TETRACYCLIC COMPOUNDS
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.