Serotonin 5-ht2b inhibitory compounds

Patent metadata

Field	Value
Publication number	US-2023071039-A1
Application number	US-202217870885-A
Country	US
Kind code	A1
Filing date	Jul 22, 2022
Priority date	Jul 26, 2021
Publication date	Mar 9, 2023
Grant date	—

Abstract

The invention describes novel serotonin c5-HT2B receptor antagonists of Formula (1), and pharmaceutically acceptable salts thereof; wherein Ring A, L, X, X′,

R 3 , R 4 , m and n are as defined herein. Also described are compositions comprising a Formula (1) compound, or a pharmaceutically acceptable salt thereof; and methods of using the compounds, or a pharmaceutically acceptable salt thereof, for the treatment of myxomatous mitral valve disease (MMVD), congestive heart failure (CHF) and/or asymptomatic heart failure in animals, preferably is a canine.

First claim

We claim:

1 . A Formula (1) compound,

wherein X is CH or N;
L is NR 1 or O;
X′ is CR 2 or N;
R 1 is H, C 1 -C 6 alkyl, phenyl or pyridinyl and wherein the phenyl or pyridinyl are each optionally substituted with one or two R 4 substituents;
R 2 is H, C 1 -C 4 alkyl, —CF 3 or halo;
R 3 is H, cyano, halo, C 1 -C 4 alkyl or —CF 3 ;
or R 2 and R 3 join together to form a 5- or 6-membered carbocyclic ring optionally substituted with methyl, halo or —CF 3 ;
Ring A is phenyl, naphthyl, a 5- or 6-membered heteroaryl ring containing at least one heteroatom selected from the group consisting of N, O and S; or a 10- or 11-membered fused heteroaryl ring containing at least one heteroatom selected from the group consisting of N, O and S;
R 4 is selected from C 1 -C 4 alkyl, halo, cyano or —CF 3 ,
m is the integer 0, 1 or 2;
n is the integer 0, 1, 2 or 3; and when n is the integer 2 or 3 then each R 4 can be the same or different; and pharmaceutically acceptable salts thereof.

2 . A Formula (1) compound of claim 1 wherein Ring A is selected from the group consisting of phenyl, thiophenyl, pyridinyl, thiazolyl, isothiazolyl and indolyl; L is NR 1 and m is the integer 1; and pharmaceutically acceptable salts thereof.

3 . A Formula (1) compound of claim 1 selected from the group consisting of:
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;
N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;
N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2,3,4,9-tetrahydro-1H-carbazole-7-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indazole-6-carboxamide;
N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(pyridin-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(pyridin-4-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-3-cyano-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide;
N-((1R,3s,5S)-8-(isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(thiazol-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide; and
N-((1R,3s,5S)-8-((4-methylthiazol-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

4 . A Formula (1) compound of claim 3 selected from the group consisting of:
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;
N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;
N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-(4-fluorophenyl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1-phenyl-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide;
N-((1R,3s,5S)-8-(isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide; and
N-((1R,3s,5S)-8-(isothiazol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

5 . A Formula (1) compound of claim 4 selected from the group consisting of:
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;
N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide;
N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-((1H-indol-5-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(thiophen-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)benzofuran-6-carboxamide; and
N-((1R,3s,5S)-8-(isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

6 . A Formula (1) compound of claim 2 that is a Formula (1A) compound

wherein R 2 is H, methyl or —CF 3 ; R 3 is H, methyl or cyano; and n is the integer 0, 1 or 2; and pharmaceutically acceptable salts thereof.

7 . A Formula (1A) compound of claim 6 selected from the group consisting of:
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(4-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-methyl-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(4-(trifluoromethyl)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide; and
N-((1R,3s,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(trifluoromethyl)-1H-indole-6-carboxamide; and pharmaceutically acceptable salts thereof.

8 . A Formula (1) compound of claim 1 that is a Formula (1B) compound,

wherein Ring A is selected from the group consisting of indolyl, thiophenyl, pyridinyl, isothiazolyl and thiazolyl; R 4 is methyl or halo; and n is the inte

Assignees

• Zoetis Services Llc

Inventors

• Ewin Richard A
• Fenwick Ashley E
• Subramanian Govindan

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• C12Q1/686

  Polymerase chain reaction [PCR] · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C12Q1/6806

  Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay (C12Q1/6804 takes precedence) · CPC title

• C07D451/04 Primary

  with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system · CPC title