Granted Patent B2

US 12,297,223 · App. 17/606,134 · Granted May 13, 2025

Inventors: Michael Joseph Bishop (Collegeville, PA); James Walter Janetka (Saint Louis, MO); Laurel Kathryn McGrane (Saint Louis, MO); Eugene Lee Stewart (Collegeville, PA); Katherine Louisa Widdowson (Collegeville, PA)

Assignees: GlaxoSmithKline Intellectual Property Development Limited; Fimbrion Therapeutics, Inc.

C07H15/26C07H15/207

Abstract

Claims (52)

1. A compound of Formula I, or a pharmaceutical salt thereof,

in which

Z is

n=1 to 3;

Q is CF 3 , CH 3 or Cl;

R is C 1-3 alkyl (optionally substituted with up to 7 fluorine atoms), C 2-6 alkynyl, phenyl, —(CH 2 ) m —OH, optionally substituted cyclopropyl, or optionally substituted vinyl;

R 1 , R 2 , and R 3 are independently H, F, Cl, Br, C 3-6 cycloalkyl, OR′,—N(C 1-6 alkyl) 2 , C 2-6 alkenyl, C 2-6 alkynyl,

C 1-6 alkyl (optionally substituted with up to 7 fluorine atoms, up to one hydroxy, up to one —N(C 1-6 alkyl) 2 , and up to one-OC 1-6 alkyl), up to one-(CO)—NH—CH 3 , or up to one cyano; provided R 2 cannot be all H at the same time;

R 4 is H or F;

R′ is independently H or C 1-6 alkyl (optionally substituted with up to 7 fluorine atoms);

Y is independently CH, N or, where permitted by the structure of Z, CR 1 , provided all Y's cannot be CH at the same time; and

m=1 to 3.

2. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein

Z is:

wherein Y 1 is N or CR 1B and Y 2 and Y 3 are selected from the group consisting of N or CH, with the proviso that at least one of Y, Y 2 and Y 3 is N; and

R 1A , R 1B , R 2A , R 2B , R 2C , R 3A and R 3B are independently selected from the group consisting of H, F, Cl, CF 3 , cyclopropyl, —(CO)—NH—CH 3 and cyano, with the provisos that:

where Y 1 is CR 1B , one of R 1A and R 1B is H;

one of R 3A and R 3B is H;

at least one of R 2A , R 2B and R 2C is not H; and

only one of R 2A , R 2B and R 2C may be —(CO)—NH—CH 3 or cyano.

3. A compound or pharmaceutically acceptable salt thereof according to claim 2 , wherein

Z is:

4. A compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein

Z is:

5. A compound or pharmaceutically acceptable salt thereof according to claim 4 , wherein:

Y 1 and Y 3 are N and Y 2 is CH; and

R 1A is cyclopropyl or —CF 3 .

6. A compound or pharmaceutically acceptable salt thereof according to claim 4 , wherein:

Y 3 is N, Y 2 is CH and Y 1 is CR 1B ; and

one of R 1A and R 1B is H and the other is selected from the group consisting of —CF 3 or cyano.

7. A compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein

Z is:

8. A compound or pharmaceutically acceptable salt thereof according to claim 7 , wherein R 2A is selected from the group consisting of H, F, CN and —(CO)—NH—CH 3 ; R 2B is selected from the group consisting of H, CN and Cl; and R 2C is selected from the group consisting of F and H; with the proviso that at least one of R 2A , R 2B and R 2C is not H, and with the proviso that only one of R 2A , R 2B and R 2C may be cyano.

9. A compound or pharmaceutically acceptable salt thereof according to claim 8 , wherein R 2A is F, R 2B is selected from the group consisting of H and Cl; and R 2C is F.

10. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein either Q is CH 3 and R 4 is H, or Q is CF 3 and R 4 is H.

11. A compound or pharmaceutically acceptable salt thereof according to claim 10 , wherein Q is CH 3 and R 4 is H.

12. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R is methyl or vinyl.

13. A compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R is methyl.

14. A compound according to claim 1 , that is selected from the group consisting of:

(2R,3S,4R,5S,6R)-2-(Hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol;

(2R,3S,4R,5S,6R)-2-(Hydroxymethyl)-6-((R)-1-(2-methyl-4-(4-(trifluoromethyl)pyridin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol;

(2R,3S,4R,5S,6R)-2-(hydroxymethyl)-6-((R)-1-(2-(trifluoromethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol;

(2R,3S,4R,5S,6R)-2-(Hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyridin-3-yl)phenyl)ethyl)tetrahydro-2H-pyran-3,4,5-triol;

(2R,3S,4R,5S,6R)-2-(Hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)propyl)tetrahydro-2H-pyran-3,4,5-triol;

(2R,3S,4R,5S,6R)-2-(Hydroxymethyl)-6-((R)-1-(2-methyl-4-(5-(trifluoromethyl)pyrazin-2-yl)phenyl)allyl)tetrahydro-2H-pyran-3,4,5-triol; and

(2R,3S,4R,5S,6R)-2-((S)-1-(4′-chloro-3′,5′-difluoro-3-methyl-[1,1′-biphenyl]-4-yl)-2-hydroxyethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; or a pharmaceutically acceptable salt thereof.

15. A method for the treatment of a bacterial infection, Crohn's disease (CD), or Inflammatory Bowel Disease (IBD) comprising the administration of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as defined in claim 1 to a human patient in need thereof.

16. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as defined in claim 1 together with a pharmaceutically acceptable carrier.

17. The method according to claim 15 , wherein the bacterial infection is an antibiotic-resistant bacterial infection.

18. The method according to claim 15 , wherein the bacterial infection is a urinary tract infection (UTI).

19. The method according to claim 18 , wherein the urinary tract infection is recurrent.

20. The method according to claim 18 , wherein the urinary tract infection is chronic.

Assignments (3)

Continuity (2)

References Cited (136)