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 method of treating schizophrenia in an individual in need thereof, comprising administering to the individual an effective amount of a compound of the Formula (E):
or a pharmaceutically acceptable 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 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; and wherein R is H or alkyl; or wherein sulfonylamino is —SO 2 NR 2 , and 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;
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)—;
each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, hydroxyl, alkoxy, cyano, or 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, or 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 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 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; and wherein R is H or alkyl; or wherein sulfonylamino is —SO 2 NR 2 , and 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;
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)—;
each R 8C , R 8d , R 8e and R 8f 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;
each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, hydroxyl, alkoxy, cyano, or 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 unsubstituted heterocyclyl;
provided that when each of X 7 , X 8 , X 9 and X 10 is CR 4 , then one of R 8e and R 8f is hydroxyl.
2. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, modulates at least one of the following receptors: adrenergic receptor, serotonin receptor, dopamine receptor and histamine receptor.
5. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has 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 or halo.
6. The method of claim 5 , wherein the compound, or a pharmaceutically acceptable salt thereof, has X 9 is CR 4 where R 4 is methyl, chloro or fluoro.
7. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has at least one of X 7 , X 8 , X 9 and X 10 is N.
8. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has one of R 8c -R 8f is hydroxyl and its geminal R 8c -R 8f is C 1 -C 8 alkyl or C 1 -C 8 perhaloalkyl.
9. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has one of R 8e and R 8f is hydroxyl and its geminal R 8e and R 8f is C 1 -C 8 alkyl or C 1 -C 8 perhaloalkyl; 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 or halo and R 1 is substituted or unsubstituted C 1 -C 8 alkyl.
10. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has one of R 8e and R 8f is hydroxyl and its geminal R 8e and R 8f is methyl, ethyl, cyclopropyl or trifluoroalkyl; 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, chloro or fluoro and R 1 is methyl or cyclopropyl.
11. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has R 8e is hydroxyl and R 8f is methyl.
12. The method of claim 11 , wherein the compound, or a pharmaceutically acceptable salt thereof, 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 or a substituted or unsubstituted C 1 -C 8 alkyl.
13. The method of claim 12 , wherein the compound, or a pharmaceutically acceptable salt thereof, has:
Q is 3-pyridyl, 4-pyridyl or 6-methyl-3-pyridyl; and
X 9 is CR 4 where R 4 is chloro or methyl.
14. The method of claim 11 , wherein the compound, or a pharmaceutically acceptable salt thereof, has two 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 or a substituted or unsubstituted C 1 -C 8 alkyl.
15. The method of claim 11 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the compound has all three 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 or a substituted or unsubstituted C 1 -C 8 alkyl.
16. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has:
at least one of R 8e , R 8d , R 8e and R 8f is other than H;
Q is an unsubstituted 3-pyridyl;
X 9 is CR 4 where R 4 is methyl; and
R 1 is methyl.
17. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has:
R 1 is methyl or ethyl;
R 8c and R 8d are both H;
R 8e and R 8f are independently H, hydroxyl or methyl;
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.
18. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has —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)(OH)—, and —CH 2 —C(OH)(CH 3 )—.
19. A method of treating schizophrenia in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (Vf),
or a pharmaceutically acceptable salt thereof, wherein:
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;
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; and wherein R is H or alkyl; or wherein sulfonylamino is —SO 2 NR 2 , and 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;
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)—;
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 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; and wherein R is H or alkyl; or wherein sulfonylamino is —SO 2 NR 2 , and 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;
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)—;
m is 1;
q is 0;
—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)(OH)—, and —CH 2 —C(OH)(CH 3 )—; 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.
20. The method of claim 19 , wherein the compound, or a pharmaceutically acceptable salt thereof, has R 4 is H, halo, substituted or unsubstituted C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, substituted or unsubstituted heterocyclyl or a substituted or unsubstituted aryl.
21. The method of claim 20 , wherein the compound, or a pharmaceutically acceptable salt thereof, has R 4 is H, halo, methyl, perfluoromethyl or cyclopropyl.
22. The method of claim 21 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl.
23. The method of claim 20 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl.
24. The method of claim 19 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl.
25. The method of claim 24 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is an unsubstituted phenyl or an unsubstituted pyridyl.
26. The method of claim 19 , wherein the compound, or a pharmaceutically acceptable salt thereof, has R 1 is methyl or ethyl.
27. A method of treating schizophrenia in an individual in need thereof, comprising administering to the individual an effective amount of a compound of formula (B):
or a pharmaceutically acceptable 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 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; and wherein R is H or alkyl; or wherein sulfonylamino is —SO 2 NR 2 , and 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;
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)—;
each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, hydroxyl, alkoxy, cyano, or 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 independently N or CR 4 provided that at least one of X 7 , X 8 , X 9 and X 10 is other than CR 4 where R 4 is H;
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 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; and wherein R is H or alkyl; or wherein sulfonylamino is —SO 2 NR 2 , and 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;
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)—;
each R 8C , R 8d , R 8e and R 8f is independently H, hydroxyl, C 1 -C 8 alkyl or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety;
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;
wherein at least one of (i) and (ii) applies: (i) at least one of X 7 , X 8 , X 9 and X 10 is N; and (ii) at least one of R 8c , R 8d , R 8e and R 8f is other than H; and
provided that when each of X 7 , X 8 , X 9 and X 10 is CR 4 , then one of R 8e and R 8f is hydroxyl.
28. The method of claim 27 , wherein the compound, or a pharmaceutically acceptable salt thereof, has at least one of X 7 , X 8 , X 9 and X 10 is N.
29. The method of claim 27 , wherein the compound, or a pharmaceutically acceptable salt thereof, has each of X 7 , X 8 , X 9 and X 10 is CR 4 .
30. The method of claim 27 , wherein the compound, or a pharmaceutically acceptable salt thereof, has —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)(OH)—, and —CH 2 —C(OH)(CH 3 )—.
31. The method of claim 27 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
32. The method of claim 27 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is a substituted or unsubstituted heteroaryl.
33. The method of claim 32 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which may be substituted with one, two or three moieties independently selected from the group consisting of C 1 -C 4 alkyl, halo, perhaloalkyl, and perhaloalkoxy.
34. The method claim 27 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is a substituted or unsubstituted aryl.
35. The method of claim 34 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is phenyl which may be substituted with one, two or three moieties independently selected from the group consisting of halo, C 1 -C 4 alkyl, —O—C 1 -C 4 alkyl, perhaloalkyl, and perhaloalkoxy.
36. The method of claim 35 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is fluoro-substituted phenyl.
37. The method of claim 36 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is para-fluoro phenyl.
38. The method of claim 27 , wherein the compound, or a pharmaceutically acceptable salt thereof, has R 1 is methyl.
39. The method of claim 27 , wherein the compound, or a pharmaceutically acceptable salt thereof, has:
R 1 is methyl or ethyl;
R 8c and R 8d are both H;
R 8e and R 8f are independently H, OH or CH 3 ;
X 7 is CH; X 8 is CH or C-halo; X 10 is CH or C-halo;
X 9 is CR 4 where R 4 is halo, CH 3 , CF 3 or ethyl; and
Q is a substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl.