(Het)aryl-p-quinone derivatives for treatment of mitochondrial diseases

1. A method of reducing oxidative stress in a subject in need thereof, comprising administering to the subject 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;

where M and M′ are independently selected from the group consisting of hydrogen, —C(O)—R′, —C(O)—(C 2 -C 6 )-alkenyl, —C(O)—(C 2 -C 6 )-alkynyl, —C(O)-aryl, —C(O)-heterocyclyl, —C(O)O—R′, —C(O)NR′R″, —SO 2 OR′, —SO 2 —(C 1 -C 6 )-alkyl, —SO 2 —(C 1 -C 6 )-haloalkyl, —SO 2 -aryl, —SO 2 —NR′R″, —P(O)(OR′)(OR″), and C-linked mono or di-peptide, where R′ and R″ are each independently of each other 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;

where either

R 1 is aryl-(C 0 -C 6 )-alkyl- or heterocyclyl-(C 0 -C 6 )-alkyl-, wherein the aryl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, halogen, (C 1 -C 6 )-haloalkyl, hydroxy, (C 1 -C 6 )-alkoxy, CN, nitro, —COOR 4 , —NR 5 R 6 , —CONR 5 R 6 , thiol, (C 1 -C 6 )-thioalkyl, and —COR 4 ; and wherein when the (C 0 -C 6 )-alkyl group is (C 1 -C 6 )-alkyl then the (C 1 -C 6 )-alkyl is optionally substituted with OH, —O(C 1 -C 4 )-alkyl, —NH 2 , —NH(C 1 -C 4 )-alkyl, —N((C 1 -C 4 )-alkyl) 2 , oxo or halogen; and

R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkoxy;

or

R 3 is aryl-(C 0 -C 6 )-alkyl- or heterocyclyl-(C 0 -C 6 )-alkyl-, wherein the aryl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, halogen, (C 1 -C 6 )-haloalkyl-, hydroxy, (C 1 -C 6 )-alkoxy, CN, nitro, —COOR 4 , —NR 5 R 6 , —CONR 5 R 6 , thiol, (C 1 -C 6 )-thioalkyl-, and —COR 4 ; and wherein when the (C 0 -C 6 )-alkyl group is (C 1 -C 6 )-alkyl then the (C 1 -C 6 )-alkyl is optionally substituted with OH, —O(C 1 -C 4 )-alkyl, —NH 2 , —NH(C 1 -C 4 )-alkyl, —N((C 1 -C 4 )-alkyl) 2 , oxo or halogen; and

R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl, and (C 1 -C 6 )-alkoxy;

where R 4 is hydrogen, (C 1 -C 6 )-alkyl, aryl, or aryl-(C 1 -C 6 )-alkyl-; and

where R 5 and R 6 are independently of each other hydroxy, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, aryl, aryl-(C 1 -C 6 )-alkyl-, heterocyclyl, or heterocyclyl-(C 1 -C 6 )-alkyl-; wherein the alkyl, alkenyl, alkynyl, aryl and heterocyclyl groups are optionally further substituted with oxo, halogen, (C 1 -C 6 )-haloalkyl, hydroxy, (C 1 -C 6 )-alkoxy, or —COOR 4 ;

or a salt, a stereoisomer, or a mixture of stereoisomers thereof and additionally optionally comprising a pharmaceutically acceptable excipient.

2. The method according to claim 1 wherein R, in the one or more compounds, is

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

3. The method of claim 2 where, in the one or more compounds,

R 1 is aryl-(C 0 -C 6 )-alkyl- or heterocyclyl-(C 0 -C 6 )-alkyl-, wherein the aryl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, halogen, (C 1 -C 6 )-haloalkyl, hydroxy, (C 1 -C 6 )-alkoxy, CN, nitro, —COOR 4 , —NR 5 R 6 , —CONR 5 R 6 , thiol, (C 1 -C 6 )-thioalkyl, and —COR 4 ; and wherein when the (C 0 -C 6 )-alkyl group is (C 1 -C 6 )-alkyl then the (C 1 -C 6 )-alkyl is optionally substituted with OH, —O(C 1 -C 4 )-alkyl, —NH 2 , —NH(C 1 -C 4 )-alkyl, —N((C 1 -C 4 )-alkyl) 2 , oxo or halogen; and

R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl, and (C 1 -C 6 )-alkoxy;

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

4. The method of claim 3 where, in the one or more compounds, R 2 and R 3 are (C 1 -C 6 )-alkyl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

5. The method of claim 3 where, in the one or more compounds, le is aryl-(C 0 -C 6 )-alkyl-, wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of (C 1 -C 6 )-alkyl, halogen, (C 1 -C 6 )-haloalkyl, hydroxy, (C 1 -C 6 )-alkoxy, CN, —COOR 4 , and —COR 4 ; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

6. The method of claim 3 where, in the one or more compounds, le is heterocyclyl-(C 0 -C 6 )-alkyl-, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 6 )-alkyl, halogen, (C 1 -C 6 )-haloalkyl, hydroxy, (C 1 -C 6 )-alkoxy, CN, nitro, —COOR 4 , —NR 5 R 6 , —CONR 5 R 6 , and —COR 4 ; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

7. The method of claim 2 where, in the one or more compounds,

R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkoxy; and

R 3 is aryl-(C 0 -C 6 )-alkyl- or heterocyclyl-(C 0 -C 6 )-alkyl-, wherein the aryl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, halogen, (C 1 -C 6 )-haloalkyl-, hydroxy, (C 1 -C 6 )-alkoxy, CN, nitro, —COOR 4 , —NR 5 R 6 , —CONR 5 R 6 , thiol, (C 1 -C 6 )-thioalkyl-, and —COR 4 ; and wherein when the (C 0 -C 6 )-alkyl group is (C 1 -C 6 )-alkyl then the (C 1 -C 6 )-alkyl is optionally substituted with OH, —O(C 1 -C 4 )-alkyl, —NH 2 , —NH(C 1 -C 4 )-alkyl, —N((C 1 -C 4 )-alkyl) 2 , oxo or halogen;

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

8. The method of claim 7 where, in the one or more compounds, R 1 and R 2 are (C 1 -C 6 )-alkyl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

9. The method of claim 7 where, in the one or more compounds, R 3 is aryl-(C 0 -C 6 )-alkyl-, wherein the aryl is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 6 )-alkyl, halogen, (C 1 -C 6 )-haloalkyl, hydroxy, (C 1 -C 6 )-alkoxy, CN, —COOR 4 , and —COR 4 ; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

10. The method of claim 7 where, in the one or more compounds, R 3 is heterocyclyl-(C 0 -C 6 )-alkyl-, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 6 )-alkyl, halogen, (C 1 -C 6 )-haloalkyl, hydroxy, (C 1 -C 6 )-alkoxy, CN, nitro, —COOR 4 , —NR 5 R 6 , —CONR 5 R 6 , and —COR 4 ; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

11. The method according to claim 3 where, in the one or more compounds, R 1 is phenyl mono-substituted with a substituent selected from the group consisting of fluoro, chloro, and trifluoromethyl.

12. The method according to claim 7 where, in the one or more compounds, R 3 is phenyl mono-substituted with a substituent selected from the group consisting of fluoro, chloro, and trifluoromethyl.

13. The method according to claim 1 wherein the one or more compounds are selected from the group consisting of:

2-(3-hydroxy-3-methylbutyl)-3,5-dimethyl-6-(4-(trifluoromethyl)phenyl)cyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-6-(4-methoxyphenyl)-3,5-dimethylcyclohexa-2,5-diene-1,4-dione;

4-(5-(3-hydroxy-3-methylbutyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)benzonitrile;

2-(3-hydroxy-3-methylbutyl)-3,5-dimethyl-6-(naphthalen-2-yl)cyclohexa-2,5-diene-1,4-dione;

2-(3,4-difluorophenyl)-6-(3-hydroxy-3-methylbutyl)-3,5-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(4-fluorophenyl)-6-(3-hydroxy-3-methylbutyl)-3,5-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(4-chlorophenyl)-6-(3-hydroxy-3-methylbutyl)-3,5-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(2,3-dihydrobenzofuran-2-yl)-6-(3-hydroxy-3-methylbutyl)-3,5-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-phenethylcyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-phenylcyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(3-phenylpropyl)cyclohexa-2,5-diene-1,4-dione;

2-(1-hydroxy-2-phenylethyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-3-(4-methoxyphenyl)-5,6-dimethyl-cyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(4-(trifluoromethyl)-phenyl)cyclohexa-2, 5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(naphthalen-2-yl)cyclohexa-2,5-diene-1,4-dione;

2-(benzofuran-2-yl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(4-ethylphenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(3-(trifluoromethyl)phenyl)-cyclohexa-2, 5-diene-1,4-dione;

2-(4-tert-butylphenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-cyclohexa-2,5-diene-1,4-dione;

2-(4-fluorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

4-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)benzonitrile;

2-(3,4-difluorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-cyclohexa-2,5-diene-1,4-dione;

2-(2-fluorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-3-(3-methoxyphenyl)-5,6-dimethyl-cyclohexa-2,5-diene-1,4-dione;

2-(4-fluoro-2-methoxyphenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2, 5-diene-1,4-dione;

2-(benzo[d][1,3]dioxo1-5-yl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2, 5-diene-1,4-dione;

2-(2,4-difluorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(3,5-bis(trifluoromethyl)phenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(2-(thiazol-2-yl)ethyl)cyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(2-(thiazol-5-yl)ethyl)cyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(2-(pyridin-2-yl)ethyl)cyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(2-(pyridazin-4-yl)ethyl)cyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(2-(thiophen-2-yl)ethyl)cyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(2-(thiophen-3-yl)ethyl)cyclohexa-2,5-diene-1,4-dione;

2-(2-(furan-2-yl)ethyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(2-(furan-3-yl)ethyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(2-(1H-pyrazol-5-yl)ethyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2, 5-diene-1,4-dione;

2-(2-(1H-pyrazol-4-yl)ethyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2, 5-diene-1,4-dione;

2-(2-(1H-pyrazol-1-yl)ethyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(2-(1H-imidazol-5-yl)ethyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(2-(1H-imidazol-2-yl)ethyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(2-(oxazol-5-yl)ethyl)cyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(2-(oxazol-2-yl)ethyl)cyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(2-(oxazol-4-yl)ethyl)cyclohexa-2,5-diene-1,4-dione; and

2-(2-(1H-indol-3-yl)ethyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione;

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

14. The method according to claim 1 , wherein the one or more compounds are selected from the group consisting of:

2-(3-hydroxy-3-methylbutyl)-3,5-dimethyl-6-(4-(trifluoromethyl)phenyl)cyclohexa-2,5-diene-1,4-dione;

2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(4-(trifluoromethyl)-phenyl)cyclohexa-2,5-diene-1,4-dione;

2-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione; and

2-(4-chlorophenyl)-6-(3-hydroxy-3-methylbutyl)-3,5-dimethylcyclohexa-2,5-diene-1,4-dione; and

or a salt thereof.

15. The method of claim 1 , where the subject in need thereof has a mitochondrial disorder, wherein the mitochondrial disorder is selected from the group consisting of an inherited mitochondrial disease; Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Myopathy; Encephalopathy; Lactacidosis; Stroke (MELAS); Leber's Hereditary Optic Neuropathy (LHON); chronic progressive external ophthalmoplegia (CPEO); Leigh Disease; Kearns-Sayre Syndrome (KSS); Friedreich's Ataxia (FA); Co-Enzyme Q10 Deficiency; Complex I Deficiency; Complex II Deficiency; Complex III Deficiency; Complex IV Deficiency; Complex V Deficiency; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); muscular dystrophy; Huntington's disease; a pervasive developmental disorder; epilepsy; macular degeneration; diabetes; cancer; a cerebral vascular accident; autism; myopathy; cardiomyopathy; renal tubular acidosis; neurodegenerative diseases; motor neuron diseases; other neurological diseases; genetic diseases; mood disorders; schizophrenia; bipolar disorder; age-associated diseases; cerebral vascular diseases; autistic disorder (ASD); Asperger's disorder; childhood disintegrative disorder (CDD); Rett's disorder; PDD-Not Otherwise Specified (PDD-NOS); Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); neuronal injury associated with seizures; and neuronal injury associated with ischemia.

16. The method of claim 2 , where the subject in need thereof has a mitochondrial disorder, wherein the mitochondrial disorder is selected from the group consisting of an inherited mitochondrial disease; Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Myopathy; Encephalopathy; Lactacidosis; Stroke (MELAS); Leber's Hereditary Optic Neuropathy (LHON); chronic progressive external ophthalmoplegia (CPEO); Leigh Disease; Kearns-Sayre Syndrome (KSS); Friedreich's Ataxia (FA); Co-Enzyme Q10 Deficiency; Complex I Deficiency; Complex II Deficiency; Complex III Deficiency; Complex IV Deficiency; Complex V Deficiency; Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis (ALS); muscular dystrophy; Huntington's disease; a pervasive developmental disorder; epilepsy; macular degeneration; diabetes; cancer; and a cerebral vascular accident; autism; myopathy; cardiomyopathy; renal tubular acidosis; neurodegenerative diseases; motor neuron diseases; other neurological diseases; genetic diseases; mood disorders; schizophrenia; bipolar disorder; age-associated diseases; cerebral vascular diseases; autistic disorder (ASD); Asperger's disorder; childhood disintegrative disorder (CDD); Rett's disorder; PDD-Not Otherwise Specified (PDD-NOS); Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); neuronal injury associated with seizures; and neuronal injury associated with ischemia.

17. The method of claim 15 , wherein the mitochondrial disorder is selected from the group consisting of Parkinson's disease; Alzheimer's disease; Huntington's disease; epilepsy; amyotrophic lateral sclerosis (ALS); and macular degeneration.