IP Library › Granted Patent US 12698282
Granted Patent B2
US 12698282 · App. 18/451,210 · Granted Aug 4, 2026

Inhibitors of myeloperoxidase

Inventors: Tord Inghardt (Södertälje, SE); Eva-Lotte Lindstedt (Södertälje, SE); Ulrik Jurva (Södertälje, SE); Nidhal Selmi (Södertälje, SE)
Assignee: AstraZeneca AB
C07D419/14
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Quick Facts
Patent No.
US 12698282
App. No.
18/451,210
Granted
Aug 4, 2026
Kind
B2
Abstract

The specification generally relates to compounds of Formula (I), (Ia), and (Ib): and pharmaceutically acceptable salts thereof, where X, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 and X 1 , X 2 , r, and q, have any of the meanings defined herein, together with compositions containing them and their use in therapy. The compounds are inhibitors of the enzyme MPO, and are thereby particularly useful in the treatment or prophylaxis of diseases or conditions in which modulation of the activity of the enzyme myeloperoxidase (MPO) is desirable, including diseases with inflammatory, cardiovascular, respiratory, renal, hepatic and/or neurological components, as well as neutrophilic driven diseases.

Claims (105)

1 . A Compound of formula (I)

wherein

X=CH or N

Y 1 =CZ 1 or N, Y 2 =CZ 2 or N, Y 3 =CZ 3 or N, Y 4 =CZ 4 or N, and Y 5 =CZ 5 or N

Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 , are, if present, independently, H, halo, CF 3 , Q or T,

provided that no more than one of Y 1 , Y 2 , Y 3 , Y 4 , or Y 5 is N, at least two of Y 1 , Y 2 , Y 3 , Y 4 , or Y 5 are CH, no more than one of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is halo or CF 3 , and one, and only one, of Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is Q or T,

Q is

 wherein m is 0, 1, 2, or 3,

T is

p is 0 or 1,

s is 0, 1 or 2,

n is 1 or 2,

A is CH 2 , CF 2 , CHF, CHR 2 , CFR 2 , NR 3 , or O,

wherein;

R 1 and R 2 , if present, are independently CH 2 F, CHF 2 , or CF 3

R 3 , if present, is independently H or CH 3 ,

or any stereoisomer thereof or pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , having the structure:

or any stereoisomer thereof or pharmaceutically acceptable salt thereof.

3 . The compound or any stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 1 , wherein Y 1 is N and Y 2 , Y 3 , are Y 4 are CH.

4 . The compound or any stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 1 wherein n is 1.

5 . The compound or any stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 1 wherein A is CH 2 , CF 2 , CHF, CHR 2 , or CFR 2 .

6 . The compound or any stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 1 , wherein A is CHR 2 .

7 . The compound or any stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 6 , wherein R 2 is CHF 2 or CF 3 .

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

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

10 . The compound or any stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 1 wherein Y 5 is CZ 5 , and Z 5 is T or Q.

11 . The compound or any stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 10 wherein Z 5 is T.

12 . The compound or any stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 11 wherein T is

13 . The compound or any stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 10 wherein Y 1 , Y 2 , Y 3 and Y 4 are CH.

14 . The compound or any stereoisomer thereof or pharmaceutically acceptable salt thereof of claim 10 wherein X is CH.

15 . A compound of claim 1 , selected from:

1-(2-(Piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(R)-1-(2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(S)-1-(2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-(4-Chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(R)-1-(4-Chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(S)-1-(4-Chloro-2-(piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-(4-Chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(R)-1-(4-Chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(S)-1-(4-Chloro-2-(pyrrolidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-(4-Chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(R)-1-(4-Chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(S)-1-(4-chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

3-(4-Chloro-2-(morpholin-3-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one,

1-(2-(Azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(R)-1-(2-(Azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(S)-1-(2-(Azepan-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(R)-3-(2-(Azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one,

(S)-3-(2-(Azepan-2-yl)-4-chlorobenzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one,

(R)-1-(2-(Morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(S)-1-(2-(Morpholin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

1-(2-(4-Methylpiperazin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

rac-2-Thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-(2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-(2-(5-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-(2-(4,4-Difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(R)-1-(2-(4,4-Difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(S)-1-(2-(4,4-Difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

rac-2-Thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

2-Thioxo-3-(2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

2-Thioxo-3-(2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

3-(2-(4,4-Difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one,

3-(2-(5-Fluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one,

2-Thioxo-1-((2-(−4-(trifluoromethyl)piperidin-2-yl) pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

rac-2-Thioxo-1-((2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl) pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((2-((cis)-4-(trifluoromethyl)piperidin-2-yl) pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((2-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl) pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((2-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl) pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

rac-2-Thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

rac-2-thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

2-thioxo-3-(2-((trans)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

2-Thioxo-3-(2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

2-Thioxo-3-(2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl)benzyl)-1,2,3,7-tetrahydro-6H-purin-6-one,

rac-1-(2-((2R,4S)-4-(Difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-(2-((2R,4S)-4-(Difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-(2-((2S,4R)-4-(difluoromethyl)piperidin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-((2-(Piperidin-2-yl) pyridin-3-yl)methyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

rac-2-Thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl) pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((3-((cis)-4-(trifluoromethyl)piperidin-2-yl) pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl) pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((3-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl) pyridin-2-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

rac-2-Thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl) pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((3-((cis)-4-(trifluoromethyl)piperidin-2-yl) pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((3-((2R,4S)-4-(trifluoromethyl)piperidin-2-yl) pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((3-((2S,4R)-4-(trifluoromethyl)piperidin-2-yl) pyridin-4-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-(4-(1-Aminocyclobutyl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-(3-(1-Aminocyclobutyl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-(2-(Piperidin-3-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-(2-(morpholin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(R)-1-(2-(Morpholin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

(S)-1-(2-(morpholin-2-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

1-(2-(Piperidin-4-yl)benzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

rac-2-Thioxo-1-((2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl) pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((2-((trans)-4-(trifluoromethyl)piperidin-2-yl) pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((2-((2R,4R)-4-(trifluoromethyl)piperidin-2-yl) pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one,

2-Thioxo-1-((2-((2S,4S)-4-(trifluoromethyl)piperidin-2-yl) pyridin-3-yl)methyl)-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one, and

pharmaceutically acceptable salts thereof.

16 . The compound of claim 1 , having the structure:

or any stereoisomer thereof or pharmaceutically acceptable salt thereof.

17 . A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.