Bridgehead amine ring-fused indoles and indolines
View Patent ↗The present application relates to indole and indoline derivatives of formula (I), formula (II), formula (III), or formula (IV) wherein a, R 2 , R 3 , h, k, m, n, L, Q, X, and Z are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods of treating disease conditions using such compounds and compositions.
1. A compound of formula (I-a):
or a pharmaceutically acceptable salt thereof, wherein
a is a single or double bond;
X is O, S, S(O), S(O) 2 , or a bond;
L is —[C(R a )(R b )] p —, —[C(R a )(R b )] q1 —[(CR c )═(CR d )]—[C(R a )(R b )] q2 —,—[C(R a ) (R b )] r1 —[C≡C]—[C(R a )(R b )] r2 —, —[C(R a ) (R b )] s -cyclopropylene-[C(R a )(R b )] t —, or a bond; or
X and L taken together are a bond;
Q is substituted or unsubstituted monocyclic aryl, substituted or unsubstituted bicyclic aryl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted bicyclic heteroaryl;
R 2 is hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl, wherein C 1 -C 4 alkyl, and the saturated carbon atoms of C 2 -C 4 alkenyl and C 2 -C 4 alkynyl, can be unsubstituted or substituted by hydroxyl, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, carboxy, or alkoxycarbonyl;
R 3 is hydrogen, halogen, C 1 -C 5 haloalkyl, C 1 -C 5 alkoxy, C 1 -C 5 haloalkoxy, or cyano;
R a , R b , R c , and R d are, at each occurrence, independently hydrogen, halogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, carboxy, or alkoxycarbonyl;
p is 1, 2, 3, 4, or 5;
q1 and q2 are independently 0, 1, 2, or 3, provided that the sum of q1 and q2 is 0, 1, 2, or 3;
r1 and r2 are independently 0, 1, 2, or 3, provided that the sum of r1 and r2 is 0, 1, 2, or 3;
s is 0, 1 or 2; and
t is 0 or 1;
wherein Q, when substituted, is independently substituted with 1, 2, 3, 4, or 5 substituents, wherein the substituent is halogen, cyano, C 1 -C 5 haloalkyl, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, hydroxy, C 1 -C 5 alkoxy, —O—C 1 -C 5 haloalkyl, —S—C 1 -C 5 alkyl, —S—C 1 -C 5 haloalkyl, —SO 2 —C 1 -C 5 alkyl, —SO 2 —C 1 -C 5 haloalkyl, C 1 -C 5 cyanoalkyl, or —NO 2 .
2. The compound of claim 1 , wherein L is —[C(R a )(R b )] p —.
3. The compound of claim 2 , wherein R 2 is hydrogen.
4. The compound of claim 2 , wherein R 2 is C 1 -C 4 alkyl.
5. The compound of claim 2 , wherein R 2 is C 2 -C 4 alkenyl.
6. The compound of claim 2 , wherein R 2 is C 2 -C 4 alkynyl.
7. The compound of claim 1 , wherein L is —[C(R a )(R b )] q1 —[(CR c )═(CR d )]—[C(R a )(R b )] q2 —.
8. The compound of claim 7 , wherein R 2 is hydrogen.
9. The compound of claim 7 , wherein R 2 is C 1 -C 4 alkyl.
10. The compound of claim 7 , wherein R 2 is C 2 -C 4 alkenyl.
11. The compound of claim 7 , wherein R 2 is C 2 -C 4 alkynyl.
12. The compound of claim 1 , wherein L is —[C(R a )(R 2 )] r1 —[C≡C]—[C(R a )(R b )] r2 —.
13. The compound of claim 12 , wherein R 2 is hydrogen.
14. The compound of claim 12 , wherein R 2 is C 1 -C 4 alkyl.
15. The compound of claim 12 , wherein R 2 is C 2 -C 4 alkenyl.
16. The compound of claim 12 , wherein R 2 is C 2 -C 4 alkynyl.
17. The compound of claim 1 , wherein X and L taken together are a bond.
18. The compound of claim 17 , wherein R 2 is hydrogen.
19. The compound of claim 17 , wherein R 2 is C 1 -C 4 alkyl.
20. The compound of claim 17 , wherein R 2 is C 2 -C 4 alkenyl.
21. The compound of claim 17 , wherein R 2 is C 2 -C 4 alkynyl.
22. The compound of claim 1 , wherein R 3 is hydrogen.
23. The compound of claim 1 , wherein R 3 is halogen.
24. The compound of claim 1 , wherein R 3 is C 1 - 0 5 haloalkyl.
25. The compound of claim 1 , wherein R 3 is C 1 -C 5 alkoxy, C 1 -C 5 haloalkoxy, or cyano.
26. A compound of formula (III-a) or formula (III-c):
or a pharmaceutically acceptable salt thereof, wherein a, R 2 , R 3 , X, L, and Q are as defined in claim 1 .
27. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
7-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(6-methylpyridin-3-yl)ethynyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(E)-2-(4-chlorophenyl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(1E)-5-phenylpent-1-enyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(E)-2-thien-3-ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-(5-phenylpentyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-[2-(6-methylpyridin-3-yl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(E)-2-(4-fluorophenyl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(E)-2-pyridin-4-ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(E)-2-pyridin-2-ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-(pyridin-3-ylethynyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(E)-2-(2,4-difluorophenyl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(E)-2-(3-fluorophenyl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[2-(3-fluorophenyl)ethyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
8-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
10-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(E)-2-phenylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-{[4-(trifluoromethoxy)phenyl]ethynyl}-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-(pyridin-4-ylethynyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
8-[(6-methylpyridin-3-yl)ethynyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
10-[(6-methylpyridin-3-yl)ethynyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-7-[(6-methylpyridin-3-yl)ethynyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
9-fluoro-7-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-(benzyloxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-quinolin-6-yl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(E)-2-pyrimidin-5ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(Z)-2-pyrimidin-5-ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-[(E)-2-pyridin-3-ylvinyl]-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
(cis)-7-[(E)-2-(6-methylpyridin-3-yl)vinyl]-3,4,5,5a,6,10b-hexahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-(6-methylpyridin-3-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-(pyrimidin-5-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-(pyridin-3-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole;
7-(pyridin-4-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole; and
7-(quinolin-3-yl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole.
28. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I-a) according to claim 1 or formula (III-a) or formula (III-c) according to claim 26 .
29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I-a) according to claim 1 or a compound of formula (III-a) or formula (III-c) according to claim 26 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
30. A compound according to claim 26 that is 7-[(E)-2-(6-methylpyridin-3-yl)vinyl]-1,2,3,4,5,6-hexahydro-2,5-ethanoazepino[4,3-b]indole 2-oxide, or a pharmaceutically acceptable salt thereof.