Alpha-keto heterocycles as FAAH inhibitors
The invention provides a series of -αketoheterocyclic compounds, for example, compounds of formula (I). The compounds can inhibit fatty acid amide hydrolase and can be useful for treatment of malconditions modulated by fatty acid amide hydrolase. The invention further provides methods of making compounds of formula (I), useful intermediates for the preparation of compounds of formula (I), and methods of using compounds of formula (I) and compositions thereof.
1. A compound of formula I:
wherein
R 1 is one of the following:
(a) furanyl, thiophenyl, or pyridinyl,
(b) —CO 2 (C 1 -C 8 )alkyl or —CO 2 H, or
(c) furanyl, thiophenyl, or pyridinyl, each of which substituted with one or more substituents selected from the group consisting of alkyl, halo, alkoxycarbonyl, carboxy, and cyano;
Het is thiazole;
linker is a (C 1 -C 20 )alkyl chain;
Ar is phenyl;
n is 1;
R 2 is H,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein R 1 is 2-pyridyl, 2-furyl, or 2-thiophenyl.
3. The compound of claim 1 wherein R 1 is —CO 2 H or —CO 2 Me.
4. The compound of claim 1 wherein the linker is a (C 1 -C 8 )alkyl.
5. A composition comprising a compound of claim 1 and a diluent or carrier.
6. A compound of formula (I) of claim 1 selected from
7-Phenyl-1-(5-(pyridin-2-yl)-thiazol-2-yl)-heptan-1-one;
1-(5-(Furan-2-yl)-thiazol-2-yl)-7-phenylheptan-1-one;
7-Phenyl-1-(5-(thiophen-2-yl)-thiazol-2-yl)-heptan-1-one;
Methyl 6-(2-(7-Phenylheptanoyl)-thiazol-5-yl)-picolinate;
6-(2-(7-Phenylheptanoyl)thiazol-5-yl)-picolinic acid;
7-Phenyl-1-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)-heptan-1-one;
1-(5-(Furan-2-yl)-1,3,4-thiadiazol-2-yl)-7-phenylheptan-1-one;
7-Phenyl-1-(5-(thiophen-2-yl)-1,3,4-thiadiazol-2-yl)-heptan-1-one;
1-(5-(6-Bromopyridin-2-yl)-1,3,4-thiadiazol-2-yl)-7-phenylheptan-1-one;
Methyl 6-(5-(7-Phenylheptanoyl)-1,3,4-thiadiazol-2-yl)-picolinate;
6-(5-(7-Phenylheptanoyl)-1,3,4-thiadiazol-2-yl)-picolinic acid;
Methyl 5-(7-Phenylheptanoyl)-1,3,4-thiadiazole-2-carboxylate;
or a salt thereof.