Inhibitors of LRRK2 kinase
Compounds having activity as inhibitors of LRRK2 kinase are provided. The compounds have Structure (I): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, B, R 1a , R 1b , R 2 , and L are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of LRRK2 kinase are also provided.
1. A compound having the following Structure (I):
or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein:
A is a phenylene or 5 or 6-membered heteroarylene, each of which is optionally substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 alkoxy;
B is a C 3 -C 8 monocyclic cycloalkyl, C 6 -C 10 spirocyclic cycloalkyl, C 6 -C 10 fused-multicyclic cycloalkyl, C 6 -C 10 bridged-multicyclic cycloalkyl, 3-8-membered monocyclic heterocyclyl, 3-8-membered monocyclic heterocyclylalkyl, 6-10-membered spirocyclic heterocyclyl, 6-10-membered fused-multicyclic heterocyclyl or 6-10-membered bridged-multicyclic heterocyclyl, each of which is optionally substituted with one or more substituents selected from amino, halo, hydroxyl, oxo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylaminylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylcarbonyl, C 1 -C 6 haloalkylcarbonyl, C 1 -C 6 alkylaminyl, C 1 -C 6 haloalkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 haloalkylcarbonylaminyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 halocycloalkylaminyl, and C 3 -C 8 cycloalkylcarbonylaminyl;
L is a direct bond, CH 2 , or C═O;
R 1a and R 1b are each independently a H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl; and
R 2 is a C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-8-membered heterocyclyl, 6-10-membered spirocyclic heterocyclyl, 6-10-membered fused-multicyclic heterocyclyl or 6-10-membered bridged-multicyclic heterocyclyl each of which is optionally substituted with one or more substituents selected from halo, cyano, C 1 -C 6 alkyl, hydroxyl, alkoxy, and C 1 -C 6 haloalkyl.
2. The compound of claim 1 , wherein A is phenylene substituted with one or more substituents selected from the group consisting of halo, and C 1 -C 6 alkoxy.
3. The compound of claim 1 , wherein A is unsubstituted phenylene.
4. The compound of claim 1 , wherein A is 5 or 6-membered heteroarylene.
5. The compound of claim 1 , wherein A is a pyridinylene or pyrazolylene.
6. The compound of claim 1 , wherein A is substituted with one or more substituents selected from halo, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 alkoxy.
7. The compound of claim 1 , wherein B is C 3 -C 8 monocyclic cycloalkyl.
8. The compound of claim 1 , wherein B is 3-8-membered monocyclic heterocyclyl.
9. The compound of claim 1 , wherein B is 3-8-membered spirocyclic heterocyclyl.
10. The compound of claim 1 , wherein B is C 3 -C 8 fused-multicyclic cycloalkyl.
11. The compound of claim 1 , wherein B is 3-8-membered monocyclic heterocyclylalkyl.
12. The compound of claim 1 , wherein B is C 6 -C 10 spirocyclic cycloalkyl.
13. The compound of claim 1 , wherein B is substituted with one or more substituents selected from the group consisting of amino, halo, hydroxyl, oxo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylaminylalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylcarbonyl, C 1 -C 6 haloalkylcarbonyl, C 1 -C 6 alkylaminyl, C 1 -C 6 haloalkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 haloalkylcarbonylaminyl, C 3 -C 8 cycloalkylcarbonylaminyl, and C 3 -C 8 halocycloalkylaminyl.
14. The compound of claim 1 , wherein B is unsubstituted.
15. The compound of claim 1 , wherein B has one of the following structures:
16. The compound of claim 1 , wherein R 1a , R 1b , or both are selected from the group consisting of H, methyl, fluoro, chloro, cyano, methoxy, trifluoromethyl, and cyclopropyl.
17. The compound of claim 1 , wherein R 2 is C 1 -C 6 alkyl.
18. The compound of claim 1 , wherein R 2 is C 3 -C 8 cycloalkyl.
19. The compound of claim 1 , wherein R 2 is 3-8-membered heterocyclyl.
20. The compound of claim 1 , wherein R 2 is 6-10-membered spirocyclic heterocyclyl.
21. The compound of claim 1 , wherein R 2 is 6-10-membered fused-multicyclic heterocyclyl.
22. The compound of claim 1 , wherein R 2 is 6-10-membered bridged-multicyclic heterocyclyl.
23. The compound of claim 1 , wherein R 2 is substituted with one or more substituents selected from the group consisting of methyl, ethyl, iso-propyl, fluoro, trifluoromethyl, and cyano.
24. The compound of claim 1 , wherein R 2 is unsubstituted.
25. The compound of claim 1 , wherein
has one of the following structures:
26. The compound of claim 1 , having one of the following structures:
or a pharmaceutically acceptable salt, or stereoisomer thereof.
27. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier, diluent, or excipient.