US2009137608A1PendingUtilityA1

Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine H4 receptor

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Assignee: EDWARDS JAMES PPriority: Mar 31, 2006Filed: Jan 15, 2009Published: May 28, 2009
Est. expiryMar 31, 2026(expired)· nominal 20-yr term from priority
Inventors:James P. EdwardsDavid E. KindrachukChristopher M. MapesDaniel J. PippelJennifer D. Venable
A61P 9/00A61P 37/00A61P 37/08A61P 9/10A61P 7/00A61P 7/04A61P 7/06A61P 37/06A61P 5/14A61P 31/22A61P 29/00A61P 27/02A61P 27/14A61P 25/00A61P 17/00A61P 11/02A61P 19/02A61P 11/06A61P 1/04A61P 1/16A61P 17/06A61P 11/00A61P 17/04A61P 15/00A61P 21/04C07D 401/14A61K 31/4184C07D 403/14A61K 31/506C07D 239/47
67
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Claims

Abstract

Benzoimidazol-2-yl pyrimidines and pyrazines, pharmaceutical compositions and methods for H 4 receptor activity modulation and for the treatment of disease states, disorders, and conditions mediated by H 4 receptor activity, including allergy, asthma, autoimmune diseases, and pruritis.

Claims

exact text as granted — not AI-modified
1 . A method for modulating histamine H 4  receptor activity, comprising exposing histamine H 4  receptor to an effective amount of at least one agent selected from a compound of Formula (I) and a pharmaceutically acceptable salt of a compound of Formula (I), 
     
       
         
         
             
             
         
       
     
     wherein
 each of R 1-4  is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, —CF 3 , —OCF 3 , —CN, halo, —NO 2 , —OC 1-4 alkyl, —SC 1-4 alkyl, —S(O)C 1-4 alkyl, —SO 2 C 1-4 alkyl, —C(O)C 1-4 alkyl, —C(O)phenyl, —C(O)NR a R b , —CO 2 C 1-4 alkyl, —CO 2 H, —C(O)NR a R b , or —NR a R b .
 wherein R a  and R b  are each independently H, C 1-4 alkyl, or C 3-7 cycloalkyl; 
 
 one of X 1  and X 2  is N and the other is C—R c ;
 where R c  is H, methyl, hydroxymethyl, dimethylaminomethyl, ethyl, propyl, isopropyl, —CF 3 , cyclopropyl, or cyclobutyl; 
 
 n is 1 or 2; 
 Z is N, CH, or C(C 1-4 alkyl); 
 R 6  is H, C 1-6 alkyl, or monocyclic cycloalkyl; 
 R 8  is H or C 1-4 alkyl; 
 R 9  and R 10  are each independently H or C 1-4 alkyl; and 
 R 11  is H or C 1-4 alkyl. 
 
   
   
       2 . A method for modulating histamine H 4  receptor activity, comprising exposing histamine H 4  receptor to an effective amount of at least one agent selected from the following chemical entities and pharmaceutically acceptable salts of the following chemical entities: 
     [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(6-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4-Fluoro-5-methyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclobutyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclobutyl-5-(4,5-difluoro-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclobutyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclobutyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Ethyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Methyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(1H-Benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Fluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [3-(1-Methyl-piperidin-4-yl)-propyl]-[4-methyl-5-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-amine; 
     [5-(5-tert-Butyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Chloro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(6-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Dichloro-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5,6-Difluoro-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(1H-Benzoimidazol-2-yl)-pyrazin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; and 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-pyrazin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine. 
   
   
       3 . A method for modulating histamine H 4  receptor activity, comprising exposing histamine H 4  receptor to an effective amount of at least one agent selected from the following chemical entities and pharmaceutically acceptable salts of the following chemical entities: 
     [5-(4,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     2-{4-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-1H-benzoimidazole-5-carbonitrile; 
     [5-(5-Methoxy-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Chloro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5,6-Dichloro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Ethyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclopropyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclopropyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclopropyl-5-(6-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclopropyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclopropyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(6-Chloro-5-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; and 
     [5-(4-Chloro-6-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine. 
   
   
       4 . A method according to  claim 3 , wherein said at least one agent is one of: 
     [5-(4,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     2-{4-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-1H-benzoimidazole-5-carbonitrile; 
     [5-(5-Methoxy-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Chloro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; and
 pharmaceutically acceptable salts thereof. 
 
   
   
       5 . A method for modulating histamine H 4  receptor activity, comprising exposing histamine H 4  receptor to an effective amount of at least one agent selected from a compound of Formula (I), a monohydrate of a compound of Formula (I), a dihydrate of a compound of formula (I), and a hemitartrate salt of a compound of Formula (I), 
     
       
         
         
             
             
         
       
     
     wherein
 each of R 1-4  is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, —CF 3 , —OCF 3 , —CN, halo, —NO 2 , —OC 1-4 alkyl, —SC 1-4 alkyl, —S(O)C 1-4 alkyl, —SO 2 C 1-4 alkyl, —C(O)C 1-4 alkyl, —C(O)phenyl, —C(O)NR a R b , —CO 2 C 1-4 alkyl, —CO 2 H, —C(O)NR a R b , or —NR a R b ; 
 wherein R a  and R b  are each independently H, C 1-4 alkyl, or C 3-7 cycloalkyl; 
 one of X 1  and X 2  is N and the other is C—R c ; 
 where R c  is H, methyl, hydroxymethyl, dimethylaminomethyl, ethyl, propyl, isopropyl, —CF 3 , cyclopropyl, or cyclobutyl; 
 n is 1 or 2; 
 Z is N, CH, or C(C 1-4 alkyl); 
 R 6  is H, C 1-6 alkyl, or monocyclic cycloalkyl; 
 R 8  is H or C 1-4 alkyl; 
 R 9  and R 10  are each independently H or C 1-4 alkyl; and 
 R 11  is H or C 1-4 alkyl. 
 
   
   
       6 . A method according to  claim 5 , wherein said at least one agent is a hemitartrate of a compound of Formula (I). 
   
   
       7 . A method for modulating histamine H 4  receptor activity, comprising exposing histamine H 4  receptor to an effective amount of at least one agent selected from the following compounds: 
     [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(6-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Difluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-methyl-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4-Fluoro-5-methyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclobutyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclobutyl-5-(4,5-difluoro-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclobutyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclobutyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-propyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Ethyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Methyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(1H-Benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Fluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [3-(1-Methyl-piperidin-4-yl)-propyl]-[4-methyl-5-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-amine; 
     [5-(5-tert-Butyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Chloro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(6-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Dichloro-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1 methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5,6-Difluoro-1H-benzoimidazol-2-yl)-4-trifluoromethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Difluoro-1H-benzoimidazol-2-yl)-4-isopropyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(1H-Benzoimidazol-2-yl)-pyrazin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-pyrazin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     2-{4-Methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidin-5-yl}-1H-benzoimidazole-5-carbonitrile; 
     [5-(5-Methoxy-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5-Chloro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(5,6-Dichloro-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-ethyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Ethyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclopropyl-5-(4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclopropyl-5-(4,5-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclopropyl-5-(6-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclopropyl-5-(4,6-dimethyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [4-Cyclopropyl-5-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(6-Chloro-5-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine; 
     [5-(4-Chloro-6-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine;
 monohydrates of said compounds, dihydrates of said compounds, and hemitartrate salts of said compounds. 
 
   
   
       8 . A method according to  claim 7 , wherein said at least one agent is a hemitartrate. 
   
   
       9 . A method for modulating histamine H 4  receptor activity, comprising exposing histamine H 4  receptor to an effective amount of at least one agent selected from a chemical entity that is a monohydrate, dihydrate or hemitartrate of one of [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine, and [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine. 
   
   
       10 . A method according to  claim 9 , wherein said at least one agent is a hemitartrate of one of [5-(5-Fluoro-4-methyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine, and [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine. 
   
   
       11 . A method according to  claim 10 , wherein said at least one agent is a hemitartrate of [5-(4,6-Dimethyl-1H-benzoimidazol-2-yl)-4-methyl-pyrimidin-2-yl]-[3-(1-methyl-piperidin-4-yl)-propyl]-amine. 
   
   
       12 . A method according to  claim 1 , wherein each of R 1-4  is independently H, methyl, tert-butyl, methoxy, —CF 3 , —CN, fluoro, chloro, methoxycarbonyl, or benzoyl. 
   
   
       13 . A method according to  claim 1 , wherein X 2  is N. 
   
   
       14 . A method according to  claim 1 , wherein X 1  is N. 
   
   
       15 . A method according to  claim 1 , wherein R c  is H, methyl, ethyl, CF 3 , cyclopropyl, or cyclobutyl. 
   
   
       16 . A method according to  claim 1 , wherein R c  is H or methyl. 
   
   
       17 . A method according to  claim 1 , wherein n is 1. 
   
   
       18 . A method according to  claim 1 , wherein Z is N or CH. 
   
   
       19 . A method according to  claim 1 , wherein Z is CH. 
   
   
       20 . A method according to  claim 1 , wherein R 6  is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. 
   
   
       21 . A method according to  claim 1 , wherein R 6  is H or methyl. 
   
   
       22 . A method according to  claim 1 , wherein R 8  is H. 
   
   
       23 . A method according to  claim 1 , wherein R 9  and R 10  are each independently H or methyl. 
   
   
       24 . A method according to  claim 1 , wherein R 9  and R 10  are both H. 
   
   
       25 . A method according to  claim 1 , wherein R 11  is H or methyl. 
   
   
       26 . A method according to  claim 1 , wherein R 11  is methyl. 
   
   
       27 . A method according to  claim 1 , wherein R 11  is methyl, R 9  and R 10  are both H, and R 6  is H or methyl. 
   
   
       28 . A method according to  claim 1 , wherein R 11  is methyl, R 9  and R 10  are both H, R 8  is H, and R 6  is H or methyl. 
   
   
       29 . A method according to  claim 1 , wherein R 11  is methyl, R 9  and R 10  are both H, R 8  is H, Z is CH, and R 6  is H or methyl. 
   
   
       30 . A method according to  claim 1 , wherein R 11  is methyl, R 9  and R 10  are both H, R 8  is H, Z is CH, n is 1, and R 6  is H or methyl.

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