Tetralone-based monoamine reuptake inhibitors

1. A compound having a structure, which is selected from Formula (II), Formula (III), and Formula (IV), or a pharmaceutically acceptable salt thereof:

wherein

n is an integer selected from 0 to 2;

D is CX—Ar 1 ;

m is an integer selected from 0 to 6;

each X is independently selected from H, halogen, CN, OR 5 , SR 5 , S(O) 2 R 5 , NR 6 R 7 , NR 6 S(O) 2 R 5 , NR 6 C(O)R 5 , acyl, ═X 1 , substituted or unsubstituted alkyl except CF 3 , substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl,

wherein

X 1 is selected from O, S, and NOR 5′ wherein R 5′ is selected from H, substituted or unsubstituted alkyl, and substituted or unsubstituted heteroalkyl;

each R 5 , R 6 and R 7 is independently selected from H, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl,

 wherein two of R 5 , R 6 and R 7 , together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring;

Ar 1 is

wherein

Y and Z are each independently Cl, CF 3 , or CN;

V and W are independently selected from H, halogen, CF 3 , CN, OR 9 , SR 9 , S(O) 2 R 9 , NR 10 R 11 , NR 10 S(O) 2 R 9 , NR 10 C(O)R 9 , acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl, or

V and W, together with the atoms to which they are attached, are joined to form a 5- to 7-membered ring;

wherein each R 9 , R 10 , and R 11 is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl;

wherein any two of R 9 , R 10 , and R 11 , together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring;

each R 1 and R 2 is independently selected from H, halogen, CN, CF 3 , OR 12 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl,

wherein

R 12 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl;

R 3 and R 4 are independently selected from H, OR 13 , acyl, S(O) 2 R 14 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl,

wherein

R 13 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl;

R 14 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; and

wherein at least two of R 1 , R 2 , R 3 and R 4 , together with the atoms to which they are attached, are optionally joined to form a 3- to 7-membered ring,

and any enantiomer, diastereoisomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form thereof

2. The compound of claim 1 , wherein said compound is chiral.

3. The compound of claim 1 , having a structure, which is selected from:

4. A composition comprising a first stereoisomer and at least one additional stereoisomer of a compound of claim 1 , wherein said first stereoisomer is present in a diastereomeric excess of at least 80% relative to said at least one additional stereoisomer.

5. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or diluent.

6. A method for treating a central nervous system disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

7. The method of claim 6 , wherein said central nervous system disorder is selected from depression, fibromyalgia, pain, sleep apnea, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless leg syndrome, schizophrenia, anxiety, obsessive compulsive disorder, post-traumatic stress disorder, seasonal affective disorder (SAD), premenstrual dysphoria, and a neurodegenerative disease.

8. The method of claim 6 , wherein said central nervous system disorder is Parkinson's disease.

9. The method of claim 6 , wherein said central nervous system disorder is neuropathic pain.

10. A method of inhibiting reuptake of one or more monoamines from the synaptic cleft, said method comprising administering to a mammalian subject a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 , wherein said monoamine is selected from serotonin, dopamine, and norepinephrine, or any combination thereof.

12. A method of modulating one or more monoamine transporters, said method comprising administering to a mammalian subject a compound of claim 1 , or a pharmaceutically acceptable salt thereof

13. The method of claim 12 , wherein said monoamine transporter is selected from serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET), or any combination thereof

14. The compound of claim 1 , wherein Y and Z are both Cl.

15. The compound of claim 14 , wherein R 3 and R 4 are independently H or substituted or unsubstituted C 1 -C 4 alkyl.

16. The compound of claim 14 , wherein m is 1, and X is H or OR 5 .

17. The compound of claim 14 , wherein m is 1, X is H or OR 5 , and R 3 and R 4 are independently H or substituted or unsubstituted C 1 -C 4 alkyl.

18. The compound of claim 17 , wherein R 5 is H.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

and any enantiomer, diastereoisomer, racemic mixture, enantiomerically enriched mixture, and enantiomerically pure form thereof.

20. A pharmaceutical composition comprising a compound of claim 19 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or diluent.

21. The compound of claim 3 , wherein Y and Z are both Cl.

22. The compound of claim 21 , wherein m is 1, X is H or OR 5 , and R 3 and R 4 are independently H or substituted or unsubstituted C 1 -C 4 alkyl.

23. The compound of claim 22 , wherein R 5 is H.