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

A compound of formula X:

• wherein,
• each of R1′ and R2′ is independently C1-C3 alkyl;
• R3′ is H, D, F, —CH3, —CF3, —OCH3 or —OCF3;
• each Z is independently H, D or F;
• a is 1, 2, 3, 4, 5, 6, 7, 8 or 9;
• and
• each of R30, R31 and R32 is independently H, D or F, provided, however, that at least one of R30, R31 or R32 is F.

A compound of formula Y:

• wherein,
• each of R1′ and R2′ is independently C1-C3 alkyl;
• R3′ is H, D, F, —CH3, —CF3, —OCH3 or —OCF3;
• b is 1, 2 or 3;
• and
• each of R33 and R34 is independently H, D, F, —CH3, —CH2F, —CHF2, or —CHF3, provided, however, that at least one of R33 and R34 is selected from F, —CH2F, —CHF2, and —CF3.

A compound of formula C-B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, hydrates, and/or solvates thereof, wherein C is a group of formula 13 or 14:

• and B is a group of formula 3, 4, 5, 6, 7, 8, 9, 10, or 11:
• wherein,
• each Q is independently a group of formula —(CR12R13)—, O or Si(CH3)2, provided that each O and each Si(CH3)2 is not directly bonded to O or Si(CH3)2;
• each of R1 and R2 is independently H, D, or C1-C6 alkyl;
• or R1 and R2 together form a 5-membered heterocyclic ring or a 6-membered heterocyclic ring;
• R3 is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• each W is independently C (carbon) or N (nitrogen) and wherein for each use of WW, 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 where:
• (i) if W is C (carbon), each of R4, R5, R6 and R7 attached thereto is independently H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy, and (ii) if W is N (nitrogen), each of R4, R5, R6 and R7 attached thereto is independently absent or selected from H, D or C1-C6 alkyl;
• L is absent or —(CR12R13)—;
• each X is independently a group of formula —(CR12R13)—;
• each Y is independently absent or a group of formula —(CR12R13)—;
• each Z is independently a group of formula —(CR14)—;
• each of R8 and R9 is each independently H, D, F, Cl, Br, I, C1-C4 alkyl or C1-C8 alkoxy;
• or taken together R8 and R9, of a group of the formula —(CR8R9)—, —(CR8R9) or —(CR8R9R10), form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring;
• each R8′, R9′ and R10′ is independently Cl, Br, I or C1-C4 alkyl;
• or taken together R8′ and R9′ form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring;
• R10 is H, D, F, Cl, Br, I, C1-C6 alkyl or C1-C6 alkoxy;
• each R12, R13 and R14 is independently H, D, F, Cl, Br, I, C1-C8 alkyl, C1-C8 alkoxy, C3-C6 cycloalkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C6-C14 aryl or —NR22R23;
• or taken together R12 and R13, of a group of the formula —(CR12R13)—, form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring;
• each R19 is independently H, C1-C4 alkyl, (unsubstituted or substituted) benzyl, R24C(O)—, R24OC(O)—, R24R25NC(O)—, or (R24O)(R25O)P(O)—;
• R20 is H, D, F, or C1-C12 alkyl or C3-C6 cycloalkyl;
• each R21 is independently H, D, F, Cl, Br, I, or C1-C4 alkyl;
• each of R22 and R23 is independently H, D, C1-C4 alkyl;
• or taken together, the R22 and R23 of the group of formula —NR22R23 form a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring,
• each of R24 and R25 is independently H, D, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, arylheteroalkyl, heteroarylheteroalkyl or T, wherein T is —(CH2)w—(O)x—[(CH2CH2)—O]q—R26;
• R26 is H, methyl, ethyl, isopropyl, or tert-butyl;
• m is 0 or 1;
• n is an integer from 0 to 12, inclusive;
• p is an integer from 0 to 20, inclusive;
• q is 0, 1, 2, 3, 4, or 5;
• x is 0 or 1;
• w is 0, 1 or 2;
• provided that if x is 0, then w is 0;
• and if w is 0, then x is 0;
• and
• *** indicates the point of attachment of A to B and ** indicates the point of attachment of B to A;
• and further provided that:
• (i) at least one of R8, R9, or R10:
• (a) is F, or (b) is a group that comprises at least one fluorine atom;
• or (ii) at least one R8 and R9, of a group of the formula —(CR8R9)—, —(CR8R9) or —(CR8R9R10), taken together forms a 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring;
• or (iii) the compound of formula C—B is the hydroquinone form of a corresponding quinone that has a calculated Log D of 2 to 7, inclusive;
• or (iv) at least one R19 is R24C(O)—, R24OC(O)—, R24R25NC(O)—, or (R24O)(R25O)P(O)—.

A compound of formula X′:

• wherein,
• each of R1′ and R2′ is independently C1-C3 alkyl;
• R3′ is H, D, F, —CH3, —CF3, —OCH3 or —OCF3;
• each Z is independently H, D or F;
• a is 1, 2, 3, 4, 5, 6, 7, 8 or 9;
• and
• each of R30, R31 and R32 is independently H, D or F, provided, however, that at least one of R30, R31 or R32 is F.

A compound of formula Y′

• wherein,
• each of R1′ and R2′ is independently C1-C3 alkyl;
• R3′ is H, D, F, —CH3, —CF3, —OCH3 or —OCF3;
• b is 1, 2 or 3;
• and
• each of R33 and R34 is independently H, D, F, —CH3, —CF2F, —CHF2, or —CHF3, provided, however, that at least one of R33 and R34 is selected from F, —CF2F, —CHF2, and —CF3.

A compound of formula Z:

• wherein,
• each of R1′ and R2′ is independently C1-C3 alkyl;
• R3′ is H, D, F, —CH3, —CF3, —OCH3 or —OCF3;
• and
• u is 1, 2, 3, 4, 5, 6, 7, or 8.

A compound of formula Z′:

• wherein,
• each of R1′ and R2′ is independently C1-C3 alkyl;
• R3′ is H, D, F, —CH3, —CF3, —OCH3 or —OCF3;
• and
• u is 1, 2, 3, 4, 5, 6, 7 or 8.

A compound comprising a quinone head-group and an aliphatic tail-group, wherein;

• a) the quinone head-group comprises at least one C1-C4 alkoxy substituent;
• and
• b) the aliphatic tail-group comprises at least one fluorine atom;
• wherein,
• (i) the compound exhibits both:
• (x) complex I by-pass activity in cell culture;
• and (y) protection against ferroptosis in cells derived from a human diagnosed with Friedreich's ataxia;
• and
• (ii) the compound has a calculated or measured Log D of between 2 and 7, inclusive.

A compound comprising a hydroquinone head-group and an aliphatic tail-group, wherein;

• a) the hydroquinone head-group comprises at least one C1-C4 alkoxy substituent;
• and
• b) the aliphatic tail-group comprises at least one fluorine atom;
• wherein,
• (i) the compound exhibits both:
• (x) complex I by-pass activity in cell culture;
• and (y) protection against ferroptosis in cells derived from a human diagnosed with Friedreich's ataxia;
• and
• (ii) the compound, when oxidized to the quinone form, has a calculated or measured Log D of between 2 and 7, inclusive.

A compound comprising a quinone head-group and an aliphatic tail-group, wherein;

• c) the quinone head-group comprises at least one C1-C4 alkoxy substituent;
• and
• d) the aliphatic tail-group comprises at least one silicon atom;
• wherein,
• (i) the compound exhibits both:
• (x) complex I by-pass activity in cell culture;
• and (y) protection against ferroptosis in cells derived from a human diagnosed with Friedreich's ataxia;
• and
• (ii) the compound has a calculated or measured Log D of between 2 and 7, inclusive.

A compound comprising a hydroquinone head-group and an aliphatic tail-group, wherein;

• a) the hydroquinone head-group comprises at least one C1-C4 alkoxy substituent;
• and
• b) the aliphatic tail-group comprises at least one silicon atom;
• wherein,
• (i) the compound exhibits both:
• (x) complex I by-pass activity in cell culture;
• and (y) protection against ferroptosis in cells derived from a human diagnosed with Friedreich's ataxia;
• and
• (ii) the compound, when oxidized to the quinone form, has a calculated or measured Log D of between 2 and 7, inclusive.