Heteroaryl amides as inhibitors of protein aggregation
The present invention relates to certain heteroaryl amide compounds, 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 and melanoma.
1. A compound of Formula (I):
wherein
R 1 is H, halo, C 1-4 alkyl, or —CF 3 ;
R 2 is —CF 3 or C 1-4 alkyl unsubstituted or substituted with halo or —CF 3 ;
A is a 5-membered heteroaryl ring with two or three heteroatom ring atoms selected from the group consisting of N, O, and S, and wherein the 5-membered heteroaryl ring is attached to
and Y via two non-adjacent carbon ring atoms;
Y is absent or is C 1-4 alkylene;
where when Y is absent, R 3 and R 4 taken together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl ring, unsubstituted or substituted with C 1-4 alkyl; and
when Y is C 1-4 alkylene, R 3 and R 4 taken together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl ring, unsubstituted or substituted with C 1-4 alkyl; or R 3 and Y taken together with the nitrogen to which R 3 is attached form a monocyclic heterocycloalkyl ring, and R 4 is H or C 1-4 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H or fluoro.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CF 3 , or is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, each unsubstituted or substituted with fluoro, chloro, bromo, or —CF 3 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CF 3 or is C 1-4 alkyl optionally substituted with halo or —CF 3 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3-4 alkyl, unsubstituted or substituted with fluoro or —CF 3 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is butyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is propyl substituted with —CF 3 .
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is in an “R” stereochemical configuration.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is in an “S” stereochemical configuration.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl ring with two heteroatom ring atoms.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl ring with two non-adjacent heteroatom ring atoms.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is thiazole, thiadiazole, oxazole, imidazole, or triazole.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is thiadiazole.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is thiazole.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is absent.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, —(CH 2 ) 3 —, —C(CH 3 ) 2 —, —(CH 2 ) 4 —, —CH((CH 2 ) 2 CH 3 )—, —CH(CH(CH 3 ) 2 ), —CH(CH 2 CH 3 )CH 2 —, —CH(CH 3 )CH(CH 3 )—, —CH(CH 3 )(CH 2 ) 2 —, or —CH 2 CH(CH 3 )CH 2 —.
18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein Y is —CH 2 —, —CH 2 CH 2 —, or —CH(CH 3 )—.
19. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein Y is —CH 2 CH 2 —.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are taken together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl ring, unsubstituted or substituted with C 1-4 alkyl.
21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 taken together with the nitrogen to which they are attached form azetidine, pyrrolidine, piperidine, azepine, piperazine, morpholine, thiomorpholine, or 1,1-dioxo-thiomorpholine, each unsubstituted or substituted with C 1-4 alkyl.
22. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 taken together with the nitrogen to which they are attached form pyrrolidine, unsubstituted or substituted with C 1-4 alkyl.
23. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 taken together with the nitrogen to which they are attached form morpholine, unsubstituted or substituted with C 1-4 alkyl.
24. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 taken together with the nitrogen to which they are attached form piperazine, unsubstituted or substituted with C 1-4 alkyl.
25. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 taken together with the nitrogen to which they are attached form piperazine or 4-methyl-piperazine.
26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is C 1-4 alkylene, and R 3 and Y taken together with the nitrogen to which R 3 is attached form a monocyclic heterocycloalkyl ring, and R 4 is H or C 1-4 alkyl.
27. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein Y and R 3 taken together with the nitrogen to which R 3 is attached form pyrrolidine or piperidine.
28. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H or methyl.
29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H, R 2 is C 1-4 alkyl, A is thiazole, Y is absent or is ethylene, and R 3 and R 4 taken together with the nitrogen to which they are attached form N-methylpiperazine.
30. A compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
31. A compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
32. A pharmaceutical composition comprising (a) at least one compound or pharmaceutically acceptable salt thereof according to claim 1 , and (b) a pharmaceutically acceptable excipient.
33. The pharmaceutical composition of claim 32 , wherein R 2 is substantially in an “R” stereochemical configuration.
34. The pharmaceutical composition of claim 32 , wherein R 2 is substantially in an “S” stereochemical configuration.
35. A method of treating a disease or medical condition associated with protein aggregation, comprising administering to a subject in need of such treatment an effective amount of at least one compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the disease or medical condition associated with protein aggregation is Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, or melanoma.
36. A method of interfering with the accumulation of protein or peptide aggregates in a cell, or preventing, slowing, reversing, or inhibiting protein or peptide aggregation in a cell, comprising contacting the cell with an effective amount of at least one compound or pharmaceutically acceptable salt according to claim 1 , wherein the contacting is in vitro ex vivo or in vivo.
37. A method of interfering with the accumulation of protein or peptide aggregates in a cell, or preventing, slowing, reversing, or inhibiting protein or peptide aggregation in a cell, comprising contacting the cell with an effective amount of a pharmaceutical composition according to claim 32 , wherein the contacting is in vitro, ex vivo, or in vivo.