Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders

1. A compound of formula (I):

wherein:

R 1 and R 2 are independently selected from the group consisting of: —C 1 -C 4 alkyl, —O—C 1 -C 4 alkyl, —H, and —C 3 -C 4 haloalkyl, and R 3 is selected from the group consisting of: —C 1 -C 12 alkyl, —H, and —O—C 1 -C 12 alkyl;

wherein two or three of R 1 , R 2 , and R 3 are not —H;

R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of: —C 1 -C 12 haloalkyl, —C(O)—N(R 13 )(R 14 ), —C 1 -C 12 alkyl, —H, —OH, —C 2 -C 12 alkenyl, —O—C 1 -C 12 alkyl, —O—C(O)—C 1 -C 12 alkyl, —O—C 1 -C 12 haloalkyl, —C 6 -C 10 aryl, —O—C 6 -C 10 aryl, —C 1 -C 6 alkyl-C 6 -C 10 aryl, —O—C 1 -C 6 alkyl-C 6 -C 10 aryl, —N—(R 8 )(R 9 ), —C(O)—O—C 1 -C 12 alkyl, —S(O) 2 —C 1 -C 12 alkyl,

wherein at least one of R 4 , R 5 , R 6 , and R 7 is independently selected from the group consisting of: —C 3 -C 12 alkyl, —C 1 -C 12 haloalkyl, —O—C 1 -C 12 alkyl, —O—C 1 -C 6 alkyl-C 6 -C 10 aryl, —N—(R 8 )(R 9 ), and

with the proviso that at least two of R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of: —H and —CH 3 ;

R 8 and R 9 are independently —H or —C 1 -C 12 alkyl;

R 13 is —H or —C 1 -C 4 alkyl;

R 14 is —C 1 -C 12 alkyl optionally substituted with hydroxy, —O—C 1 -C 4 , heterocyclyl, aryl, or heteroaryl, or wherein R 14 is —C 1 -C 15 alkyl wherein two or more of the carbons in the alkyl group have been replaced by oxygen;

m is 0, 1, 2, or 3; and

R 11 is S;

or a stereoisomer, mixture of stereoisomers, solvate, hydrate, or pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 , R 2 , and R 3 are —CH 3 .

3. The compound of claim 1 , wherein R 1 and R 2 are —OCH 3 , and R 3 is —CH 3 .

4. The compound of claim 1 , wherein R 1 and R 3 are —CH 3 , and R 2 is —H.

5. The compound of claim 1 , wherein R 1 and R 2 are —CH 3 , and wherein R 3 is -n-C 1 -C 12 alkyl.

6. The compound of claim 1 , wherein R 1 and R 2 are —OCH 3 , and wherein R 3 is n-C 1 -C 12 alkyl.

7. The compound of claim 1 , wherein three of R 4 , R 5 , R 6 , and R 7 are —H.

8. The compound of claim 1 , wherein at least one of R 4 , R 5 , R 6 , and R 7 is —C 1 -C 12 haloalkyl.

9. The compound of claim 1 , wherein at least one of R 4 , R 5 , R 6 , and R 7 is —C(O)—N(R 13 )(R 14 ).

10. The compound of claim 1 , wherein at least one of R 4 , R 5 , R 6 , and R 7 is C 3 -C 12 alkyl.

11. The compound of claim 1 , wherein at least one of R 4 , R 5 , R 6 , and R 7 is independently selected from the group consisting of C 3 -C 6 alkyl; —O—C 1 -C 6 alkyl; —N—(R 8 )(R 9 ) wherein R 8 and R 9 are independently —H or —C 1 -C 4 alkyl; —CF 3 ; —O-benzyl; and

wherein m is 1 or 2.

12. The compound of claim 1 , wherein three of R 4 , R 5 , R 6 , and R 7 are —H, and the other is selected from the group consisting of —N(CH 3 ) 2 , —O-benzyl, —O—CH 3 , —O-n-C 2 -C 5 alkyl, —CF 3 , and

wherein m is 1 or 2.

13. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a stereoisomer, mixture of stereoisomers, solvate, hydrate, or pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a stereoisomer, mixture of stereoisomers, solvate, hydrate, or pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a stereoisomer, mixture of stereoisomers, solvate, hydrate, or pharmaceutically acceptable salt thereof.

16. A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

17. A method of treating or suppressing an oxidative stress disorder selected from the group consisting of: a mitochondrial disorder; an inherited mitochondrial disease; Alpers Disease; Barth syndrome; a Beta-oxidation Defect; Carnitine-Acyl-Carnitine Deficiency; Carnitine Deficiency; a Creatine Deficiency Syndrome; Co-Enzyme Q10 Deficiency; Complex I Deficiency; Complex II Deficiency; Complex III Deficiency; Complex IV Deficiency; Complex V Deficiency; COX Deficiency; chronic progressive external ophthalmoplegia (CPEO); CPT I Deficiency; CPT II Deficiency; Friedreich's Ataxia (FA); Glutaric Aciduria Type II; Kearns-Sayre Syndrome (KSS); Lactic Acidosis; Long-Chain Acyl-CoA Dehydrogenase Deficiency (LCAD); LCHAD; Leigh Syndrome; Leigh-like Syndrome; Leber's Hereditary Optic Neuropathy (LHON); Lethal Infantile Cardiomyopathy (LIC); Luft Disease; Multiple Acyl-CoA Dehydrogenase Deficiency (MAD); Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD); Mitochondrial Myopathy, Encephalopathy, Lactacidosis, Stroke (MELAS); Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Recessive Ataxia Syndrome (MIRAS); Mitochondrial Cytopathy, Mitochondrial DNA Depletion; Mitochondrial Encephalopathy; Mitochondrial Myopathy; Myoneurogastrointestinal Disorder and Encephalopathy (MNGIE); Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP); Pearson Syndrome; Pyruvate Carboxylase Deficiency; Pyruvate Dehydrogenase Deficiency; a POLG Mutation; a Respiratory Chain Disorder; Short-Chain Acyl-CoA Dehydrogenase Deficiency (SCAD); SCHAD; Very Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD); a myopathy; cardiomyopathy; encephalomyopathy; Parkinson's disease; amyotrophic lateral sclerosis (ALS); a motor neuron disease; epilepsy; macular degeneration; metabolic syndrome; brain cancer; Huntington's Disease; a mood disorder; schizophrenia; bipolar disorder; a pervasive developmental disorder; autistic disorder; Asperger's syndrome; childhood disintegrative disorder (CDD); Rett's disorder; PDD-not otherwise specified (PDD-NOS); a cerebrovascular accident; stroke; a vision impairment; optic neuropathy; dominant inherited juvenile optic atrophy; optic neuropathy caused by a toxic agent; glaucoma; Stargardt's macular dystrophy; diabetic retinopathy; diabetic maculopathy; retinopathy of prematurity; ischemic reperfusion-related retinal injury; oxygen poisoning; a haemoglobinopathy; thalassemia; sickle cell anemia; seizures; ischemia; renal tubular acidosis; attention deficit/hyperactivity disorder (ADHD); a neurodegenerative disorder resulting in hearing or balance impairment; Dominant Optic Atrophy (DOA); Maternally inherited diabetes and deafness (MIDD); chronic fatigue; contrast-induced kidney damage; contrast-induced retinopathy damage; Abetalipoproteinemia; retinitis pigmentosum; Wolfram's disease; Tourette syndrome; cobalamin c defect; methylmalonic aciduria; glioblastoma; Down's syndrome; acute tubular necrosis; a muscular dystrophy; a leukodystrophy; Progressive Supranuclear Palsy; spinal muscular atrophy; hearing loss; noise induced hearing loss; traumatic brain injury; Juvenile Huntington's Disease; Multiple Sclerosis; NGLY1; Multisystem atrophy; Adrenoleukodystrophy; and Adrenomyeloneuropathy;

comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I):

wherein:

R 1 and R 2 are independently selected from the group consisting of: —C 1 -C 4 alkyl, —O—C 1 -C 4 alkyl, —H, and —C 1 -C 4 haloalkyl, and R 3 is selected from the group consisting of: —C 1 -C 12 alkyl, —H, —O—C 1 -C 12 alkyl, and —C 1 -C 12 haloalkyl; or

R 1 and R 2 are both —CH 3 or R 1 and R 2 are both —OCH 3 , and R 3 is selected from the group consisting of:

wherein two or three of R 1 , R 2 , and R 3 are not —H;

n is 0, 1, 2, 3, or 4;

R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of: —C 1 -C 12 haloalkyl, —C(O)—N(R 13 )(R 14 ), —C 1 -C 12 alkyl, —H, —OH, —C 2 -C 12 alkenyl, —O—C 1 -C 12 alkyl, —O—C(O)—C 1 -C 12 alkyl, —O—C 1 -C 12 haloalkyl, —C 6 -C 10 aryl, —O—C 6 -C 10 aryl, —C 1 -C 6 alkyl-C 6 -C 10 aryl, —O—C 1 -C 6 alkyl-C 6 -C 10 aryl, —N—(R 8 )(R 9 ), —C(O)—O—C 1 -C 12 alkyl, —S(O) 2 —C 1 -C 12 alkyl,

with the proviso that at least two of R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of: —H and —CH 3 ;

R 8 and R 9 are independently —H or —C 1 -C 12 alkyl;

R 13 is —H or —C 1 -C 4 alkyl;

R 14 is —C 1 -C 12 alkyl optionally substituted with hydroxy, —O—C 1 -C 4 , heterocyclyl, aryl, or heteroaryl, or wherein R 14 is —C 1 -C 15 alkyl wherein two or more of the carbons in the alkyl group have been replaced by oxygen;

m is 0, 1, 2, or 3; and

R 11 is S;

or a stereoisomer, mixture of stereoisomers, solvate, hydrate, or pharmaceutically acceptable salt thereof.

18. A compound of formula (I):

wherein:

R 1 and R 2 are both —CH 3 or R 1 and R 2 are both —OCH 3 , and R 3 is selected from the group consisting of:

n is 0, 1, 2, 3, or 4;

R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of: —C 1 -C 12 haloalkyl, —C(O)—N(R 13 )(R 14 ), —C 1 -C 12 alkyl, —H, —OH, —C 2 -C 12 alkenyl, —O—C 1 -C 12 alkyl, —O—C(O)—C 1 -C 12 alkyl, —O—C 1 -C 12 haloalkyl, —C 6 -C 10 aryl, —O—C 6 -C 10 aryl, —C 1 -C 6 alkyl-C 6 -C 10 aryl, —O—C 1 -C 6 alkyl-C 6 -C 10 aryl, —N—(R 8 )(R 9 ), —C(O)—O—C 1 -C 12 alkyl, —S(O) 2 —C 1 -C 12 alkyl,

with the proviso that at least two of R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of: —H and —CH 3 ;

R 8 and R 9 are independently —H or —C 1 -C 12 alkyl;

R 13 is —H or —C 1 -C 4 alkyl;

R 14 is —C 1 -C 12 alkyl optionally substituted with hydroxy, —O—C 1 -C 4 , heterocyclyl, aryl, or heteroaryl, or wherein R 14 is —C 1 -C 15 alkyl wherein two or more of the carbons in the alkyl group have been replaced by oxygen;

m is 0, 1, 2, or 3; and

R 11 is S;

or a stereoisomer, mixture of stereoisomers, solvate, hydrate, or pharmaceutically acceptable salt thereof.

19. The compound of claim 18 , wherein R 1 and R 2 are —CH 3 , and wherein R 3 is selected from the group consisting of:

20. The compound of claim 18 , wherein R 1 and R 2 are —OCH 3 , and wherein R 3 is selected from the group consisting of:

21. The compound of claim 18 selected form the group consisting of:

or a stereoisomer, mixture of stereoisomers, solvate, hydrate, or pharmaceutically acceptable salt thereof.

22. A pharmaceutical formulation comprising a compound according to claim 18 and a pharmaceutically acceptable excipient.