Compositions and methods for the treatment of zellweger spectrum disorder

A method of treating Zellweger spectrum disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula II:

• or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing,
• wherein:
• X1 is O, S, or NR2;
• X2 is N or CR5;
• each R1 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy;
• or an optionally substituted —NR20NR30;
• each R2 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, or an optionally substituted C2-C8 alkenyl;
• each R5 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted C2-C8 alkenyl, an optionally substituted ═NR6, or an optionally substituted —NR20R30;
• each R20 and R30 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted 5-10 membered aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 3-10 membered cycloalkyl, or an optionally substituted 5-10 membered heterocyclyl;
• each R3 and R4 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy;
• an optionally substituted C2-C8 alkenyl, or a hydroxy;
• Y and Z independently is O, S, or NR2;
• n is 0, 1, 2, or 3;
• m is 0, 1, or 2;
• and
• p is 0, 1, 2, or 3.

A method of improving peroxisome assembly in a cell in need thereof comprising administering to the cell a therapeutically effective amount of a compound of Formula I:

• or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing,
• wherein:
• is a single or a double bond;
• X is NR2 or CR5R5 when is a single bond or X is N or CR5 when is a double bond;
• X5 is N or CR5, provided that at least one of X and X5 is N or NR2;
• each R2 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, or an optionally substituted C2-C8 alkenyl;
• each R5 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted C2-C8 alkenyl, an optionally substituted ═NR6, or an optionally substituted —NR20R30;
• each R1 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy;
• or an optionally substituted —NR20R30;
• each R20 and R30 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted 5-10 membered aryl, an optionally substituted 5-10 membered heteroaryl;
• an optionally substituted 3-10 membered cycloalkyl, or an optionally substituted 5-10 membered heterocyclyl;
• each R6 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, or hydroxy;
• and
• m is 0, 1, or 2.

A method of improving peroxisome assembly in a cell in need thereof comprising administering to the cell a therapeutically effective amount of a compound of Formula II:

• or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing,
• wherein:
• X1 is O, S, or NR2;
• X2 is N or CR5;
• each R1 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy;
• or an optionally substituted —NR20NR30;
• each R2 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C5 alkoxy, or an optionally substituted C2-C8 alkenyl;
• each R5 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C5 alkoxy, an optionally substituted C2-C8 alkenyl, an optionally substituted ═NR6, or an optionally substituted —NR20R30;
• each R20 and R30 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted 5-10 membered aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 3-10 membered cycloalkyl, or an optionally substituted 5-10 membered heterocyclyl;
• each R3 and R4 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy;
• an optionally substituted C2-C8 alkenyl, or a hydroxy;
• Y and Z independently is O, S, or NR2;
• n is 0, 1, 2, or 3;
• m is 0, 1, or 2;
• and
• p is 0, 1, 2, or 3.