Cyclopropyl amide derivatives

Abstract

Disclosed herein is at least one cyclopropyl amide derivative, at least one pharmaceutical composition comprising at least one cyclopropyl amide derivative disclosed herein, and at least one method of using at least one cyclopropyl amide derivative disclosed herein for treating at least one histamine H3 receptor associated condition therewith.

1 - 28 . (canceled) 
     
     
         29 . A method for treating a condition selected from cognitive deficiency in schizophrenia, Alzheimer's disease, obesity, narcolepsy, pain, and attention deficit hyperactivity disorder in a subject in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein:
 A is phenyl, pyridinyl, or pyrazolyl; 
 m is 1 or 2; 
 n is 1, 2, 3, 4, or 5; 
 each R 1  is independently H, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkylalkyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkenyl, C 2 -C 6 alkynyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, aminocarbonylalkyl, heterocycle, arylalkenyl, cycloalkenylalkyl, heterocycloalkyl, cyano, alkylsulfinyl, haloalkyl, NR 4 R 5 , —NR 6 C(═O)R 3 , —NHS(O) 2 R 3 , —C(═O)NR 4 R 5 , alkoxy, halogen, alkylcarbonyl, or hydroxy (—OH); 
 R 2  is C 3 -C 8 cycloalkyl or C 1 -C 6 alkyl; 
 R 3  is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NHC 1 -C 6 alkyl, or —N(C 1 -C 6 alkyl) 2 , or when R 1  is —NR 6 C(═O)R 3 , R 3  and the N of the —NR 6 C(═O)R 3  group together form a 4, 5, or 6-membered heterocyclic ring having at least one heteroatom selected from O and N; 
 R 4  and R 5  are each independently selected from H and C 1 -C 6 alkyl, or R 4 , R 5  and the N to which they are attached come together to form a 4, 5, or 6-membered heterocyclic ring having at least one heteroatom selected from N; and 
 R 6  is H or absent. 
 
       
     
     
         30 . The method according to  claim 29 , wherein said condition is pain. 
     
     
         31 . The method according to  claim 30 , wherein said pain is peripheral neuropathic pain. 
     
     
         32 . The method according to  claim 29 , wherein R 1  is independently H, heteroaryl, C 1 -C 6 alkyl, cyano, haloalkyl, halogen, NR 4 R 5 , —NR 6 C(═O)R 3 , —NHS(O) 2 R 3 , or —C(═O)NR 4 R 5 . 
     
     
         33 . The method according to  claim 29 , wherein: 
       
         
           
           
               
               
           
         
         and 
         each R 1  is independently H, heteroaryl, C 1 -C 6 alkyl, cyano, haloalkyl, halogen, NR 4 R 5 , —NR 6 C(═O)R 3 , —NHS(O) 2 R 3 , or —C(═O)NR 4 R 5 . 
       
     
     
         34 . The method according to  claim 29 , wherein:
 R 1  is independently H, heteroaryl, C 1 -C 6 alkyl, cyano, haloalkyl, halogen, NR 4 R 5 , —NR 6 C(═O)R 3 , —NHS(O) 2 R 3 , or —C(═O)NR 4 R 5 ;   n is 1;   m is 1;   R 2  is C 3 -C 8 cycloalkyl or C 1 -C 6 alkyl;   R 3  is —N(C 1 -C 6 alkyl) 2  or C 1 -C 6 alkyl, or the N and the R 3  of the —NR 6 C(═O)R 3  group together form a 5 or 6-membered heterocyclic ring having at least one heteroatom selected from N; and   R 4  and R 5  are each independently selected from H and C 1-4 alkyl, or R 4 , R 5  and the N to which they are attached come together to form a 4, 5, or 6-membered heterocyclic ring having at least one heteroatom selected from N.   
     
     
         35 . The method according to  claim 29 , wherein A is phenyl, R 1  is H or C 1 -C 6 alkyl, n is 1, m is 2, and R 2  is C 3 -C 8 cycloalkyl or C 1 -C 6 alkyl. 
     
     
         36 . The method according to  claim 29 , wherein R 2  is propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. 
     
     
         37 . The method according to  claim 29 , wherein m is 1. 
     
     
         38 . The method according to  claim 29 , wherein n is 1. 
     
     
         39 . The method according to  claim 29 , wherein said compound is administered with a pharmaceutically acceptable carrier and/or diluent. 
     
     
         40 . A method for treating a condition selected from cognitive deficiency in schizophrenia, Alzheimer's disease, obesity, narcolepsy, pain, and attention deficit hyperactivity disorder in a subject in need of such treatment comprising administering a therapeutically effective amount of a compound selected from the group consisting of:
 trans-(4-Isopropylpiperazin-1-yl)-(2-phenylcyclopropyl)methanone;   trans-(4-Cyclohexylpiperazin-1-yl)-(2-phenyl-cyclopropyl)methanone;   trans-(4-Cycloheptylpiperazin-1-yl)-(2-phenylcyclopropyl)methanone;   trans-(4-Cyclobutylpiperazin-1-yl)-(2-phenylcyclopropyl)methanone;   trans-(4-Cyclopropylpiperazin-1-yl)-(2-phenylcyclopropyl)methanone;   trans-(4-Cyclopentylpiperazin-1-yl)-(2-phenylcyclopropyl)methanone;   trans-(2-Phenylcyclopropyl)-(4-propylpiperazin-1-yl)methanone;   trans-(4-Cyclobutyl-1,4-diazepan-1-yl)-(2-phenylcyclopropyl)methanone;   trans-(4-tert-Butylpiperazin-1-yl)-(2-phenylcyclopropyl)methanone;   trans-[2-(4-Fluorophenyl)cyclopropyl]-(4-isopropylpiperazin-1-yl)methanone;   trans-[2-(4-Fluorophenyl)cyclopropyl]-(4-isopropylpiperazin-1-yl)methanone, enantiomer 1;   trans-[2-(4-Fluorophenyl)cyclopropyl]-(4-isopropylpiperazin-1-yl)methanone, enantiomer 2;   trans-[2-(4-Bromophenyl)cyclopropyl]-(4-cyclobutylpiperazin-1-yl)methanone;   (1S,2S)-(2-(4-bromophenyl)cyclopropyl)(4-cyclobutylpiperazin-1-yl)methanone;   (1R,2R)-(2-(4-bromophenyl)cyclopropyl)(4-cyclobutylpiperazin-1-yl)methanone;   trans-1-{4-[2-(4-Cyclobutylpiperazine-1-carbonyl)cyclopropyl]phenyl}-3-methylimidazolidin-2-one;   trans-1-{4-[2-(4-Cyclobutylpiperazine-1-carbonyl)cyclopropyl]phenyl}pyrrolidin-2-one;   trans-N-{4-[2-(4-Cyclobutylpiperazine-1-carbonyl)cyclopropyl]phenyl}methane-sulfonamide;   trans-(4-cyclobutylpiperazin-1-yl){-2-[4-(pyrrolidin-1-yl)phenyl]cyclopropyl}methanone;   trans-{2-[4-(1H-Pyrazol-4-yl)phenyl]cyclopropyl}-(4-cyclobutylpiperazin-1-yl)methanone;   trans-4-[2-(4-Cyclobutylpiperazine-1-carbonyl)cyclopropyl]benzonitrile;   trans-4-[2-(4-Cyclobutylpiperazine-1-carbonyl)cyclopropyl]benzonitrile, enantiomer 1;   trans-4-[2-(4-Cyclobutylpiperazine-1-carbonyl)cyclopropyl]benzonitrile, enantiomer 2;   (4-cyclobutylpiperazin-1-yl)((1S,2S)-2-phenylcyclopropyl)methanone;   (4-cyclobutylpiperazin-1-yl)((1R,2R)-2-phenylcyclopropyl)methanone;   trans-(4-Cyclobutylpiperazin-1-yl)(2-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)methanone;   trans-(4-Cyclobutylpiperazin-1-yl)-[2-(4-fluorophenyl)cyclopropyl]methanone;   trans-[2-(3-Bromophenyl)cyclopropyl]-(4-cyclobutylpiperazin-1-yl)methanone;   trans-3-[2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl]benzonitrile;   trans-N-{3-[2-(4-Cyclobutylpiperazine-1-carbonyl)cyclopropyl]phenyl}methanesulfonamide;   trans-(4-Isopropylpiperazin-1-yl)-(2-phenylcyclopropyl)methanone, enantiomer 1;   trans-(4-Isopropylpiperazin-1-yl)-(2-phenylcyclopropyl)methanone, enantiomer 2;   3-(trans-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)benzamide;   trans-1-(3-(2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)phenyl)pyrrolidin-2-one;   trans-1-(3-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)phenyl)piperidin-2-one;   3-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)benzamide, enantiomer 1;   3-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)benzamide, enantiomer 2;   1-(3-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)phenyl)pyrrolidin-2-one, enantiomer 1;   1-(3-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)phenyl)pyrrolidin-2-one, enantiomer 2;   1-(3-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)phenyl)piperidin-2-one, enantiomer 1;   1-(3-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)phenyl)piperidin-2-one, enantiomer 2;   4-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)benzamide;   4-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)benzamide, enantiomer 1;   4-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)benzamide, enantiomer 2;   (4-isopropylpiperazin-1-yl)(2-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)methanone; and   (4-cyclobutylpiperazin-1-yl)((1S,2S)-2-(4-(pyrimidin-5-yl)phenyl)cyclopropyl)methanone;   or a pharmaceutically acceptable salt of any foregoing compound.   
     
     
         41 . The method according to  claim 40 , wherein said condition is pain. 
     
     
         42 . The method according to  claim 41 , wherein said pain is peripheral neuropathic pain. 
     
     
         43 . The method according to  claim 40 , wherein said compound is 4-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
         44 . The method according to  claim 40 , wherein said compound has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         45 . The method according to  claim 40 , wherein said compound has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         46 . The method according to  claim 40 , wherein said compound is administered with a pharmaceutically acceptable carrier and/or diluent. 
     
     
         47 . A method for treating a condition selected from cognitive deficiency in schizophrenia, Alzheimer's disease, obesity, narcolepsy, pain, and attention deficit hyperactivity disorder in a subject in need of such treatment comprising administering a therapeutically effective amount of 4-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)benzamide; 4-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)benzamide, enantiomer 1; or 4-((trans)-2-(4-cyclobutylpiperazine-1-carbonyl)cyclopropyl)benzamide, enantiomer 2; or
 a pharmaceutically acceptable salt of any foregoing compound, or a mixture of any of the foregoing compounds.   
     
     
         48 . The method according to  claim 47 , wherein said condition is pain. 
     
     
         49 . The method according to  claim 48 , wherein said pain is peripheral neuropathic pain. 
     
     
         50 . The method according to  claim 47 , wherein said compound has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         51 . The method according to  claim 47 , wherein said compound has the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         52 . The method according to  claim 47 , wherein said compound is administered with a pharmaceutically acceptable carrier and/or diluent.