Compositions and methods for the prevention and/or treatment of mitochondrial disease, including friedreich's ataxia

A method for treating or preventing Friedreich's ataxia or the signs or symptoms of reduced frataxin levels or activity in a mammalian subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula E-F, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and/or solvates thereof, wherein

• E is 21 or 22:
• and F is 19 or 20:
• wherein,
• J is O, S or N—R11;
• K is absent or —(CR12R13)—;
• L is —(CR12R13)—;
• each W is independently C (carbon) or N (nitrogen) and wherein for each use of W═W, the bond between each W can be a single bond or double bond and further provided that if a single bond, each C (carbon) atom will have a hydrogen atom linked hereto in addition to one of R4, R5, R6 or R7 and in either case each of R4, R5, R6 and R7 attached thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl and C1-C6 alkoxy, and if W is N (nitrogen), each of R4, R5, R6 and R7 attached thereto is independently absent (if W═W is a double bond) or selected from H, D and C1-C6 alkyl (if W═W is a single bond);
• each X is independently a group of formula —(CR12R13)—;
• each Y is independently absent or a group of formula —(CR12R13)—;
• each of R1, R2 and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring;
• each R8 and R9 is each independently H, D, F, Cl, Br, I or C1-C4 alkyl;
• R10 is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• R11 is H, D or C1-C6 alkyl;
• each of R12, R13 and R14 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• R20 is H, D, F or C1-C12 alkyl;
• each R21 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl;
• n is an integer from 0 to 12;
• *** indicates the point of attachment of E to F and ** indicates the point of attachment of F to E;
• and further provided that at least one group of formula R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R20 or R21 comprises at least one fluorine atom.

A method for reducing mitochondrial iron in a mammalian subject having or suspected of having Friedreich's ataxia, the method comprising administering to the subject a therapeutically effective amount of a compound of formula E-F, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and/or solvates thereof, wherein

• E is 21 or 22:
• and F is 19 or 20:
• wherein,
• J is O, S or N—R11;
• K is absent or —(CR12R13)—;
• L is —(CR12R13)—;
• each W is independently C (carbon) or N (nitrogen) and wherein for each use of W═W, the bond between each W can be a single bond or double bond and further provided that if a single bond, each C (carbon) atom will have a hydrogen atom linked hereto in addition to one of R4, R5, R6 or R7 and in either case each of R4, R5, R6 and R7 attached thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl and C1-C6 alkoxy, and if W is N (nitrogen), each of R4, R5, R6 and R7 attached thereto is independently absent (if W═W is a double bond) or selected from H, D and C1-C6 alkyl (if W═W is a single bond);
• each X is independently a group of formula —(CR12R13)—;
• each Y is independently absent or a group of formula —(CR12R13)—;
• each of R1, R2 and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring;
• each R8 and Ry is each independently H, D, F, Cl, Br, I or C1-C4 alkyl;
• R10 is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• R11 is H, D or C1-C6 alkyl;
• each of R12, R13 and R14 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• R20 is H, D, F or C1-C12 alkyl;
• each R21 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl;
• n is an integer from 0 to 12;
• *** indicates the point of attachment of E to F and ** indicates the point of attachment of F to E;
• and further provided that at least one group of formula R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R20 or R21 comprises at least one fluorine atom.

A method for reducing or inhibiting lipoxygenase 15 activity in a mammalian subject having or suspected of having Friedreich's ataxia, the method comprising administering to the subject a therapeutically effective amount of a compound of formula E-F, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and/or solvates thereof, wherein

• E is 21 or 22:
• and F is 19 or 20:
• wherein,
• J is O, S or N—R11;
• K is absent or —(CR12R13)—;
• L is —(CR12R13)—;
• each W is independently C (carbon) or N (nitrogen) and wherein for each use of W═W, the bond between each W can be a single bond or double bond and further provided that if a single bond, each C (carbon) atom will have a hydrogen atom linked hereto in addition to one of R4, R5, R6 or R7 and in either case each of R4, R5, R6 and R7 attached thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl and C1-C6 alkoxy, and if W is N (nitrogen), each of R4, R5, R6 and R7 attached thereto is independently absent (if W═W is a double bond) or selected from H, D and C1-C6 alkyl (if W═W is a single bond);
• each X is independently a group of formula —(CR12R13)—;
• each Y is independently absent or a group of formula —(CR12R13)—;
• each of R1, R2 and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring;
• each R8 and R9 is each independently H, D, F, Cl, Br, I or C1-C4 alkyl;
• R10 is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• R11 is H, D or C1-C6 alkyl;
• each of R12, R13 and R14 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• R20 is H, D, F or C1-C12 alkyl;
• each R21 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl;
• n is an integer from 0 to 12;
• *** indicates the point of attachment of E to F and ** indicates the point of attachment of F to E;
• and further provided that at least one group of formula R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R20 or R21 comprises at least one fluorine atom.

A method for treating Complex I deficiency in a mammalian subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula E-F, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and/or solvates thereof, wherein

• E is 21 or 22:
• and F is 19 or 20:
• wherein,
• J is O, S or N—R11;
• K is absent or —(CR12R13)—;
• L is —(CR12R13)—;
• each W is independently C (carbon) or N (nitrogen) and wherein for each use of W═W, the bond between each W can be a single bond or double bond and further provided that if a single bond, each C (carbon) atom will have a hydrogen atom linked hereto in addition to one of R4, R5, R6 or R7 and in either case each of R4, R5, R6 and R7 attached thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl and C1-C6 alkoxy, and if W is N (nitrogen), each of R4, R5, R6 and R7 attached thereto is independently absent (if W═W is a double bond) or selected from H, D and C1-C6 alkyl (if W═W is a single bond);
• each X is independently a group of formula —(CR12R13)—;
• each Y is independently absent or a group of formula —(CR12R13)—;
• each of R1, R2 and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring;
• each R8 and R9 is each independently H, D, F, Cl, Br, I or C1-C4 alkyl;
• R10 is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• R11 is H, D or C1-C6 alkyl;
• each of R12, R13 and R14 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• R20 is H, D, F or C1-C12 alkyl;
• each R21 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl;
• n is an integer from 0 to 12;
• *** indicates the point of attachment of E to F and ** indicates the point of attachment of F to E;
• and further provided that at least one group of formula R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R20 or R21 comprises at least one fluorine atom.

A method for reducing or inhibiting ferroptosis in a mammalian subject having or suspected of having Friedreich's ataxia, the method comprising administering to the subject a therapeutically effective amount of a compound of formula E-F, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and/or solvates thereof, wherein

• E is 21 or 22:
• and F is 19 or 20:
• wherein,
• J is O, S or N—R11;
• K is absent or —(CR12R13)—;
• L is —(CR12R13)—;
• each W is independently C (carbon) or N (nitrogen) and wherein for each use of W═W, the bond between each W can be a single bond or double bond and further provided that if a single bond, each C (carbon) atom will have a hydrogen atom linked hereto in addition to one of R4, R5, R6 or R7 and in either case each of R4, R5, R6 and R7 attached thereto is independently selected from H, D, F, Cl, Br, I, C1-C6 alkyl and C1-C6 alkoxy, and if W is N (nitrogen), each of R4, R5, R6 and R7 attached thereto is independently absent (if W═W is a double bond) or selected from H, D and C1-C6 alkyl (if W-W is a single bond);
• each X is independently a group of formula —(CR12R13)—;
• each Y is independently absent or a group of formula —(CR12R13)—;
• each of R1, R2 and R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• or R1 and R2 together form a 5-membered carbocyclic ring, a 5-membered heterocyclic ring, a 5-membered aromatic or heteroaromatic ring, or a 6-membered heterocyclic ring;
• each R8 and R9 is each independently H, D, F, Cl, Br, I or C1-C4 alkyl;
• R10 is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• R11 is H, D or C1-C6 alkyl;
• each of R12, R13 and R14 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• R20 is H, D, F or C1-C12 alkyl;
• each R21 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl;
• n is an integer from 0 to 12;
• *** indicates the point of attachment of E to F and ** indicates the point of attachment of F to E;
• and further provided that at least one group of formula R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R20 or R21 comprises at least one fluorine atom.