4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases
Methods of treating or suppressing mitochondrial diseases, such as Friedreich's ataxia (FRDA), Leber's Hereditary Optic Neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS), Kearns-Sayre Syndrome (KSS), are disclosed, as well as compounds useful in the methods of the invention, such as 4-(p-quinolyl)-2-hydroxybutanamide derivatives. Methods and compounds useful in treating other disorders such as amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease, and pervasive developmental disorders such as autism are also disclosed. Energy biomarkers useful in assessing the metabolic state of a subject and the efficacy of treatment are also disclosed. Methods of modulating, normalizing, or enhancing energy biomarkers, as well as compounds useful for such methods, are also disclosed.
1. A method of treating or suppressing a mitochondrial disorder selected from the group consisting of Leigh Syndrome and amyotrophic lateral sclerosis (ALS), comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I:
where R is selected from the group consisting of:
where the * indicates the point of attachment of R to the remainder of the molecule;
R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl;
R 4 is C 1 -C 6 -alkyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, C 1 -C 40 -alkyl, C 2 -C 40 -alkenyl, C 2 -C 40 -alkynyl, and aryl; where the alkyl, alkenyl, alkynyl, and aryl groups are optionally substituted with
—OR 10 , —S(O) 0-2 R 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , oxo, C 3 -C 6 -cycloalkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heterocyclyl, —C(O)—R 11 , —C(O)—C 0 -C 6 -alkyl-aryl, —C(O)—O—R 11 , —C(O)—O—C 0 -C 6 -alkyl-aryl, —C(O)—NR 11 R 11′ , —C(O)—NH—C 0 -C 6 -alkyl-aryl, —NH—C(O)—R 11 , or —NH—C(O)—C 0 -C 6 -alkyl-aryl; where the aryl, heteroaryl and heterocyclyl ring substituents are optionally further substituted with C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, oxo, hydroxy, C 1 -C 6 -alkoxy, —C(O)—C 1 -C 6 -alkyl, or —C(O)—O—C 1 -C 6 -alkyl; and where one of the carbons of the alkyl, alkenyl, and alkynyl groups is optionally substituted with a heteroatom selected from the group consisting of O, N, and S; or
R 5 and R 6 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating 1, 2, or 3 additional N, O, or S atoms, optionally substituted with oxo, —SR 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , C 1 -C 6 alkyl, C 1 -C 6 -haloalkyl, hydroxy-C 1 -C 6 -alkyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, —C(O)—OH, or —C(O)—O—C 1 -C 6 -alkyl; or
R 5 and R 6 together with the nitrogen atom to which they are attached form a N,N′-disubstituted piperazine where the nitrogen substitution at the 4-position is a group identical to the substitution at the 1-position, the one or more compound of Formula I forming a compound of Formula Iaa or Ibb, where R 1 , R 2 , R 3 , and R 4 are as defined above:
R 10 and R 10′ are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heterocyclyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, and —C(O)—C 1 -C 6 -alkyl-aryl;
R 11 and R 11′ are selected from the group consisting of hydrogen and C 1 -C 6 -alkyl; and
M and M′ are independently selected from the group consisting of hydrogen, —C(O)—R 12 , —C(O)—C 2 -C 6 -alkenyl, —C(O)—C 2 -C 6 -alkynyl, —C(O)-aryl; —C(O)-heteroaryl, —C(O)O—R 12 , —C(O)NR 12 R 12 , —SO 2 OR 12 , —SO 2 —C 1 -C 6 -alkyl, —SO 2 -haloC 1 -C 6 -alkyl, —SO 2 -aryl, —SO 2 —NR 12 R 12 , —P(O)(OR 12 )(OR 12 ), and C-linked mono or di-peptide, where R 12 is hydrogen or C 1 -C 6 -alkyl optionally substituted with —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —C(O)—OH, —C(O)—O—C 1 -C 4 -alkyl, or halogen;
or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
2. A method of treating or suppressing a mitochondrial disorder selected from the group consisting of Leigh Syndrome and amyotrophic lateral sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula Ia:
where:
R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl;
R 4 is C 1 -C 6 -alkyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, C 1 -C 40 -alkyl, C 2 -C 40 -alkenyl, C 2 -C 40 -alkynyl, and aryl; where the alkyl, alkenyl, alkynyl, and aryl groups are optionally substituted with
—OR 10 , —S(O) 0-2 R 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , oxo, C 3 -C 6 -cycloalkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heterocyclyl, —C(O)—R 11 , —C(O)—C 0 -C 6 -alkyl-aryl, —C(O)—O—R 11 , —C(O)—O—C 0 -C 6 -alkyl-aryl, —C(O)—NR 11 R 11′ , —C(O)—NH—C 0 -C 6 -alkyl-aryl, —NH—C(O)—R 11 , or —NH—C(O)—C 0 -C 6 -alkyl-aryl; where the aryl, heteroaryl and heterocyclyl ring substituents are optionally further substituted with C 1 -C 6 -alkyl, C 1 -C 6 haloalkyl, oxo, hydroxy, C 1 -C 6 -alkoxy, —C(O)—C 1 -C 6 -alkyl, or —C(O)—O—C 1 -C 6 -alkyl; and where one of the carbons of the alkyl, alkenyl, and alkynyl groups is optionally substituted with a heteroatom selected from the group consisting of O, N, and S; or
R 5 and R 6 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating 1, 2, or 3 additional N, O, or S atoms, optionally substituted with oxo, —OR 10 , —SR 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, hydroxy-C 1 -C 6 -alkyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, —C(O)—OH, or —C(O)— O—C 1 -C 6 -alkyl; or
R 5 and R 6 together with the nitrogen atom to which they are attached form a N,N′-disubstituted piperazine where the nitrogen substitution at the 4-position is a group identical to the substitution at the 1-position, the one or more compound of Formula Ia forming a compound of Formula Iaa, where R 1 , R 2 , R 3 , and R 4 are as defined above:
R 10 and R 10′ are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heterocyclyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, and —C(O)—C 1 -C 6 -alkyl-aryl; and
R 11 and R 11′ are selected from the group consisting of hydrogen and C 1 -C 6 -alkyl;
or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
3. The method of claim 2 , where the mitochondrial disorder is amyotrophic lateral sclerosis (ALS).
4. The method of claim 2 , where the mitochondrial disorder is Leigh Syndrome.
5. The method of claim 2 , where R 1 , R 2 , R 3 , and R 4 are methyl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
6. The method of claim 2 , where R 5 is hydrogen and R 6 is C 1 -C 6 alkyl substituted with hydroxy, alkoxy, or —C(O)O—C 1 -C 6 alkyl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
7. The method of claim 2 , where R 5 is hydrogen and R 6 is C 1 -C 6 alkyl substituted with —NR 10 R 10′ , where R 10 and R 10′ are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heterocyclyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, and —C(O)—C 1 -C 6 -alkyl-aryl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
8. The method of claim 2 , where R 5 is hydrogen and R 6 is C 1 -C 6 alkyl substituted with heterocyclyl or heteroaryl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
9. The method of claim 2 , where R 5 and R 6 together with the nitrogen atom to which they are attached form an optionally substituted 3 to 8-membered nitrogen containing heterocyclyl ring; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
10. The method of claim 2 , where R 5 and R 6 together with the nitrogen atom to which they are attached form a N,N′-disubstituted piperazine where the nitrogen substitution at the 4-position is a group identical to the substitution at the 1-position, the one or more compound of Formula Ia forming a compound of Formula Iaa, where R 1 , R 2 , R 3 , and R 4 are as defined in claim 2 :
or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
11. The method of claim 2 , where R 5 and R 6 independently ndependently hydrogen or C 1 -C 6 alkyl optionally substituted with aryl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
12. The method of claim 2 , where one of R 5 and R 6 is hydrogen and the other is C 1 -C 6 alkyl optionally substituted with aryl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
13. The method of claim 2 , where
R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, C 1 -C 40 -alkyl, C 2 -C 40 -alkenyl, C 2 -C 40 -alkynyl, and aryl; where the alkyl, alkenyl, alkynyl, and aryl groups are optionally substituted with
—OR 10 , —S(O) 0-2 R 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , oxo, C 3 -C 6 -cycloalkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heterocyclyl, —C(O)—R 11 , —C(O)—C 0 -C 6 -alkyl-aryl, —C(O)—O—R 11 , —C(O)—O—C 0 -C 6 -alkyl-aryl, —C(O)—NR 11 R 11′ , —C(O)—NH—C 0 -C 6 -alkyl-aryl, —NH—C(O)—R 11 , or —NH—C(O)—C 0 -C 6 -alkyl-aryl; where the aryl, heteroaryl and heterocyclyl ring substituents are optionally further substituted with C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, oxo, hydroxy, C 1 -C 6 -alkoxy, —C(O)—C 1 -C 6 -alkyl, or —C(O)—O—C 1 -C 6 -alkyl; or
R 5 and R 6 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating 1, 2, or 3 additional N, O, or S atoms, optionally substituted with oxo, —OR 10 , —SR 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, hydroxy-C 1 -C 6 -alkyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, —C(O)—OH, or —C(O)— O—C 1 -C 6 -alkyl;
or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
14. The method of claim 2 , where R 5 and R 6 are hydrogen; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
15. A method of treating or suppressing a mitochondrial disorder selected from the group consisting of Leigh Syndrome and amyotrophic lateral sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
2-hydroxy-N-isopropyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-(3-hydroxy-3-methyl-4-oxo-4-(piperidin-1-yl)butyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-(4-(azepan-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
N-hexyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-tert-butyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N,N,2-trimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-ethyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-benzyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl) butanamide;
2-hydroxy-2-methyl-N-propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(cyclopropylmethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-2-methyl-N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(3-hydroxypropyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-isopentyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-cyclopropyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-(3-hydroxy-4-(4-hydroxypiperidin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-hydroxy-N-isobutyl-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-ethyl-2-hydroxy-N,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(4-hydroxybutyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(5-hydroxypentyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(2-methoxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(1-hydroxypropan-2-yl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
methyl 2-(2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamido)acetate;
N-(3-(1H-imidazol-1-yl)propyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(2-(2-hydroxyethoxyl)ethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-2-methyl-N-(pyridin-2-ylmethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-2-methyl-N-(2-(pyridin-2-yl)ethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-2-methyl-N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(2-hydroxypropyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(6-hydroxyhexyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-(3-hydroxy-3-methyl-4-(4-methylpiperazin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-(4-(4-benzylpiperazin-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-hydroxy-2-methyl-N-((tetrahydrofuran-2-yl)methyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-2-methyl-N-(3-morpholinopropyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-methoxy-N,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N,N-bis(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(2-(dimethylamino)ethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(4-hydroxyphenethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(3-(dimethylamino)propyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
6,6′-(4,4′-(piperazine-1,4-diyl)bis(3-hydroxy-3-methyl-4-oxobutane-4,1-diyl))bis(2,3,5-trimethylcyclohexa-2,5-diene-1,4-dione);
N-butyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(2-hydroxyethyl)-N,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N,N-diethyl-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
tert-butyl 2-(2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamido)ethylcarbamate;
2-hydroxy-2-methyl-N-(pyridin-4-ylmethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-2-methyl-N-(pyridin-3-ylmethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-2-methyl-N-(3-(methylsulfonyl)propyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide
2-(2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamido)acetic acid;
2-(4-(4-acetylpiperazin-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-(4-(4-fluoropiperidin-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-(4-(4,4-difluoropiperidin-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-(3-hydroxy-3-methyl-4-oxo-4-(piperazin-1-yl)butyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
tert-butyl 4-(2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanoyl)piperazine-1-carboxylate;
2-(4-(4-benzoylpiperazin-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-(3-hydroxy-4-(4-isopropylpiperazin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
N-(2-fluorophenethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(3-fluorophenethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(4-fluorophenethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(2-chlorophenethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(3-chlorophenethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(4-chlorophenethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
2-hydroxy-N-(4-methoxyphenyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(4-fluorophenyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(4-chlorophenyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(2-fluorobenzyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(3-fluorobenzyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(4-fluorobenzyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(2-chlorobenzyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(3-chlorobenzyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide; and
N-(4-chlorobenzyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
16. The method of claim 15 , wherein the compound is selected from the group consisting of:
(R)-2-hydroxy-N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
(S)-2-hydroxy-N-(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
(R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
(S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
(R)-2-(4-(4-acetylpiperazin-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
(S)-2-(4-(4-acetylpiperazin-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
(R)-2-(3-hydroxy-4-(4-hydroxypiperidin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione; and
(S)-2-(3-hydroxy-4-(4-hydroxypiperidin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
or a salt thereof.
17. The method of claim 15 , wherein the compound is selected from the group consisting of:
2-(3-hydroxy-3-methyl-4-(4-methylpiperazin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-(3-hydroxy-4-(4-hydroxypiperidin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-(4-(4-acetylpiperazin-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(2-(dimethylamino)ethyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
N-(3-(1H-imidazol-1-yl)propyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide; and
N-(3-(dimethylamino)propyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
or a salt, a stereoisomer, or mixture of stereoisomers thereof.
18. The method of claim 15 , wherein the compound is selected from the group consisting of:
(R)-2-(3-hydroxy-4-(4-hydroxypiperidin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
(S)-2-(3-hydroxy-4-(4-hydroxypiperidin-1-yl)-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
(R)-2-(4-(4-acetylpiperazin-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
(S)-2-(4-(4-acetylpiperazin-1-yl)-3-hydroxy-3-methyl-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione;
(R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide; and
(S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide;
or a salt thereof.
19. The method of claim 14 , wherein the compound is (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, or a salt thereof.
20. The method of claim 14 , wherein the compound is (S)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, or a salt thereof.
21. A method of treating or suppressing a mitochondrial disorder selected from the group consisting of Leigh Syndrome and amyotrophic lateral sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula Ib:
where R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen and C 1 -C 6 -alkyl;
R 4 is C 1 -C 6 -alkyl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, C 1 -C 40 -alkyl, C 2 -C 40 -alkenyl, C 2 -C 40 -alkynyl, and aryl; where the alkyl, alkenyl, alkynyl, and aryl groups are optionally substituted with
—OR 10 , —S(O) 0-2 R 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , oxo, C 3 -C 6 -cycloalkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heterocyclyl, —C(O)—R 11 , —C(O)—C 0 -C 6 -alkyl-aryl, —C(O)—O—R 11 , —C(O)—O—C 0 -C 6 -alkyl-aryl, —C(O)—NR 11 R 11′ , —C(O)—NH—C 0 -C 6 -alkyl-aryl, —NH—C(O)—R 11 , or —NH—C(O)—C 0 -C 6 -alkyl-aryl; where the aryl, heteroaryl and heterocyclyl ring substituents are optionally further substituted with C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, oxo, hydroxy, C 1 -C 6 -alkoxy, —C(O)—C 1 -C 6 -alkyl, or —C(O)—O—C 1 -C 6 -alkyl; and where one of the carbons of the alkyl, alkenyl, and alkynyl groups is optionally substituted with a heteroatom selected from the group consisting of O, N, and S; or
R 5 and R 6 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating 1, 2, or 3 additional N, O, or S atoms, optionally substituted with oxo, —OR 10 , —SR 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, hydroxy-C 1 -C 6 -alkyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, —C(O)—OH, or —C(O)—O—C 1 -C 6 -alkyl; or
R 5 and R 6 together with the nitrogen atom to which they are attached form a N,N′-disubstituted piperazine where the nitrogen substitution at the 4-position is a group identical to the substitution at the 1-position, the one or more compound of Formula Ib forming a compound of Formula Ibb, where R 1 , R 2 , R 3 , and R 4 are as defined above:
R 10 and R 10′ are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heterocyclyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, and —C(O)—C 1 -C 6 -alkyl-aryl; or
R 10 and R 10′ together with the atom to which they are attached form an optionally substituted saturated or unsaturated 3-8 membered ring, optionally incorporating 1, 2, or 3 N, O, or S atoms;
R 11 and R 11′ are selected from the group consisting of hydrogen and C 1 -C 6 -alkyl; and
M and M′ are independently selected from the group consisting of hydrogen, —C(O)—R 12 , —C(O)—C 2 -C 6 -alkenyl, —C(O)—C 2 -C 6 -alkynyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)O—R 12 , —C(O)NR 12 R 12 , —SO 2 OR 12 , —SO 2 —C 1 -C 6 -alkyl, —SO 2 -haloC 1 -C 6 -alkyl, —SO 2 -aryl, —SO 2 —NR 12 R 12 , —P(O)(OR 12 )(OR 12 ), and C-linked mono or di-peptide, where R 12 is hydrogen or C 1 -C 6 -alkyl optionally substituted with —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —C(O)—OH, —C(O)—O—C 1 -C 4 -alkyl, or halogen;
or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
22. The method of claim 21 , where R 1 , R 2 , R 3 , and R 4 are methyl and M and M′ are independently hydrogen or C(O)—R 12 ; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.
23. The method of claim 21 , wherein the compound is 4-(2,5-dihydroxy-3,4,6-trimethylphenyl)-2-hydroxy-2-methylbutanamide; or a salt, a stereoisomer or mixture of stereoisomers thereof.
24. The method of claim 21 , where
R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, C 1 -C 40 -alkyl, C 2 -C 40 -alkenyl, C 2 -C 40 -alkynyl, and aryl; where the alkyl, alkenyl, alkynyl, and aryl groups are optionally substituted with
—OR 10 , —S(O) 0-2 R 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , oxo, C 3 -C 6 -cycloalkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heterocyclyl, —C(O)—R 11 , —C(O)—C 0 -C 6 -alkyl-aryl, —C(O)—O—R 11 , —C(O)—O—C 0 -C 6 -alkyl-aryl, —C(O)—NR 11 R 11′ , —C(O)—NH—C 0 -C 6 -alkyl-aryl, —NH—C(O)—R 11 , or —NH—C(O)—C 0 -C 6 -alkyl-aryl; where the aryl, heteroaryl and heterocyclyl ring substituents are optionally further substituted with C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, oxo, hydroxy, C 1 -C 6 -alkoxy, —C(O)—C 1 -C 6 -alkyl, or —C(O)—O—C 1 -C 6 -alkyl; or
R 5 and R 6 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating 1, 2, or 3 additional N, O, or S atoms, optionally substituted with oxo, —OR 10 , —SR 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, hydroxy-C 1 -C 6 -alkyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, —C(O)—OH, or —C(O)—O—C 1 -C 6 -alkyl;
or a salt, a stereoisomer, or a mixture of stereoisomers thereof.