GLP-1R modulating compounds

Patent metadata

Field	Value
Publication number	US-11858918-B2
Application number	US-202217724212-A
Country	US
Kind code	B2
Filing date	Apr 19, 2022
Priority date	Apr 21, 2021
Publication date	Jan 2, 2024
Grant date	Jan 2, 2024

Abstract

The present disclosure provides GLP-1R agonists, and compositions, methods, and kits thereof. Such compounds are generally useful for treating a GLP-1R mediated disease or condition in a human.

First claim

What is claimed is:

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein
R 1 is a phenyl or 6 membered heteroaryl optionally substituted with 1, 2, or 3 R 4 ;
X 1 is —C(H)═ or —C(R 8 )═;
X 4 is —C(H)═, —C(R 8 )═, or N;
each R 4 is independently halogen or —CN;
each R B is independently C 1-9 alkyl, C 1-8 haloalkyl, or halogen;
each R 8 is independently halogen; and
n is 0, 1, 2, or 3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is phenyl, substituted with 1, 2, or 3 halogen or —CN.

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

substituted with 1, 2, or 3 halogen or —CN.

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

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is F or Cl.

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

7. The pharmaceutical composition of claim 6 further comprising one or more additional therapeutic agents.

8. The pharmaceutical composition of claim 7 , wherein the additional therapeutic agent comprises an anti-obesity agent selected from peptide YY, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 agonist, an NPYR5 antagonist, a cannabinoid receptor type 1 (CB1 R) antagonist, a lipase inhibitor, a human proislet peptide (HIP), a melanocortin receptor 4 agonist (MC4R), a melanin concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist, apoptotic signal-regulating kinase (ASK-1) inhibitor, zonisamide, phentermine (alone or in combination with topiramate), a norepinephrine/dopamine reuptake inhibitor, an opioid receptor antagonist, a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist, a GDF-15 analog, sibutramine, a cholecystokinin agonist, amylin, leptin, a serotonergic agent, a methionine aminopeptidase 2 (MetAP2) inhibitor, phendimetrazine, diethylpropion, benzphetamine, an SGLT2 inhibitor, an SGLTL1 inhibitor, a dual SGLT2/SGLT1 inhibitor, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, biotin, a MAS receptor modulator, or a glucagon receptor agonist (alone or in combination with another GLP-1 R agonist, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fish oil, an acetyl-coA carboxylase (ACC) inhibitor, a TGFβ antagonist, GFRAL agonist, and/or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

10. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is

11. A pharmaceutical composition comprising a compound of claim 10 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

12. The pharmaceutical composition of claim 11 , further comprising one or more additional therapeutic agents.

13. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is

14. A pharmaceutical composition comprising a compound of claim 13 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

15. The pharmaceutical composition of claim 14 further comprising one or more additional therapeutic agents.

16. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is

17. A pharmaceutical composition comprising a compound of claim 16 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

18. The pharmaceutical composition of claim 17 , further comprising one or more additional therapeutic agents.

Assignees

• Gilead Sciences Inc

Inventors

• Armstrong Megan K
• Cassidy James S
• Chin Elbert
• Chou Chienhung
• Cottell Jeromy J
• Hung Chao-I
• Kolahdouzan Kavoos
• Lin David W
• Mitchell Michael L
• Roberts Ezra
• Schroeder Scott D
• Shapiro Nathan D
• Taylor James G
• Thomas-Tran Rhiannon
• Wright Nathan E
• Yang Zheng-Yu

Classifications

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title