Tetracyclic compounds

Abstract

This disclosure relates to new tetracyclic compounds that may be used to modulate a histamine receptor in an individual. The compounds in one embodiment are tetracyclic [4,3-b]indoles. 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 .- 12 . (canceled) 
     
     
         13 . 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 a compound of the Formula (E): 
       
         
           
           
               
               
           
         
       
       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;
 wherein acyl is selected from the group consisting of H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—; 
 wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 , —SO 2 NR—alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic, where R is H or alkyl, or —SO 2 NR 2 , wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring; 
 
 wherein sulfonyl is selected from the group consisting of —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic; 
 each R 2a  and R 2b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 2a  and R 2b  are taken together to form a carbonyl moiety or R 2a  and R 2b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety; 
 each R 3a  and R 3b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 3a  and R 3b  are taken together to form a carbonyl moiety or R 3a  and R 3b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety; 
 each X 7 , X 8 , X 9  and X 10  is independently N or CR 4 ; 
 m is 1; 
 q is 0; 
 each R 4  is independently H, hydroxyl, nitro, cyano, halo, C 1 -C 8  perhaloalkyl, carboxy, 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;
 wherein acyl is selected from the group consisting of H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—; 
 wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic, where R is H or alkyl, or —SO 2 NR 2 , wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring; 
 wherein sulfonyl is selected from the group consisting of —SO 2 -alkyl, —SO 2 — substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic; 
 
 each R 8c  and R 8d  is independently H, hydroxyl, C 1 -C 8  alkyl, C 1 -C 8  perhaloalkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R 8  to form a cycloalkyl moiety or a carbonyl moiety; 
 R 8e  and R 8f  are taken together with the carbon to which they are attached to form a carbonyl moiety; 
 each R 10a  and R 10b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 10a  and R 10b  are taken together to form a carbonyl moiety or R 10a  and R 10b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety; and 
 Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl; 
 provided that at least one of (i) and (ii) applies: (i) R 1  is other than isopropyl and (ii) Q is other than a substituted piperazinyl, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         14 . The method of  claim 13  wherein the compound is selected from the group consisting of compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 13 , wherein at least one of (i)-(ii) applies:
 (i) each X 7 -X 10  is CH and R 1  is H or CH 3 ; and   (ii) each X 7 -X 10  is CH and Q is a substituted or unsubstituted heteroaryl or an unsubstituted heterocyclyl,   or a pharmaceutically acceptable salt thereof.   
     
     
         16 - 18 . (canceled) 
     
     
         19 . The method of  claim 13 , wherein Q is selected from the group consisting of substituted thiazolyl, triazolyl, and oxadiazolyl. 
     
     
         20 - 22 . (canceled) 
     
     
         23 . 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 a compound of the formula (B-1): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 4  is halo or CH 3 ; 
 each X 7 , X 8  and X 10  is independently CR 4A ; 
 each R 4A  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  alkenyl, 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;
 wherein acyl is selected from the group consisting of H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—; 
 wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 , —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic, where R is H or alkyl, or —SO 2 NR 2 , wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring; 
 wherein sulfonyl is selected from the group consisting of —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic; 
 
 each R 8c and R 8d  is independently H, hydroxyl, C 1 -C 8  alkyl, C 1 -C 8  perhaloalkyl, carboxy, carbonylalkoxy, or 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 heteroaryl or a substituted or unsubstituted heterocyclyl; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         24 . The method of  claim 23 , wherein Q is an unsubstituted or substituted piperidinyl. 
     
     
         25 . The method of  claim 13 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method of  claim 13 , wherein the compound modulates at least one of the following receptors: adrenergic receptor, serotonin receptor, dopamine receptor and histamine receptor. 
     
     
         27 . The method of  claim 13 , wherein Q is a substituted or unsubstituted heteroaryl or an unsubstituted heterocyclyl. 
     
     
         28 . The method of  claim 13 , wherein R 1  is CH 3  or H. 
     
     
         29 . The method of  claim 28 , wherein each X 7 , X 8  and X 10  is CH and X 9  is CR 4  where R 4  is halo or substituted or unsubstituted C 1 -C 8  alkyl. 
     
     
         30 . The method of  claim 13 , wherein X 9  is CR 4  where R 4  is halo or CH 3 , provided that when X 9  is CR 4  where R 4  is CH 3 , R 1  is H or CH 3 . 
     
     
         31 . The method of  claim 13 , wherein Q is (a) a substituted or unsubstituted piperidinyl or (b) an unsubstituted piperizinyl or a piperizinyl substituted with a branched alkyl group. 
     
     
         32 . The method of  claim 13 , wherein R 4  is halo. 
     
     
         33 . 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 a compound of the Formula (E): 
       
         
           
           
               
               
           
         
       
       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;
 wherein acyl is selected from the group consisting of H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—; 
 wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 , —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic, where R is H or alkyl, or —SO 2 NR 2 , wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring; 
 wherein sulfonyl is selected from the group consisting of —SO 2 -alkyl, —SO 2 — substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic; 
 
 each R 2a  and R 2b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 2a  and R 2b  are taken together to form a carbonyl moiety or R 2a  and R 2b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety; 
 each R 3a  and R 3b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 3a  and R 3b  are taken together to form a carbonyl moiety or R 3a  and R 3b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety; 
 each X 7 , X 8 , X 9  and X 10  is independently CR 4 ; 
 m and q are independently 0 or 1; 
 each R 4  is independently H, hydroxyl, nitro, cyano, halo, C 1 -C 8  perhaloalkyl, carboxy, 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;
 wherein acyl is selected from the group consisting of H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—; 
 wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 , —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic, where R is H or alkyl, or —SO 2 NR 2 , wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring; 
 wherein sulfonyl is selected from the group consisting of —SO 2 -alkyl, —SO 2 — substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic; 
 
 each R 8a , R 8b , R 8c , and R 8d  is independently H, hydroxyl, C 1 -C 8  alkyl, C 1 -C 8  perhaloalkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R 8  to form a cycloalkyl moiety or a carbonyl moiety; 
 R 8e  and R 8f  are taken together with the carbon to which they are attached to form a carbonyl moiety; 
 each R 10a  and R 10b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 10a  and R 10b  are taken together to form a carbonyl moiety or R 10a  and R 10b  are taken together with the carbon to which they are attached to form a cycloalkyl moiety; and 
 Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or a unsubstituted heterocyclyl; 
 provided that at least one of (i)-(iii) applies: (i) Q is a substituted or unsubstituted piperidinyl, (ii) Q is an unsubstituted piperazinyl or a piperazinyl substituted with a branched alkyl group, and (iii) X 9  is CR 4  where R 4  is halo, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         34 . The method of  claim 33 , wherein the compound is selected from the group consisting of compounds: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.