Substituted thieno[3,2-d]pyrimidinones as MCHR1 antagonists and methods for using them
The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I. Additionally, the present application provides pharmaceutical compositions containing at least one compound according to Formula I and optionally at least one additional therapeutic agent. Finally, the present application provides methods for treating a patient suffering from an MCHR-1 modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety by administration of a therapeutically effective dose of a compound according to Formula I.
1. A compound or a pharmaceutically acceptable salt or a stereoisomer or a prodrug thereof according to formula I:
wherein,
R 1 is independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, aryl, CF 3 , CN, NR 7 R 7 , OR 6 and SR 6 ;
R 2 is selected from the group consisting of hydrogen and lower alkyl;
R 3 is independently selected from the group consisting of hydrogen and lower alkyl;
R 4 is G-D 2 -Z n ;
R 5 is selected from the group consisting of hydrogen, hydroxyl, halogen, lower alkyl, lower cycloalkyl, CF 3 , SR 6 , lower alkoxy, lower cycloalkoxy, CN, CONR 7 R 7 , SOR 6 , SO 2 R 6 , NR 7 COR 7 , NR 7 CO 2 R 7 , CO 2 R 6 , heteroaryl, NR 7 SO 2 R 6 and COR 6 ;
m is an integer from 0 to 1;
n is an integer from 1 to 3;
when G is selected from the group consisting of O and S, D 2 is selected from the group consisting of lower alkyl, lower cycloalkyl and a 4 to 6-membered non-basic heterocycle;
when G is CR 7 R 7 , D 2 is selected from the group consisting of a direct bond, lower alkyl, lower cycloalkyl and a 4 to 6-membered non-basic heterocycle;
Z is selected from the group consisting of hydroxyl, lower cycloalkyl, lower cycloalkoxy, OCOR 6 , CN, OSO 2 R 6 , SR 6 , SOR 6 , SO 2 R 6 , CO 2 R 7 , OPO(OR 6 ) 2 , and COR 6 ;
R 6 is independently selected from the group consisting of lower alkyl, lower cycloalkyl, heterocycle and heteroaryl; and
R 7 is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl and heterocycle, wherein two R 7 and the atom to which they are attached may optionally form a ring of 4 to 7 atoms;
wherein said prodrug is selected from the group consisting of an alanine ester, a valine ester, a lysine ester, an aspartate ester, a glutamate ester, a glycine ester, a phenylalanine ester, a proline ester, a leucine ester, a half oxalate ester acid, a half malonate ester acid, a half succinate ester, a phosphonate or phosphinate, a glucoside and a half glutarate ester.
2. The compound according to claim 1 wherein, R 5 is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy.
3. The compound according to claim 1 wherein, R 1 is selected from the group consisting of halogen and lower alkyl.
4. The compound according to claim 3 wherein, the halogen is chloro.
5. The compound according to claim 4 wherein, R 4 is G-D 2 -Z n ; and n is an integer from 1 to 2.
6. The compound according to claim 5 wherein G is O; and D 2 is selected from the group consisting of lower alkyl and lower cycloalkyl.
7. The compound according to claim 6 wherein R 2 is hydrogen and at least one R 3 is hydrogen.
8. A pharmaceutical composition, comprising:
at least one compound according to claim 1 and
at least one pharmaceutically acceptable diluent or carrier.
9. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or a stereoisomer thereof.
10. A compound according to claim 1 , the compound is of the following formula:
wherein:
R 1 is independently selected from the group consisting of halogen, lower alkyl, lower cycloalkyl, aryl, CF 3 , CN, OR 6 and SR 6 ;
R 2 is hydrogen;
R 4 is G-D 2 -Z n ;
R 5 is selected from the group consisting of hydrogen, hydroxyl, halogen, lower alkyl, CF 3 , SR 6 , lower alkoxy, lower cycloalkoxy, CN, CONR 7 R 7 , SOR 6 , SO 2 R 6 , NR 7 COR 7 , NR 7 CO 2 R 7 , CO 2 R 6 , heteroaryl, NR 7 SO 2 R 6 and COR 6 ;
G is O;
n is an integer from 1 to 3;
D 2 is selected from the group consisting of lower alkyl and lower cycloalkyl;
Z is selected from the group consisting of hydroxyl, lower cycloalkyl, lower cycloalkoxy, OCOR 6 , CN, OSO 2 R 6 , SR 6 , SOR 6 , SO 2 R 6 , CO 2 R 7 , OPO(OR 6 ) 2 , and COR 6 ;
R 6 is independently selected from the group consisting of lower alkyl, lower cycloalkyl, heterocycle and heteroaryl; and
R 7 is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl and heterocycle;
wherein said prodrug is selected from the group consisting of an alanine ester, a valine ester, a lysine ester, an aspartate ester, a glutamate ester, a glycine ester, a phenylalanine ester, a proline ester, a leucine ester, a half oxalate ester acid, a half malonate ester acid, a half succinate ester, a phosphonate or phosphinate, a glucoside and a half glutarate ester.
11. A compound according to claim 10 , wherein:
R 1 is independently selected from the group consisting of halogen, lower alkyl, CF 3 , CN, OR 6 and SR 6 .
12. A compound according to claim 10 , wherein:
R 5 is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy.
13. A compound according to claim 10 , wherein:
n is an integer from 1 to 2.
14. A compound according to claim 10 , wherein:
R 1 is independently selected from the group consisting of halogen, lower alkyl, CF 3 , CN, OR 6 and SR 6 ;
R 5 is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy; and
n is an integer from 1 to 2.