2-substituted-

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;

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(0)-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 independently of each other hydrogen or (C 1 -C 6 )-alkyl optionally substituted with one or more substituents independently selected from the group consisting of —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, and halogen;

R 1 is (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, heterocyclyl, or aryl, where the heterocyclyl and the aryl are optionally substituted with one or more substituents independently selected from the group consisting of —OH, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, hydroxyl-(C 1 -C 6 )alkyl-, alkoxy(C 1 -C 6 )-alkyl-, —NR 10 R 10′ , —(C 1 -C 6 )-alkyl —NR 10 R 10′ , —C(O)—(C 1 -C 6 )-alkyl, —C(O)—OH, —C(O)O—(C 1 -C 6 )-alkyl,—C(O)NR 10 R 10′ , —NR 11 C(O)R 10 , —NR 11 C(O)NR 10 R 10 —NR 11 (C(O)OR 10 , —SO 2 (C 1 -C 6 )-alkyl, —SO 2 (C 1 -C 6 )-haloalkyl, —SO 2 -aryl, —SO 2 NR 10 R 10′ , CN, haloalkyl, and halogen;

R 2 is hydrogen, (C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkoxy;

R 3 is unsubstituted (C 1 -C 6 )-alkyl;

R 4 is hydrogen or (C 1 -C 6 )-alkyl;

R 5 is —C(O)NR 6 R 7 ;

R 6 is hydrogen, (C 1 -C 6 )-alkyl, aryl, or heterocyclyl, where (C 1 -C 6 )-alkyl is optionally substituted with one or more substituents independently selected from the group consisting of:

—OR 11 , —SR 11 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , (C 3 -C 6 )-cycloalkyl, aryl, 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 10 R 10′ , C(O)NR 11 -(C 0 -C 6 )-alkyl-aryl, —NR 11 C(O)—R 10 , and —NR 11 C(O)—(C 0 -C 6 )-alkyl-aryl; wherein the aryl and heterocyclyl ring substituents may be further substituted with one or more groups independently selected from the group consisting of (C 1 -C 6 )-alkyl, halogen, (C 1 -C 6 ) -haloalkyl, CN, 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

aryl and heterocyclyl are optionally substituted with (C 1 -C 6 )-alkyl, halogen, (C 1 -C 6 )-haloalkyl, CN, oxo, hydroxy, (C 1 -C 6 )-alkoxy, —C(O)—(C 1 -C 6 )-alkyl or —C(O)—O—(C 1 -C 6 )-alkyl;

R 7 is hydrogen or (C 1 -C 6 )-alkyl; or

R 6 and R 7 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with oxo, —OH, —SH, —F, —Cl, —Br, —I, —NR 11 R 11′ , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-thioalkyl, (C 1 -C 6 )-haloalkyl, hydroxy-(C 1 -C 6 )-alkyl, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl, —C(O)OH, or —C(O)O—(C 1 -C 6 )-alkyl;

R 10 and R 10′ are independently selected from the group consisting of H, (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 a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with one or more substituents independently selected from the group consisting of oxo, —OH, —F,—Cl, —Br, —I, —NR 11 R 11′ , (C 1 C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-haloalkyl, hydroxy -(C 1 -C 6 )-alkyl-, —C(O)—H, —C(O )—(C 1 -C 6 )-alkyl, —C(O)OH, and —C(O)O—(C 1 -C 6 )-alkyl;

R 11 and R 11′ are independently selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl; and

A is (C 1 -C 4 )-alkylene, (C 2 -C 4 )-alkenylene, or (C 2 -C 4 )-alkynylene;

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

2. The compound of claim 1 of Formula Ia:

where,

R 1 is (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, heterocyclyl, or aryl, where the heterocyclyl and the aryl are optionally substituted with one or more substituents independently selected from the group consisting of —OH, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, hydroxy-(C 1 -C 6 )alkyl-, alkoxy(C 1 -C 6 )alkyl-, —NR 10 R 11′ , —(C 1 -C 6 )-alkyl —NR 10 R 10′ , —C(O)—(C 1 -C 6 )-alkyl, —C(O)—OH, —C(O)O—(C 1 -C 6 )-alkyl, —C(O)NR 10 R 10′ , —NR 11 C(O)R 10 , —NR 11 C(O)NR 10 R 10′ , —NR 11 C(O)OR 10 , —SO 2 (C 1 -C 6 )-alkyl, —SO 2 (C 1 -C 6 )-haloalkyl, —SO 2 -aryl, —SO 2 NR 10 R 10′ , CN, haloalkyl, and halogen;

R 2 is hydrogen, (C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkoxy;

R 3 is unsubstituted (C 1 -C 6 )-alkyl;

R 4 is hydrogen or (C 1 -C 6 )-alkyl;

R 5 is —C(O)NR 6 R 7 ;

R 6 is hydrogen, (C 1 -C 6 )-alkyl, aryl, or heterocyclyl, where (C 1 -C 6 )-alkyl is optionally substituted with one or more substituents independently selected from the group consisting of:

—OR 11 , —SR 11 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10′ , (C 3 -C 6 )-cycloalkyl, aryl, 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 10 R 10′ —C(O)NR 11 —(C 0 -C 6 )-alkyl-aryl, —NR 11 C(O)—R 10 , and —NR 11 C(O)—(C 0 -C 6 )-alkyl-aryl; wherein the aryl and heterocyclyl ring substituents may be further substituted with one or more groups independently selected from the group consisting of (C 1 -C 6 )-alkyl, halogen, (C 1 - C 6 )-haloalkyl, CN, 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

aryl and heterocyclyl are optionally substituted with (C 1 -C 6 )-alkyl, halogen, (C 1 -C 6 )-haloalkyl, CN, oxo, hydroxy, (C 1 -C 6 )-alkoxy, —C(O)—(C 1 -C 6 )-alkyl or —C(O)—O—(C 1 -C 6 )-alkyl;

R 7 is hydrogen or (C 1 -C 6 )-alkyl; or

R 6 and R 7 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with oxo, —OH, —SH, —F, —Cl, —Br, —I, —NR 11 R 11′ , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-thioalkyl, (C 1 -C 6 )-haloalkyl, hydroxy-(C 1 -C 6 )-alkyl, —C(O )—H, —C(O)—(C 1 -C 6 )-alkyl, —C(O)OH, or —C(O)O—(C 1 -C 6 )-alkyl;

R 10 and R 10′ are independently selected from the group consisting of H, (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 a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, 0, and S atoms, and optionally substituted with one or more substituents independently selected from the group consisting of oxo, —OH, —F, —Cl, —Br, —I, —NR 11 R 11′ , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-haloalkyl, hydroxy -(C 1 -C 6 )-alkyl-, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl, —C(O)OH, and —C(O)—O—(C 1 -C 6 )-alkyl;

R 11 and R 11′ are independently selected from the group consisting of hydrogen and (C 1 -C 6 )-alkyl; and

A is (C 1 -C 4 )-alkylene, (C 2 -C 4 )-alkenylene, or (C 2 -C 4 )-alkynylene;

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

3. The compound of claim 2 , where R 1 , R 2 and R 3 are independently (C 1 -C 4 )-alkyl;

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

4. The compound of claim 2 , where R 6 is (C 1 -C 6 )-alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of —OH, —SH, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-thioalkyl, —CN, —F, —Cl, —Br, —I, —NH 2 , —NH(C 1 -C 4 )-alkyl, and —N((C 1 -C 4 )-alkyl) 2 ;

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

5. The compound of claim 2 , where R 6 is (C 1 -C 6 )-alkyl substituted with aryl, where the aryl is optionally substituted with one, two or three substituents independently selected from the group consisting of (C 1 -C 6 )-alkyl, halogen, (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;

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

6. The compound of claim 2 , where R 6 is (C 1 -C 6 )-alkyl optionally substituted with —NR 10 R 10′ , where R 10 and R 10′ together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with one or more substituents independently selected from the group consisting of oxo, —OH, —F, —Cl, —Br, —I, —NR 11 R 11′ ,(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-haloalkyl, hydroxy-(C 1 -C 6 )-alkyl-, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl, —C(O)OH, and —C(O)—O—(C 1 -C 6 )-alkyl;

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

7. The compound of claim 2 , where R 6 is aryl or heterocyclyl optionally substituted with one, two, or three substituents independently selected from the group consisting of (C 1 -C 6 )-alkyl, halogen, (C 1 -C 6 )-haloalkyl, CN, oxo, hydroxy, (C 1 -C 6 )-alkoxy, —C(O)—(C 1 -C 6 )-alkyl, and —C(O)O—(C 1 -C 6 )-alkyl;

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

8. The compound of claim 2 , where R 4 is hydrogen;

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

9. A compound selected from the group consisting of:

1-ethyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

1-(2-hydroxyethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

1-(2-(dimethylamino)ethyl)-3 -(2- (2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

3-(2-(dimethylamino)ethyl)-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

3-ethyl-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa -1,4-dienyl)ethyl)urea;

1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

1-methyl-1-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

1-(2-(5-(4-chlorophenyl)-2,4-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)-3-ethylurea;

1-(2-morpholinoethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

4-benzyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;

1-(pyridin-2-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

1-(pyridin-4-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

1-(pyridin-3-ylmethyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

4-hydroxy-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;

N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;

1,1-diethyl-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

1-(4-chlorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

4-methyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;

4-acetyl-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperazine-1-carboxamide;

4-oxo-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;

1-(4-fluorobenzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

1-(4-(trifluoromethyl)benzyl)-3-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

1-(4-chlorobenzyl)-1 -methyl-3-(2-(2,4,5 -trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

3-(4-chlorobenzyl)-1-methyl-1-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)urea;

4,4-difluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide; and

4-fluoro-N-(2-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)piperidine-1-carboxamide;

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

10. The compound of claim 2 , additionally comprising a pharmaceutically acceptable excipient.

11. A method of treating or suppressing an oxidative stress disorder comprising administering to a subject a therapeutically effective amount of a compound of claim 1 , where the oxidative stress disorder is a mitochondrial disorder selected from the group consisting of an inherited mitochondrial disease; Myoclonic Epilepsy with Ragged Red Fibers (MERRF); Mitochondrial Myopathy, Encephalopathy, Lactacidosis, Stroke (MELAS); Maternally Inherited Diabetes and Deafness (MIDD); 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, and Huntington's Disease.

12. A method of treating or suppressing an oxidative stress disorder comprising administering to a subject a therapeutically effective amount of a compound of claim 1 , where the oxidative stress disorder is an impaired energy processing disorder, due to deprivation, poisoning or toxicity of oxygen, or of qualitative or quantitative disruption in the transport of oxygen.

13. A method of treating or suppressing a disorder comprising administering to a subject a therapeutically effective amount of a compound of claim 1 , where the disorder is a hearing or balance impairment, or a pervasive development disorder selected from the group consisting of Autistic Disorder, Asperger's Disorder, Childhood Disintegrative Disorder (CDD), Rett's Disorder, and PDD-Not Otherwise Specified (PDD-NOS).

14. The compound of claim 1 , wherein R is

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

15. The compound of claim 14 , wherein R 1 , R 2 and R 3 are independently (C 1 -C 4 )-alkyl;

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

16. The compound of claim 14 , where R 6 is (C 1 -C 6 )-alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of —OH, —SH, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-thioalkyl, —CN, —F, —Cl, —Br, —I, —NH 2 , —NH(C 1 -C 4 )-alkyl, and —N((C 1 -C 4 )-alkyl) 2 ;

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

17. The compound of claim 14 , where R 6 is (C 1 -C 6 )-alkyl substituted with aryl, where the aryl is optionally substituted with one, two or three substituents independently selected from the group consisting of (C 1 -C 6 )-alkyl, halogen, (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;

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

18. The compound of claim 14 , where R 6 is (C 1 -C 6 )-alkyl optionally substituted with —NR 10 R 10′ where R 10 and R 10′ together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with one or more substituents independently selected from the group consisting of oxo, —OH, —F, —Cl, —Br, —I, —NR 11 R 11′ , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-haloalkyl, hydroxy-(C 1 -C 6 )-alkyl-, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl, —C(O)OH, and —C(O)—O—(C 1 -C 6 )-alkyl;

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

19. The compound of claim 14 , where R 6 is aryl or heterocyclyl optionally substituted with one, two, or three substituents independently selected from the group consisting of (C 1 -C 6 )-alkyl, halogen, (C 1 -C 6 )-haloalkyl, CN, oxo, hydroxy, (C 1 -C 6 ) -alkoxy, —C(O)—(C 1 -C 6 )-alkyl, and —C(O)O—(C 1 -C 6 )-alkyl;

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

20. The compound of claim 14 , where R 4 is hydrogen;

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

21. The compound of claim 2 , where R 6 and R 7 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with oxo, —OH, —SH, —F, —Cl, —Br, —I, —NR 11 R 11′ , (C i C 6 )-alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-thioalkyl, (C 1 -C 6 )-haloalkyl, hydroxy-(C 1 -C 6 )-alkyl, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl, —C(O)OH, or —C(O)O—(C 1 -C 6 )-alkyl;

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

22. The compound of claim 14 , where R 6 and R 7 together with the atom to which they are attached form a saturated or unsaturated 3-8 membered ring, optionally incorporating one, two, or three additional heteroatoms independently selected from the group consisting of N, O, and S atoms, and optionally substituted with oxo, —OH, —SH, —F, —Cl, —Br, —I, —NR 11 R 11′ , (C 1 C 6 ) alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )-thioalkyl, (C 1 -C 6 )-haloalkyl, hydroxy-(C 1 -C 6 )-alkyl, —C(O)—H, —C(O)—(C 1 -C 6 )-alkyl, —C(O)OH, or —C(O)O—(C 1 -C 6 )-alkyl;

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