Serotonin receptor modulator

Abstract

Certain biphenyic compounds are serotonin modulators useful in the treatment of serotonin-mediated diseases.

What is claimed is: 
     
         1 . A compound selected from the group consisting of (a) compounds of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —H, monocyclic cycloalkyl, phenyl, or benzyl; 
         m is 2 or 3; 
         n is 1 or 2; 
         R 2  and R 3  are each independently —H or —C 1-4 alkyl; 
         R 4  is —H, F, C 1-4 alkyl, or R 4  is —OH when L is —CH 2 —, —CF 2 —, —CHF—, —OCH 2 —, or —OCH(CH 3 )—; 
         L is —O—, —CH 2 —, —OCH 2 —, —OCH(CH 3 )—, —CH 2 O—, —CF 2 —, or —CHF—; 
         Z is —O—, —C(O)—, —OCH(R b )—, or —OCH 2 C(R c )(R d )—;
 where R b  is —H; a —C 1-4 alkyl group unsubstituted or substituted with OH or halo; —CO 2 C 1-4 alkyl; or —CO 2 H; and 
 R c  and R d  are each independently —H, —O—C 1-4 alkyl, or halo;
 or R c  and R d  taken together form an oxime, a C 1-4 alkyl oxime, or a carbonyl group; 
 or R c  and R d  taken together with the carbon to which they are attached form a C 3-6 cycloalkyl group; 
 
 
         R 5  is:
 i) a phenyl group, unsubstituted or substituted with one, two, or three R g  substituents;
 where each R g  substituent is selected from the group consisting of: —C 1-6 alkyl, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —C(O)C 1-6 alkyl, S(O) 0-2 —C 1-6 alkyl, —OS(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , —SCF 3 , halo, —CF 3 , —OCF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —CH 2 OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl; 
 or two R g  substituents taken together form —OCH 2 O—, —OCF 2 O—, or —OCH 2 CH 2 O—; 
 
 ii) a naphthyl group, unsubstituted or substituted with C 1-4 alkyl or halo; 
 iii) a monocyclic heteroaryl group, unsubstituted or substituted with one, two, or three R g  substituents; 
 iv) a fused bicyclic heteroaryl group, unsubstituted or substituted with C 1-4 alkyl or halo; 
 v) a monocyclic cycloalkyl group, optionally fused to a phenyl ring, and unsubstituted or substituted with one or two substituents selected from the group consisting of: —C 1-4 alkyl, —OC 1-4 alkyl, halo, —CF 3 , oxime, —C 1-4 alkyl oxime, or phenyl; and 
 vi) a monocyclic heterocycloalkyl group, optionally fused to or substituted with phenyl; 
 X is C or N, 
 R 6  or R 7  are each independently —H, halo, —CF 3 , thiophene, or —C(O)N(R x )R y ; 
 wherein R x  and R y  are each independently —H or —C 1-4 alkyl; 
 and (b) pharmaceutically acceptable salts of the compounds of Formula (I). 
 
       
     
     
         2 . A compound as defined in  claim 1 , wherein R 1  is —H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , cyclopropyl, cyclobutyl, or benzyl. 
     
     
         3 . A compound as defined in  claim 2 , wherein R 1  is —H. 
     
     
         4 . (canceled) 
     
     
         5 . A compound as defined in  claim 1 , wherein m and n are each 2. 
     
     
         6 . A compound as defined in  claim 1 , wherein m is 1 and n is 2. 
     
     
         7 . A compound as defined in  claim 1 , wherein m is 3 and n is 1. 
     
     
         8 . A compound as defined in  claim 1 , wherein R 2  is —H or —CH 3 . 
     
     
         9 . A compound as defined in  claim 1 , wherein R 3  is —H or —CH 3 . 
     
     
         10 . A compound as defined in  claim 1 , wherein R 2  and R 3  are each —H. 
     
     
         11 . A compound as defined in  claim 1 , wherein R 4  is —H. 
     
     
         12 . A compound as defined in  claim 1 , wherein L is —O—, —CH 2 —, —OCH 2 —, —OCH(CH 3 )—, —CH 2 O—, —CHF—, or —CF 2 —. 
     
     
         13 . A compound as defined in  claim 1 , wherein L is —O—. 
     
     
         14 . A compound as defined in  claim 1 , wherein Z is —O—, —C(O)—, —OCH 2 —, —OCH(CH 3 )—, —OCH(CH 2 CH 3 )—, —OCH(CH 2 OH)—, —OCH(CO 2 H)—, —OCH(CH 2 F)—, —OCH 2 CH 2 —, —OCH 2 CH(F)—, —OCH 2 CH(OCH 3 )—, —OCH 2 C(NOH)—, —OCH 2 C(NOCH 3 )—, —OCH 2 CF 2 —, —OCH 2 C(O)—, or 
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound as defined in  claim 1 , wherein Z is —O—, —OCH 2 —, —OCH 2 CH 2 —, or —OCH(CH 3 )—. 
     
     
         16 . A compound as defined in  claim 1 , wherein R 5  is phenyl, optionally substituted with halo, —OCH 3 , —OSO 2 CH 3 , CF 3 , 
     
     
         17 . A compound as defined in  claim 1 , wherein R 5  is cyclohexyl, 2-indanyl, or furanyl optionally substituted with one or more substituents individually selected from halo, —CH 3 , —CF 3 , —OCF 3 , or —CN. 
     
     
         18 . A compound as defined in  claim 1 , wherein R 5  is selected from the group consisting of:
 i) cyclopropyl, cyclobutyl, 3-phenyl-cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 3- or 4-bromo-phenyl, 2-, 3- or 4-chloro-phenyl, 3,4-dichloro-phenyl, 3- or 4-cyano-phenyl, 2-, 3- or 4-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 4-chloro-3-fluoro-phenyl, 4-chloro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3-fluoro-4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3- or 4-methyl-phenyl, 3- or 4-methylsulfanyl-phenyl, 3- or 4-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 3-methanesulfonyloxy-phenyl, 3- or 4-methoxy-phenyl, 3-trifluoromethoxy-phenyl, 2-, 3- or 4-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 3- or 4-trifluoromethylsulfanyl-phenyl, 3-trifluoromethoxy-phenyl,   
       
         
           
           
               
               
           
         
       
       and
 ii) 3-azetidinyl, 1-benzyl-azetidin-3-yl, 1-benzhydryl-azetidin-3-yl, 1-isopropyl-azetidin-3-yl, benzo[1,3]dioxol-5-yl, 2,2-difluoro-benzo[1,3]dioxol-5-yl, 2-benzofuranyl, 5-benzofuranyl, 2,3-dihydro-benzofuran-2-yl, 2-benzothiazolyl, 6-benzothiazolyl, 1H-benzotriazole-6-yl, 1-methyl-1H-benzotriazole-6-yl, 2- or 3-chromanyl, 2- or 3-furanyl, 5-trifluoromethyl-2-furanyl, 2-indanyl, tetrahydro-3-furanyl, 1-Hydroxyimino-indan-2-yl, 4-methoxy-2-indanyl, 5-fluoro-1-indanyl, 5-methyl-1-indanyl, 5- or 6-chloro-1-indanyl, 6-fluoro-1-indanyl, 6-trifluoromethyl-1-indanyl, 6-methyl-1-indanyl, 5-fluoro-2-indanyl, 5-methoxy-2-indanyl, [1,2,4]oxadiazole-5-yl, 3-cyclopropyl-[1,2,4]oxadiazole-5-yl, 3-cyclobutyl-[1,2,4]oxadiazole-5-yl, 3-isopropyl-[1,2,4]oxadiazole-5-yl, phenoxy, 4-piperidinyl, 2- or 3-pyrrolidinyl, 3-methyl-[1,2,4]oxadiazole-5-yl, 5-oxazolyl, 3-, 4- or 5-pyrazolyl, 4-trifluoromethyl-2-pyridinyl, 2-, 3- or 4-pyridinyl, 6-trifluoromethyl-2-pyridinyl, 1,2,3,4-tetrahydro-naphthalen-1-yl, 1,2,3,4-tetrahydro-naphthalen-2-yl, 1-phenyl-3-azetidinyl, 4- or 5-thiazolyl, 2-methyl-thiazole-4-yl, 2-thiophen-2-yl-thiazole-4-yl, 
 
       
         
           
           
               
               
           
         
       
       5-methyl-isoxazole-3-yl. 
     
     
         19 . A compound as defined in  claim 1 , wherein R 6  and R 7  are each independently —H, halo, —CF 3 , thiophene-3-yl, or N,N-dimethyl-formamidyl. 
     
     
         20 . A compound as defined in  claim 1 , wherein R 6  is —H or halo. 
     
     
         21 . A compound as defined in  claim 1 , wherein R 6  is —H or halo and R 7  is —H, halo, —CF 3 , thiophene-3-yl, or N,N-dimethyl-formamidyl. 
     
     
         22 . A compound as defined in  claim 1 , wherein X is C. 
     
     
         23 . A compound as defined in  claim 1 , wherein X is N. 
     
     
         24 . A compound as defined in  claim 1 , selected from the group consisting of:
 (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;   (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine;   (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   4-(2-Benzyloxy-5-chloro-phenoxy)-piperidine;   4-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine;   4-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine;   4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-piperidine;   4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-piperidine;   4-[5-Bromo-2-(2-fluoro-benzyloxy)-phenoxy]-piperidine;   4-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-piperidine;   (±)-3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine;   (±)-3-(2-Benzyloxy-5-chloro-phenoxy)piperidine;   (±)-3-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-piperidine;   (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine;   (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine;   (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;   (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   (S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;   (±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   (±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   (±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   (±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine;   (±)-Methanesulfonic acid 3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;   (±)-Methanesulfonic acid 3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;   (R)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine;   (±)-4-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-piperidine;   (±)-4-[5-Chloro-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-piperidine;   (±)-4-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-piperidine;   (R,S)-3-[5-Chloro-2-[1-((R)-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine;   (±)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-piperidine;   (±)-4-[5-Chloro-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-piperidine;   4-(5-Chloro-2-phenoxy-phenoxy)-piperidine;   (S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;   (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;   (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine;   (S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;   (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;   (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine;   (S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine;   (S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine;   (S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine;   (S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine;   (S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine;   (S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine;   (S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine; and   (±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1-ethyl-pyrrolidine;   and pharmaceutically acceptable salts thereof.   
     
     
         25 . A pharmaceutical composition comprising an effective amount of at least one compound selected from compounds of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —H, monocyclic cycloalkyl, phenyl, or benzyl; 
         m is 2 or 3; 
         n is 1 or 2; 
         R 2  and R 3  are each independently —H or —C 1-4 alkyl; 
         R 4  is —H, F, C 1-4 alkyl, or R 4  is —OH when L is —CH 2 —, —CF 2 —, —CHF—, —OCH 2 —, or —OCH(CH 3 )—; 
         L is —O—, —CH 2 —, —OCH 2 —, —OCH(CH 3 )—, —CH 2 O—, —CF 2 —, or —CHF—; 
         Z is —O—, —C(O)—, —OCH(R b )—, or —OCH 2 C(R c )(R d )—;
 where
 where R b  is —H; a —C 1-4 alkyl group unsubstituted or substituted with OH or halo; —CO 2 C 1-4 alkyl; or —CO 2 H; and 
 R c  and R d  are each independently —H, —O—C 1-4 alkyl, or halo;
 or R c  and R d  taken together form an oxime, a C 1-4 alkyl oxime, or a carbonyl group; 
 or R c  and R d  taken together with the carbon to which they are attached form a C 3-6 cycloalkyl group; 
 
 
 
         R 5  is:
 i) a phenyl group, unsubstituted or substituted with one, two, or three R g  substituents;
 where each R g  substituent is selected from the group consisting of: —C 1-6 alkyl, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —OS(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , —SCF 3 , halo, —CF 3 , —OCF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —CH 2 OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl; 
 or two R g  substituents taken together form —OCH 2 O—, —OCF 2 O—, or —OCH 2 CH 2 O—; 
 
 ii) a naphthyl group, unsubstituted or substituted with C 1-4 alkyl or halo; 
 iii) a monocyclic heteroaryl group, unsubstituted or substituted with one, two, or three R g  substituents; 
 iv) a fused bicyclic heteroaryl group, unsubstituted or substituted with C 1-4 alkyl or halo; 
 v) a monocyclic cycloalkyl group, optionally fused to a phenyl ring, and unsubstituted or substituted with one or two substituents selected from the group consisting of: —C 1-4 alkyl, —OC 1-4 alkyl, halo, —CF 3 , oxime, —C 1-4 alkyl oxime, or phenyl; and 
 vi) a monocyclic heterocycloalkyl group, optionally fused to or substituted with phenyl; 
 X is C or N, 
 R 6  or R 7  are each independently —H, halo, —CF 3 , thiophene, or —C(O)N(R x )R y ; 
 wherein R x  and R y  are each independently —H or —C 1-4 alkyl; 
 and (b) pharmaceutically acceptable salts of the compounds of Formula (I). 
 
       
     
     
         26 . A pharmaceutical composition according to  claim 25 , wherein said at least one compound is selected from the group consisting of:
 (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;   (R)-3-[5-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-pyrrolidine;   (R)-3-[5-Chloro-2-(2-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   4-(2-Benzyloxy-5-chloro-phenoxy)-piperidine;   4-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine;   4-[5-Bromo-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine;   4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-piperidine;   4-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-piperidine;   4-[5-Bromo-2-(2-fluoro-benzyloxy)-phenoxy]-piperidine;   4-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-piperidine;   (±)-3-[5-Chloro-2-(5-trifluoromethyl-furan-2-ylmethoxy)-phenoxy]-piperidine;   (±)-3-(2-Benzyloxy-5-chloro-phenoxy)piperidine;   (±)-3-[5-Chloro-2-(3-trifluoromethyl-benzyloxy)-phenoxy]-piperidine;   (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine;   (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-1-methyl-pyrrolidine;   (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;   (R)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   (S)-3-[4-Chloro-2-(3-chloro-benzyloxy)-phenoxy]-pyrrolidine;   (±)-3-[5-Bromo-2-(3-chloro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   (±)-3-[5-Bromo-2-(3-methoxy-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   (±)-3-[5-Bromo-2-(3-fluoro-benzyloxy)-phenoxy]-1-methyl-pyrrolidine;   (±)-3-(2-Benzyloxy-5-bromo-phenoxy)-1-methyl-pyrrolidine;   (±)-Methanesulfonic acid 3-[4-bromo-2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;   (±)-Methanesulfonic acid 3-[2-(1-methyl-pyrrolidin-3-yloxy)-phenoxymethyl]-phenyl ester;   (R)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine;   (±)-4-[5-Chloro-2-[1-(3-chloro-phenyl)-ethoxy]-phenoxy]-piperidine;   (±)-4-[5-Chloro-2-[1-(3-trifluoromethoxy-phenyl)-ethoxy]-phenoxy]-piperidine;   (±)-4-[5-Chloro-2-[1-(2-fluoro-phenyl)-ethoxy]-phenoxy]-piperidine;   (R,S)-3-[5-Chloro-2-[14-(R)-3-trifluoromethyl-phenyl)-ethoxy]-phenoxy]-piperidine;   (±)-4-[5-Chloro-2-[1-(3-trifluoromethyl-phenyl)-propoxy]-phenoxy]-piperidine;   (±)-4-[5-Chloro-2-(2-fluoro-1-phenyl-ethoxy)-phenoxy]-piperidine;   4-(5-Chloro-2-phenoxy-phenoxy)-piperidine;   (S)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;   (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-pyrrolidine;   (R)-3-(4-Chloro-2-p-tolyloxy-phenoxy)-1-methyl-pyrrolidine;   (S)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;   (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-pyrrolidine;   (R)-3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-1-methyl-pyrrolidine;   (S)-3-(4-Chloro-2-o-tolyloxy-phenoxy)-pyrrolidine;   (S)-3-(4-Chloro-2-m-tolyloxy-phenoxy)-pyrrolidine;   (S)-3-[4-Chloro-2-(4-fluoro-3-methyl-phenoxy)-phenoxy]-pyrrolidine;   (S)-3-[4-Chloro-2-(4-chloro-phenoxy)-phenoxy]-pyrrolidine;   (S)-3-[4-Chloro-2-(3-chloro-phenoxy)-phenoxy]-pyrrolidine;   (S)-3-[2-(4-Bromo-phenoxy)-4-chloro-phenoxy]-pyrrolidine;   (S)-3-[4-Chloro-2-(4-isopropyl-phenoxy)-phenoxy]-pyrrolidine; and   (±)-3-[5-Bromo-2-(4-bromo-phenoxy)-phenoxy]-1-ethyl-pyrrolidine;   and pharmaceutically acceptable salts, thereof.   
     
     
         27 . A pharmaceutical composition according to  claim 25 , further comprising: an active ingredient selected from the group consisting of an additional active ingredient selected from the group consisting of: H 1  receptor antagonists, H 2  receptor antagonists, H 3  receptor antagonists, topiramate, norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, noradrenergic reuptake inhibitors, non-selective serotonin re-uptake inhibitors, acetylcholinesterase inhibitors, modafinil, anti-psychotics, sedatives, monoamine oxidase inhibitors, and tricyclic antidepressants. 
     
     
         28 . A method of treating a subject suffering from or diagnosed with a disease or disorder selected from the group consisting of: depression, anxiety, schizophrenia, bipolar disorders, Alzheimer's disease, Parkinson's disease, hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, urinary incontinence, glaucoma, optic neuritis, diabetic retinopathy, retinal edema and age related macular degeneration, comprising administering to the subject an effective amount of at least one agent selected from compounds of Formula (I) and pharmaceutically acceptable salts of said compounds of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is —H, monocyclic cycloalkyl, phenyl, or benzyl; 
         m is 2 or 3; 
         n is 1 or 2; 
         R 2  and R 3  are each independently —H or —C 1-4 alkyl; 
         R 4  is —H, F, C 1-4 alkyl, or R 4  is —OH when L is —CH 2 —, —CF 2 —, —CHF—, —OCH 2 —, or —OCH(CH 3 )—; 
         L is —O—, —CH 2 —, —OCH 2 —, —OCH(CH 3 )—, —CH 2 O—, —CF 2 —, or —CHF—; 
         Z is —O—, —C(O)—, —OCH(R b )—, or —OCH 2 C(R c )(R d )—;
 where
 where R b  is —H; a —C 1-4 alkyl group unsubstituted or substituted with OH or halo; —CO 2 C 1-4 alkyl; or —CO 2 H; and 
 R c  and R d  are each independently —H, —O—C 1-4 alkyl, or halo;
 or R c  and R d  taken together form an oxime, a C 1-4 alkyl oxime, or a carbonyl group; 
 or R c  and R d  taken together with the carbon to which they are attached form a C 3-6 cycloalkyl group; 
 
 
 
         R 5  is:
 i) a phenyl group, unsubstituted or substituted with one, two, or three R g  substituents;
 where each R g  substituent is selected from the group consisting of: —C 1-6 alkyl, —OH, —OC 1-6 alkyl, —CN, —NO 2 , —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —OS(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , —SCF 3 , halo, —CF 3 , —OCF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —CH 2 OH, monocyclic cycloalkyl, phenyl, thiophenyl, benzhydryl, and oxadiazolyl; 
 or two R g  substituents taken together form —OCH 2 O—, —OCF 2 O—, or —OCH 2 CH 2 O—; 
 
 ii) a naphthyl group, unsubstituted or substituted with C 1-4 alkyl or halo; 
 iii) a monocyclic heteroaryl group, unsubstituted or substituted with one, two, or three R g  substituents; 
 iv) a fused bicyclic heteroaryl group, unsubstituted or substituted with C 1-4 alkyl or halo; 
 v) a monocyclic cycloalkyl group, optionally fused to a phenyl ring, and unsubstituted or substituted with one or two substituents selected from the group consisting of: —C 1-4 alkyl, —OC 1-4 alkyl, halo, —CF 3 , oxime, oxime, or phenyl; and 
 vi) a monocyclic heterocycloalkyl group, optionally fused to or substituted with phenyl; 
 X is C or N, 
 R 6  or R 7  are each independently —H, halo, —CF 3 , thiophene, or —C(O)N(R x )R y ; 
 wherein R x  and R y  are each independently —H or —C 1-4 alkyl; 
 and (b) pharmaceutically acceptable salts of the compounds of Formula (I). 
 
       
     
     
         29 . A method according to  claim 28 , wherein the disease, disorder, or condition is selected from the group consisting of: sleep disorders, depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, cognitive disorders, mild cognitive impairment, Alzheimer's disease, Parkinson's disease, psychotic disorders, phobic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress and other stress-related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, hot flushes associated with menopause, alcohol abuse, drug abuse, addictive disorders including drug addiction and alcohol addiction, nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities. 
     
     
         30 . A method according to  claim 28 , wherein the disease, disorder, or condition is selected from the group consisting of: hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, and urinary incontinence. 
     
     
         31 . The method according to  claim 28 , wherein the disease, disorder, or medical condition is selected from the group consisting of: glaucoma, optic neuritis, diabetic retinopathy, retinal edema, and age-related macular degeneration.