Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof
The present disclosure relates generally to compounds that bind to Lysophosphatidic Acid Receptor 1 (LPAR1) and act as antagonists of LPAR1. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of LPAR1, including fibrosis and liver diseases such as non-alcoholic steatohepatitis (NASH).
1. A compound of Formula (II),
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is C 1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, and C 1-3 alkoxy;
R 3 is hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, —O—R 3A , or —N(R 3A ) 2 , wherein the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from C 1-3 alkoxy and halogen, and wherein each R 3A is independently C 1-3 alkyl optionally substituted with 1 to 3 halogens;
each R 4 is independently deuterium, halogen, C 1-6 alkyl, C 3-10 cycloalkyl, or C 1-3 alkoxy, wherein the C 1-6 alkyl or C 3-10 cycloalkyl, is optionally substituted with 1 to 3 halogens:
n is 0, 1 or 2;
R 5 is C 1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, C 1-3 alkoxy, —C(O)N(R 1A ), and —N(R 1A ) 2 wherein each R 1A is independently H, C 1-6 alkyl, or C 3-10 cycloalkyl; or
R 5 is C 3-6 cycloalkyl or 3 to 6 membered heterocyclyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl or heterocyclyl are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, C 1-3 alkyl and C 1-3 alkoxy;
Y is hydrogen or C 1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, C 1-3 alkynyl, C 1-3 alkoxy, and —C(O)NH—R y , wherein R y is C 1-3 alkyl; and
Z is C 6-10 aryl optionally substituted with 1 to 3 substituents independently selected from halogen, C 1-3 alkyl, or C 1-3 alkoxy, wherein the C 1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-3 alkoxy.
2. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIa):
3. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is C 1-3 alkyl optionally substituted with 1 to 3 substituents independently selected from F and cyano.
4. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is C 1-3 alkyl optionally substituted with cyano.
5. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1 is methyl, ethyl, isopropyl, or cyanomethyl.
6. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is hydrogen.
7. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is halogen, C 1-6 alkyl, C 3-6 cycloalkyl, —O—R 3A , or —N(R 3A ) 2 , wherein the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-3 alkoxy, and wherein each R 3A is independently —H or C 1-3 alkyl optionally substituted with 1 to 3 halogens.
8. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is halogen, C 1-6 alkyl, —O—R 3A , or —N(R 3A ) 2 , wherein the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-3 alkoxy, and wherein each R 3A is independently H or C 1-3 alkyl optionally substituted with 1 to 3 halogens.
9. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is halogen, C 1-6 alkyl, C 3-6 cycloalkyl —O—R 3A , —N(R 3A ) 2 , wherein the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-3 alkoxy, wherein each R 3A is C 1-3 alkyl optionally substituted with 1 to 3 halogens.
10. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is halogen, C 1-6 alkyl, or —O—R 3A , wherein the C 1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-3 alkoxy, wherein R 3A is C 1-3 alkyl optionally substituted with 1 to 3 halogens.
11. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is —F, —Cl, —CH 3 , —C 2 H 5 , —CHF 2 , —CH 2 —OCH 3 , —O—CH 3 , —NH—CH 3 , or
12. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is —F, —Cl, —CH 3 , or —O—CH 3 .
13. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein n is 0 or 1.
14. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein n is 0.
15. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 4 is halogen or C 1-3 alkyl optionally substituted with 1 to 3 halogens.
16. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 4 is halogen.
17. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 4 is —F.
18. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 5 is C 1-3 alkyl optionally substituted with 1 to 3 substituents independently selected from cyano and —F.
19. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 5 is methyl, ethyl or propyl, each optionally substituted with cyano.
20. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 5 is —CH 3 .
21. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Y is hydrogen.
22. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Y is C 1-3 alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, and C 1-3 alkoxy.
23. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Y is methyl optionally substituted with 1 to 3 substituents independently selected from —F, —Cl, cyano, and methoxy.
24. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Y is —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CH 2 —O—CH 3 , or —CH 2 —CN.
25. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is phenyl optionally substituted with 1 to 3 substituents independently selected from halogen, C 1-3 alkyl, or C 1-3 alkoxy, wherein the C 1-3 alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-3 alkoxy.
26. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is phenyl optionally substituted with 1 to 3 substituents independently selected from —F, —Cl, —CH 3 , —CF 3 , —CH 2 —O—CH 3 , and —O—CH 3 .
27. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is
28. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the group consisting of:
29. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the group consisting of:
30. A pharmaceutical composition comprising a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 , and a pharmaceutically acceptable excipient.