Substituted 6,11-dihydro-5H-benzo[b]carbazoles as inhibitors of ALK and SRPK
The application relates to a compound of Formula (I): which modulates the activity of ALK or SRPK, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which ALK or SRPK plays a role.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof,
wherein:
each R 1 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, halogen, NO 2 , NH 2 , OH or CN;
R 2 is H or (C 1 -C 3 ) alkyl;
R 3 is H, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) haloalkyl;
R 4 is H, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) haloalkyl;
each R 5 is independently (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, halogen, NO 2 , NH 2 , OH or CN;
R 6 is CN, COOH, N(C 1 -C 6 ) alkyl)-(CH 2 ) 1-4 —N((C 1 -C 6 ) alkyl) 2 , (C 1 -C 6 ) alkyl substituted with at least one OH, (C 2 -C 6 ) alkenyl, (C 6 -C 10 ) aryl, 6-membered heteroaryl comprising 3, 4 or 5 carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S, or 5-membered heterocyclyl comprising 2, 3 or 4 carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S, wherein the (C 2 -C 6 ) alkenyl, (C 6 -C 10 ) aryl, 6-membered heteroaryl and 5-membered heterocyclyl are each optionally substituted with one or more Q-T;
Q is a bond or (C 1 -C 6 ) alkylene;
T is (C 1 -C 6 ) alkyl, NH(C 1 -C 6 ) alkyl, N((C 1 -C 6 ) alkyl) 2 , NH 2 , C(O)NH 2 , C(O)NH(C 1 -C 6 ) alkyl, C(O)N((C 1 -C 6 ) alkyl) 2 , OH, S(O) q F or 5- or 6-membered heterocyclyl comprising 1, 2, 3, 4 or 5 carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S;
m is 0, 1, 2 or 3;
n is 1, 2 or 3; and
q is 1 or 2;
with the proviso that when R 6 is (C 2 -C 6 ) alkenyl, T is not (C 1 -C 6 ) alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein m is 0.
3. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 2 is H.
4. The compound of claim 3 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein:
R 3 is CH 3 ; and
R 4 is CH 3 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein:
R 3 is (C 1 -C 6 ) alkyl; and
R 4 is (C 1 -C 6 ) alkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein n is 1.
7. The compound of claim 6 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 5 is (C 1 -C 6 ) alkyl.
8. The compound of claim 7 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 5 is ethyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 6 is CN, COOH, N(C 1 -C 6 ) alkyl)-(CH 2 ) 1-4 —N((C 1 -C 6 ) alkyl) 2 , (C 1 -C 6 ) alkyl substituted with at least one OH, (C 6 -C 10 ) aryl, 6-membered heteroaryl comprising 3, 4 or 5 carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S, or 5-membered heterocyclyl comprising 2, 3 or 4 carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S, wherein the (C 6 -C 10 ) aryl, 6-membered heteroaryl and 5-membered heterocyclyl are each optionally substituted with one or more Q-T.
10. The compound of claim 9 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 6 is (C 6 -C 10 ) aryl, optionally substituted with one or more Q-T.
11. The compound of claim 9 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 6 is 6-membered heteroaryl comprising 3, 4 or 5 carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S, or 5-membered heterocyclyl comprising 2, 3 or 4 carbon atoms and 1, 2 or 3 heteroatoms selected from N, O and S, wherein the 6-membered heteroaryl and 5-membered heterocyclyl are each optionally substituted with one or more Q-T.
12. The compound of claim 1 , wherein the compound is of Formula (II):
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof,
wherein:
n1 is 0, 1 or 2.
13. The compound of claim 12 , wherein the compound is of Formula (IIa):
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
14. The compound of claim 13 , wherein the compound is of Formula (IIb):
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 , or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
16. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
17. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.