COMPOSITIONS AND METHODS FOR THE TREATMENT OF ZELLWEGER SPECTRUM DISORDER

1 . 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 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 NR 2 or CR 5 R 5 when is a single bond or X is N or CR 5 when is a double bond;

X 5 is N or CR 5 , provided that at least one of X and X 5 is N or NR 2 ;

each R 2 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy, or an optionally substituted C 2 -C 8 alkenyl;

each R 5 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted ═NR 6 , or an optionally substituted —NR 20 R 30 ;

each R 1 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy; or an optionally substituted —NR 20 R 30 ;

each R 20 and R 30 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 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 R 6 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy, or hydroxy; and

m is 0, 1, or 2.

2 . 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:

X 1 is O, S, or NR 2 ;

X 2 is N or CR 5 ;

each R 1 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy; or an optionally substituted —NR 20 NR 30 ;

each R 2 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy, or an optionally substituted C 2 -C 8 alkenyl;

each R 5 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted ═NR 6 , or an optionally substituted —NR 20 R 30 ;

each R 20 and R 30 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 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 R 3 and R 4 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy; an optionally substituted C 2 -C 8 alkenyl, or a hydroxy;

Y and Z independently is O, S, or NR 2 ;

n is 0, 1, 2, or 3;

m is 0, 1, or 2; and

p is 0, 1, 2, or 3.

3 . 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 Table 3, 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.

4 . The method of any one of claims 1 - 3 , wherein the Zellweger spectrum is caused by a PEX gene mutation.

5 . The method of claim 4 , wherein the PEX gene mutation causes abnormal peroxisome assembly.

6 . The method of claim 2 or 3 , wherein the compound is naltriben or naltrindole.

7 . The method of claim 2 or 3 , wherein the compound is naltriben methanesulfonate hydrate.

8 . The method of claim 2 or 3 , wherein the compound is naltrindole hydrochloride.

9 . 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 NR 2 or CR 5 R 5 when is a single bond or X is N or CR 5 when is a double bond;

X 5 is N or CR 5 , provided that at least one of X and X 5 is N or NR 2 ;

each R 2 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy, or an optionally substituted C 2 -C 8 alkenyl;

each R 5 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted ═NR 6 , or an optionally substituted —NR 20 R 30 ;

each R 1 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy; or an optionally substituted —NR 20 R 30 ;

each R 20 and R 30 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 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 R 6 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy, or hydroxy; and

m is 0, 1, or 2.

10 . 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:

X 1 is O, S, or NR 2 ;

X 2 is N or CR 5 ;

each R 1 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy; or an optionally substituted —NR 20 NR 30 ;

each R 2 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 5 alkoxy, or an optionally substituted C 2 -C 8 alkenyl;

each R 5 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 5 alkoxy, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted ═NR 6 , or an optionally substituted —NR 20 R 30 ;

each R 20 and R 30 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 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 R 3 and R 4 independently is H, an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 alkoxy; an optionally substituted C 2 -C 8 alkenyl, or a hydroxy;

Y and Z independently is O, S, or NR 2 ;

n is 0, 1, 2, or 3;

m is 0, 1, or 2; and

p is 0, 1, 2, or 3.

11 . 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 Table 3, 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.

12 . The method of any one of claims 9 - 11 , wherein the peroxisome assembly is improved by from about 20% to about 96%.

13 . The method of any one of claims 9 - 11 , wherein the peroxisome assembly is improved by at least 20%.

14 . The method of any one of claims 9 - 11 , wherein the peroxisome assembly is improved by at least 40%.

15 . The method of any one of claims 9 - 11 , wherein the peroxisome assembly is improved by at least 50%.

16 . The method of claim 10 or 11 , wherein the compound is naltriben or naltrindole.

17 . The method of claim 10 or 11 , wherein the compound is naltriben methanesulfonate hydrate.

18 . The method of claim 10 or 11 , wherein the compound is naltrindole hydrochloride.

19 . The method of claim 1 or 9 , further comprising detecting for the presence of the PEX gene mutation in a sample isolated from the subject prior to administration of the 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.

20 . The method of claim 2 or 10 , further comprising detecting for the presence of the PEX gene mutation in a sample isolated from the subject prior to administration of the 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.

21 . The method of claim 3 or 11 , further comprising detecting for the presence of the PEX gene mutation in a sample isolated from the subject prior to administration of the compound of Table 3, 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.