Triazolopyridinone derivatives for use as stearoyl CoA desaturase inhibitors
The present invention discloses triazolopyridinone derivatives for use as inhibitors of stearoyl-CoA desaturase having the structure of Formula I: The compounds are useful in treating and/or preventing various human diseases, mediated by stearoyl-CoA desaturase (SCD) enzymes, especially diseases related to abnormal lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like.
1. A compound that is an inhibitor of stearoyl-CoA desaturase having the structure of Formula I:
wherein
R 1 is hydrogen, optionally substituted C 1-20 alkyl, optionally substituted C 1-6 lower alkyl, optionally substituted C 3-20 cycloalkyl, optionally substituted C 2-20 alkenyl, optionally substituted C 2-20 alkynyl, optionally substituted C 1-20 alkoxy, optionally substituted monocyclic aryl, or optionally substituted monocyclic heteroaryl;
R 2 is hydrogen, optionally substituted C 1-20 alkyl, optionally substituted C 1-6 lower alkyl, optionally substituted C 3-20 cycloalkyl, optionally substituted C 2-20 alkenyl, optionally substituted C 2-20 alkynyl, optionally substituted C 1-20 alkoxy;
X is a moiety selected from: —O—C(O)—, —NR′—C(O)—, —C(O)—NR′—, or —O—C(O)—NR′—, wherein R′ is hydrogen or C 1-6 lower alkyl;
L 1 is a covalent bond or -Lk-Y—, wherein Lk is optionally substituted linear or branched C 1-4 alkylene and Y is selected from a covalent bond, —O—, —S—, or —NR″—, wherein R″ is hydrogen or C 1-6 lower alkyl; and
L 2 is a covalent bond or -Lk′-Y′—, wherein Lk′ is optionally substituted linear or branched C 1-4 alkylene and Y′ is selected from a covalent bond, —O—, —S—, or —NR″—, wherein R″ is hydrogen or C 1-6 lower alkyl
with the proviso that R 1 is not hydrogen when L 1 is a bond.
2. The compound of claim 1 wherein R 1 is phenyl which may be optionally substituted at the 3, 4, or 5 position with 1 to 3 substituents selected from the group consisting of lower alkyl, halogen, CF 3 , —OCF 3 , and —OCH 3 ; and
L 1 is methylene.
3. The compound of claim 1 wherein X is —NR′—C(O)—.
4. The compound of claim 3 , wherein R 1 is optionally substituted monocyclic aryl.
5. The compound of claim 4 , selected from the group consisting of:
2-(3,4-dichlorobenzyl)-N-hexyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide;
2-(3 ,4-dichlorobenzyl)-N-(2-hydroxyethyl)-3-oxo-2,3-dihydro-[1 ,2,4]triazolo[4,3 -a]pyridine-6-carboxamide; and
2-(4-chloro-3-(trifluoromethyl)benzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.
6. The compound of claim 3 , wherein L 1 is -Lk-Y—, wherein Lk is optionally substituted C 2-3 alkylene and Y is a covalent bond or —O—.
7. The compound of claim 6 , selected from the group consisting of:
2-(3-(2,5-dichlorophenoxy)propyl)-N-(2-hydroxyethyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide; and
(S)-N-butyl-2-(1-(4-fluoro-3-(trifluoromethyl)phenyl)ethyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide.
8. The compound of claim 1 wherein X is —C(O)—NR′—.
9. The compound of claim 8 , wherein R 1 is optionally substituted monocyclic aryl.
10. The compound of claim 9 , selected from the group consisting of:
N-(2-(4-chloro-3-(trifluoromethyl)benzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2-hydroxyacetamide; and
N-(2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,3-dihydroxypropanamide.
11. The compound of claim 8 , wherein L 1 is -Lk-Y—, wherein Lk is optionally substituted C 2-3 alkylene and Y is a covalent bond or —O—.
12. The compound of claim 11 , namely 2-hydroxy-N-(3-oxo-2-(3-(o-tolyloxy)propyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)acetamide.
13. The compound of claim 1 , wherein X is —O—C(O)—.
14. The compound of claim 13 , selected from the group consisting of:
ethyl 2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylate; and
2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo [4,3-a]pyridine-6-carboxylic acid.
15. The compound of claim 1 , wherein X is —O—C(O)—NR′—.
16. The compound of claim 15 , selected from the group consisting of:
tert-butyl 2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-ylcarbamate; and
butyl 2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-ylcarbamate.
17. The compound of claim 1 , wherein R 2 is optionally substituted alkyl.
18. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or ester thereof.