Mitochondria-targeting peptides

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein

AA 1 is selected from

AA 2 is selected from

R 1 is selected from

R 2a is selected from

R 2b is H or Me;

R 3 and R 4 are independently selected from H and (C1-C6)alkyl;

R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl; or R 5 and R 6 together with the N atom to which they are attached form a 4-6-membered heterocyclyl;

R 7 is selected from H, (C1-C6)alkyl, cycloalkyl, and aryl;

R 8 and R 9 are independently selected from H, (C1-C6)alkyl, cycloalkyl, and aryl; or R 8 and R 9 together with the N atom to which they are attached form a 4-6-membered heterocyclyl;

n is 1, 2, or 3;

X is selected from

and

* denotes the point of attachment of X to R 1 .

2. The compound of claim 1 , wherein R 1 is

3. The compound of claim 1 , where R 2a is

4. The compound of claim 3 , where R 8 and R 9 are independently selected from H and methyl.

5. The compound of claim 3 , where R 2a is

6. The compound of claim 3 , where R 2a is

7. The compound of claim 1 , wherein R 2a a

8. The compound of claim 7 , wherein R 2a is

9. The compound of claim 1 , wherein AA 2 is

10. The compound of claim 9 , wherein R 7 is H.

11. The compound of claim 1 , wherein AA 1 is

12. The compound of claim 1 , wherein R 2b is H.

13. The compound of claim 1 , wherein R 5 is H.

14. The compound of claim 1 , wherein R 6 is H.

15. The compound of claim 1 , wherein X is

16. The compound of claim 1 , wherein R 3 and R 4 are H.

17. The compound of claim 1 , wherein the compound is selected from

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-benzyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((R)-1′,5′-diaminopent-1′-yl)-3-benzyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-2′,6′-diaminohex-2′-yl)-3-benzyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-5′-dimethylamino-1′-aminopent-1′-yl)-3-benzyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((R)-1′,5′-diaminopent-1′-yl)-3-(2′,3′,4′,5′,6′-pentafluorobenzyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-(4-tert-butylbenzyl)-1,2,4-oxzdiazole;

D-Arg-DMT-(5-((R)-1′,5′-diaminopent-1′-yl)-3-(4-tert-butylbenzyl)-1,2,4-oxzdiazole;

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-(4′-trifluoromethylbenzyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-(4-phenylbenzyl))-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-(4′-cyclohexylbenzyl))-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-phenethyl))-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-cyclohexylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-cyclohexylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-cycloheptylmathyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-bicyclo[2,2,2]pentanylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-bicyclo[2,2,2] octanylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((1 S)-(5-(1′,5′-diaminopent-1′-yl-3-adamant-1′-yl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((1R)-(5-(1′,5′-diaminopent-1′-yl-3-adamant-1′-yl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-admantylmethyl)-1,2,4-oxzadiazole;

D-Arg-DMT-(5-(α-(S)-histamine)-3-phenyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-(S)-histamine)-3-benzyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-(S)-histamine)-3-phenethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-(S)-histamine)-3-cyclopentylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-(S)-histamine)-3-cyclohexylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-(S)-t-methylhistamine)-3-cyclohexylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-(S)-p-methylhistamine)-3-cyclohexylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-(S)-histamine)-3-cycloheptylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-(S)-histamine)-3-bicyclo[2,2,2]pentanylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-(S)-histamine)-3-bicyclo[2,2,2] octanylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-(S)-histamine)-3-admantyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-(S)-histamine)-3-admantylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((S)-(2-(1H-indol-3-yl)-1-aminoethyl)-3-benzyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-((1 S)-2-(pyridin-4-yl)-1-aminoethyl-3-admantylmethyl)-1,2,4-oxadiazole;

D-Agb-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-benzyl)-1,2,4-oxadiazole;

D-Agb-DMT-(5-((S)-1′,4′-diaminobut-1′-yl)-3-benzyl)-1,2,4-oxadiazole;

D-Agb-DMT-(5-((S)-4′-dimethylamino-1′-aminobut-1′-yl)-3-benzyl)-1,2,4-oxadiazole;

D-Agb-DMT-(5-(2′-(S)-4-histamine)-3-admantylmethyl)-1,2,4-oxadiazole;

(N,N-diMe)-D-Agb-DMT-(5-(2′-(S)-4-histamine)-3-admantyl)-1,2,4-oxadiazole;

D-Agb-DMT-(5-((S)-(2-(1H-indol-3-yl)-1-aminoethyl)-3-benzyl)-1,2,4-oxadiazole;

D-Agb-DMT-(5-((S)-(2-(1H-indol-3-yl)-1-aminoethyl)-3-admantylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((S)-1′,4′-diaminopropan-1′-yl)-3-benzyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((S)-1′,4′-diaminobut-1′-yl)-3-cyclohexylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((S)-1′,4′-diaminobut-1′-yl)-3-admantyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((S)-1′,4′-diaminobut-1′-yl)-3-admantylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((R)-1′,4′-diaminobut-1′-yl)-3-admantylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((R)-1′,4′-diaminobut-1′-yl)-3-(bicyclo[2.2.2] octanylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((S)-4′-dimethylamino-1′-aminobut-1′-yl)-3-admantylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-cyclohexylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((S)-5′-dimethylamino-1′-aminopent-1′-yl)-3-cyclohexylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-(α-(S)-histamine)-3-benzyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-(α-(S)-histamine)-3-(4-phenylbenzyl))-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-(α-(S)-histamine)-3-cyclopentylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-(α-(S)-histamine)-3-cyclohexylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-(α-(S)-histamine)-3-cycloheptylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-(α-(S)-t-methylhistamine)-3-cyclohexylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-(α-(S)-histamine)-3-cyclohexylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-(α-(S)-histamine)-3-admantylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-(α-(S)-t-methylhistamine)-3-admantylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((1S)-(2-(1H-indol-3-yl)-1-aminoethyl)-3-(4-phenylbenzyl))-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((1 S)-(2-(1-methyl-indol-3-yl)-1-aminoethyl)-3-(4-phenylbenzyl))-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((1 S)-(2-(1H-indol-3-yl)ethyl)-3-admantylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((1S)-(2-(6-fluoro-1H-indol-3-yl)ethyl)-3-admantylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-DMT-(5-((1 S)-(2-(1-methyl-indol-3-yl)-1-aminoethyl)-3-admantylmethyl)-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-(O-Me)-DMT-(5-(α-histimine)-3-(4-phenylbenzyl))-1,2,4-oxadiazole;

D-(δ-2-amino-1H-imidazol-1-yl)-Nva-(O-Me)-DMT-(5-(α-(S)-t-methylhistamine)-3-(4-phenylbenzyl))-1,2,4-oxadiazole

(Carbamimidoyl)-D-Dab-DMT-(5-((S)-1′,5′-diaminopent-1′-yl)-3-benzyl)-1,2,4-oxadiazole;

(Carbamimidoyl)-D-Dab-DMT-(5-((S)-1′,5′-diaminobutan-1′-yl)-3-benzyl)-1,2,4-oxadiazole;

(Carbamimidoyl)-D-Dab-DMT-(5-(2′-(S)-4-histamine)-3-admantylmethyl)-1,2,4-oxadiazole;

D-Arg-DMT-(5-(α-histimine))-3-benzyl)-1,3,4-oxadiazole;

D-Arg-DMT-(2-((S)-1′,5′-diaminopent-1′-yl)-4-benzyl)-1,3-oxazole;

D-Arg-DMT-(2-((S)-1′,5′-diaminopent-1′-yl)-5-benzyl)-1,3-oxazole;

D-Arg-DMT-(2-((S)-1′,5′-diaminopent-1′-yl)-4-benzyl)-1,3-thiazole;

D-Arg-DMT-(2-((S)-1′,5′-diaminopent-1′-yl)-5-benzyl)-1,3-thiazole;

D-Arg-DMT-(2-((S)-1′,5′-diaminopent-1′-yl)-4-benzyl)-furan;

D-Arg-DMT-(2-((S)-1′,5′-diaminopent-1′-yl)-5-benzyl)-furan;

D-Arg-DMT-(1-((S)-1′,5′-diaminopent-1′-yl)-3-phenoxy)-benzene;

D-Arg-DMT-(1-((S)-1′,5′-diaminopent-1′-yl)-4-phenoxy)-benzene;

D-Arg-DMT-(2-((S)-1′,5′-diaminopent-1′-yl)-4-phenoxy)-pyridine;

D-Arg-DMT-(2-((S)-1′,5′-diaminopent-1′-yl)-5-phenoxy)-pyridine;

D-Arg-DMT-(2-((S)-1′,5′-diaminopent-1′-yl)-6-benzyl)-pyridine; and

D-Arg-DMT-(2-((S)-1′,5′-diaminopent-1′-yl)-4-benzyl)-pyrimidine.

18. The compound of claim 1 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt thereof.