Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof

Patent metadata

Field	Value
Publication number	US-11548871-B2
Application number	US-202017096150-A
Country	US
Kind code	B2
Filing date	Nov 12, 2020
Priority date	Nov 15, 2019
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

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).

First claim

The invention claimed is:

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:

Assignees

• Gilead Sciences Inc

Inventors

• Bestvater Brian P
• Du Zhimin
• Farand Julie
• Notte Gregory
• Phillips Barton W
• Tang Doris T
• Venkataramani Chandrasekar
• Wang Peiyuan
• Yang Kin S
• Zagorska Anna

Classifications

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• A61P17/02

  for treating wounds, ulcers, burns, scars, keloids, or the like · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title