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 (I):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydrogen or C 1-6 alkyl optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from halogen, cyano, C 1-4 alkoxy, and C 3-10 cycloalkyl; or
R 1 is C 3-6 cycloalkyl optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from halogen, cyano, C 1-4 alkoxy, and C 1-6 alkyl;
R 4 is C 1-6 alkyl optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from halogen, cyano, C 1-4 alkoxy, —C(O)N(R 4A1 ), and —N(R 4A1 )(R 4A2 ), wherein each R 4A1 and R 4A2 is independently H, C 1-6 alkyl, or C 3-10 cycloalkyl; or
R 4 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, which can be the same or different, each independently selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy;
n is 2 or 3;
each of X 1 , X 2 , and X 3 is independently selected from CH and N;
each U is independently —CH═, —CH 2 —, —N═, —NH—, or —O—;
each Y 1 and Y 2 is independently hydrogen, deuterium, or C 1-6 alkyl optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from deuterium, halogen, cyano, C 2-3 alkynyl, C 1-4 alkoxy, and —C(O)NH—(C 1-4 H 3-9 ); and
Z is C 1-8 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-12 aryl, 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl are each optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl, wherein the C 1-4 alkyl is optionally substituted with 1 to 3 substituents, which can be the same or different, each selected from C 1-4 alkoxy and halogen; or
Y 1 and Z together with the carbon to which they are attached form C 3-6 cycloalkyl, C 6-12 aryl, 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the cycloalkyl, aryl, heterocyclyl, or heteroaryl are each optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from cyano, C 1-4 alkyl, C 1-4 alkoxy, C 6-10 aryl and halogen, wherein the C 1-4 alkyl is optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from C 1-4 alkoxy and halogen, and wherein the C 6-10 aryl is optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from C 1-4 alkyl, C 1-4 alkoxy, and halogen, and Y 2 is hydrogen or deuterium.
2. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (Ia):
3. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIIb):
4. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (Mc):
5. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIId):
6. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIIe)
7. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIIf):
8. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is of Formula (IIIg):
9. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (IVb):
10. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (IVc):
11. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (IVd):
12. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (IVe):
13. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (IVf):
14. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (IVg):
15. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (IVh):
16. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (IVi):
17. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Formula (IVj):
18. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Y 1 is —CH 3 or —CH 2 F.
19. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is
20. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is
21. A pharmaceutical composition comprising a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 , and a pharmaceutically acceptable excipient.
22. A method of treating, stabilizing, or lessening the severity or progression of an LPAR1 mediated disease or condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
23. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the group consisting of:
24. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is
25. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is
26. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is