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 method of treating a LRRK2-mediated disease or disorder selected from the group consisting of Parkinson's disease, Lewy body dementia, Alzheimer's disease, L-DOPA induced dyskinesia, kidney cancer, breast cancer, prostate cancer, a blood cancer, papillary renal and thyroid carcinomas, lung cancer, acute myelogenous leukemia, leprosy, Crohn's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, and ankylosing spondylitis, comprising administering a therapeutically effective amount of a compound having the following Structure (I):
or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein:
A is 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 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 H, halo, cyano, unsubstituted C 1 -C 6 alkyl, unsubstituted C 1 -C 6 haloalkyl, unsubstituted C 1 -C 6 alkoxy or unsubstituted C 3 -C 8 cycloalkyl; and
R 2 is 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, to a mammal in need thereof.
2. The method 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 method of claim 1 , wherein A is unsubstituted phenylene.
4. The method of claim 1 , wherein A is a 5 or 6-membered heteroarylene.
5. The method of claim 1 , wherein A is a pyridinylene or pyrazolylene.
6. The method 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 method of claim 1 , wherein B is a C 3 -C 8 monocyclic cycloalkyl.
8. The method of claim 1 , wherein B is 3-8-membered monocyclic heterocyclyl.
9. The method of claim 1 , wherein B is 3-8-membered spirocyclic heterocyclyl.
10. The method of claim 1 , wherein B is a C 3 -C 8 fused-multicyclic cycloalkyl.
11. The method of claim 1 , wherein B is 3-8-membered monocyclic heterocyclyalkyl.
12. The method of claim 1 , wherein B is C 6 -C 10 spirocyclic cycloalkyl.
13. The method 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 method of claim 1 , wherein B is unsubstituted.
15. The method of claim 1 , wherein B has one of the following structures:
16. The method 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 method of claim 1 , wherein R 2 is C 1 -C 6 alkyl.
18. The method of claim 1 , wherein R 2 is C 3 -C 8 cycloalkyl.
19. The method of claim 1 , wherein R 2 is a 3-8-membered heterocyclyl.
20. The method of claim 1 , wherein R 2 is a 6-10-membered spirocyclic heterocyclyl.
21. The method of claim 1 , wherein R 2 is a 6-10-membered fused-multicyclic heterocyclyl.
22. The method of claim 1 , wherein R 2 is a 6-10-membered bridged-multicyclic heterocyclyl.
23. The method 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 method of claim 1 , wherein R 2 is unsubstituted.
25. The method of claim 1 , wherein
has one of the following structures:
26. The method of claim 1 , wherein the compound of Structure (I) has one of the following structures:
or a pharmaceutically acceptable salt, or stereoisomer thereof.