Carbamoyloxymethyl triazole cyclohexyl acids as LPA antagonists
The present invention provides compounds of Formula (I): or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.
1. A compound according to Formula (III):
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein
R 2 is independently selected from CH 3 and CD 3 ;
R 13 is independently selected from H and C 1-4 alkyl;
R 3 is independently selected from H and C 1-4 alkyl;
R 4 is independently selected from C 1-6 alkyl substituted with 1-3 R 9 , —(CR 7 R 7 ) r —C 3-6 cycloalkyl substituted with 1-3 R 8 , and —(CR 7 R 7 ) r -aryl substituted with 1-3 R 8 ;
R 5 is independently selected from H, F, Cl, CN and C 1-4 alkyl; provided one of R 5 is H;
R 6 is
R 7 is independently selected from H, C 1-4 alkyl, and C 3-6 cycloalkyl; or R 7 and R 7 , together with the carbon atom to which they both attach, form a C 3-6 cycloalkyl ring;
R 8 is independently selected from H, C 1-6 alkyl substituted with 1-5 R 9 , C 3-6 cycloalkyl, F, Cl, Br, CN, ═O, and COOH;
R 9 is independently selected from H, F, Cl, NH 2 , OH, OC 1-5 alkyl, C 1-5 alkyl, C 3-6 cycloalkyl, and phenyl, wherein when R 9 is Cl, NH 2 or OH, it is not substituted on C 1 of the alkyl to which it is attached;
R 10 is independently selected from H, D, C 1-4 alkyl, and F;
R 11 is independently selected from CN, C(═O)R 12 , and tetrazolyl;
R 12 is independently selected from OH, OC 1-4 alkyl, NH 2 , and NHSO 2 C 1-4 alkyl; and
r is independently selected from zero, 1, 2, 3, and 4.
2. The compound of claim 1 , having Formula (IV):
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein
R 2 is independently selected from CH 3 and CD 3 ;
R 13 is independently selected from H and C 1-4 alkyl;
R 3 is independently selected from H and C 1-4 alkyl;
R 4 is independently selected from C 1-6 alkyl,
R 5 is independently selected from H, F, Cl, and C 1-4 alkyl; provided one of R 5 is H;
R 7 is independently selected from H, C 1-4 alkyl, and C 3-6 cycloalkyl;
R 8 is independently selected from H, C 1-6 alkyl substituted with 1-5 R 9 , C 3-6 cycloalkyl, F, Cl, Br, CN, ═O, and COOH;
R 9 is independently selected from H, F, Cl, NH 2 , OH, OC 1-5 alkyl, C 1-5 alkyl, C 3-6 cycloalkyl, and phenyl, wherein when R 9 is Cl, NH 2 or OH, it is not substituted on C 1 of the alkyl to which it is attached;
R 10 is independently selected from H, D, C 1-4 alkyl, and F;
R 11 is independently selected from CN, —C(═O)R 12 , and
and
R 12 is independently selected from OH and NHSO 2 C 1-4 alkyl.
3. The compound of claim 2 , or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein
R 4 is independently selected from
and
R 8 is independently selected from H, F, Cl, Br, CN, and C 1-4 alkyl.
4. The compound of claim 3 , having Formula (V):
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein
R 2 is independently selected from CH 3 and CD 3 ;
R 13 is independently selected from H and CH 3 ;
R 3 is independently selected from H and CH 3 ;
R 4 is independently selected from
R 5 is independently selected from H, F, and C 1-4 alkyl;
R 8 is independently selected from H, F, Cl, Br, CN, and C 1-4 alkyl;
R 10 is independently selected from H, D, and F; and
R 11 is independently selected from —C(═O)OH, and —C(═O)NHSO 2 Me.
5. The compound of claim 1 , wherein said compound is selected from the group of:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
6. A compound of the formula:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
7. A compound of the formula:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
8. A compound of the formula:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein the stereoisomer is an enantiomer or a diastereomer.
10. A compound of the formula:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
11. A compound of the formula:
12. A compound of the formula:
13. A compound of the formula:
14. A compound of the formula:
15. The compound of any one of claims 6 , 7 , 8 , and 10 , wherein the stereoisomer is an enantiomer or a diastereomer.
16. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 4 , 5 , 6 , 7 , 8 , and 10 to 14 , or a stereoisomer or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.