Triazole carbamate pyridyl sulfonamides as LPA receptor antagonists and uses thereof

Patent metadata

Field	Value
Publication number	US-11999717-B2
Application number	US-202218061822-A
Country	US
Kind code	B2
Filing date	Dec 5, 2022
Priority date	Nov 15, 2019
Publication date	Jun 4, 2024
Grant date	Jun 4, 2024

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 C1.6 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 5 to 12 membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkenyl, C 1-3 alkoxy, and C 3-6 cycloalkyl, wherein the C 1-3 alkyl is optionally substituted with 1 to 3 substituents selected from C 1-3 alkoxy and halogen.

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 methyl.

5. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is hydrogen.

6. 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.

7. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 3 is —F, —Cl, —CH 3 , —C 2 H 5 , —CH 2 —OCH 3 , —O—CH 3 , —NH—CH 3 , or

8. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein n is 0 or 1.

9. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein n is 0.

10. 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.

11. 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.

12. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 5 is —CH 3 .

13. 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.

14. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Y is —CH 3 , or —CHF 2 .

15. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is 5 or 6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-3 alkyl.

16. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is thiophenyl, thiazolyl, isothiazolyl, pyrazolyl or oxazolyl, each optionally substituted with 1 or 2 substituents independently selected from —CH 3 , —F and —Cl.

17. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is

18. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is

19. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is pyridyl, pyrimidyl, pyridazinyl, optionally substituted with 1 to 3 substituents independently selected from cyano, halogen, C 1-3 alkyl, C 1-3 alkenyl, or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 alkenyl, or C 1-3 alkoxy is optionally substituted with 1 to 3 halogens.

20. The compound or pharmaceutically acceptable salt thereof of claim 1 ,
wherein Z is

21. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the group consisting of:

22. 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

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title