New 2,3,4,5-tetrahydro-1h-pyrido [4,3-b] indole compounds and methods of use thereof

Abstract

This disclosure relates to new tricyclic compounds that may be used to modulate a histamine receptor in an individual. Compounds are described, including new 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole compounds. 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 - 36 . (canceled) 
     
     
         37 . A compound of the 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, 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 hydroxyl, alkoxy, nitro 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; 
 each X 7 , X 8 , X 9  and X 10  is independently N or CR 4 , provided that at least one of X 7 , X 8 , X 9  and X 10  is N; 
 m and q are independently 0 or 1; 
 n is 1; 
 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, 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  is independently H, hydroxyl, substituted or unsubstituted alkyl or is taken together with the carbon to which it is attached and a geminal R 8(a-f)  to form a cycloalkyl moiety; 
 each R 10a  and R 10b  is independently H, substituted or unsubstituted C 1 -C 8  alkyl, halo, hydroxyl, alkoxy 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 acyclic or cyclic acylamino, carbonylalkoxy, acyloxy, aminoacyl, or aminocarbonylalkoxy; 
 provided that the compound is other than a compound selected from the group consisting of compounds: 5H-Pyrrolo[2,3-c:4,5-c′]dipyridine-5-acetamide, 1,2,3,4-tetrahydro-2-(1-methylethyl)-(Compound No. 107x); 5H-Pyrrolo[2,3-c:4,5-c′]dipyridine-5-acetamide, N-cyclohexyl-1,2,3,4-tetrahydro-2-(1-methylethyl)—(Compound No. 108x); 5H-Pyrrolo[3,2-c:4,5-c′]dipyridine-5-acetamide, 1,2,3,4-tetrahydro-2-(1-methylethyl)—(Compound No. 109x); and 5H-Pyrrolo[3,2-c:4,5-c′]dipyridine-5-acetamide, N-cyclohexyl-1,2,3,4-tetrahydro-2-(1-methylethyl)—(Compound No. 110x); and salts thereof. 
 
     
     
         38 . The compound of  claim 37 , or a salt thereof, wherein if each m and q is 0, R 8e  and R 8f  are H, and each R 2a , R 2b , R 3a , R 3b , R 10a  and R 10b  is H, then R 1  is other than isopropyl. 
     
     
         39 . The compound of  claim 37 , or a salt thereof, wherein R 1  is other than isopropyl. 
     
     
         40 . The compound of  claim 37 , or a salt thereof, wherein one of X 7 , X 8 , X 9  and X 10  is N and three of X 7 , X 8 , X 9  and X 10  are CR 4 . 
     
     
         41 . The compound of  claim 37 , or a salt thereof, wherein two of X 7 , X 8 , X 9  and X 10  is N and two of X 7 , X 8 , X 9  and X 10  are CR 4 . 
     
     
         42 . The compound of  claim 37 , or a salt thereof, wherein X 9  is N. 
     
     
         43 . The compound of  claim 42 , or a salt thereof, wherein R 1  is substituted C 1 -C 8  alkyl, or unsubstituted C 1 -C 8  alkyl other than isopropyl. 
     
     
         44 . The compound of  claim 43 , or a salt thereof, wherein R 1  is methyl. 
     
     
         45 . The compound of  claim 42 , or a salt thereof, wherein each X 7 , X 8  and X 10  is CH. 
     
     
         46 . The compound of  claim 42 , or a salt thereof, wherein each R 2a , R 2b , R 3a , R 3b , R 10a  and R 10b  is H. 
     
     
         47 . The compound of  claim 42 , or a salt thereof, wherein q is 0 and m is 1. 
     
     
         48 . The compound of  claim 42 , or a salt thereof, wherein Q is acyclic acylamino, aminoacyl or carbonylalkoxy. 
     
     
         49 . The compound of  claim 37 , or a salt thereof, wherein Q is acyclic acylamino other than —C(O)NMe 2  and —C(O)NH 2 . 
     
     
         50 . The compound of  claim 37 , or a salt thereof, wherein Q is aminoacyl of the formula —NHC(O)R′ where R′ is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, alkoxy or substituted alkoxy. 
     
     
         51 . The compound of  claim 50 , or a salt thereof, wherein R′ is substituted heteroaryl. 
     
     
         52 . The compound of  claim 37 , or a salt thereof, wherein X 7  is N. 
     
     
         53 . The compound of  claim 52 , or a salt thereof, wherein the compound is of the formula (IIIg): 
       
         
           
           
               
               
           
         
       
     
     
         54 . The compound of  claim 53 , 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 or is taken together with the carbon to which it is attached and a geminal R 8(a-f)  to form a cycloalkyl moiety. 
     
     
         55 . The compound of  claim 54 , or a salt thereof, wherein q, m, R 8a , R 8b , R 8c , R 8d , R 8e  and R 8f  are taken together to form a moiety selected from the group consisting of: —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 —C(H)(OH)—, —C(H)(OH)—CH 2 —, —CH 2 —C(OH)(CH 3 )—, —C(OH)(CH 3 )—CH 2 —, —CH 2 —C(H)(CH 3 )—, —C(H)(CH 3 )—CH 2 —, —CH 2 —C(CH 3 )(CH 3 )—, —C(CH 2 CH 2 )—CH 2 — and —CH 2 —C(CH 2 CH 2 )—. 
     
     
         56 . The compound of  claim 53 , or a salt thereof, wherein R 4  is H, halo, unsubstituted C 1 -C 4  alkyl, C 1 -C 4  perhaloalkyl, or substituted or unsubstituted aryl. 
     
     
         57 . The compound of  claim 53 , or a salt thereof, wherein Q is acyclic acylamino, carbonylalkoxy or aminoacyl. 
     
     
         58 . The compound of  claim 53 , or a salt thereof, wherein Q is aminoacyl. 
     
     
         59 . The compound of  claim 58 , 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. 
     
     
         60 . The compound of  claim 59 , or a salt thereof, wherein R a  is H. 
     
     
         61 . The compound of  claim 60 , or a salt thereof, wherein R b  is substituted or unsubstituted heteroaryl. 
     
     
         62 . A pharmaceutical composition comprising a compound according to  claim 37  or a salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         63 . 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 37  or a salt thereof. 
     
     
         64 . A kit comprising a compound according to  claim 37  or a salt thereof, and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.