Bridged heterocyclic compounds and methods of use

Abstract

This disclosure relates to new compounds that may be used to modulate a histamine receptor in an individual. Novel compounds are described, including new bridged heterocyclic [4,3-b]indole compounds. Pharmaceutical compositions are also provided. Pharmaceutical compositions comprising the compounds are also provided, as are 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 (E): 
       
         
           
           
               
               
           
         
       
       where:
 R 1  is H, hydroxyl, 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, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, amino sulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; 
 R 2  is H, hydroxyl, alkoxy or substituted or unsubstituted C 1 -C 8  alkyl; 
 each R 3a  and R 3b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy or R 3a  and R 3b  are taken together to form a cycloalkyl moiety or a carbonyl moiety; 
 each X 7 , X 8 , X 9  and X 10  is independently N or CR 4 ; 
 p is 1 or 2; 
 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, amino sulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; 
 each R 8a , R 8b , R 8c  and R 8d  is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 8 alkenyl, C 1 -C 8  perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R 8(a-d)  to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH 2 CH 2 O—, or is taken together with a geminal R 8(a-d)  and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R 8(a-d)  and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted C 3 -C 8  cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety, or is taken together with a vicinal R 8(a-d)  to form a bond provided when an R 8(a-d)  is taken together with a vicinal R 8(a-d)  to form a bond, the geminal R 8(a-d)  is other than hydroxyl; 
    represents a single or double bond, provided that when   is a double bond, R 8a  and R 8c  are absent and R 8b  and R 8d  are other than OH; 
 R 10  is H, hydroxyl, alkoxy or a substituted or unsubstituted C 1 -C 8  alkyl; 
 Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted C 3 -C 8  cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino; 
 provided that when X 7 , X 8  and X 10  are CR 4  where R 4  is H and X 9  is CR 4  and each R 2 , R 3a , R 3b  and R 10  is H then at least one of R 8(a-d)  is hydroxyl or alkoxy and/or Q is other than a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or heterocyclyl moiety; or a salt or solvate thereof. 
 
     
     
         2 . A compound is of the formula (F): 
       
         
           
           
               
               
           
         
       
       where:
 R 1  is H, hydroxyl, 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, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; 
 R 2  is H, substituted or unsubstituted C 1 -C 8  alkyl, halo, cyano, hydroxyl, alkoxy or nitro; 
 each R 3a  and R 3b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy or R 3a  and R 3b  are taken together to form a cycloalkyl or a carbonyl moiety; 
 each X 7 , X 8 , X 9  and X 10  is independently N or CR 4 ; 
 m and q are independently 0 or 1; 
 p is 1 or 2; 
 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, amino sulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; 
 each R 8a , R 8b , R 8c  and R 8d  is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 8 alkenyl, C 1 -C 8  perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R 8(a-d)  to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH 2 CH 2 O—, or is taken together with a geminal R 8(a-d)  and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety; 
 R 10  is H, halo, a substituted or unsubstituted C 1 -C 8  alkyl, hydroxyl, alkoxy, cyano or nitro; 
 each R 11  and R 12  is independently H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted C 2 -C 8  alkenyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, carboxy, carbonylalkoxy or C 1 -C 8  perhaloalkyl and the  bond indicates the presence of either an E or Z double bond configuration, or R 11  and R 12  are taken together to form a bond; 
 Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted C 3 -C 8  cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino; 
 provided that when X 7 -X 10  is CR 4 , and each R 2 , R 3a , R 3b  and R 10  is H, then (i) at least one of R 8(a-d)  is hydroxyl or alkoxy, and/or (ii) at least one of R 11  or R 12  is alkyl or alkoxy and/or (iii) Q is other than a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or heterocyclyl; 
 or a salt or solvate thereof. 
 
     
     
         3 . A compound of the formula (F-1): 
       
         
           
           
               
               
           
         
       
       where:
 R 1  is H, hydroxyl, 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, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; 
 each R 2  and R 10  is independently H, hydroxyl, alkoxy or substituted or unsubstituted C 1 -C 8  alkyl; 
 each R 3a  and R 3b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino or acyloxy or R 3a  and R 3b  are taken together to form a cycloalkyl or a carbonyl moiety; 
 p is 1 or 2; 
 each X 7 , X 8 , X 9  and X 10  is independently N or CR 4 ; 
 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 11  and R 12  is independently H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8  alkyl, substituted or unsubstituted C 2 -C 8  alkenyl, substituted or unsubstituted C 3 -C 8  cycloalkyl, carboxy, carbonylalkoxy or C 1 -C 8  perhaloalkyl and the  bond indicates the presence of either an E or Z double bond configuration, or R 11  and R 12  are taken together to form a bond; and 
 Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8  cycloalkyl, substituted or unsubstituted C 3 -C 8  cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino; 
 provided that when X 7 -X 10  is CR 4 , and each R 2 , R 3a , R 3b  and R 10  is H then (i) at least one of R 11  or R 12  is alkyl or alkoxy, and/or (ii) Q is other than a substituted or unsubstituted aryl or heteroaryl. 
 or a salt thereof. 
 
     
     
         4 . A compound selected from the group consisting of compounds 1 to 7, J-1 to J-30, K-1 to K-60 and L-1 to L-61, or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A compound according to any formulae detailed herein. 
     
     
         6 . The compound of any of  claims 1  to  5  wherein the compound modulates at least one of the following receptors: adrenergic receptor (e.g., a 1A , a 1B , a 1D , a 2A , a 2B  and/or a 2C ), serotonin receptor (e.g., 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 5A , 5-HT 6  and/or 5-HT 7 ), dopamine receptor (e.g., D 2L ) and histamine receptor (e.g., H 1 , H 2  and/or H 3 ). 
     
     
         7 . 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 of any of  claims 1  to  6 . 
     
     
         8 . A pharmaceutical composition comprising a compound according to any of  claims 1  to  6  and a pharmaceutically acceptable carrier. 
     
     
         9 . A kit comprising a compound according to any of  claims 1  to  6  and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.