Compounds and their use

Patent metadata

Field	Value
Publication number	US-12503445-B2
Application number	US-202418612849-A
Country	US
Kind code	B2
Filing date	Mar 21, 2024
Priority date	Jul 2, 2021
Publication date	Dec 23, 2025
Grant date	Dec 23, 2025

Abstract

The specification generally relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, where R 1 , R 2A , R 2B , R 2C , R 2D , W, X, Y, and Z have the meanings defined herein. Such compounds are useful in inhibiting NLRP3 inflammasome activity and may be useful as therapeutic agents. The specification also relates to the use of such compounds to treat or prevent diseases and conditions in which the NLRP3 inflammasome is implicated. The specification further relates to compositions comprising such compounds.

First claim

The invention claimed is:

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from

each R 3 is independently selected from —H and —C 1-3 alkyl;
R 4 is selected from —H and —C 1-3 alkyl;
R 2A , R 2B , R 2C , and R 2D are each independently selected from —H, —F, —Cl, —C 1-3 alkyl substituted with 0-3 —F substituents, cyclopropyl, —OCF 3 , and —SO 2 Me;
W, X, Y and Z are each independently selected from CR 5 and N; zero or one of W, X, Y and Z are N, and the remainder of W, X, Y, and Z are CR 5 ;
each R 5 is independently selected from —H, -Me, and —F.

2 . The compound of claim 1 , wherein R 1 is selected from

3 . The compound of claim 1 , wherein each R 3 is independently selected from —H and -Me.

4 . The compound of claim 1 , wherein each R 3 is -Me.

5 . The compound of claim 1 , wherein R 4 is selected from —H and -Me.

6 . The compound of claim 1 , wherein R 4 is —H.

7 . The compound of claim 1 , wherein two, three, or four of R 2A , R 2B , R 2C , and R 2D are —H, and the remainder of R 2A , R 2B , R 2C , and R 2D are not —H.

8 . The compound of claim 1 , wherein two or three of R 2A , R 2B , R 2C , and R 2D are —H, and the remainder of R 2A , R 2B , R 2C , and R 2D are not —H.

9 . The compound of claim 1 , wherein R 2A and R 2C are —H.

10 . The compound of claim 1 , wherein R 2B is selected from —H, —F, —CF 3 , and —SO 2 Me.

11 . The compound of claim 1 , wherein R 2D is selected from —H and —F.

12 . The compound of claim 1 , wherein R 2B is selected from —H and —Cl, and R 2D is —F.

13 . The compound of claim 1 , wherein R 2B is not —H.

14 . The compound of claim 1 , wherein R 2A is —H, R 2B is —CF 3 , R 2C is —H, and R 2D is —H.

15 . The compound of claim 1 , wherein W, X, Y, and Z are each CR 5 .

16 . The compound of claim 1 , wherein W, X, and Z are each CR 5 and Y is N.

17 . The compound of claim 1 , wherein one of W, X, Y, and Z is CR 5 ; zero or one of W, X, Y, and Z is N; and the remainder of W, X, Y, and Z are CH.

18 . The compound of claim 1 , wherein each R 5 is —H.

19 . The compound of claim 1 , wherein the compound is selected from:
2-[4-[[3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-methylsulfonyl-phenol; 2-[4-[[2-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]cycloheptanol; 2-(4-((3-hydroxycyclohexyl)amino) phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-[[3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[1-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-4-yl]-5-(trifluoromethyl)phenol; 5-chloro-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-fluoro-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 5-chloro-3-fluoro-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-fluoro-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy) phenol; 2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-3-(trifluoromethyl)phenol; 5-ethyl-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 5-cyclopropyl-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 4-fluoro-2-[4-[[3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[3-hydroxy-3-methyl-cyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 5-chloro-2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy) phenol; 5-chloro-3-fluoro-2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]phenol; 3-fluoro-2-[4-[(2-hydroxy-2-methyl-propyl)amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[3-hydroxycyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 5-fluoro-2-(4-((3-hydroxycyclopentyl)amino) pyrido[3,4-d]pyridazin-1-yl)phenol; 3-fluoro-2-(1-((3-hydroxycyclopentyl)amino) pyrido[3,4-d]pyridazin-4-yl)phenol; 2-[8-[[3-hydroxycyclohexyl]amino]pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; 2-[8-[[3-hydroxycyclohexyl]amino]-2-methyl-pyrido[2,3-d]pyridazin-5-yl]-5-(trifluoromethyl)phenol; or a pharmaceutically acceptable salt thereof.

20 . The compound of claim 1 , wherein the compound is selected from:
2-[4-[[(1R,3R)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3S)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3S)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3R)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3R)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-methylsulfonyl-phenol; 2-[4-[[(1S,3S)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-methylsulfonyl-phenol; 2-[4-[[(1R,3S)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-methylsulfonyl-phenol; 2-[4-[[(1S,3R)-3-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-methylsulfonyl-phenol; 2-[4-[[(1R,2S)-2-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,2R)-2-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,2R)-2-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,2S)-2-hydroxycyclopentyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; (1R,2R)-2-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]cycloheptanol; (1S,2S)-2-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]cycloheptanol; (1R,2S)-2-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]cycloheptanol; (1S,2R)-2-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]cycloheptanol; 2-(4-(((1R,3R)-3-hydroxycyclohexyl)amino) phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-(4-(((1S,3S)-3-hydroxycyclohexyl)amino) phthalazin-1-yl)-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3R)-3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3S)-3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3S)-3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3R)-3-hydroxy-3-methyl-cyclopentyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1R,3S)-3-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol; 2-[4-[[(1S,3R)-3-hydroxycyclohexyl]amino]pyrido[

Assignees

• Astrazeneca Ab
• Mitsubishi Tanabe Pharma Corp

Inventors

• Johansson Lars Anders Mikael
• Bergonzini Giulia
• Gradén Henrik
• Sugama Hiroshi
• Matsumura Takehiko

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P19/06

  Antigout agents, e.g. antihyperuricemic or uricosuric agents · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P13/12

  of the kidneys · CPC title