Compounds, compositions, and methods for modulating ferroptosis and treating excitotoxic disorders

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to formula (I):

• wherein:
• R1 and R2, are independently selected from the group consisting of no atom, H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-4alkyl, CF3, and combinations thereof;
• and
• R3 is independently selected from the group consisting of H, C1-12aliphatic, C1-6-alkyl-aryl and C1-6-alkyl-heteroaryl;
• or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof,
• with the proviso that:
• when R3 is ethyl, R1 and R2 cannot be both H, O, or
• and
• when R3 is ethyl and at least one of R1 or R2 is H, R1 or R2 cannot be

A method for treating or ameliorating the effects of a disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound having the structure of formula (I):

• wherein:
• R1 and R2, are independently selected from the group consisting of no atom, H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-4alkyl, CF3, and combinations thereof;
• and
• R3 is independently selected from the group consisting of H, C1-12aliphatic, C1-6-alkyl-aryl and C1-6-alkyl-heteroaryl;
• or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof,
• with the proviso that:
• when R3 is ethyl, R1 and R2 cannot be both H, O, or
• and
• when R3 is ethyl and at least one of R1 or R2 is H, R1 or R2 cannot be

A method for treating or ameliorating the effects of a disorder in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound having the structure of formula (I):

• wherein:
• R1 and R2, are independently selected from the group consisting of no atom, H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-4alkyl, CF3, and combinations thereof;
• and
• R3 is independently selected from the group consisting of H, C1-12aliphatic, C1-6-alkyl-aryl and C1-6-alkyl-heteroaryl;
• or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof,
• with the proviso that:
• when R3 is ethyl, R1 and R2 cannot be both H, O, or
• and
• when R3 is ethyl and at least one of R1 or R2 is H, R1 or R2 cannot be

A method of modulating ferroptosis in a subject in need thereof comprising administering to the subject an effective amount of a ferroptosis inhibitor, which comprises a compound having the structure of formula (I):

• wherein:
• R1 and R2, are independently selected from the group consisting of no atom, H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-4alkyl, CF3, and combinations thereof;
• and
• R3 is independently selected from the group consisting of H, C1-12aliphatic, C1-6-alkyl-aryl and C1-6-alkyl-heteroaryl;
• or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof,
• with the proviso that:
• when R3 is ethyl, R1 and R2 cannot be both H, O, or
• and
• when R3 is ethyl and at least one of R1 or R2 is H, R1 or R2 cannot be

A method of reducing reactive oxygen species (ROS) in a cell comprising contacting a cell with a ferroptosis modulator, which comprises a compound having the structure of formula (I):

• wherein:
• R1 and R2, are independently selected from the group consisting of no atom, H, D, O, halo, C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl, wherein the C1-6alkyl, C1-6alkyl-aryl, C1-6alkyl-heteroaryl, C1-6alkenyl, C1-6alkenyl-aryl, and C1-6alkenyl-heteroaryl may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-4alkyl, CF3, and combinations thereof;
• and
• R3 is independently selected from the group consisting of H, C1-12aliphatic, C1-6-alkyl-aryl and C1-6-alkyl-heteroaryl;
• or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof,
• with the proviso that:
• when R3 is ethyl, R1 and R2 cannot be both H, O, or
• and
• when R3 is ethyl and at least one of R1 or R2 is H, R1 or R2 cannot be

A compound according to formula (IV):

• wherein:
• R1 is selected from the group consisting of aryl, C1-6alkyl-aryl, and C3-10carbocycle, wherein the aryl, C1-6alkyl-aryl, and C3-10carbocycle may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-6alkyl, CF3, and combinations thereof;
• R2 is a triazole, an oxazole, an oxadiazole, or a ketone;
• and
• R3 is a C3-12carbocycle, optionally substituted with C1-10 alkyl or halo;
• or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to formula (IV):

• wherein:
• R1 is selected from the group consisting of aryl, C1-6alkyl-aryl, and C3-10carbocycle, wherein the aryl, C1-6alkyl-aryl, and C3-10carbocycle may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-6alkyl, CF3, and combinations thereof;
• R2 is a triazole, an oxazole, an oxadiazole, or a ketone;
• and
• R3 is a C3-12carbocycle, optionally substituted with C1-10 alkyl or halo;
• or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

A method for treating or ameliorating the effects of a disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound having the structure of formula (IV):

• wherein:
• R1 is selected from the group consisting of aryl, C1-6alkyl-aryl, and C3-10carbocycle, wherein the aryl, C1-6alkyl-aryl, and C3-10carbocycle may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-6alkyl, CF3, and combinations thereof;
• R2 is a triazole, an oxazole, an oxadiazole, or a ketone;
• and
• R3 is a C3-12carbocycle, optionally substituted with C1-10 alkyl or halo;
• or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

A method for treating or ameliorating the effects of a disorder in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound having the structure of formula (IV):

• wherein:
• R1 is selected from the group consisting of aryl, C1-6alkyl-aryl, and C3-10carbocycle, wherein the aryl, C1-6alkyl-aryl, and C3-10carbocycle may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-6alkyl, CF3, and combinations thereof;
• R2 is a triazole, an oxazole, an oxadiazole, or a ketone;
• and
• R3 is a C3-12carbocycle, optionally substituted with C1-10 alkyl or halo;
• or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

A method of modulating ferroptosis in a subject in need thereof comprising administering to the subject an effective amount of a ferroptosis inhibitor, which comprises a compound having the structure of formula (IV):

• wherein:
• R1 is selected from the group consisting of aryl, C1-6alkyl-aryl, and C3-10carbocycle, wherein the aryl, C1-6alkyl-aryl, and C3-10carbocycle may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-6alkyl, CF3, and combinations thereof;
• R2 is a triazole, an oxazole, an oxadiazole, or a ketone;
• and
• R3 is a C3-12carbocycle, optionally substituted with C1-10 alkyl or halo;
• or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.

A method of reducing reactive oxygen species (ROS) in a cell comprising contacting a cell with a ferroptosis modulator, which comprises a compound having the structure of formula (IV):

• wherein:
• R1 is selected from the group consisting of aryl, C1-6alkyl-aryl, and C3-10carbocycle, wherein the aryl, C1-6alkyl-aryl, and C3-10carbocycle may be optionally substituted with an atom or a group selected from the group consisting of halo, deuterium, C1-6alkyl, CF3, and combinations thereof;
• R2 is a triazole, an oxazole, an oxadiazole, or a ketone;
• and
• R3 is a C3-12carbocycle, optionally substituted with C1-10 alkyl or halo;
• or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.