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

Abstract

This disclosure relates to new heterocyclic compounds that may be used to modulate a histamine receptor in an individual. Pyrido[3,4-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 - 24 . (canceled) 
     
     
         25 . A compound of formula (E): 
       
         
           
           
               
               
           
         
       
       or a salt thereof, 
       wherein:
 R 1  is H, hydroxyl, nitro, cyano, halo, substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted C 2 -C 8  alkenyl, substituted or unsubstituted C 2 -C 8  alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8  perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; 
 each R 2a  and R 2b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, cyano, hydroxyl, alkoxy or nitro, or R 2a  and R 2b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety; 
 each R 3a  and R 3b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substituted amino, cycloalkyl, acylamino or acyloxy or R 3a  and R 3b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety; 
 X 7 , X 8  and X 10  are each CR 4  and X 9  is N; or X 7  and X 10  are each N, and X 8  and X 9  are each CR 4 ; 
 m and q are independently 0 or 1; 
 n is 1 or 0, provided that n is 0 only when Q is a substituted heterocycle wherein the substituted heterocycle is a lactam; 
 each R 4  is independently 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, thiol, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; 
 each R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is independently H, hydroxyl, C 1 -C 8  alkyl, carboxy, carbonylalkoxy, is taken together with the carbon to which it is attached and a geminal R 8(a-f)  to form a cycloalkyl moiety or a carbonyl moiety, is taken together with a geminal R 8(a-f)  to form a methylene or a substituted methylene, is taken together with a vicinal R 8(a-f)  and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3-8  cycloalkyl, substituted or unsubstituted C 3-8  cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R 8(a-f)  to form a bond, provided that when an R 8(a-f)  is taken together with a vicinal R 8  to form a bond, the geminal R 8(a-f)  is other than hydroxyl; 
 each R 10a  and R 10b  is independently H, halo, a substituted or unsubstituted C 1 -C 8  alkyl, hydroxyl, alkoxyl, cyano or nitro, or R 10a  and R 10b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety; and 
 Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or a unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl. 
 
     
     
         26 . The compound of  claim 25 , or a salt thereof, wherein X 7 , X 8  and X 10  are each CR 4  and X 9  is N. 
     
     
         27 . The compound of  claim 25 , or a salt thereof, wherein X 7  and X 10  are each N, and X 8  and X 9  are each CR 4 . 
     
     
         28 . The compound of  claim 25 , or a salt thereof, wherein X 7 , X 8 , X 9  and X 10  are taken together to provide an aromatic moiety selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound of  claim 25 , or a salt thereof, wherein each R 4  is independently H, hydroxyl, 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, thiol, carbonylalkoxy, thioalkyl, alkylsulfonylamino or acyl. 
     
     
         30 . The compound of  claim 25 , or a salt thereof, wherein each R 4  is independently nitro, cyano, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, or carbonylalkylenealkoxy; 
     
     
         31 . The compound of  claim 25 , or a salt thereof, wherein each R 4  is independently H, halo. substituted or unsubstituted C 1 -C 8  alkyl, or C 1 -C 8  perhaloalkyl. 
     
     
         32 . The compound of  claim 25 , or a salt thereof, wherein each R 4  is independently methyl, CF 3 , CH 2 F, CHF 2 , chloro or fluoro. 
     
     
         33 . The compound of  claim 28 , or a salt thereof, wherein the compound contains at least one R 4  and wherein each R 4  is independently halo, substituted or unsubstituted C 1 -C 8  alkyl, or perhaloalkyl. 
     
     
         34 . The compound of  claim 28 , or a salt thereof, wherein the compound contains at least one R 4  and wherein each R 4  is methyl, CH 2 F, CHF 2 , CF 3 , chloro or fluoro. 
     
     
         35 . The compound of  claim 25 , or a salt thereof, wherein q is 0, and m is 1. 
     
     
         36 . The compound of  claim 25 , or a salt thereof, wherein R 1  is substituted or unsubstituted C 1 -C 8  alkyl. 
     
     
         37 . The compound of  claim 36 , or a salt thereof, wherein R 1  is methyl. 
     
     
         38 . The compound of  claim 25 , or a salt thereof, wherein each R 2a , R 2b , R 3a , R 3b , R 10a  and R 10b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, or halo. 
     
     
         39 . The compound of  claim 25 , or a salt thereof, wherein each R 2a , R 2b , R 3a , R 3b , R 10a  and R 10b  is H. 
     
     
         40 . The compound of  claim 25 , or a salt thereof, wherein:
 each R 2a  and R 2b  is independently H, unsubstituted C 1 -C 8  alkyl, halo or R 2a  and R 2b  are taken together to form a carbonyl moiety; and   each R 3a  and R 3b  is independently H, unsubstituted C 1 -C 8  alkyl, halo.   
     
     
         41 . The compound of  claim 25 , or a salt thereof, wherein each R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is independently H, hydroxyl, unsubstituted C 1 -C 4  alkyl, is taken together with the carbon to which it is attached and a geminal R 8(a-f)  to form a carbonyl moiety or is taken together with a geminal R 8(a-f)  to form a methylene or a substituted methylene. 
     
     
         42 . The compound of  claim 25 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is hydroxyl, C 1 -C 8  alkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R 8(a-f)  to form a cycloalkyl moiety or a carbonyl moiety. 
     
     
         43 . The compound of  claim 25 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is taken together with a geminal R 8(a-f)  to form a methylene or a substituted methylene, is taken together with a vicinal R 8(a-f)  and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3-8  cycloalkyl, substituted or unsubstituted C 3-8  cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or is taken together with a vicinal R 8(a-f)  to form a bond, provided that when an R 8(a-f)  is taken together with a vicinal R 8  to form a bond, the geminal R 8(a-f)  is other than hydroxyl. 
     
     
         44 . The compound of  claim 25 , or a salt thereof, wherein each R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is H. 
     
     
         45 . The compound of  claim 25 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is other than H. 
     
     
         46 . The compound of  claim 25 , or a salt thereof, wherein at least one of R 8c , R 8d , R 8e  and R 8f , where present, is other than H. 
     
     
         47 . The compound of  claim 25 , or a salt thereof, wherein at least one of R 8e  and R 8f , where present, is other than H. 
     
     
         48 . The compound of  claim 25 , or a salt thereof, wherein Q is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. 
     
     
         49 . The compound of  claim 48 , or a salt thereof, wherein Q is a substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl. 
     
     
         50 . The compound of  claim 48 , or a salt thereof, wherein Q is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein each R 9  is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted C 2 -C 8  alkenyl, substituted or unsubstituted C 2 -C 8  alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. 
       
     
     
         51 . The compound of  claim 25 , or a salt thereof, wherein Q is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or a unsubstituted heterocyclyl. 
     
     
         52 . The compound of  claim 51 , or a salt thereof, wherein Q is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each R 9  is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted C 2 -C 8  alkenyl, substituted or unsubstituted C 2 -C 8  alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino. 
       
     
     
         53 . The compound of  claim 25 , or a salt thereof, wherein Q is unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl. 
     
     
         54 . The compound of  claim 53 , or a salt thereof, wherein Q is aminoacyl. 
     
     
         55 . The compound of  claim 54 , or a salt thereof, wherein Q is aminoacyl of the formula —NR a C(O)R b  where R a  is H or alkyl and R b  is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. 
     
     
         56 . The compound of  claim 55 , or a salt thereof, wherein R a  is H. 
     
     
         57 . The compound of  claim 56 , or a salt thereof, wherein R b  is unsubstituted or substituted heteroaryl. 
     
     
         58 . The compound of  claim 25 , or a salt thereof, wherein:
 R 1  is unsubstituted alkyl;   each R 2a , R 2b , R 3a , R 3b , R 10a  and R 10b  is H; and   each R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is independently H, hydroxyl, C 1 -C 8  alkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R 8(a-f)  to form a cycloalkyl moiety or a carbonyl moiety.   
     
     
         59 . The compound of  claim 57 , or a salt thereof, wherein each R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is H. 
     
     
         60 . The compound of  claim 57 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f , where present, is other than H. 
     
     
         61 . The compound of  claim 58 , or a salt thereof, wherein at least one of R 8c , R 8d , R 8e  and R 8f , where present, is other than H. 
     
     
         62 . The compound of  claim 58 , or a salt thereof, wherein at least one of R 8e  and R 8f , where present, is other than H. 
     
     
         63 . The compound of  claim 58 , or a salt thereof, wherein Q is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl. 
     
     
         64 . The compound of  claim 63 , or a salt thereof, wherein Q is a substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl. 
     
     
         65 . The compound of  claim 58 , or a salt thereof, wherein Q is unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, cyano or alkynyl. 
     
     
         66 . The compound of  claim 65 , wherein Q is aminoacyl. 
     
     
         67 . The compound of  claim 66 , or a salt thereof, wherein Q is aminoacyl of the formula —NR a C(O)R b  where R a  is H or alkyl and R b  is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. 
     
     
         68 . The compound of  claim 67 , or a salt thereof, wherein R a  is H. 
     
     
         69 . The compound of  claim 68 , or a salt thereof, wherein R b  is unsubstituted or substituted heteroaryl. 
     
     
         70 . The compound of  claim 57 , or a salt thereof, wherein each R 4  is independently H, halo, substituted or unsubstituted C 1 -C 8  alkyl, or perhaloalkyl. 
     
     
         71 . A pharmaceutical composition comprising a compound according to  claim 25  or a salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         72 . A method of treating a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of compound according to  claim 25  or a salt thereof. 
     
     
         73 . A kit comprising a compound according to  claim 25  or a salt thereof, and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder. 
     
     
         74 . A pharmaceutical composition comprising a compound according to  claim 58  or a salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         75 . A method of treating a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder in an individual comprising administering to an individual in need thereof an effective amount of compound according to  claim 58  or a salt thereof. 
     
     
         76 . A kit comprising a compound according to  claim 58  or a salt thereof, and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.