Gpr52 modulator compounds

Patent metadata

Field	Value
Publication number	US-2024254101-A1
Application number	US-202117909792-A
Country	US
Kind code	A1
Filing date	Mar 15, 2021
Priority date	Mar 13, 2020
Publication date	Aug 1, 2024
Grant date	—

Abstract

The disclosures herein relate to novel compounds of Formula (1); and salts thereof, wherein X, Y, R 1 , R 2 , R 3 and R 4 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with GPR52 receptors.

First claim

1 .- 25 . (canceled)

26 . A compound of Formula (1):

or a salt thereof, wherein;
X is N or CR 5 ;
Y is N or CR 6 ;
R 1 is H, C 1-6 alkyl optionally substituted with OH or 1 to 6 fluorine atoms, C 3-6 cycloalkyl optionally substituted with OH or 1 to 6 fluorine atoms, wherein when the C 1-6 alkyl or C 3-6 cycloalkyl group is not substituted with OH, one atom of the C 1-6 alkyl or C 3-6 cycloalkyl group may be optionally replaced by an O atom which is not directly attached to the N or attached to a carbon atom which is directly attached to the N; or R 1 is joined to R 2 to form a 4, 5, 6 or 7-membered ring which is optionally substituted with OH or 1 to 6 fluorine atoms;
R 2 is H or C 1-3 alkyl optionally substituted with OH or 1 to 6 fluorine atoms; or R 2 is joined to R 1 to form a 4, 5, 6 or 7-membered ring which is optionally substituted with OH or 1 to 6 fluorine atoms;
R 4 , R 5 and R 6 are independently selected from H, CN, halo, C 1-6 alkyl optionally substituted with OH or 1 to 6 fluorine atoms, C 3-6 cycloalkyl optionally substituted with OH or 1 to 6 fluorine atoms and C 1-6 alkoxy optionally substituted with 1 to 6 fluorine atoms, wherein when the C 1-6 alkyl or C 3-6 cycloalkyl group is not substituted with OH, one atom of the C 1-6 alkyl or C 3-6 cycloalkyl group may be optionally replaced by O;
R 3 is a group of the formula:

L is CH 2 or CHOH;
the group:

R 8 , R 9 and R 10 are independently selected from H, CN, halo, C 1-6 alkyl optionally substituted with 1 to 6 fluorine atoms and C 1-6 alkoxy optionally substituted with 1 to 6 fluorine atoms, wherein one atom of the C 1-6 alkyl group may be optionally replaced by a heteroatom selected from O, N, S and oxidised forms thereof.

27 . The compound according to claim 26 , wherein R 1 is selected from: H, methyl, oxetanyl, CH 2 CH 2 OH and CH 2 CH 2 OCH 3 , or wherein R 1 is joined to R 2 to form a 5-membered ring.

28 . The compound according to claim 26 , wherein R 2 is H or methyl, or is joined to R 1 to form a 5-membered ring.

29 . The compound according to claim 26 , which is a compound of formula (2a):

or a salt thereof.

30 . The compound according to claim 26 , wherein X is N, CH, CCH 3 or CCH 2 OH.

31 . The compound according to claim 26 , wherein Y is N, CH or CCH 3 .

32 . The compound according to claim 26 , wherein R 4 is selected from: H, methyl, methoxy, Cl, CHF 2 , CF 3 , ethyl, CN, cyclopropyl, CH 2 OH and CH 2 OCH 3 .

33 . The compound according to claim 26 , wherein, R 5 and R 6 are independently selected from H, methyl and CH 2 OH.

34 . The compound according to claim 26 , which is a compound of formula (3a), (3b), (3c) or (3d):

or a salt thereof.

35 . The compound according to claim 26 , wherein R 3 is:

36 . The compound according to claim 26 , wherein L is CH 2 .

37 . The compound according to claim 26 , which is a compound of formula (4a), (4b), (4c), (4d), (4e) or (4f):

or a salt thereof.

38 . The compound according to claim 26 , which is a compound of formula (4b), (4c), (4d), (4e) or (4f):

or a salt thereof.

39 . The compound according to claim 26 , wherein R 1 , R 9 and R 10 are independently selected from H, F, CHF 2 and CF 3 .

40 . The compound according to claim 26 , wherein the group:

41 . The compound according to claim 26 which is selected from the group consisting of:
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-4-carboxamide;
1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide;
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-methyl-1H-pyrazole-4-carboxamide;
2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-2H-1,2,3-triazole-4-carboxamide;
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methyl-1H-pyrazole-4-carboxamide;
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3, 5-dimethyl-1H-pyrazole-4-carboxamide;
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxamide;
1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1H-pyrazole-4-carboxamide;
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-1H-pyrazole-3-carboxamide;
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-methyl-1H-pyrazole-3-carboxamide;
1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methoxy-1H-pyrazole-4-carboxamide;
2-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-5-methyl-2H-1,2,3-triazole-4-carboxamide;
2-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-2H-1,2,3-triazole-4-carboxamide;
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-3-methoxy-1H-pyrazole-4-carboxamide;
1-(6-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-4-methyl-1H-pyrazole-3-carboxamide;
(1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-1H-pyrazol-4-yl)(pyrrolidin-1-yl)methanone;
1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N,3-dimethyl-1H-pyrazole-4-carboxamide;
1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N,N,3-trimethyl-1H-pyrazole-4-carboxamide;
1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-methyl-N-(oxetan-3-yl)-1H-pyrazole-4-carboxamide;
1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N-(2-hydroxyethyl)-3-methyl-1H-pyrazole-4-carboxamide;
1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-N-(2-methoxyethyl)-3-methyl-1H-pyrazole-4-carboxamide;
3-chloro-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide;
3-(difluoromethyl)-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide;
1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;
3-ethyl-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide;
3-cyano-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide;
3-cyclopropyl-1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-4-carboxamide;
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N,5-dimethyl-1H-pyrazole-3-carboxamide;
1-(2-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-4-yl)-1H-pyrazole-3-carboxamide;
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-5-methyl-1H-pyrazole-3-carboxamide;
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N-methyl-1H-pyrazole-3-carboxamide;
1-(4-(3-fluoro-5-(trifluoromethyl)benzyl)pyridin-2-yl)-N,N-dimethyl-1H-pyrazole-3-carboxamide;
(1-(4-(3-fluoro-5-(trifluoromethyl)be

Assignees

• Heptares Therapeutics Ltd

Inventors

• Bucknell Sarah Joanne
• Watson Stephen Paul
• O'Brien Michael Alistair

Classifications

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D249/16 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title