Indole compounds and analogues thereof
Disclosed are compounds of formula I, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of the complement system. Also provided are pharmaceutical compositions comprising a compound of formula I, and methods involving use of the compounds and compositions in the treatment and prevention of diseases and conditions characterized by aberrant complement system activity.
1. A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof:
wherein, independently for each occurrence:
R 1 represents substituted aryl or heteroaryl;
R 2 and R 3 each independently represent H;
R 4 represents H or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aralkyl, heteroaralkyl, hydroxyalkyl, or haloalkyl;
X represents CH 2 ;
Y is absent or represents CH 2 , CR 15 R 16 , or optionally substituted arylene;
R a represents H;
m is 1;
n is 0 or 1;
R 15 and R 16 are each independently selected from the group consisting of H alkyl, or hydroxyalkyl, wherein alkyl is optionally substituted with one or more substituents selected from the group consisting of —OR 17 and —NR 17 R 18 ;
R 17 and R 18 are each independently selected from the group consisting of H and alkyl
represents
Z 1 represents N;
Z 2 represents CH;
Z 3 represents C;
Z 4 represents CR 8 ;
Z 5 represents CR 5 ;
Z 6 represents CR 6 ;
Z 7 represents CR 9 ;
R 5 and R 6 each independently represent H, halogen, —CN, —NO 2 , —OR 13 , —NR 13 R 14 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , NR 13 C(O)R 14 , —NR 13 C(O)OR 14 , —NR 13 C(O)NR 13 R 14 , —NR 13 S(O) p (R 14 ), or optionally substituted alkyl, alkynyl, heteroaryl, aryl, or heterocycloalkyl;
L represents —C(O)R 7 ;
R 7 , independently for each occurrence, represents NH 2 , CH 3 , CF 3 ;
R 8 and R 9 each independently represent H, or —C(O)NR 13 R 14 ;
R 13 and R 14 , independently for each occurrence, represent H or optionally substituted alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl; or, when R 13 and R 14 are attached to the same atom, R 13 and R 14 taken together with the atom may form an optionally substituted heterocyclic ring; and
p is 0, 1, or 2.
2. The compound of claim 1 , wherein n is 1.
3. The compound of claim 1 , wherein R 1 represents aryl or heteroaryl, substituted by one or more substituents independently selected from the group consisting of halogen, —CN, alkoxy, haloalkoxy, haloalkyl, dialkylamino, heterocycloalkyl, aryl, and heteroaryl; or R 1 represents aryl or heteroaryl, substituted by one or more substituents, at least one of which is halogen.
4. The compound of claim 1 , wherein Y is absent, Y is CH 2 , or Y is CR 15 R 16 .
5. The compound of claim 4 , wherein Y is CR 15 R 16 , and R 15 and R 16 are selected from the group consisting of H, alkyl, or hydroxyalkyl;
wherein alkyl is optionally substituted with OR 17 , —NR 17 R 18 ; and
further wherein R 17 and R 18 are each independently selected from the group consisting of H and alkyl.
6. The compound of claim 1 , wherein R 4 represents H or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, aralkyl, hydroxyalkyl, or haloalkyl.
7. The compound of claim 1 , wherein R 4 represents H or optionally substituted alkyl or cycloalkyl.
8. The compound of claim 1 , having the structure of Formula (Ib):
9. The compound of claim 8 , wherein Z 4 and Z 7 each represent CH.
10. The compound of claim 8 , wherein Z 5 represents CR 5 ; and Z 6 represents CR 6 ; and
R 5 and R 6 each independently represent H, halogen, —NR 13 R 14 , —C(O)R 13 , —C(O)OR 13 , —C(O)NHR 14 , —NHC(O)NR 13 R 14 , —NHS(O) 2 (R 14 ), or optionally substituted alkyl, alkynyl, heteroaryl, or aryl.
11. The compound of claim 10 , wherein R 5 and R 6 each independently represent H or alkyl, alkynyl, heteroaryl, or aryl, optionally substituted with one or more substituents selected from the group consisting of aryl, heteroaryl, silyl, alkyl, amino, alkylamino, dialkylamino, —C(O)(alkyl), and halogen.
12. The compound of claim 10 , wherein R 13 and R 14 , independently for each occurrence, represent H or optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, or (cycloalkyl)alkyl.
13. The compound of claim 1 , wherein R 7 represents NH 2 or CH 3 .
14. The compound of claim 1 , wherein R 7 represents CH 3 .
15. A pharmaceutical composition, comprising a compound of claim 1 ; and a pharmaceutically acceptable carrier.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the following table:
17. The compound of claim 1 , wherein R 4 represents optionally substituted alkyl, cycloalkyl, or hydroxyalkyl.
18. The compound of claim 1 , wherein Y is CH 2 .
19. The compound of claim 1 , wherein Y is optionally substituted arylene.