(Het)aryl-p-quinone 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;

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 the (C 0 -C 6 )-alkyl group 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 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 , or the 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-, (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 the (C 0 -C 6 )-alkyl group 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; provided that the compound is not

2. The compound according to claim 1 , wherein R is:

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

3. The compound according to claim 2 , wherein:

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 the (C 0 -C 6 )-alkyl group 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 compound of claim 3 , where R 2 and R 3 are (C 1 -C 6 )-alkyl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

5. The compound of claim 3 , where R 1 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 compound of claim 3 , where R 1 is heterocyclyl-(C 0 -C 6 )-alkyl-, wherein the heterocyclyl 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, 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 compound according to claim 2 , wherein:

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 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 , or the 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-, (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 the (C 0 -C 6 )-alkyl group 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 compound of claim 7 , where R 1 and R 2 are (C 1 -C 6 )-alkyl; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.

9. The compound of claim 7 , where R 3 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.

10. The compound of claim 7 , where R 3 is heterocyclyl-(C 0 -C 6 )-alkyl-, wherein the heterocyclyl 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, (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 compound according to claim 1 , wherein the compound is 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]dioxol-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-hydroxy-3-methylbutyl)-3-(4-methoxyphenyl)-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-(4-chlorophenyl)-6-(3-hydroxy-3-methylbutyl)-3,5-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.

12. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

13. A composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier.

14. The compound according to claim 1 , wherein the compound is 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;

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

15. The compound according to claim 3 , wherein R 1 is phenyl mono-substituted with a substituent selected from the group consisting of fluoro, chloro, and trifluoromethyl.

16. The compound according to claim 7 , wherein R 3 is phenyl mono-substituted with a substituent selected from the group consisting of fluoro, chloro, and trifluoromethyl.