Pyrido[4,3-b]indoles and methods of use

Abstract

New heterocyclic compounds that may be used to modulate a histamine receptor in an individual are described. Pyrido[4,3-b]indoles are described, as are pharmaceutical compositions comprising the compounds and methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

1 . A compound of the formula (A): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3  and R 4  are independently H, halo, C 1 -C 8  unsubstituted alkyl or C 1 -C 8  unsubstituted alkoxy, provided that R 3  is other than methyl or chloro when R 1 , R 2  and R 4  are each H and X is OH and Y is methyl; 
 R 5  is unsubstituted C 1 -C 8  alkyl or a C 1 -C 8  alkyl substituted with a perhaloalkyl moiety; 
 R 6  is H or an unsubstituted C 1 -C 8  alkyl; 
 X is OH, C 1 -C 8  alkyl or is taken together with Y to form a cyclopropyl moiety; and 
 Y is H, C 1 -C 8  alkyl or is taken together with X to form a cyclopropyl moiety, 
 or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing. 
 
     
     
         2 . The compound of  claim 1 , wherein R 5  is methyl, ethyl, cyclopropyl, trifluoromethyl, trifluoroethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl, cyclobutyl, cyclopentyl, or cyclohexyl. 
     
     
         3 . The compound of  claim 2 , wherein R 5  is methyl. 
     
     
         4 . The compound of  claim 1 , wherein R 3  is halo or C 1 -C 8  unsubstituted alkyl. 
     
     
         5 . The compound of  claim 4 , wherein R 3  is chloro or methyl. 
     
     
         6 . The compound of  claim 1 , wherein X is OH and Y is C 1 -C 8  alkyl. 
     
     
         7 . The compound of  claim 6 , wherein Y is methyl. 
     
     
         8 . A compound of the formula (B): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 7  is H, hydroxyl, nitro, cyano, halo, C 1 -C 8  perhaloalkyl, substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted C 2 -C 8  alkenyl, substituted or unsubstituted C 2 -C 8  alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8  perhaloalkoxy, C 1 -C 8  alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; and 
 Z is H, halo or C 1 -C 8  alkyl, 
 
       or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing. 
     
     
         9 . The compound of  claim 8 , wherein R 7  is halo or C 1 -C 8  unsubstituted alkyl. 
     
     
         10 . The compound of  claim 9 , wherein R 7  is chloro or methyl. 
     
     
         11 . The compound of  claim 8 , wherein Z is H or halo. 
     
     
         12 . A compound of the formula (C2): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3  and R 4  are independently H, halo, C 1 -C 8  unsubstituted alkyl or C 1 -C 8  unsubstituted alkoxy; 
 R 5  is C 1 -C 6  unsubstituted alkyl or CF 3 ; 
 R 8  is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; and 
 X is a C 4 -C 6  unsubstituted n-alkyl or cycloalkyl or a C 3 -C 6  unsubstituted branched alkyl, 
 or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing. 
 
     
     
         13 . The compound of  claim 12 , wherein R 5  is CH 3 . 
     
     
         14 . The compound of  claim 12 , wherein X is a C 4 -C 6  unsubstituted n-alkyl or cycloalkyl or a C 3 -C 6  unsubstituted branched alkyl. 
     
     
         15 . The compound of  claim 12 , wherein R 3  is halo or C 1 -C 8  unsubstituted alkyl. 
     
     
         16 . The compound of  claim 13 , wherein R 3  is chloro or methyl. 
     
     
         17 . The compound of  claim 16 , wherein R 8  is a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, oxadiazolyl, furanyl, pyrrolyl or thiophenyl group. 
     
     
         18 . A compound of the formula (D2): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3  and R 4  are independently H, halo, C 1 -C 8  unsubstituted alkyl or C 1 -C 8  unsubstituted alkoxy; 
 X is H or a C 1 -C 3  unsubstituted alkyl; and 
 V is a halo, 
 
       or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing. 
     
     
         19 . The compound of  claim 18 , wherein X is H. 
     
     
         20 . The compound of  claim 18 , wherein X is CH 3 . 
     
     
         21 . The compound of  claim 18 , wherein R 3  is halo or C 1 -C 8  unsubstituted alkyl. 
     
     
         22 . The compound of  claim 21 , wherein R 3  is chloro or methyl. 
     
     
         23 . A compound of the formula (E2): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3  and R 4  are independently H, halo, C 1 -C 8  unsubstituted alkyl or C 1 -C 8  unsubstituted alkoxy; 
 R 8  is 6-pyrimidyl, 2-pyrazinyl, 3-methyl-4-pyridyl or a phenyl substituted either: (i) with at least one alkoxy or hydroxyl group or (ii) with at least two halo groups; and 
 R 9  is an unsubstituted C 1 -C 3  alkyl, 
 
       or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing. 
     
     
         24 . The compound of  claim 23 , wherein R 9  is methyl. 
     
     
         25 . A compound of the formula (F2): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3  and R 4  are independently H, halo, C 1 -C 8  unsubstituted alkyl or C 1 -C 8  unsubstituted alkoxy; 
 R 5  is 
 
       
         
           
           
               
               
           
         
       
       where T is 3 or 4
 X is H or OH; 
 Y is H or C 1 -C 8  alkyl; and 
 R 8  is a substituted or unsubstituted heteroaryl, 
 
       or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing. 
     
     
         26 . The compound of  claim 25 , wherein R 3  is halo or C 1 -C 8  unsubstituted alkyl. 
     
     
         27 . The compound of  claim 26 , wherein R 3  is chloro or methyl. 
     
     
         28 . The compound of  claim 25 , wherein X is OH and Y is C 1 -C 8  alkyl. 
     
     
         29 . The compound of  claim 28 , wherein Y is methyl. 
     
     
         30 . The compound of  claim 25 , wherein R 8  is a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl, oxadiazolyl, furanyl, pyrrolyl or thiophenyl group. 
     
     
         31 . A compound of the formula (G): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2  and R 4  are independently H, halo, C 1 -C 8  unsubstituted alkyl or C 1 -C 8  unsubstituted alkoxy; 
 R 3  is methyl or chloro, provided that R 3  is methyl when R 8  is a substituted heteroaryl; 
 X is H or OH; 
 Y is H or C 1 -C 8  alkyl; and 
 R 8  is a substituted or unsubstituted heteroaryl, 
 
       or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing. 
     
     
         32 . The compound of  claim 31 , wherein R 3  is halo or C 1 -C 8  unsubstituted alkyl. 
     
     
         33 . The compound of  claim 31 , wherein R 3  is chloro or methyl. 
     
     
         34 . The compound of  claim 31 , wherein X is OH and Y is C 1 -C 8  alkyl. 
     
     
         35 . The compound of  claim 34 , wherein Y is methyl. 
     
     
         36 . A compound of the formula (H): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3  and R 4  are independently H, halo, C 1 -C 8  unsubstituted alkyl or C 1 -C 8  unsubstituted alkoxy; 
 R 5 , R 6  and R 7  are each independently H or unsubstituted C 1 -C 8  alkyl; and 
 R 8  is a 6-substituted pyridin-3-yl, 
 
       or a salt thereof, such as a pharmaceutically acceptable salt thereof, or solvate of the foregoing. 
     
     
         37 . The compound of  claim 36 , wherein R 3  is chloro or methyl. 
     
     
         38 . The compound of  claim 36 , wherein R 5  is H or methyl. 
     
     
         39 . A compound selected from the group consisting of:
 1-Cyclohexyl-2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanol;   2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanol;   1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(3-fluoro-4-methoxyphenyl)propan-2-ol;   1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-methoxyphenyl)propan-2-ol;   1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-fluorophenyl)butan-2-ol;   2-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5 (2H)-yl)-1-cyclobutyl-1-(4-fluorophenyl)ethanol;   1-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-fluorophenyl)hexan-2-ol;   2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5 (2H)-yl)-1-(pyridine-4-yl)ethanol;   1-(8-Fluoro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5 (2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   1-(6-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5 (2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   2-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5 (2H)-yl)-1-(pyridine-4-yl)ethanol;   1-(7-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5 (2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   1-(6-Fluoro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   1-(2-Methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   4-(1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)phenol;   1-(8-Methoxy-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   1-(7,8-Dichloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   1-(8,9-Dichloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   (R)-1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-methoxyphenyl)propan-2-ol;   (S)-1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-methoxyphenyl)propan-2-ol;   1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-methyl-2-(pyridine-4-yl)butan-2-ol;   1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-methyl-2-(pyridine-4-yl)butan-2-ol;   1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)butan-2-ol;   1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)butan-2-ol;   1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyrimidin-4-yl)propan-2-ol;   1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyrimidin-4-yl)propan-2-ol;   1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyrazin-2-yl)propan-2-ol;   1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyrazin-2-yl)propan-2-ol;   1-(8-Methyl-2-(2,2,2-trifluoroethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   1-(2-Cyclopropyl-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   1-(6-Methoxy-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   1-(7-Isopropyl-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   2-(Pyridin-4-yl)-1-(2,3,8-trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol;   3-(8-Methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)propanenitrile;   2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-phenylethanone;   2-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-phenylethanone;   2-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanone;   2-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-chlorophenyl)ethanone;   2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanone   3-(5-(2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethyl)pyridine-2-yl)propan-1-amine;   8-Methyl-5-(2-(6-(trifluoromethyl)yridine-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;   3-(8-Methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)propan-1-ol;   4-(8-Methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-2(5H)-yl)butan-1-ol;   2,3,8-Trimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;   2,3,8-Trimethyl-5-(2-(6-(trifluoromethyl)yridine-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;   2,8-Dimethyl-5-(2-(yridine-4-yl)propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;   2,3,8-Trimethyl-5-(2-(6-methylpyridin-3-yl)propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;   8-Chloro-2,3-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;   2,8-Dimethyl-5-(2-methyl-2-(yridine-4-yl)propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;   2,8-Dimethyl-5-((1-(yridine-4-yl)cyclopropyl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;   2,4,8-Trimethyl-5-(2-(6-(trifluoromethyl)yridine-3-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;   1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)propan-2-ol;   1-(2-Ethyl-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-fluorophenyl)propan-2-ol;   1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-3-yl)propan-2-ol;   1-(8-Methyl-2-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(6-methylpyridin-3-yl)propan-2-ol;   1-(2-Cyclopropyl-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(2-methylpyridin-4-yl)propan-2-ol;   1-(8-Chloro-2-isopropyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-chlorophenyl)propan-2-ol;   2-(2,4-Difluorophenyl)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propan-2-ol;   1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(3-fluoro-4-methoxyphenyl)propan-2-ol;   (R)-1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-fluorophenyl)butan-2-ol;   (R)-1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-fluorophenyl)hexan-2-ol;   (S)-1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)butan-2-ol;   (R)-1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridine-4-yl)butan-2-ol;   1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-fluorophenyl)hexan-2-ol;   8-Methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;   (S)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-fluorophenyl)butan-2-ol; and   (S)-1-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(4-fluorophenyl)hexan-2-ol,   or a pharmaceutically acceptable salt thereof.   
     
     
         40 . A method of modulating a histamine receptor in an individual comprising administering to an individual in need thereof a compound according to any of  claims 1 - 39 . 
     
     
         41 . A pharmaceutical composition comprising (a) a compound of any of  claims 1 - 39 , or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier. 
     
     
         42 . A kit comprising a compound according to any of  claims 1 - 39  and instructions for use. 
     
     
         43 . A method of treating a cognitive disorder or a disorder characterized by causing at least one symptom associated with impaired cognition comprising administering to an individual in need thereof an effective amount of a compound of any of  claims 1 - 39 , or a pharmaceutically acceptable salt thereof.