Compounds for therapeutic use

Abstract

Chemical entities of Formula (I): Including enantiomers thereof, wherein R 1 has any of the values described herein, and compositions comprising such chemical entities; their preparation; and their use in various methods, including the treatment of depression, pain, cognitive disorders, neurodegenerative disorders, and other neurological and peripheral disorders.

What is claimed is: 
     
         1 . A method of treating a neurological disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —H; or 
         R 1  is —C 1-6 alkyl, optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, -alkoxy, -amino and -carboxyl; or 
         R 1  is —C 3-8 alkenyl or —C 3-8 alkynyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, —C 1-4  alkyl, —C 1-4 alkoxy, and amino; or 
         R 1  is —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, or —(CH 2 ) n heterocycloalkyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, —C 1-4  alkyl, —C 1-4  alkoxy, and amino, wherein n is independently an integer selected from 0, 1, 2, 3, and 4; or 
         R 1  is —COR 2 , —CONR 3 R 4 , —CR 5 R 6 NR 7 R 8 , —CHR 9 R 10 , or —C(OH)R 11 R 12 , 
         wherein R 2 , R 3 , R 4 , R 7  and R 8  are each independently selected from the group consisting of: —H, —C 1-8 alkyl, and —C 1-8 haloalkyl; 
         R 5  and R 6  are each independently selected from the group consisting of: —H, -halo, —NH 2 , —C 1-8 alkyl, —C 1-8 haloalkyl, —(CH 2 ) n CONH 2 , —(CH 2 ) n COOH, —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, and —(CH 2 ) n heterocycloalkyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy, -amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide, —(CH 2 ) n CONR 1A R 1B , —(CH 2 ) n NHC(═O)R 1A , —(CH 2 ) n NR 1A R 1B , —(CH 2 ) n OR 1C , —(CH 2 ) n SR 1C  and —(CH 2 ) n SeR 1C , wherein n is independently an integer selected from 0, 1, 2, 3, and 4; 
         each R 1A  is independently selected from the group consisting of: —H—C 1-8 alkyl, —(CH 2 ) n CONH 2 , and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4; 
         each R 1B  is independently selected from the group consisting of: —H, —C 1-8 alkyl, and —(CH 2 ) n CONH 2 , wherein n is independently an integer selected from 0, 1, 2, 3, and 4; 
         each R 1C  is independently selected from the group consisting of: —H—C 1-8 alkyl, —C 1-8 haloalkyl, —(CH 2 ) n CONH 2 , —(CH 2 ) n COOH, —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4; 
         R 9  and R 10  are each independently selected from the group consisting of: —H, —C 1-8 alkyl, and —C 1-8 haloalkyl, said alkyl optionally substituted with up to 3 members, each independently selected from the group consisting of: -amino, -hydroxy and -carboxyl; or optionally R 9  and R 10  taken together with the carbon to which they are attached form an optionally substituted five membered heteroaryl or heterocycloalkyl ring; and 
         R 11  and R 12  are independently selected from the group consisting of: —H, —C 1-6 alkyl, and —C 1-6 haloalkyl, said —C 1-6 alkyl, and —C 1-6 haloalkyl optionally substituted with up to 3 members, each independently selected from the group consisting of: -hydroxy and amino; 
         wherein the neurological disorder is selected from the group consisting of a depressive disorder, a bipolar disorder, an anxiety disorder, a pain disorder, a cognitive disorder, and a neurodegenerative disorder. 
       
     
     
         2 . The method of  claim 1 , wherein:
 R 1  is —H; or   R 1  is —C 1-6 alkyl, optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, -alkoxy, -amino and -carboxyl; or   R 1  is —C 3-8 alkenyl or —C 3-8 alkynyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, —C 1-4  alkyl, —C 1-4  alkoxy, and amino; or   R 1  is —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, or —(CH 2 ) n heterocycloalkyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, —C 1-4  alkyl, —C 1-4  alkoxy, and -amino, wherein n is independently an integer selected from 0, 1, 2, 3, and 4; or   R 1  is —CR 5 R 6 NR 7 R 8 , —CHR 9 R 10 , or —C(OH)R 11 R 12 ,   wherein R 7  and R 8  are independently selected from the group consisting of: —H, —C 1-8 alkyl, and —C 1-8 haloalkyl;   R 5  and R 6  are each independently selected from the group consisting of: —H, -halo, —NH 2 , —C 1-8 alkyl, —C 1-8 haloalkyl, —(CH 2 ) n CONH 2 , —(CH 2 ) n COOH, —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, and —(CH 2 ) n heterocycloalkyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy, -amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide, —(CH 2 ) n NR 1A R 1B , —(CH 2 ) n OR 1C , —(CH 2 ) n SR 1C  and —(CH 2 ) n SeR 1C , wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1A  is independently selected from the group consisting of: —H—C 1-8 alkyl, and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1B  is independently selected from the group consisting of: —H and —C 1-8 alkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1C  is independently selected from the group consisting of: —H, —C 1-8 alkyl, —C 1-8 haloalkyl, —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   R 9  and R 10  are each independently selected from the group consisting of: —H, —C 1-8 alkyl, and —C 1-8 haloalkyl, said alkyl optionally substituted with up to 3 members, each independently selected from the group consisting of -amino, -hydroxy, and -carboxyl; or optionally R 9  and R 10  taken together with the carbon to which they are attached can form an optionally substituted five membered heteroaryl or heterocycloalkyl ring; and   R 11  and R 12  are each independently selected from the group consisting of: —H, —C 1-6 alkyl, and —C 1-6 haloalkyl, said —C 1-6 alkyl, and —C 1-6 haloalkyl optionally substituted with up to 3 members, each independently selected from the group consisting of: -hydroxy and -amino.   
     
     
         3 . The method of  claim 1 , wherein:
 R 1  is —CR 5 R 6 NR 7 R 8  or —CR 9 R 10 ,   wherein R 5  and R 6  are independently selected from the group consisting of: —H, —F, —Cl, —Br, —NH 2 , -methyl, -ethyl, -n-propyl, -isopropyl, -butyl, -pentyl, —NH 2 , —C 1-8 haloalkyl, —(CH 2 ) n CONH 2 , —(CH 2 ) n COOH, —(CH 2 ) n aryl, —(CH 2 ) n benzyl, —(CH 2 ) n heteroaryl, —(CH 2 )indole, —(CH 2 )imidazole, —(CH 2 ) n cycloalkyl, —(CH 2 ) n heterocycloalkyl, —(CH 2 ) n pyrrolidine, —(CH 2 )furan, and —(CH 2 ) n thiophene, optionally substituted with up to 3 members, each independently selected from the group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy, -amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide, —(CH 2 ) n NR 1A R 1B , —(CH 2 ) n OR 1C , —(CH 2 ) n SR 1C  and —(CH 2 ) n SeR 1C , wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1A  is independently selected from the group consisting of: —H, —C 1-8 alkyl, and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1B  is independently selected from the group consisting of: —H and —C 1-8 alkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1C  is independently selected from the group consisting of: —H—C 1-8 alkyl, —C 1-8 haloalkyl, —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   R 7  and R 8  are H; and   R 9  and R 10  are independently selected from the group consisting of: —H, —C 1-8 alkyl, and —C 1-8 haloalkyl; or optionally R 9  and R 10  taken together with the carbon to which they are attached can form an optionally substituted five membered heteroaryl or heterocycloalkyl ring.   
     
     
         4 . The method of  claim 1 , wherein the neurological disorder is a depressive disorder. 
     
     
         5 . The method of  claim 4 , wherein the depressive disorder is a major depressive episode associated with a bipolar disorder, a major depressive disorder, treatment-refractory depression, or treatment-resistant depression. 
     
     
         6 . The method of  claim 4 , wherein the depressive disorder is treatment-refractory depression or treatment-resistant depression. 
     
     
         7 . The method of  claim 4 , wherein a symptom of the depressive disorder is suicide ideation. 
     
     
         8 . The method of  claim 4 , wherein the therapeutically effective amount is an amount sufficient to achieve remission on a depression symptoms rating scale. 
     
     
         9 . A method of treating a neurological disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
 (1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic acid;   (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoic acid;   (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide;   (S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide;   (1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine;   (1R,5R)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoic acid;   2-(((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)methyl)-2-hydroxysuccinic acid;   5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentanoic acid;   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoic acid;   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic acid;   (1R,5R)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(1-amino-3-hydroxypropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-N-ethylbutanamide;   (1R,5R)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   1-(4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)urea;   1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)urea;   1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)guanidine;   1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)ethyl)guanidine;   (1R,5R)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;   (1R,5R)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (S)-3-amino-3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic acid;   (S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoic acid;   (S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide;   (S)-3-amino-3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide;   (1S,5S)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   1-((S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine;   (1S,5S)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoic acid;   2-(((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)methyl)-2-hydroxysuccinic acid;   5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentanoic acid;   3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoic acid;   3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic acid;   (1S,5S)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(1-amino-3-hydroxypropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-N-ethylbutanamide;   (1S,5S)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   1-(4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)urea;   1-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)urea;   1-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)guanidine;   1-(2-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)ethyl)guanidine;   (1S,5S)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   N-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;   (1S,5S)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1S,5S)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   and pharmaceutically acceptable salts thereof;   wherein the neurological disorder is selected from the group consisting of a depressive disorder, a bipolar disorder, an anxiety disorder, a pain disorder, a cognitive disorder, and a neurodegenerative disorder.   
     
     
         10 . The method of  claim 9 , wherein the compound is selected from the group consisting of:
 (1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic acid;   (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoic acid;   (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide;   (S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide;   (1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine;   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoic acid;   2-(((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)methyl)-2-hydroxysuccinic acid;   5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentanoic acid;   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoic acid;   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic acid;   4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-N-ethylbutanamide;   1-(4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)urea;   1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)urea;   1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)guanidine;   1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)ethyl)guanidine;   N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;   and pharmaceutically acceptable salts thereof.   
     
     
         11 . The method of  claim 9 , wherein the compound is selected from the group consisting of:
 (1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   (S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic acid;   (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoic acid;   (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide;   (S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide;   (1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;   1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine;   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoic acid;   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoic acid;   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic acid;   and pharmaceutically acceptable salts thereof.   
     
     
         12 . The method of  claim 9 , wherein the neurological disorder is a depressive disorder. 
     
     
         13 . The method of  claim 12 , wherein the depressive disorder is a major depressive episode associated with a bipolar disorder, a major depressive disorder, treatment-refractory depression, or treatment-resistant depression. 
     
     
         14 . The method of  claim 12 , wherein the depressive disorder is treatment-refractory depression or treatment-resistant depression. 
     
     
         15 . The method of  claim 12 , wherein a symptom of the depressive disorder is suicide ideation. 
     
     
         16 . The method of  claim 12 , wherein the therapeutically effective amount is an amount sufficient to achieve remission on a depression symptoms rating scale. 
     
     
         17 . A method of treating a depressive disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —H; or 
         R 1  is —C 1-6 alkyl, optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, -alkoxy, -amino and -carboxyl; or 
         R 1  is —C 3-8 alkenyl or —C 3-8 alkynyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, —C 1-4  alkyl, —C 1-4 alkoxy, and amino; or 
         R 1  is —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, or —(CH 2 ) n heterocycloalkyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, —C 1-4  alkyl, —C 1-4  alkoxy, and -amino, wherein n is independently an integer selected from 0, 1, 2, 3, and 4; or 
         R 1  is —COR 2 , —CONR 3 R 4 , —CR 5 R 6 NR 7 R 8 , —CHR 9 R 10 , or —C(OH)R 11 R 12 , 
         wherein R 2 , R 3 , R 4 , R 7  and R 8  are each independently selected from the group consisting of: —H, —C 1-8 alkyl, and —C 1-8 haloalkyl; 
         R 5  and R 6  are each independently selected from the group consisting of: —H, -halo, —NH 2 , —C 1-8 alkyl, —C 1-8 haloalkyl, —(CH 2 ) n CONH 2 , —(CH 2 ) n COOH, —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, and —(CH 2 ) n heterocycloalkyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy, -amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide, —(CH 2 ) n CONR 1A R 1B , —(CH 2 ) n NHC(═O)R 1A , —(CH 2 ) n NR 1A R 1B , —(CH 2 ) n OR 1C , —(CH 2 ) n SR 1C  and —(CH 2 ) n SeR 1C , wherein n is independently an integer selected from 0, 1, 2, 3, and 4; 
         each R 1A  is independently selected from the group consisting of: —H, —C 1-8 alkyl, —(CH 2 ) n CONH 2 , and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4; 
         each R 1B  is independently selected from the group consisting of: —H, —C 1-8 alkyl, and —(CH 2 ) n CONH 2 , wherein n is independently an integer selected from 0, 1, 2, 3, and 4; 
         each R 1C  is independently selected from the group consisting of: —H, —C 1-8 alkyl, —C 1-8 haloalkyl, —(CH 2 ) n CONH 2 , —(CH 2 ) n COOH, —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4; 
         R 9  and R 10  are each independently selected from the group consisting of: —H, —C 1-8 alkyl, and —C 1-8 haloalkyl, said alkyl optionally substituted with up to 3 members, each independently selected from the group consisting of: -amino, -hydroxy and -carboxyl; or optionally R 9  and R 10  taken together with the carbon to which they are attached form an optionally substituted five membered heteroaryl or heterocycloalkyl ring; and 
         R 11  and R 12  are independently selected from the group consisting of: —H, —C 1-6 alkyl, and —C 1-6 haloalkyl, said —C 1-6 alkyl, and —C 1-6 haloalkyl optionally substituted with up to 3 members, each independently selected from the group consisting of: -hydroxy and amino; or pharmaceutically acceptable salt thereof. 
       
     
     
         18 . The method of  claim 17 , wherein:
 R 1  is —H; or   R 1  is —C 1-6 alkyl, optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, -alkoxy, -amino and -carboxyl; or   R 1  is —C 3-8 alkenyl or —C 3-8 alkynyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, —C 1-4  alkyl, —C 1-4  alkoxy, and amino; or   R 1  is —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, or —(CH 2 ) n heterocycloalkyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -halo, -hydroxy, —C 1-4  alkyl, —C 1-4  alkoxy, and -amino, wherein n is independently an integer selected from 0, 1, 2, 3, and 4; or   R 1  is —CR 5 R 6 NR 7 R 8 , —CHR 9 R 10 , or —C(OH)R 11 R 12 ,   wherein R 7  and R 8  are independently selected from the group consisting of: —H, —C 1-8 alkyl, and —C 1-8 haloalkyl;   R 5  and R 6  are each independently selected from the group consisting of: —H, -halo, —NH 2 , —C 1-8 alkyl, —C 1-8 haloalkyl, —(CH 2 ) n CONH 2 , —(CH 2 ) n COOH, —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, and —(CH 2 ) n heterocycloalkyl, each optionally substituted with one or more members, each independently selected from the group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy, -amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide, —(CH 2 ) n NR 1A R 1B , —(CH 2 ) n OR 1C , —(CH 2 ) n SR 1C  and —(CH 2 ) n SeR 1C , wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1A  is independently selected from the group consisting of: —H—C 1-8 alkyl, and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1B  is independently selected from the group consisting of: —H and —C 1-8 alkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1C  is independently selected from the group consisting of: —H, —C 1-8 alkyl, —C 1-8 haloalkyl, —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   R 9  and R 10  are each independently selected from the group consisting of: —H, —C 1-8 alkyl, and —C 1-8 haloalkyl, said alkyl optionally substituted with up to 3 members, each independently selected from the group consisting of -amino, -hydroxy, and -carboxyl; or optionally R 9  and R 10  taken together with the carbon to which they are attached can form an optionally substituted five membered heteroaryl or heterocycloalkyl ring; and   R 11  and R 12  are each independently selected from the group consisting of: —H, —C 1-6 alkyl, and —C 1-6 haloalkyl, said —C 1-6 alkyl, and —C 1-6 haloalkyl optionally substituted with up to 3 members, each independently selected from the group consisting of: -hydroxy and -amino.   
     
     
         19 . The method of  claim 17 , wherein:
 R 1  is —CR 5 R 6 NR 7 R 8  or —CR 9 R 10 ,   wherein R 5  and R 6  are independently selected from the group consisting of: —H, —F, —Cl, —Br, —NH 2 , -methyl, -ethyl, -n-propyl, -isopropyl, -butyl, -pentyl, —NH 2 , —C 1-8 haloalkyl, —(CH 2 ) n CONH 2 , —(CH 2 ) n COOH, —(CH 2 ) n aryl, —(CH 2 ) n benzyl, —(CH 2 ) n heteroaryl, —(CH 2 )indole, —(CH 2 )imidazole, —(CH 2 ) n cycloalkyl, —(CH 2 ) n heterocycloalkyl, —(CH 2 ) n pyrrolidine, —(CH 2 )furan, and —(CH 2 ) n thiophene, optionally substituted with up to 3 members, each independently selected from the group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy, -amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide, —(CH 2 ) n NR 1A R 1B , —(CH 2 ) n OR 1C , —(CH 2 ) n SR 1C  and —(CH 2 ) n SeR 1C , wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1A  is independently selected from the group consisting of: —H, —C 1-8 alkyl, and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1B  is independently selected from the group consisting of: —H and —C 1-8 alkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   each R 1C  is independently selected from the group consisting of: —H—C 1-8 alkyl, —C 1-8 haloalkyl, —(CH 2 ) n aryl, —(CH 2 ) n heteroaryl, —(CH 2 ) n cycloalkyl, and —(CH 2 ) n heterocycloalkyl, wherein n is independently an integer selected from 0, 1, 2, 3, and 4;   R 7  and R 8  are H; and   R 9  and R 10  are independently selected from the group consisting of: —H, —C 1-8 alkyl, and —C 1-8 haloalkyl; or optionally R 9  and R 10  taken together with the carbon to which they are attached can form an optionally substituted five membered heteroaryl or heterocycloalkyl ring.   
     
     
         20 . The method of  claim 17 , wherein the depressive disorder is a major depressive episode associated with a bipolar disorder, a major depressive disorder, treatment-refractory depression, or treatment-resistant depression.