LPA receptor antagonists and uses thereof

Patent metadata

Field	Value
Publication number	US-11980609-B2
Application number	US-202217741222-A
Country	US
Kind code	B2
Filing date	May 10, 2022
Priority date	May 11, 2021
Publication date	May 14, 2024
Grant date	May 14, 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), interstitial lung disease (TLD), or chronic kidney disease (CKD).

First claim

The invention claimed is:

1. A compound of Formula (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (IIj), (IIk), or (IIl):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1A1 is C 1-6 alkyl optionally substituted with 1 to 4 R 1B , which can be the same or different, wherein each R 1B is independently selected from halogen, cyano, hydroxy, C 1-4 alkoxy, and C 3-6 cycloalkyl; or
R 1A1 is —O—R 1F1 , wherein R 1F1 is C 1-6 alkyl optionally substituted with 1 to 3 halogens; or
R 1A1 is cyclopropyl or cyclobutyl, each optionally substituted with 1 to 4 R 1B , which can be the same or different, each independently selected from —F, —CN, —CHF 2 , —CF 3 , —OCH 3 , and pyridyl; or
R 1A1 is bicyclopentanyl optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from —F, —CN, —CHF 2 , and oxetanyl; or
R 1A1 is pyridinyl or pyrimidinyl, each optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from —Cl, —CHF 2 , and —CF 3 ;
R 2 is halogen or C 1-6 alkyl optionally substituted with 1 to 3 substituents, which can be the same or different, independently selected from halogen, cyano, C 1-4 alkoxy, and C 3-10 cycloalkyl;
Y 1 is hydrogen, or methyl optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from —F, —Cl, —CN, and —O—CH 3 ; and
Z is C 6-12 aryl, 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 independently selected from C 1-4 alkoxy and halogen; or
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, which can be the same or different, each independently selected from halogen and C 1-4 alkyl.

2. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1A1 is —CH 3 ,

3. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1A1 is

4. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1A1 is

5. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1A1 is

6. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein R 1A1 is

7. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein each R 2 is independently selected from —F and —CH 3 .

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

9. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is phenyl, optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from —F and —Cl.

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

11. The compound or pharmaceutically acceptable salt thereof of claim 1 , wherein Z is pyridyl, optionally substituted with 1 to 3 substituents, which can be the same or different, each independently selected from —F and —Cl.

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

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

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 , and a pharmaceutically acceptable excipient.

Assignees

• Gilead Sciences Inc

Inventors

• Bestvater Brian P
• Kaplan Joshua A
• Neubig Megan E
• Yang Kin S
• Zagorska Anna

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K31/4155 Primary

  non condensed and containing further heterocyclic rings · CPC title

• C07D231/40 Primary

  Acylated on said nitrogen atom · CPC title

• C07D401/04

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

• C07D403/04

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