Compounds and their use

Patent metadata

Field	Value
Publication number	US-11970463-B2
Application number	US-202217810367-A
Country	US
Kind code	B2
Filing date	Jul 1, 2022
Priority date	Jul 2, 2021
Publication date	Apr 30, 2024
Grant date	Apr 30, 2024

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 each R 3 is —H.

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

4. The compound of claim 1 , wherein R 1 is

5. The compound of claim 1 , wherein R 1 is

6. 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.

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

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

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

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

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

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

13. The compound of claim 1 , wherein W, X, and Z are each CH, and Y is CH or N.

14. The compound of claim 1 , wherein the compound is selected from:
3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-(4-chloro-3-fluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-(4,5-difluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-(2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-(4-chloro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-[2-hydroxy-4-(trifluoromethoxy)phenyl]phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-[2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-(2,4-difluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-(4-chloro-2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-(2-chloro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-(2-hydroxy-4-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-(2-hydroxy-5-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-7-methyl-phthalazin-1-yl]amino]propane-1,2-diol;
3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-6-methyl-phthalazin-1-yl]amino]propane-1,2-diol;
2-[4-[[2-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol;
4-fluoro-2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol;
3-fluoro-2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol;
2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethoxy)phenol;
5-chloro-3-fluoro-2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol;
5-chloro-2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]phenol;
5-fluoro-2-(4-((2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;
3-fluoro-2-(4-((2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol;
3-fluoro-2-(1-((2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol;
5-fluoro-2-(1-((2-hydroxycyclohexyl)amino)pyrido[3,4-d]pyridazin-4-yl)phenol;
2-[4-[[2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol;
3-[[1-[2-hydroxy-4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]amino]propane-1,2-diol; and
3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]-2-methyl-propane-1,2-diol;
or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein the compound is selected from:
(2S)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-(4-chloro-3-fluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-(4-chloro-3-fluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-(4,5-difluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-(4,5-difluoro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-(2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-(2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-(4-chloro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-(4-chloro-2-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-[2-hydroxy-4-(trifluoromethoxy)phenyl]phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-[2-hydroxy-4-(trifluoromethoxy)phenyl]phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-[2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-[2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl]phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-(2,4-difluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-(2,4-difluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-(4-chloro-2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-(4-chloro-2-fluoro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-(2-chloro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-(2-chloro-6-hydroxy-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-(2-hydroxy-4-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-(2-hydroxy-4-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-(2-hydroxy-5-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-(2-hydroxy-5-methyl-phenyl)phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-7-methyl-phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-7-methyl-phthalazin-1-yl]amino]propane-1,2-diol;
(2S)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-6-methyl-phthalazin-1-yl]amino]propane-1,2-diol;
(2R)-3-[[4-[2-hydroxy-4-(trifluoromethyl)phenyl]-6-methyl-phthalazin-1-yl]amino]propane-1,2-diol;
2-[4-[[(1R,2S)-2-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol;
2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol;
2-[4-[[(1S,2R)-2-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol;
2-[4-[[(1S,2S)-2-hydroxycyclohexyl]amino]phthalazin-1-yl]-5-(trifluoromethyl)phenol;
4-fluoro-2-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol;
4-fluoro-2-[4-[[(1S,2R)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol;
4-fluoro-2-[4-[[(1R,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(trifluoromethyl)phenol;
4-fluoro-2-[4-[[(1S,2S)-2-hydroxycyclohexyl]amino]pyrido[3,4-d]pyridazin-1-yl]-5-(tri

Assignees

• Astrazeneca Ab
• Mitsubishi Tanabe Pharma Corp

Inventors

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

Classifications

• C07D237/28 Primary

  Cinnolines · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D237/34 Primary

  with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals · CPC title

• A61K31/502

  ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title