IP Library › Granted Patent US 12678419

Granted Patent B2

US 12678419 · App. 18/034,122 · Granted Jul 14, 2026

Compounds

Inventors: Matthew Colin Thor Fyfe (Oxford, GB); Barry John Teobald (Oxford, GB)

Assignee: Sitryx Therapeutics Limited

A61K31/225 A61K45/06 A61P37/06 C07C67/08 C07C69/593

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Quick Facts

Patent No.: US 12678419
App. No.: 18/034,122
Granted: Jul 14, 2026
Kind: B2

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Abstract

The invention relates to compounds of formula (I) and to their use in treating or preventing an inflammatory disease or a disease associated with an undesirable immune response: wherein R A1 , R A2 , R A3 , R B , R C , R D , m, n and p are as defined herein.

Claims (86)

1 . A compound of formula (I):

wherein:

R A1 is selected from the group consisting of H, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, —SC 1-4 alkyl, —SC 1-4 haloalkyl and SF 5 ;

R A2 is selected from the group consisting of halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy;

R A3 is C 1-2 alkyl;

m is 0, 1 or 2;

n is 1 or 2;

p is 0 or 1; and

R B is selected from the group consisting of CH 2 COOH, CH 2 CH 2 COOH, CH 2 tetrazolyl and CH 2 CH 2 tetrazolyl, wherein R B is optionally substituted on an available carbon atom by one or more R B1 wherein R B1 is selected from the group consisting of difluoromethyl, trifluoromethyl and methyl, and/or wherein R B is optionally substituted by two R B1 groups, attached to the same carbon atom, that are joined to form a C 3-6 cycloalkyl or a 4-6-membered heterocyclyl ring; and

R C and R D are each independently H, C 1-2 alkyl, hydroxy, methoxy or fluoro;

or a pharmaceutically acceptable salt and/or solvate thereof.

2 . The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein R A1 is halo.

3 . The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein R A2 is halo.

4 . The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein m is 1.

5 . The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein n is 1.

6 . The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein p is 0.

7 . The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein R B is CH 2 COOH optionally substituted on an available carbon atom by one or more R B1 ; or wherein R B is CH 2 CH 2 COOH optionally substituted on an available carbon atom by one or more R B1 .

8 . The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein R B is not substituted.

9 . The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein R B is substituted by one or more R B1 , wherein R B1 is trifluoromethyl.

10 . The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 , wherein R C is H and/or wherein R D is H.

11 . The compound according to claim 1 which is selected from the list consisting of:

2-((4-((5-chloro-2,3-dihydro-1H-inden-2-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid;

2-((4-((4,6-dichloro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 1);

2-((4-((4,6-dichloro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 2);

2-((4-((5,6-dichloro-2,3-dihydro-1H-inden-2-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid;

2-((4-((5,6-dichloro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 1);

2-((4-((5,6-dichloro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 2);

2-((4-((5-chloro-2-methyl-2,3-dihydro-1H-inden-2-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid;

2-((4-((5,7-dichloro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 1);

2-((4-((5,7-dichloro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 2);

2-((4-((6,8-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 1);

2-((4-((6,8-dichloro-1,2,3,4-tetrahydronaphthalen-2-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 2);

2-((4-((5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 1);

2-((4-((5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 2);

3-((4-((4,6-dichloro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)propanoic acid (Enantiomer 1);

2-((4-((4-bromo-6-fluoro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 1);

2-((4-((4-bromo-6-fluoro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 2);

2-((2-methylene-4-oxo-4-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)oxy) butanoyl)oxy)acetic acid;

2-((2-methylene-4-oxo-4-((6-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl)oxy)butanoyl)oxy)acetic acid;

2-((4-((4-chloro-6-fluoro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 1);

2-((4-((4-chloro-6-fluoro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 2);

2-((4-((5,6-dichloro-2-methyl-2,3-dihydro-1H-inden-2-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid;

(3R)-3-((4-((4,6-dichloro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)-4,4,4-trifluorobutanoic acid (Diastereomer A);

(3S)-3-((4-((4,6-dichloro-2,3-dihydro-1H-inden-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)-4,4,4-trifluorobutanoic acid (Diastereomer B);

2-((4-((5,7-dichloro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 1);

2-((4-((5,7-dichloro-1,2,3,4-tetrahydronaphthalen-1-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid (Enantiomer 2);

2-((4-((5,6-difluoro-1,1,3,3-tetramethyl-2,3-dihydro-1H-inden-2-yl)oxy)-2-methylene-4-oxobutanoyl)oxy)acetic acid;

2-((2-methylene-4-oxo-4-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)oxy) butanoyl)oxy)acetic acid (Enantiomer 1);

2-((2-methylene-4-oxo-4-((6-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl)oxy) butanoyl)oxy)acetic acid (Enantiomer 1);

2-((2-methylene-4-oxo-4-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)oxy) butanoyl)oxy)acetic acid (Enantiomer 2);

2-((2-methylene-4-oxo-4-((6-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl)oxy) butanoyl)oxy)acetic acid (Enantiomer 2); and

2-((2-methylene-4-oxo-4-((6-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)oxy) butanoyl)oxy)acetic acid (Enantiomer 1);

or a pharmaceutically acceptable salt and/or solvate of any one thereof.

12 . A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 .

13 . A compound selected from the group consisting of:

(a) a compound of formula (II):

wherein R A1 , R A2 , R A3 , R C , R D , m, n and p are defined in claim 1 and R B′ is a protected derivative of R B ;

or a salt thereof;

(b) a compound of formula (XI):

wherein R A1 , R A2 , R A3 , R C , R D , m, n and p are defined in claim 1 , R B′ is a protected derivative of R B , and R 11 and R 12 are independently C 1-4 alkyl optionally substituted with halo;

or a salt thereof;

wherein R A1 , R A2 , R A3 , R C , R D , m, n and p are defined in claim 1 , and R 11 and R 12 are independently C 1-4 alkyl optionally substituted with halo;

or a salt thereof; and

(d) a compound of formula (XIV):

wherein R A1 , R A2 , R A3 , R C , R D , m, n and p are defined in claim 1 , and X 2 is a leaving group;

or a salt thereof.

14 . A compound of formula (XVI):

or a salt thereof;

wherein R A1 , R A2 , R A3 , R C , R D , m, n and p are defined in claim 1 ;

or a salt thereof.

15 . A compound according to claim 14 selected from the group consisting of:

1-(2-(tert-butoxy)-2-oxoethyl) 4-(5-chloro-2,3-dihydro-1H-inden-2-yl) 2-methylenesuccinate;

1-(2-(tert-butoxy)-2-oxoethyl) 4-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl) 2-methylenesuccinate (enantiomer 1);

1-(2-(tert-butoxy)-2-oxoethyl) 4-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl) 2-methylenesuccinate (enantiomer 2);

1-(2-(tert-butoxy)-2-oxoethyl) 4-(5,6-dichloro-2,3-dihydro-1H-inden-2-yl) 2-methylenesuccinate;

4-(5,6-dichloro-2,3-dihydro-1H-inden-1-yl) 1-(2-oxo-2-(2,2,2-trichloroethoxy)ethyl) 2-methylenesuccinate (enantiomer 1);

4-(5,6-dichloro-2,3-dihydro-1H-inden-1-yl) 1-(2-oxo-2-(2,2,2-trichloroethoxy)ethyl) 2-methylenesuccinate (enantiomer 2);

4-(5-chloro-2-methyl-2,3-dihydro-1H-inden-2-yl) 1-(2-oxo-2-(2,2,2-trichloroethoxy)ethyl) 2-methylenesuccinate;

4-(5,7-dichloro-2,3-dihydro-1H-inden-1-yl) 1-(2-oxo-2-(2,2,2-trichloroethoxy)ethyl) 2-methylenesuccinate (enantiomer 1);

4-(5,7-dichloro-2,3-dihydro-1H-inden-1-yl) 1-(2-oxo-2-(2,2,2-trichloroethoxy)ethyl) 2-methylenesuccinate (enantiomer 2);

3-((3-oxo-3-(2,2,2-trichloroethoxy)propoxy)carbonyl)but-3-enoic acid;

3-((2,2,2-trichloroethoxy)carbonyl)but-3-enoic acid;

4-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl) 1-(3-oxo-3-(2,2,2-trichloroethoxy)propyl) 2-methylenesuccinate; and

4-(4,6-dichloro-2,3-dihydro-1H-inden-1-yl) 1-((R)-1,1,1-trifluoro-4-oxo-4-(2,2,2-trichloroethoxy)butan-2-yl) 2-methylenesuccinate;

or a salt thereof.