Bicyclic bis-heteroaryl derivatives as modulators of protein aggregation
The present invention relates to certain bicyclic bis-heteroaryl compounds of Formula (I), pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia, fronto-temporal dementia, Huntington's Disease, amyotrophic lateral sclerosis, and multiple system atrophy, and cancer including melanoma.
1. A compound of Formula (I):
wherein
B is a 9- or 10-membered heteroaryl, or a 5- or 6-membered heterocycloalkyl, each unsubstituted or substituted with —(R 1 ) m ;
wherein m is 0, 1, or 2; and
each R 1 is independently C 1-4 alkyl (optionally substituted with one or more halogen or —OC 1-4 alkyl groups), halogen, —OH, or —OC 1-4 alkyl;
R 2 is H, C 1-5 alkyl (unsubstituted or substituted with one or more halo substituents), —OC 1-4 alkyl, or —SC 1-4 alkyl, or an aryl, monocyclic cycloalkyl, or C 1-4 alkyl-(monocyclic cycloalkyl) group, wherein each aryl or cycloalkyl is unsubstituted or substituted with halo, C 1-4 alkyl, or halo-C 1-4 alkyl;
R 3 is H or C 1-4 alkyl;
A is a 5-membered heteroaryl ring;
C is a 5 or 6 membered ring, wherein Y is a bond or CH 2 ; and X is C or N; and
D is a 5 or 6 membered ring fused to ring C to form a bicyclic ring system which is optionally substituted with —(R 4 ) n , wherein n is 0, 1, 2, or 3; and each R 4 is independently C 1-4 alkyl, optionally substituted with one or more halogen or —OC 1-4 alkyl groups, halogen, —OH (including its keto form ═O), —CN, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 1-4 branched alkyl or —OC 1-4 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is optionally substituted indole, benzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzisoxazole, imidazopyridine, or pyrrolopyridine.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein B is optionally substituted indole.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is a methyl, ethyl, propyl, tert-butyl, n-butyl, pentyl or hexyl group.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2 is n-butyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, triazole, oxadiazole, thiadiazole, or tetrazole.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein A is a thiazole.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is a substituted or unsubstituted indole.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein C is a pyrrolidine, piperidine, or piperazine, each optionally substituted with one or more halo, —OH, —CN, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 1-4 branched alkyl or —OC 1-4 alkyl groups.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein D is a pyrazole, isoxazole, triazole, imidazole, pyridine, or pyrimidine, each optionally substituted with one or more halo, —OH (including its keto form ═O), —CN, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 1-4 branched alkyl or —OC 1-4 alkyl groups.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the bicyclic moiety CD is a pyrazolopyrrolidine, pyrazolopiperidine, isoxazolopiperidine, triazolopiperazine, pyrazolopiperazine, imidazopiperazine, pyridonopiperazine, or pyrimidonopiperazine, each optionally substituted with one or more halogen, —OC 1-4 alkyl, —OH (including its keto form ═O), —CN, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, or C 1-4 branched alkyl groups.
13. A compound of claim 1 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
15. A method of treating Parkinson's Disease, comprising administering to a subject in need of such treatment an effective amount of at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
16. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein B is an optionally substituted 3-indole.
17. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein B is a substituted or unsubstituted 3-indole.