Alkoxy bis-heteroaryl derivatives as modulators of protein aggregation
The present invention relates to certain bis-heteroaryl 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 including melanoma.
1. A compound of Formula (I):
wherein
B is indole, 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 —O—C 1-4 alkyl groups), halogen, —OH, or —O—C 1-4 alkyl;
R 2 is a C 1-5 alkyl substituted with an C 1-5 alkoxy, said C 1-5 alkoxy being either unsubstituted or substituted with one or more halogen groups, or R 2 is a heterocycloalkyl, the heteroatom(s) in said heterocycloalkyl being one or two oxygen(s);
A is 1,3-thiazole;
when Y is absent or is C 1-4 alkylene, R 3 and R 4 taken together with the nitrogen to which they are attached form a monocyclic or bicyclic heterocycloalkyl, unsubstituted or substituted with one or more R g substituents;
wherein each R g substituent is independently C 1-4 alkyl (unsubstituted or substituted with one or more C 1-4 alkoxy, halo-C 1-4 alkoxy, or halogen groups), C 3-7 cycloalkyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, or halo; or
when Y is C 1-4 alkylene, R 3 and Y taken together with the nitrogen to which R 3 is attached form a monocyclic or bicyclic heterocycloalkyl ring, which ring is unsubstituted or substituted with C 1-4 alkyl or halo; and R 4 is H or C 1-4 alkyl; and
R 5 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 m is 0.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is amethoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxyisobutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxyisobutyl, ethoxypentyl, ethoxyhexyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxyisobutyl, propoxypentyl, propoxyhexyl, tetrahydrofurane, oxane (tetrahydropyrane), dioxane, methylene-tetrahydrofurane, methyleneoxane, methylene-dioxane, ethylene-tetrahydrofurane, ethylene-oxane, or ethylene-dioxane.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, or tetrahydropyrane.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is absent.
6. 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 —.
7. The compound of claim 1 , 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, piperazine, morpholine, thiomorpholine, 1,1-dioxo-thiomorpholine, azepine, or diazepine, each unsubstituted or substituted with one or more C 1-4 alkyl groups.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 taken together with the nitrogen to which they are attached form piperazine, substituted with C 1- alkyl.
9. The compound of claim 1 , which is a compound of Formula (III):
wherein
B′ and B″ together are indole;
Y is absent;
R 3 and R 4 taken together with the nitrogen to which they are attached form piperazine, unsubstituted or substituted with a methyl, ethyl, propyl, or butyl; and
R 1 , R 2 , R 5 , and m are as defined in claim 1 ;
or a pharmaceutically acceptable salt thereof.
10. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
12. A method of treating Alzheimer's disease, Parkinson's disease, idiopathic Parkinson's disease, Parkinson's disease with dementia, fronto-temporal dementia, Lewy body disease, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, melanoma, or Crohn's disease, the method 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.
13. A method of treating Alzheimer's disease, Parkinson's disease, idiopathic Parkinson's disease, Parkinson's disease with dementia, fronto-temporal dementia, Lewy body disease, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, melanoma, or Crohn's disease, the method comprising administering to a subject in need of such treatment an effective amount of a pharmaceutical composition according to claim 11 .