2-heterocyclylaminoalkyl-(p-quinone) derivatives for treatment of oxidative stress diseases

1. A method of treating or suppressing an oxidative stress disorder, comprising administering to a subject in need thereof 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;

n is 0 or 1;

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

R 3 is (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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

Het is optionally substituted pyridine;

M and M′ are independently selected from the group consisting of hydrogen, —C(O)—R 10 , —C(O)(C 2 -C 6 )-alkenyl, —C(O)(C 2 -C 6 )-alkynyl, —C(O)-aryl, —C(O)-heterocyclyl, —C(O)O—R 10 , —C(O)NR 10a R 10b , —SO 2 OR 10 , —SO 2 —C 1 -C 6 -alkyl, —SO 2 —(C 1 -C 6 )-haloalkyl, —SO 2 -aryl, —SO 2 —NR 10a R 10b , —P(O)(OR 10a )(OR 10b ), and C-linked amino acid or di-peptide, and

R 10 , R 10a , and R 10b are independently 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;

or a pharmaceutically acceptable salt, a solvate, or a hydrate thereof; wherein the oxidative stress disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON); Friedreich's Ataxia (FA); CoQ10 deficiency; Parkinson's disease; Huntington's Disease; and diabetes.

2. 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;

n is 0 or 1;

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

R 3 is (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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

Het is optionally substituted pyridine;

M and M′ are independently selected from the group consisting of hydrogen, —C(O)—R 10 , —C(O)(C 2 -C 6 )-alkenyl, —C(O)(C 2 -C 6 )-alkynyl, —C(O)-aryl, —C(O)-heterocyclyl, —C(O)O—R 10 , —C(O)NR 10a R 10b , —SO 2 OR 10 , —SO 2 —C 1 -C 6 -alkyl, —SO 2 —(C 1 -C 6 )-haloalkyl, —SO 2 -aryl, —SO 2 —NR 10a R 10b , —P(O)(OR 10a )(OR 10b ), and C-linked amino acid or di-peptide, and

R 10 , R 10a , and R 10b are independently 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;

or a salt, a solvate, or a hydrate thereof.

3. A compound of Formula Ia:

where:

n is 0 or 1;

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

R 3 is (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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

Het is pyridine optionally substituted with (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, nitro, cyano, —C(O)(C 1 -C 4 )alkyl, —C(O)(C 1 -C 6 )cycloalkyl, —C(O)OH, —C(O)O(C 1 -C 4 )-alkyl or oxo;

or a salt, a solvate, or a hydrate thereof.

4. The compound of claim 3 , where n is 0, or a salt, a solvate, or a hydrate thereof.

5. The compound of claim 3 where R 1 , R 2 , and R 3 are independently (C 1 -C 4 )-alkyl, or a salt, a solvate, or a hydrate thereof.

6. The compound of claim 3 where R 4 is hydrogen, or a salt, a solvate, or a hydrate thereof.

7. A compound of claim 3 , additionally comprising a pharmaceutically acceptable excipient.

8. A method of treating or suppressing an oxidative stress disorder, comprising administering a therapeutically effective amount of one or more compounds of claim 3 to a subject in need thereof;

wherein the oxidative stress disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON); Friedreich's Ataxia (FA); CoQ10 deficiency; Parkinson's disease; Huntington's Disease; and diabetes.

9. The method of claim 8 , where the oxidative stress disorder is selected from group consisting of Leber's Hereditary Optic Neuropathy (LHON); Friedreich's Ataxia (FA); and CoQ10 deficiency.

10. The method of claim 8 , wherein the oxidative stress disorder is Huntington's disease.

11. The method of claim 8 , wherein the oxidative stress disorder is Parkinson's disease.

12. A method of treating or suppressing an oxidative stress disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of claim 3 ; wherein the oxidative stress disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON); Friedreich's Ataxia (FA); CoQ10 deficiency; Parkinson's disease; Huntington's Disease; and diabetes.

13. A compound of formula Ib

where:

n is 0 or 1;

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

R 3 is (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

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

Het is pyridine optionally substituted with (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, halogen, nitro, cyano, —C(O)(C 1 -C 4 )alkyl, —C(O)(C 1 -C 6 )cycloalkyl, —C(O)OH, —C(O)O(C 1 -C 4 )-alkyl or oxo;

M and M′ are independently selected from the group consisting of hydrogen, —C(O)—R 10 , —C(O)(C 2 -C 6 )-alkenyl, —C(O)(C 2 -C 6 )-alkynyl, —C(O)-aryl, —C(O)-heterocyclyl, —C(O)O—R 10 , —C(O)NR 10a R 10b , —SO 2 OR 10 , —SO 2 —C 1 -C 6 -alkyl, —SO 2 —(C 1 -C 6 )-haloalkyl, —SO 2 -aryl, —SO 2 —NR 10a R 10b , —P(O)(OR 10a )(OR 10b ) and C-linked amino acid or di-peptide, and

R 10 , R 10a , and R 10b are independently 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;

or a salt, a solvate, or a hydrate thereof.

14. The compound of claim 13 , where n is 0, or a salt, a solvate, or a hydrate thereof.

15. The compound of claim 13 where R 1 , R 2 , and R 3 are methyl and M and M′ are independently hydrogen or C(O)—R 10 , or a salt, a solvate, or a hydrate thereof.

16. A compound of claim 13 , additionally comprising a pharmaceutically acceptable excipient.

17. A method of treating or suppressing an oxidative stress disorder, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of claim 13 ; wherein the oxidative stress disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON); Friedreich's Ataxia (FA); CoQ10 deficiency; Parkinson's disease; Huntington's Disease; and diabetes.

18. The method of claim 17 , wherein the oxidative stress disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON); Friedreich's Ataxia (FA) and CoQ10 deficiency.

19. The method of claim 17 , wherein the oxidative stress disorder is selected from the group consisting of Huntington's disease and Parkinson's disease.

20. A method of treating or suppressing an oxidative stress disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising one or more compounds of claim 13 ; wherein the oxidative stress disorder is selected from the group consisting of Leber's Hereditary Optic Neuropathy (LHON); Friedreich's Ataxia (FA); CoQ10 deficiency; Parkinson's disease; Huntington's Disease; and diabetes.

21. The method of claim 8 , wherein the oxidative stress disorder is diabetes.

22. The method of claim 17 , wherein the oxidative stress disorder is diabetes.

23. The method of claim 1 , wherein the method is a method of treating the oxidative stress disorder.

24. The method of claim 12 , wherein the method is a method of treating the oxidative stress disorder.

25. The method of claim 20 , wherein the method is a method of treating the oxidative stress disorder.

26. The compound of claim 3 where R 1 , R 2 , and R 3 are methyl, or a salt, a solvate, or a hydrate thereof.

27. The compound of claim 3 , where n is 1, or a salt, a solvate, or a hydrate thereof.

28. The compound of claim 3 , where R 1 , R 2 , and R 3 are independently (C 1 -C 4 )alkyl, and R 4 is (C 1 -C 4 )alkyl or hydrogen, or a salt, a solvate, or a hydrate thereof.

29. The compound of claim 3 , where R 1 and R 2 are independently (C 1 -C 4 )alkoxy, and R 3 is (C 1 -C 4 )alkyl, or a salt, a solvate, or a hydrate thereof.

30. The compound of claim 3 , where R 1 and R 2 are methoxy, and R 3 is methyl, or a salt, a solvate, or a hydrate thereof.

31. The compound of claim 2 , wherein the compound is selected from the group consisting of:

2,3,5-trimethyl-6-(2-(pyridin-2-ylamino)ethyl)cyclohexa-2,5-diene-1,4-dione;

2,3,5-trimethyl-6-(2-(4-(trifluoromethyl)pyridin-2-ylamino)ethyl)cyclohexa-2,5-diene-1,4-dione;

2,3,5-trimethyl-6-(2-(5-(trifluoromethyl)pyridin-2-ylamino)ethyl)cyclohexa-2,5-diene-1,4-dione;

2,3,5-trimethyl-6-(2-(6-(trifluoromethyl)pyridin-2-ylamino)ethyl)cyclohexa-2,5-diene-1,4-dione;

2,3,5-trimethyl-6-(2-(3-(trifluoromethyl)pyridin-2-ylamino)ethyl)cyclohexa-2,5-diene-1,4-dione;

2,3,5-trimethyl-6-(2-(methyl(pyridin-2-yl)amino)ethyl)cyclohexa-2,5-diene-1,4-dione;

2,3,5-trimethyl-6-(3-(pyridin-2-ylamino)propyl)cyclohexa-2,5-diene-1,4-dione; and

2,3,5-trimethyl-6-(3-(5-(trifluoromethyl)pyridin-2-ylamino)propyl)cyclohexa-2,5-diene-1,4-dione;

or a salt, a solvate, or a hydrate thereof.