocompatible silicon, metal, ceramic, or polymer. They can 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 wells, followed by solvent removal by drying, evaporation, or lyophilization, or by placing the drug in tablet or particulate form into the wells. In a preferred embodiment, the drug is loaded onto the top of a hydrogel pad within the microwell. The hydrogel pad expands during implantation to deliver the drug to the surrounding tissue. The pharmacokinetics of drug release is a function of the drug's solubility, additives, well dimensions, and the tissue into which the device is implanted (release is faster in highly vascularized tissues than in less vascularized tissues).

[0246] In some embodiments, the system provided herein is directly implanted into a solid tumor or tissue to be biopsied. Once implanted, the system provided herein locally releases a series of active agents in microdoses. Analysis of the tumor response to the series of active agents can then be used to identify specific drugs, drug combinations, and / or dosages that are effective for treating solid tumors in patients. By using a microassay device to locally deliver a series of drugs in microdoses, patient response to a wide range of regimens can be examined rapidly and under realistic physiological conditions without inducing systemic toxicity. These data can be used in combination with genomic data, if necessary, to accurately predict systemic drug response.

[0247] Without limitation, the systems provided herein can administer the agents provided herein by any of the methods provided herein. For example, the systems provided herein can be used to deliver microdoses of agents to tissues in vivo. The systems described herein include those for sustained administration of a therapeutic amount of a ferroptosis-inducing agent to tissue, wherein the sustained administration of the therapeutic amount is at least about 10 ng / mm 2 in the tissue for a period of at least 4 hours. 2 The sustained administration may include providing a ferroptosis-inducing agent to the tissue in an amount sufficient to achieve a distribution of ferroptosis-inducing agents in the tissue, thereby inducing ferroptosis in the tissue. In some embodiments, the sustained administration further forms a gradient of a subtherapeutic amount of the ferroptosis-inducing agent adjacent to the administration site within the tissue. In some embodiments, the sustained administration of the therapeutic amount of the ferroptosis-inducing agent is for at least 10 hours. In some embodiments, the therapeutic amount of the ferroptosis-inducing agent is at a concentration of at least about 1 μM to 10 μM. In some embodiments, the system provided herein is implanted into a tumor. In some embodiments, the system delivers one or more ferroptosis-inducing agents to the tumor.

[0248] Illustrative Embodiments 1. A method of inducing ferroptosis in a tissue of a subject, the method comprising sustained administration to the tissue of a therapeutic amount of a ferroptosis-inducing agent, wherein the sustained administration of the therapeutic amount is at least about 10 ng / mm 3 in the tissue for a period of at least 4 hours. 2Provided herein is a method comprising providing a ferroptosis-inducing agent to the tissue in an amount sufficient to achieve a distribution of ferroptosis in the tissue, thereby inducing ferroptosis in the tissue. Further provided herein is a method wherein the sustained administration further forms a gradient of a subtherapeutic amount of the ferroptosis-inducing agent adjacent to the administration site within the tissue. Further provided herein is a method wherein the sustained administration of the ferroptosis-inducing agent comprises an additional administration step. Further provided herein is a method wherein the tissue comprises a heterogeneous population of cells, the heterogeneous population of cells comprising at least one of precancerous cells and noncancerous cells. Further provided herein is a method wherein the tissue comprises a heterogeneous population of cells, the heterogeneous population of cells comprising a population of immune cells. Further provided herein is a method wherein the tissue comprises a heterogeneous population of cells, the heterogeneous population of cells comprising a first cell population comprising a higher concentration of selenium or iron compared to a predetermined level of selenium or iron, and a second cell population comprising a normal concentration of selenium or iron compared to the predetermined level of selenium or iron. Further provided herein is a method wherein the tissue comprises a homogeneous population of cells. Further provided herein is a method wherein the tissue comprises a plurality of cancer cells. Further provided herein is a method wherein the tissue comprises a plurality of cells expressing one or more markers indicative of a mesenchymal state. Further provided herein is a method wherein the one or more markers are selected from the group consisting of ZEB1, ACSL4, FADS2, PPARγ, Fsp1, SLC7A11, SLC3A2, and LPCAT3. Further provided herein is a method wherein the tissue comprises a plurality of cells with reduced expression of one or more endothelial cell markers. Further provided herein is a method wherein the endothelial cell marker is vimentin, E-cadherin, or beta (β)-actin. Further provided herein is a method wherein the tissue comprises a histological abnormality. Further provided herein is a method wherein the histological abnormality is determined by tissue biopsy before or during targeted, sustained administration of a ferroptosis-inducing agent to the tissue. Further provided herein is a method wherein the histological abnormality is hyperplasia or fibrosis. Further provided herein is a method wherein the tissue isFurther provided herein is a method, comprising a plurality of cells having polyunsaturated fatty acid (PUFA) concentration higher than the PUFA concentration in cells of normal tissue.Further provided herein is a method, wherein the PUFA concentration in a plurality of cells is higher than a predetermined PUFA concentration.Further provided herein is a method, wherein tissue comprises a plurality of cells having a peroxidation potential index (PI) higher than the PI in cells of normal or healthy tissue, and ferroptosis is induced in a plurality of cells.Further provided herein is a method, wherein the PI in a plurality of cells is higher than a predetermined PI. Further provided herein is a method in which the ferroptosis inducer is an inhibitor of glutathione peroxidase 4 (GPX4), glutathione synthetase, glutamate-cysteine ligase, phosphoseryl-tRNA kinase (PSTK), eukaryotic elongation factor selenocysteine-tRNA specific (EEFSEC), selenophosphate synthetase 2 (SEPHS2), Sep(O-phosphoserine)TRNA:Sec(selenocysteine)TRNA synthase (SEPSECS), or SECIS binding protein 2 (SECISBP2). Further provided herein is a method in which the inhibitor is a small molecule, peptide, or nucleic acid. Further provided herein is a method in which the ferroptosis inducer is any one or more of the agents in Table 1. Further provided herein is a method in which the ferroptosis inducer is any one or more of the agents in Table 2 or Table 3. Further provided herein is a method in which the ferroptosis inducer is selected from the group consisting of Table 1, e.g., (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jacaric acid, buthionine sulfoximine (BSO), trigonelline, glutamate, sulfasalazine, auranofin, brusatol, sorafenib, sorafenib-d3, sorafenib tosylate, trigonelline, FIN56, FINO2, CIL56, dihydroisotanshinone I, GPX4-IN-3, analogs or derivatives thereof. Further provided herein is a method in which the ferroptosis inducer is contacted with the tissue at the localization site for about 6 hours. Further provided herein is a method in which the ferroptosis inducer is contacted with the tissue at the localization site for about 10 hours.Further provided herein are methods. Further provided herein are methods wherein the ferroptosis inducer contacts the tissue at the localization site for about 24 hours. Further provided herein are methods wherein the ferroptosis inducer contacts the tissue at the localization site for about 48 hours. Further provided herein are methods wherein the ferroptosis inducer contacts the tissue at the localization 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 comprising a plurality of 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 a leukemia or lymphoma. Further provided herein are methods wherein the solid tumor is a carcinoma, melanoma, or sarcoma. Further provided herein is a method wherein the melanoma is dedifferentiated melanoma or amelanotic melanoma. Further provided herein is a method wherein the subject has or is at risk of developing cancer. The cancer may be selected from the group consisting of acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary tract cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast adenocarcinoma, breast medullary carcinoma), brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, and ovarian cancer. Mixed tissue carcinoma; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial 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)), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal carcinoma,oropharyngeal cancer); hematopoietic cancers (e.g., leukemias such as acute lymphocytic 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); Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell B-cell lymphomas such as idiopathic lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (e.g., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma lymphomas, such as 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; mixtures of one or more of the above leukemias / lymphomas; and multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal inflammatory myofibroblastic tumors; immune cell amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma, hepatocellular carcinoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndromes (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), angiogenic myelodysplasia (AMM),Also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CIVIL), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES); neuroblastoma; neurofibromas (e.g., type 1 or type 2 neurofibromatosis (NF), schwannomatosis); neuroendocrine cancers (e.g., gastrointestinal pancreatic neuroendocrine tumors (GEP)) NETs, carcinoid tumors); osteosarcomas (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), pancreatic islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; 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 Further provided herein are methods for treating a cancer that is selected from the group consisting of: bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; or vulvar cancer (e.g., Paget's disease of the vulva).

[0249] Further provided herein is a method for inducing iron-dependent cell death in a subject's tissue, the method comprising contacting an effective amount of an iron-dependent cell death agent with in vivo tissue for a duration of at least 4 hours, wherein the tissue comprises one or more of: (a) a plurality of cells comprising a selenium concentration higher than that in a corresponding normal tissue; (b) a plurality of cells comprising an iron concentration higher than that in a corresponding normal tissue; (c) a plurality of cells comprising a PUFA concentration higher than that in a 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 comprising a peroxidation potential index (PI) higher than that in a corresponding normal tissue, wherein the effective amount of the iron-dependent cell death agent is at a concentration of at least about 0.1 μM to 500 μM in the tissue for the duration. Further provided herein is a method wherein the iron-dependent cell death agent is any one of the agents listed in Table 1. Further provided herein is a method wherein the iron-dependent cell death agent is any one of the agents listed in Table 2 or Table 3. Further provided herein is a method in which the ferroptosis inducer is selected from the group consisting of Table 1, e.g., (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jacalic acid, buthionine sulfoximine (BSO), trigonelline, glutamate, sulfasalazine, auranofin, brusatol, sorafenib, sorafenib-d3, sorafenib tosylate, trigonelline, FIN56, FINO2, CIL56, dihydroisotanshinone I, GPX4-IN-3, analogs or derivatives thereof. Further provided herein is a method in which the iron-dependent cell death agent contacts the tissue at the localized site for about 6 hours. Further provided herein is a method in which the iron-dependent cell death agent contacts the tissue at the localized site for about 10 hours. Further provided herein are methods in which the iron-dependent cell death agent is in contact with the site of the tumor for about 24 hours, further provided herein are methods in which the iron-dependent cell death agent is in contact with the site of the tumor for about 48 hours, and further provided herein are methods in which the iron-dependent cell death agent is in contact with the site of the tumor for about 72 hours.Further provided herein is a method wherein the tissue is a tumor or a precancerous lesion. Further provided herein is a method wherein the tumor is resistant to one or more anti-apoptotic agents. Further provided herein is a method wherein the tumor is a carcinoma, melanoma, or sarcoma. Further provided herein is a method wherein the melanoma is dedifferentiated melanoma or amelanotic melanoma. Further provided herein is a method further comprising the step of obtaining a biopsy of the tissue for histological analysis. Further provided herein is a method wherein the tissue comprises a histological abnormality, the histological abnormality being hyperplasia or fibrosis. Further provided herein is a method wherein the one or more markers indicative of a mesenchymal state are selected from the group consisting of ZEB1, ACSL4, FADS2, PPARγ, Fsp1, SLC7A11, SLC3A2, and LPCAT3. Further provided herein is a method wherein the tissue comprises a plurality of cells having reduced expression of one or more endothelial cell markers. Further provided herein is a method wherein the endothelial cell marker is vimentin, E-cadherin, or beta (β)-actin. Further provided herein is a method, wherein the agent reduces tissue size or tissue volume by at least 5%. Further provided herein is a method, wherein the agent is administered together with one additional agent. Further provided herein is a method, wherein the additional agent is a cell death inducer or a nutritional supplement.

[0250] 1. A method of inducing targeted cell death in vivo in mammalian tissue, the method comprising: (a) contacting the mammalian tissue with a priming agent; (b) contacting the mammalian tissue with an in vivo effective amount of a ferroptosis-inducing agent for a duration of at least four hours, wherein the ferroptosis-inducing agent induces in vivo targeted cell death in the mammalian tissue, if a plurality of cells in the mammalian tissue are responsive to the priming agent as determined by detecting: (i) a plurality of cells comprising a concentration of selenium that is higher than the concentration of selenium in the mammalian tissue prior to contact with the priming agent; (ii) a plurality of cells comprising a concentration of iron that is higher than the concentration of iron in the mammalian tissue prior to contact with the priming agent; (iii) a plurality of cells comprising a concentration of PUFAs that is higher than the concentration of PUFAs in the mammalian tissue prior to contact with the priming agent; (iv) a plurality of cells expressing one or more markers indicative of a mesenchymal state; (v) a plurality of cells comprising a peroxidative potential index (PI) that is higher than the PI in the mammalian tissue prior to contact with the priming agent; and / or (vi) hyperproliferation of cells in the mammalian tissue. Further provided herein is a method for inducing targeted cell death in vivo. Further provided herein is a method wherein step (a) is performed in vivo, in vitro, or ex vivo. Further provided herein is a method further comprising obtaining a biopsy of mammalian tissue for histological analysis. Further provided herein is a method further comprising detecting a plurality of cells in the mammalian tissue as responding to the priming agent. Further provided herein is a method wherein the detecting step is by histological assay or immunohistological assay. Further provided herein is a method wherein the priming agent is any one of the agents listed in Table 4. Further provided herein is a method wherein the priming agent is liproxstatin-1, ferrostatin-1, deferoxamine (DFO), iron, vitamin E, polyunsaturated fatty acid, or selenium. Further provided herein is a method further comprising administering a cell death-inducing agent.Further provided herein is a method, wherein the cell death inducer is a chemotherapeutic agent. Further provided herein is a method, wherein the ferroptosis inducer is any one of the agents listed in Table 1. Further provided herein is a method, wherein the ferroptosis inducer is selected from the group consisting of Table 1, for example, (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jacaric acid, buthionine sulfoximine (BSO), trigonelline, glutamate, sulfasalazine, auranofin, brusatol, sorafenib, sorafenib-d3, sorafenib tosylate, trigonelline, FIN56, FINO2, CIL56, dihydroisotanshinone I, GPX4-IN-3, analogs or derivatives thereof. Further provided herein is a method, wherein the ferroptosis inducer is contacted with mammalian tissue for about 6 hours. Further provided herein is a method wherein the ferroptosis inducer contacts the mammalian tissue for about 10 hours. Further provided herein is a method wherein the ferroptosis inducer contacts the mammalian tissue for about 24 hours. Further provided herein is a method wherein the ferroptosis inducer contacts the mammalian tissue for about 48 hours. Further provided herein is a method wherein the ferroptosis inducer contacts the mammalian tissue for about 72 hours. Further provided herein is a method wherein the effective amount of the ferroptosis inducer is at a concentration of at least about 1 μM to 10 μM. Further provided herein is a method wherein, after contact with the ferroptosis inducer, cell death can be detected at or after contacting the mammalian tissue with the ferroptosis inducer. Further provided herein is a method wherein, after contact with the ferroptosis inducer, immune cell recruitment can be detected at or after contacting the mammalian tissue with the ferroptosis inducer. Further provided herein is a method wherein the tissue is human tissue. Further provided herein are 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.Further provided herein are methods wherein the administering or contacting step is by intravenous, intraarterial, intramuscular, or subcutaneous administration.

[0251] Further provided herein is a system comprising an implantable microdevice configured for localized administration to tissue, the microdevice comprising: (a) a cylindrical support structure having at least one microwell formed on or within the support structure; (b) a microdose of a ferroptosis inducer in the at least one microwell; and (c) a compound release mechanism for sustained administration to control release of the ferroptosis inducer from the microwell, wherein the microdose of the ferroptosis inducer forms a gradient of a subtherapeutic dose of the ferroptosis inducer at an administration site within the tissue for a duration of at least four hours; the microdevice configured to allow implantation within the tissue using a catheter, cannula, or biopsy needle; and the microdevice further configured to release the ferroptosis inducer from the at least one microwell to an administration site within the apoptosis-resistant tissue adjacent to the at least one microwell.

[0252] 1. A system for screening for ferroptosis-induced cell death in vivo, the system comprising: (a) an animal model containing a target tissue of interest; (b) a microdevice configured to allow implantation into the tissue in the animal model using a catheter, cannula, or biopsy needle, the microdevice comprising: (i) at least one microwell containing one or more active agents; (ii) at least one microwell containing one or more ferroptosis inhibitors; (ii) a microdose of the one or more active agents and / or the one or more ferroptosis inhibitors in the at least one microwell; and (iii) a microwell Further provided herein is a system comprising a microdevice comprising a compound release mechanism comprising a polymer matrix for controlling the release of one or more active agents from the microdevice into the tissue, wherein the system measures the outcome of ferroptosis induction in an animal model after administration of the one or more active agents to the tissue compared to baseline tissue not administered the one or more active agents, and the system measures the outcome of ferroptosis induction in an animal model after administration of the one or more active agents to the tissue compared to administration of the one or more active agents and one or more ferroptosis inhibitors, and identifies that the one or more active agents induce ferroptosis in the tissue.

[0253] 1. A system for screening for ferroptosis-induced cell death in vivo, the system comprising: (a) an animal model containing a target tissue of interest; (b) a microdevice configured to allow implantation into the tissue in the animal model using a catheter, cannula, or biopsy needle, the microdevice comprising: (i) at least one microwell containing one or more active agents; (ii) at least one microwell containing one or more ferroptosis inhibitors; (ii) a microdose of the one or more active agents and / or the one or more ferroptosis inhibitors in the at least one microwell; and (iii) a microwell Further provided herein is a system comprising a microdevice comprising a compound release mechanism comprising a polymer matrix for controlling the release of one or more active agents from the microdevice into a tissue, wherein the system measures the outcome of ferroptosis induction in an animal model after administration of one or more active agents to the tissue compared to a baseline tissue not administered with the one or more active agents, and the system measures the outcome of ferroptosis induction in an animal model after administration of one or more active agents to the tissue compared to administration of one or more active agents and one or more ferroptosis inhibitors, identifying that the one or more active agents induce ferroptosis in the tissue. Further provided herein is a system wherein the ferroptosis inhibitor is liproxstatin-1 or ferrostatin-1.

[0254] Further provided herein is a method for modulating ferroptosis in vivo, the method comprising: (a) contacting mammalian tissue with an effective amount of a ferroptosis inducer for a duration of at least 4 hours in vivo, wherein the ferroptosis inducer induces targeted cell death in the mammalian tissue in vivo; and (b) contacting mammalian tissue with effective amounts of a ferroptosis inducer and a ferroptosis inhibitor in vivo, thereby modulating ferroptosis in vivo. Further provided herein is a method, wherein the ferroptosis inhibitor is liproxstatin-1, ferrostatin-1, deferoxamine (DFO), iron, vitamin E, polyunsaturated fatty acid, or selenium. Further provided herein is a method, wherein the ferroptosis inducer is an inhibitor of glutathione peroxidase 4 (GPX4), glutathione synthetase, glutamate-cysteine ligase, phosphoseryl-TRNA kinase (PSTK), eukaryotic elongation factor selenocysteine-TRNA specific (EEFSEC), selenophosphate synthetase 2 (SEPHS2), Sep(O-phosphoserine)TRNA:Sec(selenocysteine)TRNA synthase (SEPSECS), or SECIS binding protein 2 (SECISBP2). Further provided herein is a method in which the ferroptosis inducer is selected from the group consisting of (1S,3R)-RSL3, ML-162, ML-210, JKE-1674, JKE-1716, erastin, jacaric acid, buthionine sulfoximine (BSO), trigonelline, glutamate, sulfasalazine, auranofin, brusatol, sorafenib, sorafenib-d3, sorafenib tosylate, trigonelline, FIN56, FINO2, CIL56, dihydroisotanshinone I, GPX4-IN-3, analogs or derivatives thereof. Further provided herein is a method in which the ferroptosis inducer is contacted with mammalian tissue for about 6 hours. Further provided herein is a method in which the ferroptosis inducer is contacted with mammalian tissue for about 10 hours. Further provided herein is a method in which the ferroptosis inducer is contacted with mammalian tissue for about 24 hours.Further provided herein is a method in which the ferroptosis inducer is contacted with the mammalian tissue for about 48 hours. Further provided herein is a method in which the ferroptosis inducer is contacted with the mammalian tissue for about 72 hours. Further provided herein is a method in which the effective amount of the ferroptosis inducer is at a concentration of at least about 1 μM to 10 μM. Further provided herein is a method in which, after contact with the ferroptosis inducer, cell death can be detected at or after contacting the mammalian tissue with the ferroptosis inducer. Further provided herein is a method in which, after contact with the ferroptosis inducer, immune cell recruitment can be detected at or after contacting the mammalian tissue with the ferroptosis inducer. Further provided herein is a method in which the tissue is human tissue. Further provided herein is a method in which 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. Further provided herein is a method, wherein administering or contacting is by intravenous administration, intraarterial administration, intramuscular administration or subcutaneous administration.Further provided herein is a method, wherein the method further comprises measuring one or more parameters that are indicative of ferroptosis in mammalian tissue, wherein the one or more parameters are selected from selenium concentration, iron concentration, PUFA concentration, the expression of one or more markers that are indicative of mesenchymal state, peroxidative potential index (PI); and / or cell proliferation.

[0255] Further provided herein are compositions, and systems provided herein, for the treatment of a disease or disorder, comprising any one of the agents or combinations of agents in Table 1.

[0256] Further provided herein is a pharmaceutical composition for the treatment of a disease or disorder, comprising any one of the agents, or a combination of agents, in Table 1, and a pharmaceutically acceptable excipient. Further provided herein is a pharmaceutical composition for the treatment of a disease or disorder, comprising any one of the agents, or a combination of agents, in Table 1, Table 2, and a pharmaceutically acceptable excipient.

[0257] In some embodiments, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0258] In some embodiments, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt of any of the foregoing; or a deuterated derivative of any of the foregoing.

[0259] In some embodiments, [ka] [ka] or a pharmaceutically acceptable salt of any of the foregoing; or a deuterated derivative of any of the foregoing.

[0260] In some embodiments, the compound of Formula XVIII: [ka] , a diastereomer or enantiomer of a compound of formula XVIII, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, are described herein, wherein in the compound of formula XVIII: Each R1, R2 or R3 is independently H, linear or branched C1-C 10 Alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C3-C 10heteroaryl, biphenyl, halogenated biphenyl, indole, triazole, isothiazole, oxazoline, linear or branched C1-C6 alkyl ether, -CH3, phenyl, -C(O)OR5, -C(O)NH2, -O-, -S-, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, -Cl, -Br, -I, or or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, which is optionally substituted with linear or branched C1-C6 alkyl, C1-C6 cycloalkyl, halogen, -CF3, or -F; or R1, R2 and R3 together form a C3-C6 cycloheteroaryl; Each R1, R2 or R3 is deuterium, halogen, fluorine, -CF3, chlorine, straight or branched chain C1-C 10 each independently and optionally substituted with substituents selected from the group consisting of 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, anhydride, and any combination thereof; R4 is H or linear or branched C1-C6 alkyl; R5 is a linear or branched C1-C alkyl group optionally substituted with at least one heteroatom, halogen, or C1-C3 alkyl ether. 10 It is alkyl.

[0261] In some embodiments, the compound of formula XIX: [ka] or a diastereomer or enantiomer of a 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, linear or branched C1-C 10 Alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C3-C 10 heteroaryl, biphenyl, halogenated biphenyl, indole, triazole, isothiazole, oxazoline, linear or branched C1-C6 alkyl ether, -C(O)OR5, -C(O)NH2, -O-, -S-, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, -Cl, -Br, -I, or or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, which is optionally substituted with linear or branched C1-C6 alkyl, C1-C6 cycloalkyl, halogen, -CF3, or -F; or R1, R2 and R3 together form a C3-C6 cycloheteroaryl; Each R1, R2 or R3 is deuterium, halogen, fluorine, -CF3, chlorine, straight or branched chain C1-C 10 each independently and optionally substituted with substituents selected from the group consisting of 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, anhydride, and any combination thereof; R4 is H or linear or branched C1-C6 alkyl; R5 is a linear or branched C1-C alkyl group optionally substituted with at least one heteroatom, halogen, or C1-C3 alkyl ether. 10 It is alkyl.

[0262] In some embodiments, the compound of formula XX: [ka] A diastereomer or enantiomer of a compound of formula XX, or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, wherein: Each R1, R2 or R3 is independently H, linear or branched C1-C4 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C5-C6 heteroaryl, biphenyl, halogenated biphenyl, triazole, isothiazole, oxazoline, linear or branched C1-C6 alkyl ether, -C(O)OR5, -OH, -NH2, -NH-, halogen, -CF3, -CN, -F, or or R1 and R2, R2 and R3, or R1 and R3 together form a C3-C6 cycloalkyl, which is optionally substituted with linear or branched C1-C6 alkyl, C1-C6 cycloalkyl, halogen, -CF3, or -F; Each R1, R2 or R3 is deuterium, halogen, fluorine, -CF3, chlorine, straight or branched chain C1-C 10 each independently and optionally substituted with substituents selected from the group consisting of 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; R4 is H or linear or branched C1-C6 alkyl; R5 is a linear or branched C1-C alkyl group optionally substituted with at least one heteroatom, halogen, or C1-C3 alkyl ether. 10 It is alkyl.

[0263] In some embodiments, the present invention is a pharmaceutical composition comprising a compound of Formula XVIII, XIX, XX, or a compound described herein, any diastereomer or enantiomer thereof, any pharmaceutically acceptable salt thereof, or any deuterated derivative thereof, 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 ranging from about 0.001 mg to about 25,000 mg. In some embodiments, the present invention is a kit comprising a 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 single-use container. In some embodiments, the container is a resealable container.

[0264] Also described herein are methods for treating cancer in a subject. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a 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, any diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt thereof, or any deuterated derivative thereof, 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 SWI / SNF-deficient complex cancer. In some embodiments, the administering step is selected from the group consisting of oral, injection; subcutaneous, intratumoral; systemic, topical, intravenous, intraperitoneal, intramuscular, and any combination thereof.

[0265] Also described herein are methods of modulating ferroptosis in a tissue, 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 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 administering or contacting step 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 a year, or for life, as needed. In some embodiments, the therapeutically effective amount or effective amount is in the range of about 0.001 mg to about 25,000 mg.

[0266] Also described herein are methods of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein, thereby treating the disease or condition. Similarly, described herein are methods of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein, any diastereomer or enantiomer described above, or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, thereby treating the disease or condition. In some embodiments, the disease or condition is fibrosis or kidney damage.

[0267] Likewise, the crystalline forms of the compounds described herein are described herein.

[0268] The following examples are provided to more clearly illustrate to those skilled in the art the principles and practice of the embodiments disclosed herein, and should not be construed as limiting the scope of any claimed embodiments. Unless otherwise specified, all parts and percentages are by weight. [Example]

[0269] Example 1 Compound synthesis, purification and characterization The compounds herein and intermediates used in preparing the compounds herein can be prepared using the procedures and related procedures shown in the following examples. The methods and conditions used in these examples, as well as the actual compounds prepared in these examples, are not intended to be limiting, but are intended to demonstrate how the compounds of the present disclosure can be prepared. The starting materials and reagents used in these examples, if not prepared by the procedures described herein, are generally either commercially available, reported in the chemical literature, or can be prepared by using procedures described in the chemical literature. Column chromatography was performed using pre-packed silica gel cartridges or manually packed column chromatography systems. Preparative high-performance liquid chromatography (HPLC) used the indicated reverse-phase column of appropriate size for the amount of material to be separated, generally eluting with a gradient of increasing concentrations of methanol or acetonitrile in water (also containing 0.05% or 0.1% trifluoroacetic acid or 10 mM ammonium acetate) at an elution rate suitable for the column size and the separation achieved. In some cases, chiral chromatography was performed to separate stereoisomers. Chemical names were determined using ChemDraw Ultra, version 20.1 (CambridgeSoft). The following abbreviations are used: Å Angstrom AIBN 2,2'-azobis(2-methylpropionitrile) aq. Water-based Ac2O acetic anhydride Brine Saturated aqueous sodium chloride 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 grams h time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High Performance Liquid Chromatography i-PrOH iso-propanol KHMDS Potassium bis(trimethylsilyl)amide LAH Lithium aluminum hydride LCMS Liquid Chromatography-Mass Spectrometry m-CPBA meta-chloroperbenzoic acid MeCN acetonitrile MeOH Methanol MHz Megahertz MS Molecular Sieves 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 Nosil Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2 Palladium Acetate Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride pet ether PIDA (diacetoxyiodo)benzene PhI(OAc)2(diacetoxyiodo)benzene PPTS Pyridinium para-toluenesulfonate p-TsOH para-toluenesulfonic acid Ts Tosil TsCl para-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 Tetrapropylammonium perruthenate HPLC conditions: A. Phenomnex Luna C18, 2 x 50 mm, 5 micron, column temperature 40°C, 0-30% B for 3 minutes, then 100% B for 1 minute. Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN. 1 mL / min. B. XBridge C18, 2.1 x 50 mm, 5 micron, column temperature 40°C, 3.85 min, 0-95% B. Solvent A 10 mM NH4CO3 in water, Solvent B MeCN, 1 mL / min or preferably 0.8 mL / min. C. Phenomnex Luna C18, 2 x 50 mm, 5 micron, 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 x 50 mm, 5 micron, column temperature 40°C, 0 to 60% B for 5 min, then 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 x 50 mm, 5 micron, 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 x 50 mm, 5 micron, 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 x 50 mm, 5 micron, 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 x 50 mm, 5 micron, 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 x 50 mm, 5 micron, column temperature 40 °C, 0 to 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 EVO C18, 2 x 30 mm, 5 micron, column temperature 40 °C, 5 to 95% B in 0.7 min, then 95% B in 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 x 50 mm, 5 micron, 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 x 25 mm, column temperature: 40°C, 0-30% B for 3.5 min, then 30% B for 0.3 min. Flow rate: 0.8 mL / min, Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN. M. Merck Chomolith Flash® RP-18e, column temperature: 40°C, 0-30% B for 1.2 min, then 30% B for 0.4 min. Flow rate: 1.5 mL / min, Solvent A 0.04% TFA in water, Solvent B 0.02% TFA in MeCN. N. Agilent poroshell 120 EC-C18 3.0 × 50 mm, 2.7 micron, column temperature: 45 °C, 5–99% B for 3 min, then 99% B for 1 min. Flow rate: 1 mL / min, Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN. O. Waters XSelect HSS T3 4.6 x 50 mm, 3.5 micron, column temperature: 40 °C, 0-30% B for 3 min, then 100% B for 1 min. Flow rate: 1 mL / min, Solvent A 0.04% TFA in water, Solvent B 0.02% TFA in MeCN. P. Agilent ZORBAX SB-Aq, 2.1 x 50 mm, 5 micron, column temperature: 45 °C, 0–80% B for 3.4 min, then 100% B for 0.5 min. Flow rate: 0.6 mL / min, Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN. Q. Kinetex® EVO C18 2.1 x 30 mm, 5 micron, column temperature: 45°C, 0-60% B in 3.6 min, then 60% B in 0.25 min. Flow rate: 0.6 mL / min, Solvent A 0.04% TFA in water, Solvent B 0.02% TFA in MeCN. R. Waters XSelect HSS T3 4.6 x 50 mm, 3.5 micron, column temperature: 40 °C, 0-60% B for 3 min, then 100% B for 1 min. Flow rate: 1 mL / min, Solvent A 0.04% TFA in water, Solvent B 0.02% TFA in MeCN. S. Agilent ZORBAX RX-SIL, 4.6 x 150 mm, 5 micron, column temperature: 40 °C, 7 min, 0–85% B. Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN, 1 mL / min. T. Agilent XBridge C18, 2.1 x 50 mm, 5 micron, column temperature: 40 °C, 0 to 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 x 30 mm, 5 micron, column temperature: 40 °C, 10 to 100% B in 0.5 min, then 100% B for 0.4 min. Flow rate: 2 mL / min, Solvent A: 0.04% TFA in water, Solvent B: 0.02% TFA in MeCN.

[0270] Exemplary embodiment 1a [ka] (2S)-2-Amino-4-(2-(4-chlorophenyl)ethylsulfonimidoyl)butanoic acid [ka]

[0271] To a mixture of (chlorophenyl)ethan-1-ol (100 mg, 6.39 mmol) and TEA (19.2 mmol, 2.67 mL) in DCM (10 mL) was added MsCl (19.2 mmol, 1.48 mL) at 0 °C. 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 NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1, 1 / 1) to give 4-chlorophenethyl methanesulfonate (1 g, 66.7% yield) as a colorless oil. 1 H 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). [ka]

[0272] To a mixture of 4-chlorophenethyl methanesulfonate (375 mg, 1.6 mmol) and tert-butyl (tert-butoxycarbonyl)-L-homocysteinate (400 mg, 1.6 mmol) in DMF, KI (2.4 mmol) and K2CO3 (4.8 mmol) were added under Ar. The mixture was stirred at 25-70 °C for 16 h, quenched with water, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. Preparative TLC (petroleum ether:ethyl acetate = 2:1, R f =0.50) to give (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-((4-chlorophenethyl)thio)butanoate (0.37 g, 60% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3-d) δ 7.29 - 7.25 (m, 3H), 7.14 (d, J = 8.44 Hz, 2H), 5.10 (br d, 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). [ka]

[0273] A mixture of (S)-methyl-2-((tert-butoxycarbonyl)amino)-4-((4-chlorophenethyl)thio)butanoate (170 mg, 0.44 mmol), PhI(OAc) (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 NaSO, 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 = 5 / 1, 0 / 1) to give (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(2-(4-chlorophenyl)ethylsulfonimidoyl)butanoate (0.1 g, 56% yield) as a colorless oil. 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 (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(2-(4-chlorophenyl)ethylsulfonimidoyl)butanoate (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)ethylsulfonimidoyl)butanoic 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 H 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 [ka] (2S)-2-Amino-4-(2-phenylethylsulfonimidoyl)butanoic acid [ka]

[0276] To a solution of benzyl (2S)-2-(tert-butoxycarbonylamino)-4-sulfanylbutanoate (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)-benzyl 2-((tert-butoxycarbonyl)amino)-4-(phenethylthio)butanoate (1.1 g, crude) as a colorless oil. 1 H 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). [ka]

[0277] To a solution of (S)-benzyl 2-((tert-butoxycarbonyl)amino)-4-(phenethylthio)butanoate (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 NaHCO (20 mL) and then extracted with DCM (20 mL × 2). The combined organic phases were washed with NaSO (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 1:1 to 1:2) to afford (2S)-benzyl 2-((tert-butoxycarbonyl)amino)-4-(phenethylsulfinyl)butanoate (910 mg, 88% yield) as a colorless oil. 1 H 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). [ka]

[0278] To a solution of (2S)-benzyl 2-((tert-butoxycarbonyl)amino)-4-(phenethylsulfinyl)butanoate (910 mg, 2.04 mmol) in MeOH (10 mL) was added ammonium carbamate (797 mg, 10.2 mmol) and PhI(OAc) (1.97 g, 6.13 mmol). The mixture was stirred at 20 °C for 2 hours. 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 phase was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate=1:1 to 1:2) to give (2S)-benzyl 2-((tert-butoxycarbonyl)amino)-4-(2-phenylethylsulfonimidoyl)butanoate (620 mg, 66% yield) as a colorless oil. 1 H 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). [ka]

[0279] To a solution of (2S)-benzyl 2-((tert-butoxycarbonyl)amino)-4-(2-phenylethylsulfonimidoyl)butanoate (0.40 g, 868 mmol) in THF (5 mL) and HO (1 mL) was added LiOH.HO (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 pH of the aqueous phase was adjusted to approximately 4 with 2 N HCl and extracted with DCM (10 mL × 3). The combined organic extracts were concentrated to give (2S)-2-((tert-butoxycarbonyl)amino)-4-(2-phenylethylsulfonimidoyl)butanoic acid (274 mg, 85% yield) as a white solid. 1 H NMR (400 MHz, CDCl3-d) δ7.39 - 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)butanoic acid (80.0 mg, 216 mmol) in HCl / dioxane (4 M, 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)butanoic 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 H 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 listed in Table 5 were prepared using the methods described above. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10]

[0282] Exemplary Embodiment 1c [ka] (2S)-2-Amino-4-(3-methyl-3-phenylbutylsulfonimidoyl)butanoic acid [ka]

[0283] To a solution of 3-methyl-3-phenylbutanoic acid (1.00 g, 5.61 mmol) in THF (12 mL) was added LiAlH (213 mg, 5.61 mmol) at 0 °C. The mixture was stirred at 20 °C under N 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 NaSO, 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 H 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). [ka]

[0284] To a solution of 3-methyl-3-phenylbutan-1-ol (640 mg, 3.90 mmol) and TEA (592 mg, 5.84 mmol, 813 mL) in DCM (6 mL) was added MsCl (536 mg, 4.68 mmol, 362 mL) at 0 °C. 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 Na SO , filtered, and concentrated. The residue was purified by column chromatography (SiO , petroleum ether:ethyl acetate = 92:8) to afford 3-methyl-3-phenylbutyl methanesulfonate (880 mg, 93% yield) as a colorless oil. 1 H 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). [ka]

[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 under Ar at 25 °C 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 (SiO, 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 H 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). [ka]

[0286] To a solution of (S)-tert-butyl 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) (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 Na SO , filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate=70:30) to give (2S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-4-(3-methyl-3-phenylbutylsulfonimidoyl)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 (2S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-4-(3-methyl-3-phenylbutylsulfonimidoyl)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-phenylbutylsulfonimidoyl)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 H 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 [ka] (2S)-4-(3-(1H-pyrazol-4-yl)propylsulfonimidoyl)-2-aminobutanoic acid [ka]

[0289] To a solution of (S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-4-mercaptobutanoate (500 mg, 1.72 mmol) and 4-(3-chloropropyl)-1H-pyrazole (372 mg, 2.06 mmol, HCl) in DMF (5 mL) was added K2CO3 (711 mg, 5.15 mmol) and KI (569 mg, 3.43 mmol). The mixture was stirred under Ar 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 (SiO, 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)butanoate (600 mg, 88% yield) as a yellow oil. 1H NMR (400MHz, 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). [ka]

[0290] To a solution of (S)-tert-butyl 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) (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 Na SO , filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (0.2% FA)-MeCN]; B%: 10% to 40%, 12 min) to give (2S)-tert-butyl 4-(3-(1H-pyrazol-4-yl)propylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoate (70 mg, 33% yield) as a white solid. 1 H 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 (2S)-tert-butyl 4-(3-(1H-pyrazol-4-yl)propylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoate (30 mg, 70 mmol) in a mixture of HCl / dioxane (1 mL) was stirred at 20° C. for 1 hour. 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 H 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 = 7.8Hz, 2H).

[0292] The compounds listed in Table 6 were prepared using the methods outlined above. "HPLC rt" refers to the retention time in the analytical HPLC experiment consistent with the purification method described above. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5]

[0293] Exemplary Embodiment 1e [ka]

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

[0295] A mixture of (S)-methyl 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 analyzed by preparative TLC (petroleum ether:ethyl acetate = 1:1, R f =0.12) to give (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-((2-(pyrazin-2-yl)ethyl)thio)butanoate (0.25 g, 83% yield) as a colorless oil. 1 H 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). [ka]

[0296] To a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-((2-(pyrazin-2-yl)ethyl)thio)butanoate (200 mg, 563 μmol) in MeOH (5 mL) was added PhI(OAc) (453 mg, 1.41 mmol) and ammonium carbamate (220 mg, 2.81 mmol) at 25° C. The mixture was stirred at 25° C. for 2 hours, concentrated, and analyzed by preparative TLC: (ethyl acetate:methanol=10:1, R f =0.28) to give (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(2-(pyrazin-2-yl)ethylsulfonimidoyl)butanoate (0.2 g, 92% yield) as a colorless oil. 1 H 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 (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(2-(pyrazin-2-yl)ethylsulfonimidoyl)butanoate (50 mg, 129 mmol) in DCM (5 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL) at 15 °C, and the mixture was stirred for 1 h. Toluene (50 mL) was added to the mixture, which was concentrated to give a residue, to which HO (20 mL) was added and extracted with DCM (20 mL × 2). The aqueous phase was lyophilized to give (2S)-methyl 2-amino-4-(2-(pyrazin-2-yl)ethylsulfonimidoyl)butanoate (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; 1 H 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 [ka] (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 (4 M, 3 mL) was stirred at 20 °C for 16 h. The mixture was concentrated, water (5 mL) was added, and 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 H 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 [ka] (2S)-Methyl 4-(2-(1H-tetrazol-5-yl)ethylsulfonimidoyl)-2-aminobutanoate [ka]

[0301] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-mercaptobutanoate (300 mg, 1.2 mmol) and 3-bromopropanenitrile (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 under Ar at 20 °C 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. Preparative TLC (SiO2, ethyl acetate:methanol = 1:1, R f =0.62) to afford (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-((2-cyanoethyl)thio)butanoate (330 mg, 91% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3-d) δ 5.12 (br s, 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). [ka]

[0302] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-((2-cyanoethyl)thio)butanoate (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 microns; mobile phase: [water (0.2% formic acid)-MeCN]; B%: 20%-50%, 12 min) to afford (S)-methyl 4-((2-(1H-tetrazol-5-yl)ethyl)thio)-2-((tert-butoxycarbonyl)amino)butanoate (145 mg, 64% yield) as a yellow oil. 1 H 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). [ka]

[0303] To a solution of (S)-methyl 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) (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 microns; mobile phase: [water (0.2% formic acid)-MeCN]; B%: 1% to 30%, 10 min) to afford (2S)-methyl 4-(2-(1H-tetrazol-5-yl)ethylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoate (43 mg, 27% yield) as a white solid. 1 H 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 solution of (2S)-methyl 4-(2-(1H-tetrazol-5-yl)ethylsulfonimidoyl)-2-((tert-butoxycarbonyl)amino)butanoate (10 mg, 26.5 mmol) in a mixture of HCl / MeOH (1 mL) was stirred at 20° C. for 1 hour. The reaction mixture was concentrated to give (2S)-methyl 4-(2-(1H-tetrazol-5-yl)ethylsulfonimidoyl)-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 conditions: A; 1H 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 [ka] (2S)-Methyl 2-amino-4-(3-phenylpropylsulfonimidoyl)butanoate [ka]

[0306] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-mercaptobutanoate (200 mg, 0.8 mmol) in DMF (2 mL) under argon, K2CO3 (277 mg, 2.01 mmol) and 3-bromopropylbenzene (160 mg, 0.8 mmol, 121 mL) were added. 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 afford (S)-methyl 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, 2 H), 7.23 - 7.21 (m, 3 H), 5.10 (br d, J=6.4 Hz, 1 H), 4.41 (br s, 1 H), 3.75 (s, 3 H), 2.72 (t, J=7.6 Hz, 2 H), 2.61 - 2.47 (m, 4 H), 2.17 - 2.03 (m, 1 H), 1.97 - 1.81 (m, 3 H), 1.45 (s, 9 H). [ka]

[0307] A mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-((3-phenylpropyl)thio)butanoate (120 mg, 327 mmol), PhI(OAc) (316 mg, 980 mmol), and ammonium carbamate (127 mg, 1.63 mmol) in MeOH (2 mL) was degassed and purged with N three times. The mixture was stirred under a N atmosphere at 30 °C for 16 h. 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 NaSO, filtered, and concentrated to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=30:1) to afford (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(3-phenylpropylsulfonimidoyl)butanoate (40 mg, 31% yield) as a yellow oil. 1 H 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 (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(3-phenylpropylsulfonimidoyl)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 (2S)-methyl 2-amino-4-(3-phenylpropylsulfonimidoyl)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 H NMR (400 MHz, D2O) δ 7.44 - 7.38 (m, 2 H), 7.35 - 7.30 (m, 3 H), 4.34 (dd, J=7.6, 5.6 Hz, 1 H), 3.87 (s, 3 H), 3.81 - 3.65 (m, 2 H), 3.62 - 3.47 (m, 2 H), 2.85 (t, J=7.2 Hz, 2 H), 2.58 - 2.37 (m, 2 H), 2.28 - 2.17 (m, 2 H).

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

[0310] To a mixture of 3-cyclopropylpropan-1-ol (100 mg, 998 mmol) in DCM (2 mL) was added MsCl (172 mg, 1.5 mmol, 116 mL) and TEA (303 mg, 3 mmol, 417 mL) at 15 °C. The mixture was stirred at 15 °C for 1 h, and the mixture was quenched with saturated NaHCO (20 mL) and extracted with DCM (20 mL × 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. 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 H 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). [ka]

[0311] To a mixture of 3-cyclopropylpropyl methanesulfonate (70 mg, 393 mmol) (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-mercaptobutanoate (97.9 mg, 393 mmol) in DMF (1 mL) was added K2CO3 (163 mg, 1.18 mmol) at 25 °C. The mixture was stirred under Ar at 25 °C for 16 h. The mixture was added to HO (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. 1 H 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). [ka]

[0312] To a mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-((3-cyclopropylpropyl)thio)butanoate (100 mg, 302 mmol) in MeOH (2 mL) was added PhI(OAc) (243 mg, 754 mmol) and ammonium carbamate (118 mg, 1.51 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h, concentrated, and purified by preparative TLC (petroleum ether:ethyl acetate = 0:1, R f= The residue was purified by HPLC (0.13) to give (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(3-cyclopropylpropylsulfonimidoyl)butanoate (0.04 g, 37% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3-d) δ 5.35 (br d, 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 (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(3-cyclopropylpropylsulfonimidoyl)butanoate (40 mg, 110 mmol) in DCM (1 mL) was added TFA (1.23 g, 10.8 mmol, 0.8 mL) at 15 °C, and the mixture was stirred at 15 °C for 1 h. The mixture was concentrated, and the residue was added to HO (30 mL) and extracted with DCM (30 mL × 2). The aqueous phase was lyophilized to give (2S)-methyl 2-amino-4-(3-cyclopropylpropylsulfonimidoyl)butanoate (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 [ka] (2S)-Butyl 2-amino-4-(3,3-dimethylbutylsulfonimidoyl)butanoate [ka]

[0315] To a solution of butyl (tert-butoxycarbonyl)-L-homocysteinate (3.00 g, 10.3 mmol) in DMF was added K2CO3 (20.6 mmol), KI (10.3 mmol), and 1-bromo-3,3-dimethylbutane (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)-butyl 2-((tert-butoxycarbonyl)amino)-4-((3,3-dimethylbutyl)thio)butanoate (3.74 g, 97% yield) as a colorless oil. 1 H 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). [ka]

[0316] To a solution of (S)-butyl 2-((tert-butoxycarbonyl)amino)-4-((3,3-dimethylbutyl)thio)butanoate (1.8 g, 4.79 mmol) in MeOH was added PhI(OAc) (4 equivalents) and ammonium carbamate (5 equivalents). The mixture was stirred at 20 °C for 6 hours. 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)-butyl 2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfonimidoyl)butanoate (1.57 g, 81% yield) as a colorless oil. 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] (2S)-butyl 2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfonimidoyl)butanoate (60 mg, 147 mmol) in HCl / dioxane (4N, 3 mL). The mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated and lyophilized to dryness to give (2S)-butyl 2-amino-4-(3,3-dimethylbutylsulfonimidoyl)butanoate (30 mg, 59% yield) as a white solid. LCMS: Rt=1.930 min, (ES + ) m / z (M+H) + =307.1;HPLC conditions:C; 1 H 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 [ka] (2S)-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-amino-4-(butylsulfonimidoyl)butanoate [ka]

[0319] To a solution of (2S)-2-((tert-butoxycarbonyl)amino)-4-(butylsulfonimidoyl)butanoic 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. Preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1, R f =0.25) to afford (2S)-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-((tert-butoxycarbonyl)amino)-4-(butylsulfonimidoyl)butanoate (50 mg, 37% yield) as a yellow oil. 1 H 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)-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-((tert-butoxycarbonyl)amino)-4-(butylsulfonimidoyl)butanoate (50 mg, 115 mmol) in DCM (2 mL) and TFA (0.2 mL) was stirred at 20° C. for 2 hours. The reaction mixture was concentrated at 35° C. Water (10 mL) was added and extracted with DCM (10 mL×3). The aqueous phase was lyophilized to give (2S)-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-amino-4-(butylsulfonimidoyl)butanoate (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 listed in Table 7 were prepared using the general methods outlined above. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7]

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

[0323] To a solution of methyl N-(tert-butoxycarbonyl)-S-(3,3-dimethylbutyl)-L-homocysteinate (3 g, 9 mmol) in MeOH (24 mL) was added PhI(OAc) (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 extracted with ethyl acetate (45 mL × 3). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 1:1) to give (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfonimidoyl)butanoate (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). [ka]

[0324] To a solution of (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfonimidoyl)butanoate (1.60 g, 4.39 mmol) in THF (12 mL) and HO (4 mL) was added LiOH.HO (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 NaSO, filtered, and concentrated to give (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfonimidoyl)butanoate (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). [ka]

[0325] To a mixture of (2S)-methyl 2-((tert-butoxycarbonyl)amino)-4-(3,3-dimethylbutylsulfonimidoyl)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 stirr...

Claims

1. Compounds of Formula I: 【Hua 637】 or a diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, During the ceremony, R １ teeth, C(O)OH, or C(O)OX (X is an organic cation, an inorganic cation, or Na ＋ , K. ＋ , Mg ２＋ , Ca ２＋ , Zn ２＋ or Mn ２＋ is), or 【Chemical Formula 638】 【Chemical Formula 639】 ,or C(O)OR ３ (R ３ is a linear or branched alkyl, cycloalkyl, cyclic ether, or linear or branched alkyl ether, any of which is optionally independently substituted or or R ３ teeth, 【Hua 640】 or R ３ teeth, 【Hua 641】 is), or C(O)N(R ４ R ５ ) (In the formula, R ４ is H, or R ４ is a straight or branched chain alkyl, a straight or branched chain C １ ~C １０ Alkynyl, CH ２ -CCHalkyne, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally independently substituted; R ５ does not exist or R ５ is H, or R ５ is a straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally and independently substituted; or R ５ is S(O) ２ is alkyl, or R ５ is S(O) ２ CF ３ or R ５ is S(O) ２ NH ２ or R ５ 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 R ５ teeth, 【Chemical 642】 or R ５ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or R ５ is pyrrolidinyl, or R ５ is 2-tetrahydropyranyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl, or R ５ teeth, 【Chemical Formula 643】 or R ５ is alkylaryl or benzyl, or R ５ teeth, 【Chemical Formula 644】 or R ５ is 2-pyridyl, 3-pyridyl or 4-pyridyl, or R ５ teeth, 【Chemical 645】 or R ５ teeth, 【Chemical 646】 or R ５ teeth, 【Hua 647】 or R ５ teeth, 【Chemical Formula 648】 or R ５ teeth, 【Chemical Formula 649】 is), or CN, or 【Chemistry 650】 and R ２ is NH ２ , NHC(O)OMe or NHMe, R ６ is H, C(O)Me or P(O)(OH) ２ and R ７ is a straight or branched chain C １ ~C ３ Or C ５ ~C １０ Alkyl, straight or branched chain C １ ~C １０ Alkenyl or straight or branched chain C １ ~C １０ alkynyl, any of which may have an alkyl ring or alkyl ether ring, which ring is selected from the group consisting of the straight or branched chain C １ ~C ３ Or C ５ ~C １０ Alkyl, the straight or branched chain C １ ~C １０ Alkenyl or the straight or branched chain C １ ~C １０ alkynyl, any of which may be independently optionally substituted, and ３ - when alkyl is substituted at the terminal carbon atom by a methyl group, the linear C substituted at the terminal carbon atom by said methyl group ３ -alkyl may contain further substitutions, ２ - if alkyl is substituted at the terminal carbon atom by an ethyl group, the C is substituted at the terminal carbon atom by an ethyl group ２ -alkyl may contain further substitutions, １ When alkyl is substituted at the terminal carbon atom with an n-propyl group, the C is substituted at the terminal carbon atom with an n-propyl group. １ -alkyl may contain further substitutions or R ７ teeth, 【Chemistry 651】 【652】 【Chemistry 653】 【Chemical 654】 【Chemistry 655】 【Hua 656】 【Hua 657】 【658】 【Chemical Formula 659】 【Hua 660】 【Chemical 661】 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, wherein:

2. R １ but, C(O)OH, or C(O)OR ３ and R ３ is a straight or branched chain alkyl, a straight or branched chain C １ ~C １０ Alkyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, n-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, cycloalkyl, C １ ~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, cyclic alkyl ether, tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, tetrahydrofuranyl, 2-tetrahydrofuranyl, 2-tetrahydrofuranyl, alkylaryl, benzyl; Any of these may contain one or more C １ ~C １０ alkyl, one or more halogens, one or more fluoro, one or more chloro, one or more deuteriums, bromo, one or more iodo, aryl, C ６ Aryl, C １０ Aryl, heteroaryl, C １ ~C ７ optionally independently substituted with alkylcycloalkyl, unsubstituted tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, or 4-tetrahydropyranyl, or any combination thereof; 10. A compound of formula I according to claim 1, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing.

3. R １ But C(O)N(R ４ R ５ ) and R ５ but, Linear or branched chain C １ ~C １０ alkyl, methyl, ethyl, propyl, or butyl, any of which may contain one or more deuterium atoms, straight or branched C １ ~C １０ 10. The compound of formula I of claim 1, its diastereomer or enantiomer, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, optionally or independently substituted with alkyl, one or more halo, one or more fluoro, one or more chloro, one or more iodo, one or more or any combination thereof.

4. R １ But C(O)N(R ４ R ５ ) and R ５ is heteroaryl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or R ５ But S(O) ２ 2. The compound of formula I of claim 1, wherein R is Me, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing.

5. R ７ is a straight chain or branched chain C １ ~C ３ Or C ５ ~C １０ Alkyl, straight or branched chain C １ ~C １０ Alkenyl or straight or branched chain C １ ~C １０ alkynyl, any of which may have an alkyl ring or alkyl ether ring, and these rings are the same as those described above in connection with the straight or branched chain C １ ~C ３ Or C ５ ~C １０ Alkyl, the straight or branched chain C １ ~C １０ Alkenyl or the straight or branched chain C １ ~C １０ Alkynyl contains one carbon, and any of the above can be deuterium, straight chain C １ ~C １０ Alkyl, methyl, ethyl, branched chain C １ ~C １０ Alkyl, halogen, fluoro, chloro, bromo, iodo, hydroxyl, amino, carboxylic acid or a pharmaceutically acceptable salt thereof, amide, carbamate, urea, ester, alkoxy, methoxy, ethoxy, trifluoromethoxy, ether, cyclic ether, C １ ~C ７ Alkyl ether, cyclic C １ ~C ７ alkyl 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, tricyclic aliphatic, adamantyl, cyano, acetal, ketal, or any combination thereof and optionally substituted independently by one or more substituents which may be The linear C ３ - when alkyl is substituted at a terminal carbon atom by a methyl group substituent, the linear C substituted at a terminal carbon atom by said methyl group substituent ３ -alkyl may contain further substitutions, ２ - if alkyl is substituted at the terminal carbon atom by an ethyl group, the C substituted at the terminal carbon atom by an ethyl group ２ -alkyl may contain further substitutions, １ When alkyl is substituted at the terminal carbon atom with an n-propyl group, the C is substituted at the terminal carbon atom with an n-propyl group. １ - alkyl contains further substitutions, The linear C １ ~C １０ the alkyl substituent, the methyl substituent, the ethyl substituent, the branched chain C １ ~C １０ alkyl substituents, the hydroxyl substituents, the amino substituents, the carboxylic acid or pharmaceutically acceptable salt thereof substituents, the amide substituents, the carbamate substituents, the urea substituents, the ester substituents, the alkoxy substituents, the methoxy substituents, the ethoxy substituents, the ether substituents, the cyclic ether substituents, the C １ ~C ７ alkyl ether substituent, the cyclic C １ ~C ７ ether substituents, the aryl substituents, the heteroaryl substituents, the fused aryl substituents, the biaryl substituents, the fused aryl-heteroaryl substituents, the fused diaryl substituents, the fused aryl-heteroaryl substituents, the 5-membered heteroaryl substituents, the 6-membered heteroaryl substituents, the naphthyl substituents, the cycloalkyl substituents, the cyclopropyl substituents, the cyclobutyl substituents, the cyclopentyl substituents, the cyclohexyl substituents, the cycloheptyl substituents, the tert-butyl substituents, the bicyclic aliphatic substituents, the tricyclic aliphatic substituents, the adamantyl substituents, or any combination thereof; Linear C １ ~C １０ Alkyl, methyl, ethyl, branched chain C １ ~C １０ Alkyl, halogen, fluoro, chloro, bromo, iodo, hydroxyl, alkoxy, methoxy, ethoxy, carbamate, urea, amide, ester, amine, trifluoromethoxy, ether, C １ ~C ７ Alkyl ether, cyclic C １ ~C ７ ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic, tricyclic aliphatic, adamantyl, cyano, acetal, ketal, or any combination thereof 10. The compound of formula I of claim 1, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, optionally substituted independently with one or more of:

6. Compounds of Formula I: 【Chemical 662】 or a diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, During the ceremony, R １ teeth, C(O)OH, or C(O)OX (X is an organic cation, an inorganic cation, or Na ＋ , K. ＋ , Mg ２＋ , Ca ２＋ , Zn ２＋ or Mn ２＋ is), or 【Chemical Formula 663】 【Chemical 664】 ,or C(O)OR ３ (R ３ is a linear or branched alkyl, cycloalkyl, cyclic ether, or linear or branched alkyl ether, any of which is optionally independently substituted or or R ３ teeth, 【Chemical 665】 or R ３ teeth, 【Chemical Formula 666】 is), or C(O)N(R ４ R ５ ) (In the formula, R ４ is H, or R ４ is a straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally independently substituted; R ５ is H, or R ５ is a straight or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, any of which is optionally and independently substituted; or R ５ is S(O) ２ is alkyl, or R ５ is S(O) ２ CF ３ or R ５ is S(O) ２ NH ２ or R ５ 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 R ５ teeth, 【Chemical 667】 or R ５ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or R ５ is pyrrolidinyl, or R ５ is 2-tetrahydropyranyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl, or R ５ teeth, 【Chemical 668】 or R ５ is alkylaryl or benzyl, or R ５ teeth, 【Chemical 669】 or R ５ is 2-pyridyl, 3-pyridyl or 4-pyridyl, or R ５ teeth, 【Chemistry 670】 or R ５ teeth, 【671】 or R ５ teeth, 【Chemical 672】 or R ５ teeth, 【Chemical 673】 or R ５ teeth, 【Chemical 674】 is), or CN, or 【675】 and R ２ is NH ２ , NHC(O)OMe or NHMe, R ６ is H, C(O)Me or P(O)(OH) ２ and R ７ is a straight or branched chain alkyl, alkenyl, or alkynyl, any of which may be optionally and independently substituted; or R ７ teeth, 【Chemical 676】 【Chemical 677】 【Chemical 678】 【Chemical 679】 【Chemistry 680】 【681】 and The compound of Formula I is not buthionine sulfoximine (BSO) or a salt of BSO, a compound of Formula I, a diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing.

7. R １ but, C(O)OH, or C(O)OR ３ (R ３ is alkyl, straight or branched chain C １ ~C １０ Alkyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, n-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, cycloalkyl, C １ ~C １０ Cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, alkylcyclohexyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl, alkyl ether, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypropyl, cyclic alkyl ether, tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, tetrahydrofuranyl, 2-tetrahydrofuranyl, 2-tetrahydrofuranyl, alkylaryl, benzyl, any of which may contain one or more deuterium atoms, straight or branched C １ ~C １０ alkyl, one or more halogens, one or more fluoro, one or more chloro, one or more bromo, one or more iodo, aryl, C ６ Aryl, C １０ Aryl, heteroaryl, C １ ~C ７ and optionally independently substituted with alkylcycloalkyl, unsubstituted tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, or 4-tetrahydropyranyl, or any combination thereof.

7. The compound of formula I of claim 6, wherein:

8. R １ But C(O)N(R ４ R ５ ) and R ５ but, Linear or branched chain C １ ~C １０ alkyl, methyl, ethyl, propyl, or butyl, any of which may contain one or more deuterium atoms, straight or branched C １ ~C １０ 10. The compound of formula I of claim 6, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, optionally or independently substituted with alkyl, one or more halo, one or more fluoro, one or more chloro, one or more iodo, one or more or any combination thereof.

9. R １ But C(O)N(R ４ R ５ ) and R ５ is heteroaryl, 2-pyridyl, 3-pyridyl or 4-pyridyl or R ５ But S(O) ２ 7. The compound of formula I of claim 6, wherein R is Me, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing.

10. R ７ is a straight chain or branched chain C １ ~C １０ Alkyl, straight or branched chain C １ ~C １０ Alkenyl or straight or branched chain C １ ~C １０ alkynyl, any of which may have an alkyl ring or alkyl ether ring, and these rings are the same as those described above in connection with the straight or branched chain C １ ~C １０ Alkyl, the straight or branched chain C １ ~C １０ Alkenyl or the straight or branched chain C １ ~C １０ Any of the above containing one carbon atom of alkynyl Deuterium, linear C １ ~C １０ Alkyl, methyl, ethyl, branched chain C １ ~C １０ Alkyl, halogen, fluoro, chloro, bromo, iodo, hydroxyl, amino, carboxylic acid or a pharmaceutically acceptable salt thereof, amide, carbamate, urea, ester, alkoxy, methoxy, ethoxy, trifluoromethoxy, ether, cyclic ether, linear or branched C １ ~C ７ Alkyl ether, cyclic C １ ~C ７ alkyl 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, tricyclic aliphatic, adamantyl, cyano, acetal, ketal, or any combination thereof may be independently substituted by one or more substituents, The linear C １ ~C １０ the alkyl substituent, the methyl substituent, the ethyl substituent, the branched chain C １ ~C １０ alkyl substituents, the hydroxyl substituents, the amino substituents, the carboxylic acid or pharmaceutically acceptable salt thereof substituents, the amide substituents, the carbamate substituents, the urea substituents, the ester substituents, the alkoxy substituents, the methoxy substituents, the ethoxy substituents, the ether substituents, the cyclic ether substituents, the linear or branched C １ ~C ７ alkyl ether substituent, the cyclic C １ ~C ７ ether substituents, the aryl substituents, the heteroaryl substituents, the fused aryl substituents, the biaryl substituents, the fused aryl-heteroaryl substituents, the fused diaryl substituents, the fused aryl-heteroaryl substituents, the 5-membered heteroaryl substituents, the 6-membered heteroaryl substituents, the naphthyl substituents, the cycloalkyl substituents, the cyclopropyl substituents, the cyclobutyl substituents, the cyclopentyl substituents, the cyclohexyl substituents, the cycloheptyl substituents, the tert-butyl substituents, the bicyclic aliphatic substituents, the tricyclic aliphatic substituents, the adamantyl substituents, or any combination thereof; Deuterium, linear C １ ~C １０ Alkyl, methyl, ethyl, branched chain C １ ~C １０ Alkyl, halogen, fluoro, chloro, bromo, iodo, hydroxyl, alkoxy, methoxy, ethoxy, carbamate, urea, amide, ester, amine, trifluoromethoxy, ether, linear or branched C １ ~C ７ Alkyl ether, cyclic C １ ~C ７ ether, trihalomethyl, trifluoromethyl, aryl, heteroaryl, 5-membered heteroaryl, 6-membered heteroaryl, naphthyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tert-butyl, bicyclic aliphatic, tricyclic aliphatic, adamantyl, cyano, acetal, ketal, or any combination thereof 10. The compound of formula I of claim 6, a diastereomer or enantiomer thereof, a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, optionally substituted independently with one or more of:

11. R １ but, 【682】 10. A compound of formula I according to claim 1 or claim 6, wherein:

12. R １ but, 【683】 10. A compound of formula I according to claim 1 or claim 6, wherein:

13. R ２ But NH ２ 10. A compound of formula I according to claim 1 or claim 6, wherein:

14. R ６ is H, a diastereomer or enantiomer as described above, or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above.

15. R ７ but 【Chemical 684】 【Chemistry 685】 【Hua 686】 【687】 【Hua 688】 【689】 10. A compound of formula I according to claim 1 or claim 6, wherein:

16. below: 【690】 【Chemical Formula 691】 【Chemical Formula 692】 【Chemical Formula 693】 【Chemical Formula 694】 【Chemical Formula 695】 【Chemical Formula 696】 【Chemical Formula 697】 【Chemical 698】 【Chemical Formula 699】 【Chemical 700】 【Chemistry 701】 【Chemistry 702】 【Chemistry 703】 【Chemistry 704】 【Chemistry 705】 【Chemistry 706】 【Chemistry 707】 【Chemistry 708】 【Chemistry 709】 【Chemistry 710】 【Chemical 711】 【Chemical 712】 or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, selected from the group consisting of:

17. below: 【Chemical 713】 【Chemical 714】 【Chemistry 715】 【Chemical 716】 【Hua717】 【Chemical 718】 【Chemical 719】 or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, selected from the group consisting of:

18. Compound of Formula II 【Hua720】 , a diastereomer or enantiomer of a 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 deuterium, halogen, fluorine, chlorine, straight or branched chain C １ ~C １０ straight or branched chain C optionally independently substituted with substituents selected from the group consisting of alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and any combination thereof; １ , C ２ , C ３ , C ４ , C ５ , C ６ , C ７ , C ８ , C ９ or C １０ A compound of Formula II, a diastereomer or enantiomer of a compound of Formula II, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein:

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 to 18, any diastereomer or enantiomer thereof, or a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, and a pharmaceutically acceptable excipient, diluent, or carrier.

20. 20. The pharmaceutical composition of claim 19 in unit dosage form.

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

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

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

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

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

26. 25. The kit of claim 24, wherein the container is an IV bag.

27. 25. The kit of claim 24, wherein the container is disposable.

28. 25. The kit of claim 24, wherein the container is a single-use container.

29. 25. The kit of claim 24, wherein the container is a resealable container.

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

31. 20. A method of treating cancer in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula I, a compound of formula II, or a compound of any one of claims 1 to 18, any diastereomer or enantiomer 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. 32. The method of claim 30 or claim 31, wherein the administering step is selected from the group consisting of oral, injection; subcutaneous, intratumoral; systemic, topical, intravenous, intraperitoneal, intramuscular, and any combination thereof.

33. 24. A method of modulating ferroptosis in a tissue, comprising contacting said tissue with the pharmaceutical composition of any one of claims 19 to 23 in an amount effective to modulate said ferroptosis in said tissue.

34. 34. The method of claim 33, wherein the tissue is contained in a subject.

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

36. 36. The method of claim 34 or 35, wherein the subject is a mammal.

37. 37. The method of claim 36, wherein the subject is a human.

38. 38. The method of any one of claims 30-37, wherein the administering or contacting step is once daily, twice daily, three times daily, weekly, once every two weeks, once every three weeks, monthly, once every six months, once a year, or lifelong, as needed.

39. 39. The method of any one of claims 30-38, wherein the therapeutically effective amount or the effective amount is in the range of about 0.001 mg to about 25,000 mg.

40. below: 【Hua721】 【Chemical 722】 【Chemical 723】 【Chemical 724】 【Chemical 725】 【Chemical 726】 【Hua727】 【Chemical 728】 【Chemical 729】 【Chemistry 730】 【Hua731】 【Chemical 732】 【Chemical 733】 【Chemical 734】 【Chemical Formula 735】 【Chemical 736】 【Hua737】 【Chemical 738】 【Chemical 739】 【Chemical 740】 【Chemical 741】 【Chemical Formula 742】 【Chemical 743】 【Chemical 744】 【Chemical 745】 【Chemical 746】 【Hua747】 【Chemical 748】 【Chemical 749】 【Chemistry 750】 【Chemistry 751】 【Chemical 752】 【Chemical 753】 【Chemical 754】 【Chemistry 755】 【Chemical 756】 or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, selected from the group consisting of:

41. below: 【Chemical 757】 【Chemical Formula 758】 【Chemical 759】 【Hua760】 【Chemical 761】 【Chemical 762】 【Chemical 763】 【Chemical 764】 【Chemical 765】 【Chemical 766】 【Chemical 767】 【Chemical 768】 【Chemical 769】 【Chemical 770】 or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, selected from the group consisting of:

42. below: 【Chemical 771】 or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, selected from the group consisting of:

43. Compound of Formula XVIII: 【Chemical Formula 772】 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 R １ , R ２ or R ３ are independently H, linear or branched C １ ~C １０ Alkyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １０ Aryl, C ３ ~C １０ Heteroaryl, biphenyl, halogenated biphenyl, indole, triazole, isothiazole, oxazoline, linear or branched C １ ~C ６ Alkyl ether, —CH ３ , phenyl, —C(O)OR ５ , —C(O)NH ２ , -O-, -S-, -OH, -NH ２ , —NH—, halogen, —CF ３ , -CN, -F, -Cl, -Br, -I, or R １ and R ２ , R ２ and R ３ or R １ and R ３ Together, C ３ ~C ６ Forming a cycloalkyl, ３ ~C ６ Cycloalkyl is a linear or branched C １ ~C ６ Alkyl, C １ ~C ６ Cycloalkyl, halogen, —CF ３ or optionally substituted by -F; or R １ and R ２ and R ３ Together, C ３ ~C ６ forming a cycloheteroaryl, Each R １ , R ２ or R ３ represents deuterium, halogen, fluorine, -CF ３ , chlorine, linear or branched chain C １ ~C １０ Alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, C ３ ~C ６ Cycloalkyl, phenyl, halogenated phenyl, biphenyl, halogenated biphenyl, isothiazole, triazole, furan, oxazoline, C ３ ~C ６ each independently optionally substituted with substituents selected from the group consisting of heteroaryl, urea, anhydride, and any combination thereof; R ４ is H or linear or branched C １ ~C ６ is alkyl, R ５ is at least one heteroatom, halogen or C １ ~C ３ Linear or branched C optionally substituted with alkyl ether １ ~C １０ A compound of Formula XVIII, a diastereomer or enantiomer of a compound of Formula XVIII, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein: XVIII is alkyl.

44. Compound of Formula XIX: 【Chemical 773】 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 R １ , R ２ or R ３ are independently H, linear or branched C １ ~C １０ Alkyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １０ Aryl, C ３ ~C １０ Heteroaryl, biphenyl, halogenated biphenyl, indole, triazole, isothiazole, oxazoline, linear or branched C １ ~C ６ Alkyl ether, —C(O)OR ５ , —C(O)NH ２ , -O-, -S-, -OH, -NH ２ , —NH—, halogen, —CF ３ , -CN, -F, -Cl, -Br, -I, or R １ and R ２ , R ２ and R ３ or R １ and R ３ Together, C ３ ~C ６ Forming a cycloalkyl, ３ ~C ６ Cycloalkyl is a linear or branched C １ ~C ６ Alkyl, C １ ~C ６ Cycloalkyl, halogen, —CF ３ or optionally substituted by -F; or R １ and R ２ and R ３ Together, C ３ ~C ６ forming a cycloheteroaryl, Each R １ , R ２ or R ３ represents deuterium, halogen, fluorine, -CF ３ , chlorine, linear or branched chain C １ ~C １０ Alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, C ３ ~C ６ Cycloalkyl, phenyl, halogenated phenyl, biphenyl, halogenated biphenyl, isothiazole, triazole, furan, oxazoline, C ３ ~C ６ each independently optionally substituted with substituents selected from the group consisting of heteroaryl, urea, anhydride, and any combination thereof; R ４ is H or linear or branched C １ ~C ６ is alkyl, R ５ is at least one heteroatom, halogen or C １ ~C ３ Linear or branched C optionally substituted with alkyl ether １ ~C １０ A compound of Formula XIX, a diastereomer or enantiomer of a compound of Formula XIX, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing, wherein: X is alkyl.

45. Compound of Formula XX: 【Chemical 774】 A diastereomer or enantiomer of a compound of formula XX, or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, wherein in the compound of formula XX: Each R １ , R ２ or R ３ are independently H, linear or branched C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １０ Aryl, C ５ ~C ６ Heteroaryl, biphenyl, halogenated biphenyl, triazole, isothiazole, oxazoline, linear or branched C １ ~C ６ Alkyl ether, —C(O)OR ５ , —OH, —NH ２ , —NH—, halogen, —CF ３ , -CN, -F, or or R １ and R ２ , R ２ and R ３ or R １ and R ３ Together, C ３ ~C ６ Forming a cycloalkyl, ３ ~C ６ Cycloalkyl is a linear or branched C １ ~C ６ Alkyl, C １ ~C ６ Cycloalkyl, halogen, —CF ３ or optionally substituted by —F, Each R １ , R ２ or R ３ represents deuterium, halogen, fluorine, -CF ３ , chlorine, linear or branched chain C １ ~C １０ Alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, C ３ ~C ６ Cycloalkyl, phenyl, halogenated phenyl, biphenyl, halogenated biphenyl, isothiazole, triazole, oxazoline, C ３ ~C ６ each independently optionally substituted with substituents selected from the group consisting of heteroaryl and any combination thereof; R ４ is H or linear or branched C １ ~C ６ is alkyl, R ５ is at least one heteroatom, halogen or C １ ~C ３ Linear or branched C optionally substituted with alkyl ether １ ~C １０ A compound of Formula XX, a diastereomer or enantiomer of a compound of Formula XX, or a pharmaceutically acceptable salt of any of the above, or a deuterated derivative of any of the above, wherein:

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

47. 47. The pharmaceutical composition of claim 46, in unit dosage form.

48. 48. The pharmaceutical composition of claim 46 or claim 47, further comprising an additional active agent or a pharmaceutically acceptable salt thereof.

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

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

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

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

53. 52. The kit of claim 51, wherein the container is an IV bag.

54. 52. The kit of claim 51, wherein the container is disposable.

55. 52. The kit of claim 51, wherein the container is a single-use container.

56. 52. The kit of claim 51, wherein the container is a resealable container.

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

58. 43. A method of treating cancer in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound of Formula XVIII, Formula XIX, Formula XX, or a compound of any one of claims 40-42, any diastereomer or enantiomer 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. 59. The method of claim 58, wherein the cancer is a carcinoma, a sarcoma, or a melanoma.

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

61. 59. The method of claim 58, wherein the carcinoma is liver cancer.

62. 59. The method of claim 58, wherein the cancer is a SWI / SNF-deficient complex cancer.

63. 63. The method of any one of claims 58-62, wherein the administering step is selected from the group consisting of oral, injection; subcutaneous, intratumoral; systemic, topical, intravenous, intraperitoneal, intramuscular, and any combination thereof.

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

65. 65. The method of claim 64, wherein the tissue is contained in a subject.

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

67. 59. The method of claim 57 or 58, wherein the subject is a mammal.

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

69. 69. The method of any one of claims 57-68, wherein said administering or contacting step is once daily, twice daily, three times daily, weekly, once every two weeks, once every three weeks, monthly, once every six months, once a year or lifelong, as needed.

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

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

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

73. 73. The method of claim 71 or 72, wherein the disease or condition is fibrosis or kidney damage.

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