Alkynyl-(heteroaryl)-carboxamide HCN1 inhibitors

Patent metadata

Field	Value
Publication number	US-12528784-B2
Application number	US-202217830215-A
Country	US
Kind code	B2
Filing date	Jun 1, 2022
Priority date	Dec 2, 2019
Publication date	Jan 20, 2026
Grant date	Jan 20, 2026

Abstract

The present invention provides compounds of formula I

wherein R 1 , R 2 or R 3 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula I, pharmaceutical compositions comprising them and their use as medicaments.

First claim

What is claimed is:

1 . A compound of formula I or a pharmaceutically acceptable salt thereof

wherein
X 1 is either N or C,
X 2 is either N or C, and
X 3 is either N or C,

provided that
at least one of X 1 , X 2 and X 3 is N,
no more than two of X 1 , X 2 and X 3 are N, and
if X 1 is N, then X 2 is not N, and

wherein the dotted lines represent a single or double bond to enable the five-membered ring to be aromatic;
R 1 is phenyl or N-heteroaryl, wherein said N-heteroaryl comprises 1, 2 or 3 nitrogen ring atoms, and wherein each of said phenyl or said N-heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from R 4 , wherein each of R 4 is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, haloC 1 -C 6 alkyl and haloC 1 -C 6 alkoxy;
R 2 is hydrogen or C 1 -C 6 alkyl, provided that if X 2 is N, then R 2 is not hydrogen; and
R 3 is heteroaryl or phenyl, wherein each of said heteroaryl or said phenyl are optionally substituted with 1, 2, 3 or 4 substituents selected from R 5 , wherein
each of R 5 is independently selected from hydroxy, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl and haloC 1 -C 6 alkoxy, or
wherein two vicinal R 5 groups form a five-membered or six-membered heterocyclyl fused with R 3 , wherein the heterocyclyl is optionally substituted with one or more groups independently selected from hydroxy, halogen, C 1 -C 6 alkyl, C 1 -Calkoxy, haloC 1 -C 6 alkyl and haloC 1 -C 6 alkoxy.

2 . The compound according to claim 1 , wherein the compound is of formula Ia

or pharmaceutically acceptable salts thereof.

3 . The compound according to claim 1 , wherein the compound is of formula Ib

or pharmaceutically acceptable salts thereof.

4 . The compound according to claim 1 , wherein the compound is of formula Ic

or pharmaceutically acceptable salts thereof.

5 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridinyl.

6 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, pyrazinyl, pyridazinyl or pyridinyl, wherein said phenyl, said pyrazinyl, said pyridazinyl or said pyridinyl are optionally substituted with 1 or 2 substituents selected from R 4 .

7 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy.

8 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from fluoro, chloro, methyl and methoxy.

9 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 6 alkyl.

10 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.

11 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl, pyrazolyl, pyridinyl, pyrimidinyl or thiophenyl, wherein said phenyl, said pyrazolyl, said pyridinyl, said pyrimidinyl or said thiophenyl are optionally substituted with 1 or 2 substituents selected from R 5 .

12 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from halogen, cyano, methyl, trifluoromethyl and methoxy, or wherein two vicinal R 5 groups form dioxolanyl.

13 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 are each independently phenyl or pyridinyl.

14 . The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from:
4-((2-Chloro-3-methylpyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide;
4-((2-Chloro-3-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide;
4-[2-(5-Chlorothiophen-3-yl)ethynyl]-5-methyl-1-(6-methylpyridin-3-yl)imidazole-2-carboxamide;
4-[2-(3-Chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide;
4-((3-Cyanophenyl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide;
4-(2-Chloro-pyridin-4-ylethynyl)-5-methyl-1-(6-methyl-pyridin-3-yl)-1H-imidazole-2-carboxylic acid amide;
4-((2-Chloro-5-fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide;
4-((3-Methoxyphenyl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide;
4-[2-(4-Chlorophenyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide;
5-Methyl-1-(6-methylpyridin-3-yl)-4-(m-tolylethynyl)-1H-imidazole-2-carboxamide;
5-Methyl-1-(6-methylpyridin-3-yl)-4-((2-(trifluoromethyl)pyridin-4-yl)ethynyl)-1H-imidazole-2-carboxamide;
4-[2-(2-Fluoro-4-pyridyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide;
4-(Benzo[d][1,3]dioxol-4-ylethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide;
4-((6-Chloropyridin-2-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide;
4-((2-Chloropyrimidin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide;
4-((3-Fluoropyridin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide;
4-[2-(5-Chloro-3-pyridyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)imidazole-2-carboxamide;
4-((4-Chloropyridin-2-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide;
4-((6-Chloropyrimidin-4-yl)ethynyl)-5-methyl-1-(6-methylpyridin-3-yl)-1H-imidazole-2-carboxamide;
5-Methyl-1-(6-methyl-3-pyridyl)-4-[2-(3-pyridyl)ethynyl]imidazole-2-carboxamide;
5-Methyl-1-(6-methyl-3-pyridyl)-4-[2-(4-pyridyl)ethynyl]imidazole-2-carboxamide;
5-Methyl-1-(6-methylpyridin-3-yl)-4-((2-methylpyridin-4-yl)ethynyl)-1H-imidazole-2-carboxamide;
4-[2-(2-Chloro-3-methyl-4-pyridyl)ethynyl]-5-methyl-1-(5-methylpyrazin-2-yl)imidazole-2-carboxamide;
4-[2-(2-Chloro-3-methyl-4-pyridyl)ethynyl]-5-methyl-1-(6-methylpyridazin-3-yl)imidazole-2-carboxamide;
4-[2-(2-Chloro-3-methyl-4-pyridyl)ethynyl]-5-methyl-1-(5-methyl-3-pyridyl)imidazole-2-carboxamide;
4-[2-(2-Chloro-3-methyl-4-pyridyl)ethynyl]-1-(6-chloro-3-pyridyl)-5-methyl-imidazole-2-carboxamide;
4-[2-(2-Chloro-3-methyl-4-pyridyl)ethynyl]-1-(6-methoxy-3-pyridyl)-5-methyl-imidazole-2-carboxamide;
4-[2-(2-Chloro-3-methyl-4-pyridyl)ethynyl]-5-methyl-1-(5-methyl-2-pyridyl)imidazole-2-carboxamide;
4-[2-(2-Chloro-3-methyl-4-pyridyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide;
4-[2-(3-Chloro-2-methyl-phenyl)ethynyl]-5-methyl-1-(3-pyridyl)imidazole-2-carboxamide;
4-[2-(2-Chloro-4-pyridyl)ethynyl]-5-methyl-1-(6-methyl-3-pyridyl)pyrrole-2-carboxamide;
2-[2-(2-Chloro-4-pyridyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide;
2-[2-(3-Chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide;
2-[2-(3-Chlorophenyl)ethynyl]-1-methyl-5-(6-methyl-3-pyridyl)imidazole-4-carboxamide;
2-[2-(3-Chloro-2-methyl-phenyl)ethynyl]-1-methyl-5-(3-pyridyl)imidazole-4-carboxamide formic acid salt;
2-[2-(2-Chloro-3-methyl-4-pyridyl)ethynyl]-1-methyl-5-

Assignees

• Hoffmann La Roche

Inventors

• Bartels Bjoern
• Dupont Amanda Lee
• Hall Benjamin J
• Wach Jean-Yves
• Schnider Christian
• Schnider Patrick
• Reutlinger Michael
• O'Connor Eoin
• Harde Eva Katrin
• Weber Michael

Classifications

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D233/90

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title