Pyrazine modulators of cannabinoid receptors
The present application describes compounds according to Formula I, wherein A, G 1 , G 2 and R 1 are described herein. Additionally, the present application describes pharmaceutical compositions comprising at least one compound according to Formula I and optionally one or more additional therapeutic agents. Finally, the present application describes methods of treatment using the compounds according to Formula I both alone and in combination with one or more additional therapeutic agents
1. A compound according to Formula I
including all pharmaceutically acceptable salts and stereoisomers, wherein:
G 1 and G 2 are independently selected from the group consisting of aryl or heteroaryl wherein heteroaryl is selected from the group consisting of isooxazole,
A is C(O)NR 2 R 3 ;
R 1 is selected from the group consisting of hydrogen, halogen, OH, CN, alkyl, aryl and heteroaryl;
R 3 is hydrogen;
R 2 is selected from the group consisting of substituted alkyl, substituted cycloalkyl, alkoxy, C(O)R 10 , iminoalkyl, S(O)R 8 and S(O) 2 R 8 , wherein
alkyl is substituted with one or more members selected from the group consisting of alkenyl, alkynyl, hydroxyl, alkoxyl, arylalkyloxy, heteroaryloxy, heteroarylalkyloxy, heterocyclyl, alkanoyl, halo, haloalkyl, thio, alkylthio, nitro, cyano, carboxyl, carbalkoyl, carboxamido, alkylamino, dialkylamino, amido, arylamido, heteroarylamido, azido, guanidino, amidino, phosphonic, phosphinic, sulfonic, sulfonamido, CF 3 , OCF 3 , aryloxy, cycloalkylalkoxyalkyl, and cycloheteroalkyl;
wherein cycloalkyl is substituted with one or more members selected from the group consisting of haloalkyl, alkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, fluorenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, nitro, oxo, cyano, carboxamido, amido, azido, guanidino, amidino, phosphonic, phosphinic, sulfonic, sulfonamide, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl;
R 8 is selected from the group consisting of alkyl, cycloalkyl, aminoalkyl, aminocycloalkyl, aminoheterocyclyl, aminoaryl, aminoheteroaryl, heterocyclyl and aryl; and
R 10 is selected from the group consisting of alkyl, aryl, heteroaryl, and alkoxy.
2. A compound according to Formula I
including all pharmaceutically acceptable salts and stereoisomers, wherein:
G 1 and G 2 are independently selected from the group consisting of aryl and heteroaryl;
A is C(O)NR 2 R 3 ;
R 1 is selected from the group consisting of hydrogen, halogen, OH, CN, alkyl, aryl and heteroaryl;
R 2 is alkyl which is substituted by at least one member selected from the group consisting of alkenyl, alkynyl, hydroxyl, alkoxyl, arylalkyloxy, heteroaryloxy, heteroarylalkyloxy, alkanoyl, halo, haloalkyl, thio, alkylthio, nitro, cyano, carboxyl, carbalkoyl, carboxamido, amido, azido, guanidino, amidino, sulfonamido, CF 3 , OCF 3 , aryloxy and a heteroaryl group that is fused to another aryl and heteroaryl group; or
R 2 is cycloalkyl which is substituted by at least one member selected from the group consisting of alkenyl, alkynyl, alkoxyl, arylalkyloxy, heteroaryloxy, heteroarylalkyloxy, alkanoyl, haloalkyl, thio, alkylthio, nitro, cyano, carbalkoyl, carboxamido, aminoaryl, amido, azido, guanidino, amidino, sulfonamido, CF 3 , OCF 3 , aryloxy and a heteroaryl group that is fused to another aryl and heteroaryl;
R 3 is selected from hydrogen, alkyl, heterocyclyl, alkoxy, heteroaryl, C(O)R 10 , aminoalkyl and iminoalkyl; and
R 10 is selected from the group consisting of alkyl, aryl, heteroaryl, and alkoxy.
3. The compound according to either of claim 1 or 2 , wherein G 1 and G 2 are aryl substituted with 1 or more members selected from the group consisting of hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, fluorenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, heteroarylalkyloxy, heteroarylalkyloxyalkyl, hydroxy, nitro, oxo, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylalkylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino and arylsulfonaminocarbonyl.
4. The compound according to claim 3 , wherein G 1 and G 2 are each
wherein Y is selected from the group consisting of methyl and chloro.
5. The compound according to either of claims 1 or 2 , wherein the compound is selected from
6. A pharmaceutical composition comprising at least one compound according to any one of claims 1 , 2 and 3 to 5 and a pharmaceutically acceptable carrier or diluent.
7. A method for the treatment of obesity or bulimia, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in either of claim 1 or claim 2 .