Substituted benzyl amine compounds

Abstract

Certain substituted benzyl amine compounds are histamine H 3 receptor and/or serotonin transporter modulators useful in the treatment of histamine H 3 receptor- and/or serotonin-mediated diseases.

1 . A compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 one of R 1a  and R 1b  is 
 
     
       
         
         
             
             
         
       
        and the other is —H; 
       R 2  and R 3  taken together with the nitrogen to which they are attached form a piperazine group unsubstituted or substituted on a carbon ring member with one, two, or three R d  moieties and substituted on a nitrogen ring member with an R e  moiety;
 where each R d  moiety is independently selected from the group consisting of: —C 1-6 alkyl; —C 1-4 alkyl-OH; halo; —OH; —OC 1-16 alkyl; ipso-substituted —OC 2-3 alkylO—; —CN; —NO 2 ; —N(R g )R h ; —C(O)N(R g )R h ; —N(R g )SO 2 C 1-6 alkyl; —C(O)C 1-6 alkyl; —S(O) 0-2 —C 1-6 alkyl; —SO 2 N(R g )R h ; —SCF 3 ; —CF 3 ; —OCF 3 ; —CO 2 H; and —CO 2 C 1-6 alkyl;
 where R g  and R h  are each independently —H or —C 1-6 alkyl, or R g  and R h  taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group; and 
 
 where R e  is selected from the group consisting of: —H; a —C 1-6 alkyl or —C(O)C 1-6 alkyl group unsubstituted or substituted with halo, —CN, —OH, —OC 1-4 alkyl, or —CF 3 ; —C(O)CF 3 ; —S(O) 0-2 —C 1-6 alkyl; —CO 2 C 1-6 alkyl; and a phenyl, monocyclic carbon-linked heteroaryl, monocyclic cycloalkyl, or monocyclic carbon-linked heterocycloalkyl group, each unsubstituted or substituted with —C 1-4 alkyl, halo, —CN, —OH, —OC 1-4 alkyl, or —CF 3 ; 
 
       q is 0 or 1; 
       each R 4  is independently —H or methyl, or both R 4  substituents taken together form a carbonyl; 
       Y is —O—, —OCH 2 —, —S—, —SO—, or —SO 2 —; 
       R 5  is —H or —C 1-6 alkyl; 
       R 6  is —H; or —C 1-6 alkyl, —C 3-6 alkenyl, —C 3-6 alkynyl, monocyclic cycloalkyl, or —C 1-6 alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —CO 2 H, or —CO 2 C 1-4 alkyl; 
       R 7  is —H; or —C 1-6 alkyl, —C 3-6 alkenyl, —C 3-6 alkynyl, monocyclic cycloalkyl, or —C 1-6 alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —CO 2 H, or —CO 2 C 1-4 alkyl; 
       or R 6  and R 7  taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with —C 1-4 alkyl, —OC 1-4 alkyl, or halo; and 
       Cyc is a phenyl or monocyclic carbon-linked heteroaryl group, unsubstituted or substituted with one, two, or three R k  moieties;
 where each R k  moiety is independently selected from the group consisting of: —C 1-6 alkyl, —CHF 2 , —CF 3 , —C 2-6 alkenyl, —C 2-6 alkynyl, —OH, —OC 1-6 alkyl, —OCHF 2 , —OCF 3 , —OC 3-6 alkenyl, —OC 3-6 alkynyl, —CN, —NO 2 , —N(R l )R m , —N(R l )C(O)R m , —N(R l )SO 2 C 1-6 alkyl, —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —C(O)N(R l )R m , —SO 2 N(R l )R m , —SCF 3 , halo, —CO 2 H, and —CO 2 C 1-6 alkyl; or two R k  moieties on adjacent carbon atoms of attachment together are —OC 1-4 alkyleneO— to form a cyclic ring which is unsubstituted or substituted with one or two fluoro substituents; 
 where R l  and R m  are each independently —H or —C 1-6 alkyl; 
 
     
     or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof. 
   
   
       2 . A compound as defined in  claim 1 , wherein R 1b  is 
     
       
         
         
             
             
         
       
     
   
   
       3 . A compound as defined in  claim 1 , wherein R 2  and R 3  are each independently —H; or methyl, ethyl, propyl, isopropyl, sec-butyl, 2-methylpropyl, cyclopropyl, cyclobutyl, or cyclopentyl, each unsubstituted or substituted as previously described. 
   
   
       4 . A compound as defined in  claim 1 , wherein R 2  and R 3  are each independently —H, methyl, ethyl, propyl, isopropyl, sec-butyl, 2-hydroxyethyl, 2-methoxyethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2-(cyclopropyl-methyl-amino)-ethyl, 2-pyrrolidin-1-yl-ethyl, 2-hydroxy-2-methylpropyl, 3-dimethylaminopropyl, cyclopropyl, cyclobutyl, or cyclopentyl. 
   
   
       5 . A compound as defined in  claim 1 , wherein R 2  and R 3  are each independently —H, methyl, cyclopropyl, dimethylaminoethyl, or dimethylaminopropyl. 
   
   
       6 . A compound as defined in  claim 1 , wherein R a  and R b  are each independently —H, methyl, or cyclopropyl, or R a  and R b  taken together form pyrrolidinyl. 
   
   
       7 . A compound as defined in  claim 1 , wherein R 2  and R 3  taken together with the nitrogen to which they are attached form or piperazinonyl, each unsubstituted or substituted as previously described. 
   
   
       8 . A compound as defined in  claim 1 , wherein R 2  and R 3  taken together with the nitrogen to which they are attached form piperazin-1-yl, 4-ethyl-piperazin-1-yl, 4-(2-fluoroethyl)-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4-cyclobutyl-piperazin-1-yl, 4-cyclopentyl-piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(2-methoxyethyl)-piperazin-1-yl, 4-(tert-butoxycarbonyl)piperazin-1-yl, 4-phenylpiperazin-1-yl, 4-(2-hydroxyphenyl)piperazinyl, 4-(4-trifluoromethyl-phenyl)-piperazin-1-yl, 4-thiazol-2-yl-piperazin-1-yl, 4-(2-thiophenyl)piperazinyl, 4-pyridin-4-yl-piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-isobutyryl-piperazin-1-yl, 4-piperazin-2-onyl, 1-isopropyl-4-piperazin-2-onyl, 4-isopropyl-1-piperazin-2-onyl, or 1-cyclopropyl-4-piperazin-2-onyl. 
   
   
       9 . A compound as defined in  claim 1 , wherein R 2  and R 3  taken together with the nitrogen to which they are attached form piperazinyl, 4-methyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-(2-fluoroethyl)-piperazin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4-cyclobutyl-piperazin-1-yl, 4-cyclopentyl-piperazin-1-yl, 4-pyridin-4-yl-piperazin-1-yl, 4-piperazin-2-onyl, or 1-isopropyl-4-piperazin-2-onyl. 
   
   
       10 . A compound as defined in  claim 1 , wherein each R d  moiety is independently selected from the group consisting of: methyl, ethyl, isopropyl, hydroxyethyl, fluoro, methoxy, dimethylamino, piperidinyl, morpholinyl, acetyl, trifluoromethyl, —CO 2 H, and —CO 2 -methyl. 
   
   
       11 . A compound as defined in  claim 1 , wherein R g  and R h  are each independently —H, methyl, ethyl, or isopropyl, or R g  and R h  taken together with their nitrogen of attachment form pyrrolidinyl, piperidinyl, morpholinyl, or thiomorpholinyl. 
   
   
       12 . A compound as defined in  claim 1 , wherein R e  is selected from the group consisting of: —H, methyl, ethyl, isopropyl, 2-fluoroethyl, hydroxyethyl, methoxypropyl, acetyl, tert-butoxycarbonyl, phenyl, 4-pyridyl, cyclopropyl, cyclobutyl, cyclopentyl, and piperidinyl. 
   
   
       13 . A compound as defined in  claim 1 , wherein R e  is selected from the group consisting of: —H, isopropyl, and cyclopropyl. 
   
   
       14 . A compound as defined in  claim 1 , wherein q is 1 and both R 4  substituents taken together form a carbonyl. 
   
   
       15 . A compound as defined in  claim 1 , wherein q is 0. 
   
   
       16 . A compound as defined in  claim 1 , wherein q is 1 and each R 4  is —H. 
   
   
       17 . A compound as defined in  claim 1 , wherein Y is —O— or —S—. 
   
   
       18 . A compound as defined in  claim 1 , wherein Cyc is a phenyl or pyridyl group unsubstituted or substituted with one, two, or three R k  moieties. 
   
   
       19 . A compound as defined in  claim 1 , wherein Cyc is a thiophenyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, or pyrazinyl group unsubstituted or substituted with one, two, or three R k  moieties. 
   
   
       20 . A compound as defined in  claim 1 , wherein Cyc is phenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-iodophenyl, 4-iodophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-fluoro-3-chlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3-chloro-4-fluorophenyl, 4-fluoro-3-methylphenyl, 3-chloro-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-chloro-4-difluoromethoxyphenyl, 4-chloro-3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl, 3-nitrophenyl, 4-nitrophenyl, 4-aminophenyl, 4-dimethylaminophenyl, 4-carbamoylphenyl, 4-methanesulfanylphenyl, 4-methanesulfinylphenyl, 4-methanesulfonylphenyl, 4-trifluoromethanesulfanylphenyl, 3-methyl-4-methylsulfanylphenyl, benzo[1,3]dioxol-4-yl, benzo[1,3]dioxol-5-yl, thiophen-2-yl, thiophen-3-yl, oxazol-5-yl, thiazol-5-yl, thiazol-2-yl, 2H-pyrazol-3-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 4-trifluoromethyl-pyridin-2-yl, 2,6-dimethyl-pyridin-3-yl, 6-methyl-pyridin-3-yl, 2-chloro-5-pyridinyl, 2-dimethylamino-5-pyridinyl, 6-methoxy-pyridin-3-yl, 6-methylsulfanyl-pyridin-3-yl, 2-hydroxy-5-pyridinyl, 6-bromo-pyridin-3-yl, or pyrazin-2-yl. 
   
   
       21 . A compound as defined in  claim 1 , wherein Cyc is phenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-2-fluorophenyl, 4-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 4-trifluoromethylphenyl, 4-methanesulfanylphenyl, 3-methyl-4-methanesulfanylphenyl, 2-pyridinyl, 3-pyridinyl, or 6-methyl-3-pyridinyl. 
   
   
       22 . A compound as defined in  claim 1 , wherein each R k  moiety is independently selected from the group consisting of: methyl, methoxy, fluoro, chloro, trifluoromethyl, methanesulfanyl, trifluoromethanesulfanyl, cyano, and trifluoromethoxy. 
   
   
       23 . A compound as defined in  claim 1 , wherein R l  and R m  are each independently —H or methyl. 
   
   
       24 . A compound as defined in  claim 1 , wherein R 5  is —H or methyl. 
   
   
       25 . A compound as defined in  claim 1 , wherein R 5  is —H. 
   
   
       26 . A compound as defined in  claim 1 , wherein R 6  is —H, methyl, ethyl, isopropyl, sec-butyl, cyclopropyl, cyclobutyl, or cyclopentyl, each unsubstituted or substituted as previously described. 
   
   
       27 . A compound as defined in  claim 1 , wherein R 6  is —H or methyl. 
   
   
       28 . A compound as defined in  claim 1 , wherein R 7  is —H, methyl, ethyl, propyl, isopropyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl, each unsubstituted or substituted as previously described. 
   
   
       29 . A compound as defined in  claim 1 , wherein R 7  is methyl, ethyl, isopropyl, sec-butyl, cyclopropyl, cyclobutyl, or cyclopentyl. 
   
   
       30 . A compound as defined in  claim 1 , wherein R 7  is methyl, ethyl, isopropyl, or cyclopropyl. 
   
   
       31 . A compound as defined in  claim 1 , wherein R 6  and R 7  taken together with their nitrogen of attachment form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-1λ 6 -thiomorpholin-4-yl, homopiperidinyl, diazepanyl, or homomorpholinyl, each unsubstituted or substituted as previously described. 
   
   
       32 . A compound as defined in  claim 1 , wherein R 6  and R 7  taken together with their nitrogen of attachment form piperidinyl, pyrrolidinyl, morpholinyl, 4-isopropyl-piperazin-1-yl, or homomorpholinyl. 
   
   
       33 . A compound selected from the group consisting of: 
     [4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone; 
     (4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone; 
     (4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl]-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 
     (4-Isopropyl-piperazin-1-yl)-[4-(3-methoxy-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 
     [4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 
     [4-(4-Chloro-phenoxy)-3-cyclopropylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 
     (4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-methanone; 
     [4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-(3-methylaminomethyl-4-phenoxy-phenyl)-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[4-(3-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-trifluoromethyl-phenoxy)-phenyl]-methanone; 
     [3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl]-methanone; 
     [3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 
     [4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[4-(4-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-methanone; 
     [4-(3-Chloro-4-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 
     [4-(4-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 
     [4-(3-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 
     [4-(4-Chloro-phenylsulfanyl)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-2-ylsulfanyl)-phenyl]-methanone; 
     [4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 
     [4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 
     (4-Isopropyl-piperazin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone; 
     [3-(4-Chloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 
     [3-(3,4-Dichloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 
     [3-(3-Chloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[3-(3,4-dichloro-phenoxy)-4-methylaminomethyl-phenyl]-methanone 
     [5-(4-Isopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine; 
     Methyl-[5-(4-methyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine; 
     [5-(4-Cyclobutyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine; 
     Methyl-[2-(4-methylsulfanyl-phenoxy)-5-(4-pyridin-4-yl-piperazin-1-yl)-benzyl]-amine; 
     [5-[4-(2-Fluoro-ethyl)-piperazin-1-yl]-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine; 
     [5-(4-Cyclopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine 
     [5-(4-Cyclopropyl-piperazin-1-yl)-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-amine; 
     [2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-piperazin-1-yl)-benzyl]-methyl-amine; 
     1-[3-Methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-piperazin-2-one; 
     4-Isopropyl-1-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-piperazin-2-one; 
     1-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-4-isopropyl-piperazin-2-one; 
     (4-Cyclopropyl-piperazin-1-yl)-[4-(3,4-dichloro-benzyloxy)-3-methylaminomethyl-phenyl]-methanone; 
     Cyclopropyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine; 
     [5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine; 
     [5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-dimethyl-amine; 
     Ethyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine; 
     Isopropyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine; 
     5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzylamine; 
     4-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-1-isopropyl-piperazin-2-one; 
     1-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-4-isopropyl-piperazin-2-one; 
     [4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclobutyl-piperazin-1-yl)-methanone; 
     (4-Cyclobutyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 
     (4-Cyclopentyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone; 
     [4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopentyl-piperazin-1-yl)-methanone; 
     [4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclobutyl-piperazin-1-yl)-methanone; 
     [4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopentyl-piperazin-1-yl)-methanone; 
     (4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-trifluoromethyl-pyridin-2-ylsulfanyl)-phenyl]-methanone; 
     (4-Cyclopropyl-piperazin-1-yl)-[4-dimethylaminomethyl-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl]-methanone; 
     (3-Benzyloxy-4-dimethylaminomethyl-phenyl)-(4-cyclopropyl-piperazin-1-yl)-methanone; 
     [4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone; 
     [3-(2,6-Dimethyl-pyridin-3-yloxy)-4-morpholin-4-ylmethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone; 
     (4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-phenoxy-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone; and 
     [5-(4-Isopropyl-piperazine-1-carbonyl)-2-(3-methoxy-phenoxy)-benzyl]-methyl-carbamic acid tert-butyl ester; 
     and pharmaceutically acceptable salts thereof. 
   
   
       34 . A compound or pharmaceutically acceptable salt according to  claim 1 . 
   
   
       35 . A pharmaceutical composition for treating a disease, disorder, or medical condition mediated by histamine H 3  receptor and/or serotonin transporter activity, comprising:
 (a) an effective amount of a compound of  claim 1  and   (b) a pharmaceutically acceptable excipient.   
   
   
       36 . A pharmaceutical composition according to  claim 35 , further comprising: an active ingredient selected from the group consisting of H 1  receptor antagonists, H 2  receptor antagonists, H 3  receptor antagonists, serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, noradrenergic reuptake inhibitors, non-selective serotonin re-uptake inhibitors, acetylcholinesterase inhibitors, and modafinil. 
   
   
       37 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by histamine H 3  receptor and/or serotonin transporter activity, comprising administering to the subject in need of such treatment an effective amount of a compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein
 one of R 1a  and R 1b  is 
 
     
       
         
         
             
             
         
       
        and the other is —H; 
       R 2  and R 3  are each independently selected from the group consisting of: —H; a —C 1-6 alkyl group unsubstituted or substituted with —OH, —OC 1-4 alkyl, —NH 2 , —N(R a )R b , or —F; —CO 2 C 1-4 alkyl; and a monocyclic cycloalkyl group unsubstituted or substituted with —C 1-4 alkyl, —OH, halo, or —CF 3 ;
 where R a  and R b  are each independently —H, —C 1-6 alkyl, or monocyclic cycloalkyl, or R a  and R b  taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group;
 provided that R 2  and R 3  are not both H; 
 
 
       or, alternatively, 
       R 2  and R 3  taken together with the nitrogen to which they are attached form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted on a carbon ring member with one, two, or three R d  moieties and substituted on a nitrogen ring member with an R e  moiety;
 where each R d  moiety is independently selected from the group consisting of: —C 1-6 alkyl; —C 1-4 alkyl-OH; halo; —OH; —OC 1-6 alkyl; ipso-substituted —OC 2-3 alkylO—; —CN; —NO 2 ; —N(R g )R h ; —C(O)N(R g )R h ; —N(R g )SO 2 C 1-6 alkyl; —C(O)C 1-6 alkyl; —S(O) 0-2 —C 1-6 alkyl; —SO 2 N(R g )R h ; —SCF 3 ; —CF 3 ; —OCF 3 ; —CO 2 H; and —CO 2 C 1-6 alkyl;
 where R g  and R h  are each independently —H or —C 1-6 alkyl, or R g  and R h  taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group; and 
 
 where R e  is selected from the group consisting of: —H; a —C 1-6 alkyl or —C(O)C 1-6 alkyl group unsubstituted or substituted with halo, —CN, —OH, —OC 1-4 alkyl, or —CF 3 ; —C(O)CF 3 ; —S(O) 0-2 —C 1-6 alkyl; —CO 2 C 1-6 alkyl; and a phenyl, monocyclic carbon-linked heteroaryl, monocyclic cycloalkyl, or monocyclic carbon-linked heterocycloalkyl group, each unsubstituted or substituted with —C 1-4 alkyl, halo, —CN, —OH, —OC 1-4 alkyl, or —CF 3 ; 
 
       q is 0 or 1; 
       each R 4  is independently —H or methyl, or both R 4  substituents taken together form a carbonyl; 
       Y is —O—, —OCH 2 —, —S—, —SO—, or —SO 2 —; 
       R 5  is —H or —C 1-6 alkyl; 
       R 6  is —H; or —C 1-6 alkyl, —C 3-6 alkenyl, —C 3-6 alkynyl, monocyclic cycloalkyl, or —C 1-6 alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —CO 2 H, or —CO 2 C 1-4 alkyl; 
       R 7  is —H; or —C 1-6 alkyl, —C 3-6 alkenyl, —C 3-6 alkynyl, monocyclic cycloalkyl, or —C 1-6 alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with —C 1-4 alkyl, —OH, —OC 1-4 alkyl, halo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —CO 2 H, or —CO 2 C 1-4 alkyl; 
       or R 6  and R 7  taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with —C 1-4 alkyl, —OC 1-4 alkyl, or halo; and 
       Cyc is a phenyl or monocyclic carbon-linked heteroaryl group, unsubstituted or substituted with one, two, or three R k  moieties;
 where each R k  moiety is independently selected from the group consisting of: —C 1-6 alkyl, —CHF 2 , —CF 3 , —C 2-6 alkenyl, —C 2-6 alkynyl, —OH, —OC 1-16 alkyl, —OCHF 2 , —OCF 3 , —OC 3-6 alkenyl, —OC 3-6 alkynyl, —CN, —NO 2 , —N(R l )R m , —N(R l )C(O)R m , —N(R l )SO 2 C 1-6 alkyl, —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —C(O)N(R l )R m , —SO 2 N(R l )R m , —SCF 3 , halo, —CO 2 H, and —CO 2 C 1-6 alkyl; or two R k  moieties on adjacent carbon atoms of attachment together are —OC 1-4 alkyleneO— to form a cyclic ring which is unsubstituted or substituted with one or two fluoro substituents;
 where R l  and R m  are each independently —H or —C 1-6 alkyl; 
 
 
       provided that when both R 4  substituents taken together form a carbonyl, then R 2  and R 3  taken together are not diazepanyl; 
     
     or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof. 
   
   
       38 . The method according to  claim 37 , wherein the disease, disorder, or medical condition is selected from the group consisting of: cognitive disorders, sleep disorders, psychiatric disorders, and other disorders. 
   
   
       39 . The method according to  claim 37 , wherein the disease, disorder, or medical condition is selected from the group consisting of: dementia, Alzheimer's disease, cognitive dysfunction, mild cognitive impairment, pre-dementia, attention deficit hyperactivity disorders, attention-deficit disorders, and learning and memory disorders. 
   
   
       40 . The method according to  claim 37 , wherein the disease, disorder, or medical condition is selected from the group consisting of: learning impairment, memory impairment, and memory loss. 
   
   
       41 . The method according to  claim 37 , wherein the disease, disorder, or medical condition is selected from the group consisting of: insomnia, disturbed sleep, narcolepsy with or without associated cataplexy, cataplexy, disorders of sleep/wake homeostasis, idiopathic somnolence, excessive daytime sleepiness, circadian rhythm disorders, fatigue, lethargy, and jet lag. 
   
   
       42 . The method according to  claim 37 , wherein the disease, disorder, or medical condition is selected from the group consisting of: sleep apnea, perimenopausal hormonal shifts, Parkinson's disease, multiple sclerosis, depression, chemotherapy, and shift work schedules. 
   
   
       43 . The method according to  claim 37 , wherein the disease, disorder, or medical condition is selected from the group consisting of: schizophrenia, bipolar disorders, manic disorders, depression, obsessive-compulsive disorder, and post-traumatic stress disorder. 
   
   
       44 . The method according to  claim 37 , wherein the disease, disorder, or medical condition is selected from the group consisting of: motion sickness, vertigo, epilepsy, migraine, neurogenic inflammation, eating disorders, obesity, and substance abuse disorders. 
   
   
       45 . The method according to  claim 37 , wherein the disease, disorder, or medical condition is selected from the group consisting of: depression, disturbed sleep, fatigue, lethargy, cognitive impairment, memory impairment, memory loss, learning impairment, attention-deficit disorders, and eating disorders. 
   
   
       46 . A pharmaceutical composition according to  claim 35 , further comprising topiramate. 
   
   
       47 . The method according to  claim 37 , wherein the disease, disorder, or medical condition is selected from the group consisting of: age-related cognitive decline, REM-behavioral disorder, benign postural vertigo, tinitus, movement disorders, restless leg syndrome, eye-related disorders, macular degeneration, and retinitis pigmentosis.