Fused tetracyclic pyrido [4,3-B] indole and pyrido [3,4-B] indole derivatives and methods of use
View Patent ↗This disclosure is directed to fused tetracyclic pyrido[4,3-b]indoles and pyrido[3,4-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. A compound of the formula (VA):
or a salt or solvate thereof; wherein:
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, 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, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;
each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;
each R 4a and R 4b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 4a and R 4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;
each R 5a and R 5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino, or R 5a and R 5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 5a and R 7c are taken together to form a bond;
each X 1 , X 2 and X 3 is independently CH or CR 6 ;
Y 1 is CR 7a R 7b ;
Y 2 is CR 7c R 7d ;
Y 3 is taken together with Y 4 to form a bond (rendering the Y 1 -containing ring a six-membered ring);
each R 6 is independently 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, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted 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;
each R 7a and R 7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino, or R 7a and R 7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7a and R 7c are taken together to form a bond; and
each R 7c and R 7d is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino, or R 7c and R 7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7c and R 7a are taken together to form a bond, or R 7c and are taken together to form a bond;
provided that:
(i) at least one of R 5a , R 5b , R 7a , R 7b , R 7c , and R 7d is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, or a substituted C 1 -C 8 alkyl wherein the substituted C 1 -C 8 alkyl is substituted with at least one substituted or unsubstituted heteroaryl; and
(ii) when each X 1 , X 2 and X 3 is CH,
then at least one of R 5a , R 5b , R 7a , R 7b , R 7c and R 7d is an unsubstituted aryl other than unsubstituted phenyl, substituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, or a substituted C 1 -C 8 alkyl wherein the substituted C 1 -C 8 alkyl is substituted with at least one substituted or unsubstituted heteroaryl.
2. The compound of claim 1 , wherein at least one of R 5a , R 5b , R 7a , R 7b , R 7c , and R 7d is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or a substituted C 1 -C 8 alkyl wherein the substituted C 1 -C 8 alkyl is substituted with at least one substituted or unsubstituted heteroaryl.
3. The compound of claim 1 , wherein at least one of R 5a , R 5b , R 7a , R 7b , R 7c , and R 7d is a substituted or unsubstituted aryl.
4. The compound of claim 1 , wherein at least one of R 5a , R 5b , R 7a , R 7b , R 7c , and R 7d is a substituted or unsubstituted heteroaryl.
5. The compound of claim 1 , wherein at least one of R 5a , R 5b , R 7a , R 7b , R 7c , and R 7d is a substituted or unsubstituted aralkyl.
6. The compound of claim 1 , wherein at least one of R 5a , R 5b , R 7a , R 7b , R 7c , and R 7d is a substituted C 1 -C 8 alkyl wherein the substituted C 1 -C 8 alkyl is substituted with at least one substituted or unsubstituted heteroaryl.
7. The compound of claim 1 , wherein the compound is of the formula (IIA2):
wherein:
R 1 is H or substituted or unsubstituted C 1 -C 8 alkyl;
X 2 is CH or CR 6 ;
each R 5a and R 5b is independently H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aralkyl, or R 5a is taken together with R 7c to form a bond;
Y 1 is CR 7a R 7b ;
Y 2 is CR 7c R 7d ;
R 6 is chloro, or substituted or unsubstituted C 1 -C 8 alkyl; and
each R 7a , R 7b , R 7c , and R 7d is independently H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aralkyl, or R 7c is taken together with R 7a to form a bond, or R 7c is taken together with R 5a to form a bond.
8. The compound of claim 1 , wherein the compound is of the formula (IIA):
or a salt or solvate thereof;
wherein:
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, 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, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;
each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted or unsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;
each R 4a and R 4b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro, substituted or unsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocyclyl, or R 4a and R 4b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;
each R 5a and R 5b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino, or R 5a and R 5b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 5a and R 7c are taken together to form a bond;
each X 1 , X 2 and X 3 is independently CH or CR 6 ;
Y 1 is CR 7a R 7b ;
Y 2 is CR 7c R 7d ;
each R 6 is independently 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, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted 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;
each R 7a and R 7b is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino, or R 7a and R 7b are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7a and R 7c are taken together to form a bond; and
each R 7c and R 7d is independently H, hydroxyl, halo, nitro, cyano, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, C 1 -C 8 perhaloalkyl, C 1 -C 8 perhaloalkoxy, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino, acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino, aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino, or R 7c and R 7d are taken together with the carbon to which they are attached to form a carbonyl moiety, or R 7c and R 7a are taken together to form a bond, or R 7c and R 5a are taken together to form a bond
provided that:
when R 7a , R 7b , R 7c and R 7d are each H, then one or more of provisions (i) - (iii) apply: (i) at least one of R 5a and R 5b is other than H and at least one of X 1 , X 2 and X 3 is CR 6 ; (ii) when each of R 5a and R 5b is H, at least one of X 1 , X 2 and X 3 is CR 6 where R 6 is chloro or substituted or unsubstituted alkyl; and (iii) when each of X 1 , X 2 and X 3 is CH, at least one of R 5a and R 5b is other than H, phenyl and CH 2 CH 2 NMe 2 .
9. The compound of claim 1 , wherein the compound is selected from the group consisting of compounds 1, 3, 7, 16, 21-24, 26-30, 59-76, 85-102, 158, 183, 185-203, 214, 215, 218, 220, and 221:
Compound
No.
Structure
1
3
7
16
21
22
23
24
26
27
28
29
30
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
158
183
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
214
215
218
220
221
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising (a) a compound of claim 1 or a pharmaceutically acceptable salt thereof and (b) and a pharmaceutically acceptable carrier.