Tetracyclic compounds
View Patent ↗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. 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;
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 with the carbon to which they are attached 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 with the carbon to which they are attached 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, provided that at least one of m and q is 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 , R 8d , R 8e and R 8f is independently H, C 1 -C 8 alkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety, provided that at least one of R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is other than H;
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 with the carbon to which they are attached 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.
2. The compound of claim 1 , or a salt thereof, wherein at least one of R 8c , R 8d , R 8e , and R 8f is other than H.
3. The compound of claim 1 , or a salt thereof, wherein at least one of R 8e and R 8f is other than H.
4. The compound of claim 3 , or a salt thereof, wherein X 7 , X 8 and X 10 are each CR 4 where R 4 is H, and X 9 is CR 4 where R 4 is substituted or unsubstituted C 1 -C 8 alkyl, perhaloalkyl, or halo.
5. The compound of claim 4 , or a salt thereof, wherein X 9 is CR 4 where R 4 is methyl, CHF 2 , CH 2 F, CF 3 , chloro or fluoro.
6. The compound of claim 1 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is C 1 -C 8 alkyl.
7. The compound of claim 6 , or a salt thereof, wherein the compound has one or more of the following structural features:
R 1 is methyl;
Q is a substituted or unsubstituted pyridyl; and
X 9 is CR 4 where R 4 is halo, a substituted or unsubstituted C 1 -C 8 alkyl, or perhaloalkyl.
8. The compound of claim 1 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is methyl.
9. The compound of claim 1 , or a salt thereof, wherein —R 8c R 8d —R 8e R 8f — and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —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 )—.
10. The compound of claim 1 , or a salt thereof, wherein q is 0, and m is 1.
11. The compound of claim 1 , or a salt thereof, wherein each R 4 is independently H, hydroxyl, 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, thioalkyl, alkylsulfonylamino or acyl.
12. The compound of claim 1 , or a salt thereof, wherein each R 4 is independently nitro, cyano, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, or carbonylalkylenealkoxy.
13. The compound of claim 1 , or a salt thereof, wherein X 7 , X 8 and X 10 are each CR 4 where R 4 is H, and X 9 is CR 4 where R 4 is substituted or unsubstituted C 1 -C 8 alkyl, perhaloalkyl or halo.
14. The compound of claim 13 , or a salt thereof, wherein X 9 is CR 4 where R 4 is methyl, CF 3 , CH 2 F, CHF 2 , chloro or fluoro.
15. The compound of claim 1 , or a salt thereof, wherein each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, or halo.
16. The compound of claim 15 , or a salt thereof, wherein each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is H.
17. The compound of claim 1 , or a salt thereof, wherein Q is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
18. The compound of claim 17 , or a salt thereof, wherein Q is selected from the group consisting of:
wherein each R 9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino.
19. The compound of claim 1 , or a salt thereof, wherein Q is substituted or unsubstituted pyridyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyrazinyl.
20. The compound of claim 1 , or a salt thereof, wherein Q is unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl.
21. The compound of claim 20 , or a salt thereof, wherein Q is selected from the group consisting of:
wherein each R 9 is independently a halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino.
22. The compound of claim 1 , or a salt thereof, wherein:
at least one of R 8c , R 8d , R 8e and R 8f is C 1 -C 8 alkyl;
X 7 , X 8 and X 10 are each CR 4 where R 4 is H;
X 9 is CR 4 where R 4 is substituted or unsubstituted C 1 -C 8 alkyl, perhaloalkyl, or halo; and
R 1 is substituted or unsubstituted C 1 -C 8 alkyl.
23. The compound of claim 1 , or a salt thereof, wherein:
at least one of R 8c , R 8d , R 8e and R 8f is methyl, ethyl or cyclopropyl;
X 7 , X 8 and X 10 are each CR 4 where R 4 is H;
X 9 is CR 4 where R 4 is methyl, CHF 2 , CH 2 F, CF 3 , chloro or fluoro; and
R 1 is methyl or cyclopropyl.
24. The compound of claim 1 , or a salt thereof, wherein the compound has one or more of the following structural features:
R 1 is methyl;
Q is a substituted or unsubstituted pyridyl; and
X 9 is CR 4 where R 4 is halo, a substituted or unsubstituted C 1 -C 8 alkyl, or perhaloalkyl.
25. The compound of claim 1 , or a salt thereof, wherein the compound has one or more of the following structural features:
R 1 is methyl;
Q is a substituted or unsubstituted phenyl; and
X 9 is CR 4 where R 4 is halo, a substituted or unsubstituted C 1 -C 8 alkyl, or perhaloalkyl.
26. The compound of claim 1 , or a salt thereof, wherein:
R 1 is methyl or ethyl;
each R 8c , R 8d , R 8e and R 8f is independently H or C 1 -C 8 alkyl;
X 7 is CR 4 where R 4 is H;
X 8 and X 10 are independently CR 4 where R 4 is H or halo;
X 9 is CR 4 where R 4 is halo, methyl, trifluoromethyl or ethyl; and
Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl, provided that when X 9 is CR 4 where R 4 is halo, then only one of X 8 and X 10 is CR 4 where R 4 is halo.
27. The compound of claim 1 , or a salt thereof, wherein:
R 1 is unsubstituted C 1 -C 8 alkyl;
each of R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is H; and
each R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is independently H, C 1 -C 8 alkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R 8(a-f) to form a cycloalkyl moiety.
28. The compound of claim 27 , or a salt thereof, wherein —R 8c R 8d —R 8e R 8f — and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —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 )—.
29. The compound of claim 27 , or a salt thereof, wherein Q is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
30. The compound of claim 1 , or a salt thereof, wherein the compound is selected from the group consisting of:
No.
Structure
113
114
115
116
117
118
122
123
124
125
126
127
131
132
133
134
135
136
381
382
383
384
450
451
455
456
477
478
479
480
521
522
524
525
527
528
31. A compound of the formula (B):
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;
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 with the carbon to which they are attached to form a carbonyl moiety;
each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano or nitro or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety;
each X 7 , X 8 , X 9 and X 10 is 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, 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 , R 8d , R 8e and R 8f is independently H, 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, provided that at least one of R 8c , R 8d , R 8e and R 8f is other than H;
each R 10a and R 10b is independently H, halo, a substituted or unsubstituted C 1 -C 8 alkyl, hydroxyl, alkoxyl or R 10a and R 10b are taken together with the carbon to which they are attached to form a carbonyl; and
Q is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.
32. The compound of claim 31 , or a salt thereof, wherein at least one of R 8e and R 8f is other than H.
33. The compound of claim 31 , or a salt thereof, wherein at least one of R 8c , R 8d , R 8e and R 8f is C 1 -C 8 alkyl.
34. The compound of claim 31 , or a salt thereof, wherein —R 8c R 8d —R 8e R 8f — and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —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 )—.
35. The compound of claim 31 , or a salt thereof, wherein:
R 1 is substituted or unsubstituted C 1 -C 8 alkyl;
X 7 is CR 4 where R 4 is H;
X 8 and X 10 are independently CR 4 where R 4 is H or halo;
X 9 is CR 4 where R 4 is halo, methyl, CHF 2 , CH 2 F, CF 3 , or ethyl; and
Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl, provided that when X 9 is CR 4 where R 4 is halo, then only one of X 8 and X 10 is CR 4 where R 4 is halo.
36. The compound of claim 31 , or a salt thereof, wherein:
R 1 is unsubstituted C 1 -C 8 alkyl;
each of R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is H; H and
each R 8c , R 8d , R 8e and R 8f is independently H, C 1 -C 8 alkyl, or is taken together with the carbon to which it is attached and a geminal R 8(c-f) to form a cycloalkyl moiety.
37. The compound of claim 31 , or a salt thereof, wherein:
Q is 3-pyridyl, 4-pyridyl or 6-methyl-3-pyridyl; and
X 9 is CR 4 where R 4 is chloro, methyl, CHF 2 , CH 2 F, or CF 3 .
38. The compound of claim 31 , or a salt thereof, wherein
Q is an unsubstituted 3-pyridyl;
X 9 is CR 4 where R 4 is methyl, CHF 2 , CH 2 F or CF 3 ; and
R 1 is methyl.
39. A pharmaceutical composition comprising a compound according to claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier.
40. A kit comprising a compound according to claim 1 , or a salt thereof, and instructions.
41. A pharmaceutical composition comprising a compound according to claim 31 , or a salt thereof, and a pharmaceutically acceptable carrier.
42. A kit comprising a compound according to claim 31 , or a salt thereof, and instructions.