Serotonin 5-HT2B inhibitory compounds

Patent metadata

Field	Value
Publication number	US-12209084-B2
Application number	US-202217870885-A
Country	US
Kind code	B2
Filing date	Jul 22, 2022
Priority date	Jul 26, 2021
Publication date	Jan 28, 2025
Grant date	Jan 28, 2025

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 ;
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, indolyl, or a 5- or 6-membered 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 and isothiazolyl; 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-(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-(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-(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-(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 (1) 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 integer 0 or 1; and pharmaceutically acceptable salts thereof.

9. A Formula (1B) compound of claim 8 selected from the group consisting of:
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-(pyridin-2-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-indole-6-carboxamide;
N-((1R,3s,5S)-8-(isothiazol-5-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-i

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

• 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

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/46

  8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine · CPC title

• C12Q1/689

  for bacteria · CPC title