4-(p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases

1. A compound 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 hydrogen and C 1 -C 6 -alkyl;

R 4 is C 1 -C 6 -alkyl;

R 5 and R 6 are independently selected from hydrogen, hydroxy, alkoxy, C 1 -C 40 -alkyl, C 1 -C 40 -alkenyl, C 1 -C 40 -alkynyl, and aryl; where the alkyl, alkenyl, alkynyl, or aryl groups may optionally be substituted with

—OR 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)—N—R 11 R 11 , —C(O)—N—C 0 -C 6 -alkyl-aryl, —N—C(O)—R 11 , —N—C(O)—C 0 -C 6 -alkyl-aryl; where the aryl, heteroaryl and heterocyclyl ring substituents may be 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 and —C(O)—O—C 1 -C 6 -alkyl; and

where one of the carbons of the alkyl, alkenyl, or alkynyl groups may be substituted with a heteroatom selected from —O— or —N—;

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 hydrogen and C 1 -C 6 -alkyl; and

M and M′ are independently selected from hydrogen, —C(O)—R 12 , —C(O)—C 1 -C 6 -alkenyl, —C(O)—C 1 -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;

with the proviso that the compound is not N-(6-amino-3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide or N-(6-amino-3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(2,5-dihydroxy-3,4,6-trimethylphenyl)-2-hydroxy-2-methylbutanamide;

or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

2. A compound of Formula Ia:

where

R 1 , R 2 , and R 3 are independently selected from hydrogen and C 1 -C 6 -alkyl;

R 4 is C 1 -C 6 -alkyl;

R 5 and R 6 are independently selected from hydrogen, hydroxy, alkoxy, C 1 -C 40 -alkyl, C 1 -C 40 -alkenyl, C 1 -C 40 -alkynyl, and aryl; where the alkyl, alkenyl, alkynyl, or aryl groups may optionally be substituted with —OR 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)—N—R 11 R 11 , —C(O)—N—C 0 -C 6 -alkyl-aryl, —N—C(O)—R 11 , —N—C(O)—C 0 -C 6 -alkyl-aryl; where the aryl, heteroaryl and heterocyclyl ring substituents may be 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 and —C(O)—O—C 1 -C 6 -alkyl; and where one of the carbons of the alkyl, alkenyl, or alkynyl groups may be substituted with a heteroatom selected from O or N;

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 hydrogen and C 1 -C 6 -alkyl;

with the proviso that the compound is not N-(6-amino-3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)-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.

3. The compound 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.

4. The compound 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.

5. The compound of claim 2 , where R 5 is hydrogen and R 6 is independently selected from 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.

6. The compound of claim 5 where R 5 is hydrogen and R 6 is independently selected from C 1 -C 6 alkyl substituted with heterocyclyl or heteroaryl group, or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

7. The compound of claim 2 , where R 5 and R 6 are independently hydrogen or C 1 -C 6 alkyl optionally substituted with aryl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

8. The compound of claim 2 , where one of R 5 and R 6 is hydrogen and the other group is C 1 -C 6 alkyl optionally substituted with aryl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

9. The compound of claim 2 , where R 5 and R 6 are hydrogen; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

10. The compound of claim 2 selected from:

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;

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-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;

(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;

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-hydroxyethoxy)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-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;

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-(2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamido)acetic acid;

(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;

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;

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.

11. A compound of claim 2 additionally comprising a pharmaceutically acceptable excipient.

12. A compound of formula Ib

R 1 , R 2 , and R 3 are independently selected from hydrogen and C 1 -C 6 -alkyl;

R 4 is C 1 -C 6 -alkyl;

R 5 and R 6 are independently selected from hydrogen, hydroxy, alkoxy, C 1 -C 40 -alkyl, C 1 -C 40 -alkenyl, C 1 -C 40 -alkynyl, and aryl; where the alkyl, alkenyl, alkynyl, or aryl groups may optionally be substituted with —OR 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)—N—R 11 R 11 , —C(O)—N—C 0 -C 6 -alkyl-aryl, —N—C(O)—R 11 , —N—C(O)—C 0 -C 6 -alkyl-aryl; where the aryl, heteroaryl and heterocyclyl ring substituents may be 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 and —C(O)—O—C 1 -C 6 -alkyl; and where one of the carbons of the alkyl, alkenyl, or alkynyl groups may be substituted with a heteroatom selected from O or N; 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 hydrogen and C 1 -C 6 -alkyl; and

M and M′ are independently selected from hydrogen, —C(O)—R 12 , —C(O)—C 1 -C 6 -alkenyl, —C(O)—C 1 -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;

with the proviso that the compound is not N-(6-amino-3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(2,5-dihydroxy-3,4,6-trimethylphenyl)-2-hydroxy-2-methylbutanamide;

or a salt, a stereoisomer, or a mixture of stereoisomers.

13. The compound of claim 12 , where R 1 , R 2 , R 3 , and R 4 are methyl and M and M′ are hydrogen or C(O)—R 12 , or a salt, a stereoisomer, or a mixture of stereoisomers.

14. A compound of claim 12 , additionally comprising a pharmaceutically acceptable excipient.