Compositions and methods for inducing ferroptosis

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 forgoing,
• wherein:
• R1 is:
• C(O)OH;
• or
• C(O)OX, wherein X is an organic cation, an inorganic cation, Na+, K+, Mg2+, Ca2+, Zn2+, or Mn2+;
• or
• or
• C(O)OR3, wherein R3 is a linear or branched alkyl, a cycloaklyl, a cyclic ether, or a linear or branched alkyl ether, wherein any of these is optionally and independently substituted;
• or
• R3 is
• or
• R3 is
• or
• C(O)N(R4R5)
• wherein R4 is H;
• or
• R4 is a linear or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• wherein any of these is optionally and independently substituted;
• and
• R5 is H;
• or
• R5 is a linear or branched chain alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• wherein any of these is optionally and independently substituted;
• or
• R5 is S(O)2alkyl;
• or
• R5 is S(O)2CF3;
• or
• R5 is S(O)2NH2;
• or
• R5 is S(O)2cycloalkyl, S(O)2cyclopropyl, S(O)2cyclobutyl, S(O)2cyclopentyl, S(O)2cyclohexyl, or S(O)2cycloheptyl;
• or
• R5 is
• or
• R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;
• or
• R5 is pyrrolidinyl;
• or
• R5 is 2-tetrahydropyranyl, 3-tetrahydropyranyl;
• or 4-tetrahydropyranyl;
• or
• R5 is
• or
• R5 is alkylaryl or benzyl;
• or
• R5 is
• or
• R5 is 2-pyridyl, 3-pyridyl or 4-pyridyl;
• or
• R5 is
• or
• R5 is
• or
• R5 is
• or
• R5 is
• or
• R5 is
• or
• CN;
• or
• and
• R2 is:
• NH2, NHC(O)OMe, or NHMe;
• and
• R6 is:
• H, C(O)Me, or P(O)(OH)2;
• and
• R7 is:
• linear or branched chain:
• alkyl, alkenyl, or alkynyl, any of which can optionally and independently be substituted;
• or
• R7 is:
• and wherein the compound of Formula I is not buthionine sulfoximine (BSO) or a salt of BSO.

A compound of Formula II

• a diastereomer or an enantiomer of the compound of Formula II, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing;
• wherein in the compound of Formula II, R is a:
• C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10 linear or branched chain alkyl, optionally and independently substituted by a substituent selected from the group consisting of:
• a deuterium, a halogen, a fluorine, a chlorine, a C1-C10 linear or branched chain alkyl, a methyl, an ethyl, a propyl, an iso-propyl, a butyl, an isobutyl, a sec-butyl, a tert-butyl, and any combination of these.

A compound of Formula XVIII:

• a diastereomer or an enantiomer of the compound of Formula XVIII, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing;
• wherein in the compound of Formula XVIII:
• each R1, R2, or R3 is independently:
• H, a C1-C10 linear or branched alkyl, a C3-C6 cycloalkyl, a C6-C10 aryl, a C3-C10 heteroaryl, a biphenyl, a halogenated biphenyl, an indole, a triazole, an isothiazole, an oxazoline, a C1-C6 linear or branched alkyl ether, —CH3, phenyl, —C(O)OR5, —C(O)NH2, —O—, —S—, —OH, —NH2, —NH—, a halogen, —CF3, —CN, —F, —Cl, —Br, —I,
• or R1 and R2, R2 and R3, or R1 an R3 are taken together to form a C3-C6 cycloalkyl and wherein the C3-C6 cycloalkyl may be optionally substituted with a C1-C6 linear or branched alkyl, a C1-C6 cycloalkyl, a halogen, —CF3, or —F,
• or R1 and R2 and R3 are taken together to form a C3-C6 cycloheteroaryl;
• and
• wherein each R1, R2, or R3 is each independently and optionally substituted by a substituent selected from the group consisting of:
• a deuterium, a halogen, a fluorine, —CF3, a chlorine, a C1-C10 linear or branched chain alkyl, a methyl, an ethyl, a propyl, an iso-propyl, a butyl, an isobutyl, a sec-butyl, a tert-butyl, a C3-C6 cycloalkyl, a phenyl, a halogenated phenyl, a biphenyl, a halogenated biphenyl, an isothiazole, a triazole, a furan, an oxazoline, a C3-C6 heteroaryl, a urea, an anhydride and any combination of these;
• wherein R4 is H, or a C1-C6 linear or branched alkyl;
• and
• wherein R5 is a C1-C10 linear or branched alkyl optionally substituted with at least one heteroatom, a halogen, or a C1-C3 alkyl ether.

A compound of Formula XIX:

• a diastereomer or an enantiomer of the compound of Formula XIX, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing;
• wherein in the compound of Formula XIX:
• each R1, R2, or R3 is independently:
• H, a C1-C10 linear or branched alkyl, a C3-C6 cycloalkyl, a C6-C10 aryl, a C3-C10 heteroaryl, a biphenyl, a halogenated biphenyl, an indole, a triazole, an isothiazole, an oxazoline, a C1-C6 linear or branched alkyl ether, —C(O)OR5, —C(O)NH2, —O—, —S—, —OH, —NH2, —NH—, a halogen, —CF3, —CN, —F, —Cl, —Br, —I,
• or R1 and R2, R2 and R3, or R1 an R3 are taken together to form a C3-C6 cycloalkyl and wherein the C3-C6 cycloalkyl may be optionally substituted with a C1-C6 linear or branched alkyl, a C1-C6 cycloalkyl, a halogen, —CF3, or —F,
• or R1 and R2 and R3 are taken together to form a C3-C6 cycloheteroaryl;
• and
• wherein each R1, R2, or R3 is each independently and optionally substituted by a substituent selected from the group consisting of:
• a deuterium, a halogen, a fluorine, —CF3, a chlorine, a C1-C10 linear or branched chain alkyl, a methyl, an ethyl, a propyl, an iso-propyl, a butyl, an isobutyl, a sec-butyl, a tert-butyl, a C3-C6 cycloalkyl, a phenyl, a halogenated phenyl, a biphenyl, a halogenated biphenyl, an isothiazole, a triazole, a furan, an oxazoline, a C3-C6 heteroaryl, a urea, an anhydride and any combination of these;
• wherein R4 is H, or a C1-C6 linear or branched alkyl;
• and
• wherein R5 is a C1-C10 linear or branched alkyl optionally substituted with at least one heteroatom, a halogen, or a C1-C3 alkyl ether.

A compound of Formula XX:

• a diastereomer or an enantiomer of the compound of Formula XX, or a pharmaceutically acceptable salt of any of the foregoing, or a deuterated derivative of any of the foregoing;
• wherein in the compound of Formula XX:
• each R1, R2, or R3 is independently:
• H, a C1-C4 linear or branched alkyl, a C3-C6 cycloalkyl, a C6-C10 aryl, a C5-C6 heteroaryl, a biphenyl, a halogenated biphenyl, a triazole, an isothiazole, an oxazoline, a C1-C6 linear or branched alkyl ether, —C(O)OR5, —OH, —NH2, —NH—, a halogen, —CF3, —CN, —F,
• or R1 and R2, R2 and R3, or R1 an R3 are taken together to form a C3-C6 cycloalkyl and wherein the C3-C6 cycloalkyl may be optionally substituted with a C1-C6 linear or branched alkyl, a C1-C6 cycloalkyl, a halogen, —CF3, or —F;
• and
• wherein each R1, R2, or R3 is each independently and optionally substituted by a substituent selected from the group consisting of:
• a deuterium, a halogen, a fluorine, —CF3, a chlorine, a C1-C10 linear or branched chain alkyl, a methyl, an ethyl, a propyl, an iso-propyl, a butyl, an isobutyl, a sec-butyl, a tert-butyl, a C3-C6 cycloalkyl, a phenyl, a halogenated phenyl, a biphenyl, a halogenated biphenyl, an isothiazole, a triazole, an oxazoline, a C3-C6 heteroaryl, and any combination of these;
• wherein R4 is H, or a C1-C6 linear or branched alkyl;
• and
• wherein R5 is a C1-C10 linear or branched alkyl optionally substituted with at least one heteroatom, a halogen, or a C1-C3 alkyl ether.