Piperazinyl and diazapanyl benzamides and benzthioamides

Abstract

Substituted piperazinyl and diazepanyl benzamides and benzthioamides of formula (I), compositions containing them, and methods of making and using them to treat histamine-mediated conditions.

1 . A composition comprising a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is C 1-10  alkyl, C 3-8  alkenyl, C 3-8  cycloalkyl, (C 3-8  cycloalkyl)C 1-6  alkyl, (C 3-8  cycloalkyl)C 3-8  alkenyl, or (C 1-8  alkylcarbonyl)C 1-8  alkyl;  
 n is 1 or 2;  
 X is O or S;  
 one of R 2 , R 3  and R 4  is G and the other two independently are hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, or C 1-3 alkoxy;  
 G is LQ;  
 L is unbranched —(CH 2 ) m — wherein m is an integer from 1 to 7;  
 Q is NR 8 R 9  wherein R 8  is independently selected from hydrogen, C 1-6  alkyl, C 3-6  alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (6-9-membered heterocyclyl)C 1-6  alkylene, and (phenyl)C 1-6  alkylene; and R 9  is independently selected from C 1-6  alkyl, C 3-6  alkenyl, 6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (6-9-membered heterocyclyl)C 1-6  alkylene, and (phenyl)C 1-6  alkylene; or  
 Q is a saturated 3-12 membered N-linked heterocyclyl, wherein, in addition to the N-linking nitrogen, the 3-12 membered heterocyclyl may optionally contain between 1 and 3 additional heteroatoms independently selected from O, S, and NH;  
 wherein Q is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halo, carboxamide, C 1-6  alkyl, 5-9 membered or 6-9 membered heterocyclyl, —N(C 1-6  alkyl)(5-9 membered or 6-9 membered heterocyclyl), —NH(5-9 membered or 6-9 membered heterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C 1-3  alkylene, C 1-6  alkoxy, (C 3-6  cycloalkyl)-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O—, where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from trifluoromethyl, methoxy, halo, nitro, cyano, hydroxy, and C 1-3  alkyl;  
 provided however that when R 1  is methyl, G is not piperidin-1-ylmethyl; and  
 wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and aryl groups may each be independently and optionally substituted with between 1 and 3 substituents independently selected from trifluoromethyl, methoxy, halo, amino, nitro, hydroxy, and C 1-3  alkyl;  
 or a pharmaceutically acceptable salt, ester, tautomer, solvate or amide thereof.  
 
     
     
         2 . A compound of  claim 1 , wherein R 1  is C 1-10  alkyl.  
     
     
         3 . A compound of  claim 1 , wherein R 1  is C 3-5  alkyl.  
     
     
         4 . A compound of  claim 1 , wherein R 1  is isopropyl.  
     
     
         5 . A compound of  claim 1  wherein n is 1.  
     
     
         6 . A compound of  claim 1 , wherein X is O.  
     
     
         7 . A compound of  claim 1 , wherein one of R 3  and R 4  is G.  
     
     
         8 . A compound of  claim 1 , wherein R 4  is G.  
     
     
         9 . A compound of  claim 1 , wherein L is unbranched —(CH 2 ) m —, wherein m is an integer from 1 to 4.  
     
     
         10 . A compound of  claim 1 , wherein L is —CH 2 —.  
     
     
         11 . A compound of  claim 1 , wherein L is —CH 2 CH 2 —.  
     
     
         12 . A compound of  claim 1  wherein Q is a saturated N-linked nitrogen-containing heterocyclyl.  
     
     
         13 . A compound of  claim 1 , wherein Q is selected from substituted or unsubstituted piperidinyl, diazepanyl, azepanyl, decahydroisoquinolin-2-yl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, or morpholinyl.  
     
     
         14 . A compound of  claim 1 , wherein Q is unsubstituted piperidinyl, diazepanyl, azepanyl, decahydroisoquinolin-2-yl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, or morpholinyl.  
     
     
         15 . A compound of  claim 14 , wherein Q is unsubstituted diazepanyl, azepanyl, morpholinyl, decahydroisoquinolin-2-yl, piperidinyl, or pyrrolidinyl;  
     
     
         16 . A compound of  claim 1 , wherein substituted Q are selected from N—(C 1-6  alkyl)piperazinyl, N-phenyl-piperazinyl, 1,3,8-triaza-spiro{4.5}decyl, and 1,4-dioxa-8-aza-spiro{4.5}decyl.  
     
     
         17 . A compound of  claim 1 , wherein Q is a monovalent radical of an amine selected from aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine, 1-phenyl-1,3,8-triaza-spiro{4.5}decan-4-one, piperidine-3-carboxylic acid diethylamide, 1,2,3,4,5,6-hexahydro-{2,3′}bipyridinyl, 4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine, piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine, {2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thiomorpholinyl, allyl-cyclopentyl-amine, {2-(1H-indol-3-yl)-ethyl}-methyl-amine, 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one, 2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine, phenylamine, pyridin-2-ylamine.  
     
     
         18 . A compound of  claim 1 , wherein Q is selected from diazepanyl, azepanyl, morpholinyl, piperidinyl, and pyrrolidinyl, optionally substituted with between 1 and 3 substituents selected from hydroxy, halo, carboxamide, C 1-6  alkyl, 5-9 membered or 6-9 membered heterocyclyl, —N(C 1-6  alkyl)(5-9 membered or 6-9 membered heterocyclyl), —NH(5-9 membered or 6-9 membered heterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C 1-3  alkylene, C 1-6  alkoxy, (C 3-6  cycloalkyl)-O—, phenyl, (phenyl)C 1-3  alkylene, and (phenyl)C 1-3  alkylene-O—, where each of above heterocyclyl, phenyl, and alkyl groups may be optionally substituted with from 1 to 3 substituents independently selected from trifluoromethyl, methoxy, halo, nitro, cyano, hydroxy, and C 1-3  alkyl.  
     
     
         19 . A compound of  claim 12 , wherein Q is substituted with a substituent comprising a 5-9 membered heterocyclyl group selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C 1-6  alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C 1-6  alkylene, tetrazolyl, (triazolyl)C 1-6  alkylene, triazolyl, (pyrrolyl)C 1-6  alkylene, pyrrolidinyl, and pyrrolyl.  
     
     
         20 . A compound of  claim 19 , wherein Q is piperidinyl.  
     
     
         21 . A compound of  claim 1 , wherein R 8  is hydrogen.  
     
     
         22 . A compound of  claim 1 , wherein R 9  is C 1-6  alkyl.  
     
     
         23 . A compound of  claim 1 , wherein R 9  is unsubstituted or substituted phenyl.  
     
     
         24 . A compound of  claim 1 , wherein R 8  and R 9  independently are C 1-6  alkyl.  
     
     
         25 . A compound of  claim 1 , wherein R 8  and R 9  are methyl.  
     
     
         26 . A compound of  claim 1 , wherein R 8  and R 9  are ethyl.  
     
     
         27 . A compound of  claim 21 , wherein R 9  is selected from phenyl or 5-9 membered aromatic heterocyclyl, wherein said phenyl or aromatic heterocyclyl is optionally substituted with 1-3 substituents selected from methoxy, hydroxy, halo, nitro, cyano, trifluoromethyl, and C 1-3  alkyl.  
     
     
         28 . A compound of  claim 27 , wherein R 9  is selected from substituted or unsubstituted phenyl, pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C 1-6  alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C 1-6  alkylene, tetrazolyl, (triazolyl)C 1-6  alkylene, triazolyl, (pyrrolyl)C 1-6  alkylene, pyrrolidinyl, and pyrrolyl.  
     
     
         29 . A compound of  claim 28 , wherein R 9  is phenyl.  
     
     
         30 . A compound of  claim 28 , wherein R 9  is substituted or unsubstituted pyridyl.  
     
     
         31 . A compound of  claim 1  wherein 
 R 1  is C 1-10  alkyl;    X is O;    R 4  is G;    L is —CH 2 —; and    Q is a saturated N-linked nitrogen-containing heterocyclyl.    
     
     
         32 . A compound of  claim 31  wherein R 1  is branched.  
     
     
         33 . A compound of  claim 31  wherein R 1  is C 3-5  alkyl.  
     
     
         34 . A compound of  claim 31 , wherein R 1  is isopropyl.  
     
     
         35 . A compound of  claim 31 , wherein Q is selected from substituted or unsubstituted piperidinyl, diazepanyl, azepanyl, decahydroisoquinolin-2-yl, piperazinyl, pyrrolinyl, pyrrolidinyl, thiomorpholinyl, or morpholinyl.  
     
     
         36 . A compound of  claim 31 , wherein Q is unsubstituted azepanyl, diazepanyl, morpholinyl, decahydroisoquinolin-2-yl, piperidinyl, or pyrrolidinyl.  
     
     
         37 . A compound of  claim 1  selected from the group consisting of: 
 (4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;    (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;    (4-Azepan-1-ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;    (4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;    (4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;    (4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone;    (4-Butyl-piperazin-1-yl)-{4-{(4-trifluoromethyl-phenylamino)-methyl}-phenyl}-methanone;    (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-Diethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    (4-Dimethylaminomethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-(3-morpholin-4-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-amino]-methyl}-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)-phenyl}-methanone;    (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-methanone;    (4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminomethyl)-phenyl]-methanone;    (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-1-methyl-ethylamino)-methyl]-phenyl}-methanone;    (4-Isopropyl-piperazin-1-yl)-{4-{(4-trifluoromethyl-phenylamino)-methyl}-phenyl}-methanone;    (4-Isopropyl-piperazin-1-yl)-{4-{(4-trifluoromethyl-pyridin-2-ylamino)-methyl}-phenyl}-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-{4-{(5-trifluoromethyl-pyridin-2-ylamino)-methyl}-phenyl}-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-{4-{(6-trifluoromethyl-pyridin-3-ylamino)-methyl}-phenyl}-methanone dihydrochloride;    (4-Methyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride;    (4-Methyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone dihydrochloride;    (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride;    (4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone dihydrochloride;    {3-(4-Benzyl-piperidin-1-ylmethyl)-phenyl}-(4-methyl-piperazin-1-yl)-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-phenylaminomethyl-phenyl)-methanone dihydrochloride;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone dihydrochloride;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyl)-phenyl}-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-{(4-trifluoromethyl-phenylamino)-methyl}-phenyl}-methanone dihydrochloride;    {4-(1-Methyl-heptyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone;    {4-(1-Methyl-heptyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;    {4-(Benzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    {4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone; and    {4-{(5-Chloro-pyridin-2-ylamino)-methyl}-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride.    
     
     
         38 . A compound of  claim 1  selected from the group consisting of: 
 (4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;    (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;    (4-Azepan-1-ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;    (4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;    (4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;    (4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone;    (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-Diethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    (4-Dimethylaminomethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-amino]-methyl}-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone    5 dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)-phenyl}-methanone;    (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-methanone;    (4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminomethyl)-phenyl]-methanone;    (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-1-methyl-ethylamino)-methyl]-phenyl}-methanone;    (4-Isopropyl-piperazin-1-yl)-{4-{(5-trifluoromethyl-pyridin-2-ylamino)-methyl}-phenyl}-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-{4-{(6-trifluoromethyl-pyridin-3-ylamino)-methyl}-phenyl}-methanone dihydrochloride;    (4-Methyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride;    (4-Methyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone dihydrochloride;    (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride;    (4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone dihydrochloride;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone dihydrochloride;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyl)-phenyl}-methanone;    {4-(Benzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    {4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone; and    {4-{(5-Chloro-pyridin-2-ylamino)-methyl}-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride.    
     
     
         39 . A compound of  claim 1  selected from the group consisting of: 
 (4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;    (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;    (4-Azepan-1-ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;    (4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;    (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-Diethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    (4-Dimethylaminomethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-amino]-methyl}-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-methanone;    (4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminomethyl)-phenyl]-methanone;    (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-1-methyl-ethylamino)-methyl]-phenyl}-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride;    (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone dihydrochloride;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyl)-phenyl}-methanone;    {4-(Benzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride; and    {4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone.    
     
     
         40 . A compound of  claim 1  selected from the group consisting of: 
 (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone dihydrochloride;    (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;    (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone dihydrochloride;    (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone dihydrochloride;    (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone; and    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone.    
     
     
         41 . A compound of  claim 1  selected from the group consisting of: 
 (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;    (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;    (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride; and    {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone dihydrochloride.    
     
     
         42 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically-acceptable excipient.  
     
     
         43 . A compound of  claim 1  isotopically-labelled to be detectable by PET or SPECT.  
     
     
         44 . A method of inhibiting histamine H 3  receptor activity in a subject, comprising administering an effective amount of a compound of  claim 1  to a subject in need of such inhibition of histamine H 3  receptor activity.  
     
     
         45 . A method of treating a subject having a disease or condition modulated by histamine H 3  receptor activity, comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 .  
     
     
         46 . A method of  claim 45 , wherein said disease or condition is selected from the group consisting of sleep/wake disorders, arousal/vigilance disorders, migraine, asthma, dementia, cognitive dysfunction, neurogenic inflammation, mild cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eating disorders, obesity, motion sickness, vertigo, attention deficit hyperactivity disorders, learning disorders, memory retention disorders, schizophrenia, substance abuse, bipolar disorders, manic disorders and depression, nasal congestion, itch, allergic rhinitis, and upper airway allergic response.  
     
     
         47 . A method for treating a disease or condition modulated by at least one receptor selected from the histamine H 1  receptor and the histamine H 3  receptor, said method comprising (a) administering to a subject a jointly effective amount of a histamine H 1  receptor antagonist compound, and (b) administering to the subject a jointly effective amount of a compound of  claim 1 , said method providing a jointly therapeutically effective amount of said compounds.  
     
     
         48 . The method of  claim 47  wherein the histamine H 1  receptor antagonist and the compound of  claim 1  are present in the same dosage form.  
     
     
         49 . A method for treating diseases or conditions modulated by at least one receptor selected from the histamine H 2  receptor and the histamine H 3  receptor in a subject, comprising (a) administering to the subject a jointly effective amount of a histamine H 2  receptor antagonist compound, and (b) administering to the subject a jointly effective amount of a compound of  claim 1 , said method providing a jointly therapeutically effective amount of said compounds.  
     
     
         50 . The method of  claim 39  wherein the histamine H 2  receptor antagonist and the compound of  claim 1  are present in the same dosage form.  
     
     
         51 . A method for treating one or more disorders or conditions selected from the group consisting of sleep/wake disorders, narcolepsy, and arousal/vigilance disorders, comprising administering to a subject a therapeutically effective amount of a compound of  claim 1 .  
     
     
         52 . A method for treating attention deficit hyperactivity disorders (ADHD), comprising administering to a subject a therapeutically effective amount of a compound of  claim 1 .  
     
     
         53 . A method for treating one or more disorders or conditions selected from the group consisting of dementia, mild cognitive impairment (pre-dementia), cognitive dysfunction, schizophrenia, depression, manic disorders, bipolar disorders, and learning and memory disorders, comprising administering to a subject a therapeutically effective amount of a compound of  claim 1 .  
     
     
         54 . A method for treating or preventing upper airway allergic response, itch, nasal congestion, or allergic rhinitis, comprising administering to a subject a therapeutically effective amount of a compound of  claim 1 .  
     
     
         55 . A method for studying disorders mediated by the histamine H 3  receptor, comprising using an  18 F-labeled or  11 C-labelled compound of  claim 1  as a positron emission tomography (PET) molecular probe.