Substituted 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-C]pyridines, their use as medicament, and pharmaceutical preparations comprising them

Patent metadata

Field	Value
Publication number	US-9598410-B2
Application number	US-201514822361-A
Country	US
Kind code	B2
Filing date	Aug 10, 2015
Priority date	Sep 16, 2011
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

The invention relates to substituted 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridines of formula (I), their use as medicament, and pharmaceutical preparations comprising them. The compounds of formula (I) act on the TASK-1 potassium channel. The compounds are particularly suitable for the treatment or prevention of atrial arrhythmias, for example atrial fibrillation (AF) or arterial flutter.

First claim

The invention claimed is:

1. A compound of the formula I

wherein
A is a five- or six-membered heteroaryl comprising 1-3 heteroatoms selected from the group N, O and S, provided that the five- or six-membered heteroaryl is not pyrimidin-2-yl, the five- or six-membered heteroaryl being substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C 1 -C 6 )-alkyl-, (C 1 -C 6 )-alkyl-O— and (C 1 -C 6 )-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine;
X is (C 6 -C 10 )-aryl or a five- or six-membered heteroaryl comprising 1-3 heteroatoms selected from the group N, O and S, wherein the aryl and heteroaryl are optionally substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C 1 -C 6 )-alkyl-, (C 1 -C 6 )-alkyl-O—, (C 1 -C 6 )-alkyl-S—, (C 1 -C 6 )-alkyl-C(O)— and (C 1 -C 6 )-alkyl-SO 2 —, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine;
R1 is R5-C(═O)— or (C 1 -C 6 )-alkyl-SO 2 —;
R2 is H, (C 1 -C 6 )-alkyl- or (C 3 -C 6 )-cycloalkyl-;
R3 is H or (C 1 -C 4 )-alkyl-;
R4 is H or (C 1 -C 4 )-alkyl-;
or R3 and R4 together form a (C 2 -C 3 )-alkylene bridge;
R5 is H, (C 1 -C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-, (C 1 -C 6 )-alkyl-O—, (C 1 -C 6 )-alkyl-S—, (C 1 -C 6 )-alkyl-O—(C 1 -C 6 )-alkyl-, HO—(C 1 -C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-(C 1 -C 6 )-alkyl-, (C 6 -C 10 )-aryl-, (C 6 -C 10 )-aryl-(C 1 -C 6 )-alkyl-, R7R6N—, heteroaryl, heteroaryl-(C 1 -C 6 )-alkyl-or aliphatic heterocycle,
wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, and
wherein the aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and four- to seven-membered aliphatic heterocycles comprising an oxygen atom, each optionally substituted with 1 to 3 substituents independently selected from F, OH, (C 1 -C 6 )-alkyl-O— and (C 1 -C 6 )-alkyl-, and
wherein the heteroaryl residues are five- or six-membered ring systems comprising 1-3 heteroatoms selected from the group N, O and S, and
wherein the aryl and heteroaryl are optionally substituted with 1-3 groups selected independently from F, Cl, Br, CF 3 , (C 1 -C 6 )-alkyl-, (C 1 -C 6 )-alkyl-O—, CN, (C 1 -C 2 )-alkyl-SO 2 —;

R6 is H, (C 1 -C 6 )-alkyl- or (C 3 -C 6 )-cycloalkyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy or (C 1 -C 6 )-alkyl-O—, and wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine; and
R7 is H or (C 1 -C 6 )-alkyl-, wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine;
or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof;
with the proviso if R5 is methyl and R2, R3 and R4 are H and X is a phenyl residue, the residue A is not thiophen-2-yl.

2. The compound according to claim 1 , wherein A is selected from the group consisting of thiophen-2-yl, thiophen-3-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrid-2-yl, pyrid-3-yl and pyrid-4-yl, each substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C 1 -C 6 )-alkyl-, (C 1 -C 6 )-alkyl-O— and (C 1 -C 6 )-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine.

3. The compound according to claim 1 , wherein A is selected from the group consisting of thiophen-2-yl, thiophen-3-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrid-2-yl, pyrid-3-yl and pyrid-4-yl, each substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C 1 -C 6 )-alkyl-, (C 1 -C 6 )-alkyl-O— and (C 1 -C 6 )-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine.

4. The compound according to claim 1 , wherein
A is selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thiophen-2-yl and thiophen-3-yl, each substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C 1 -C 6 )-alkyl-, (C 1 -C 6 )-alkyl-O— and (C 1 -C 6 )-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; and
X is a five- or six-membered heteroaryl comprising 1-3 heteroatoms selected from the group N, O and S, wherein the heteroaryl group is optionally substituted with 1-3 residues selected independently from F, Cl, Br, CN, (C 1 -C 6 )-alkyl-, (C 1 -C 6 )-alkyl-O—, (C 1 -C 6 )-alkyl-S—, (C 1 -C 6 )-alkyl-O—C(O)— and (C 1 -C 6 )-alkyl-SO 2 —, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine;
or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 , wherein
X is phenyl, thiophen-2-yl or thiophen-3-yl, each optionally substituted with 1-3 groups selected independently from F, Cl, Br, CN, (C 1 -C 6 )-alkyl-, (C 1 -C 6 )-alkyl-O—, (C 1 -C 6 )-alkyl-S—, (C 1 -C 6 )-alkyl-O—C(O)— and (C 1 -C 6 )-alkyl-SO 2 —, wherein one or more hydrogen atoms of the alkyl moieties may be replaced by fluorine;
or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof.

6. A compound according to claim 5 , wherein
A is pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, wherein the pyridyl residues are substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C 1 -C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 , and (C 1 -C 2 )-alkyl-S—;
X is phenyl, thiophen-2-yl or thiophen-3-yl, wherein these residues are substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C 1 -C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 , (C 1 -C 2 )-alkyl-S—, (C 1 -C 2 )-alkyl-O—C(O)— and methyl-SO 2 —;
R1 is R5-C(═O)— or (C 1 -C 2 )-alkyl-SO 2 —;
R2 is H, methyl, ethyl, cyclopropyl;
R3 and R4 is H; and
R5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl
or R5 is cyclopropyl, cyclobutyl, cyclopentyl or (C 3 -C 6 )-cycloalkyl-(C 1 -C 2 )-alkyl-;
or R5 is (C 1 -C 2 )-alkyl-O—, (C 1 -C 2 )-alkyl-S—, or OCF 3 ,
or R5 is (C 1 -C 4 )-alkyl-O-methyl-, HO—(C 1 -C 2 )-alkyl-,
or R5 is phenyl or phenylmethyl-,
wherein the phenyl residues are optionally substituted with 1-3 groups selected independently from F, Cl, Br, CF 3 , (C 1 -C 2 )-alkyl-, (C 1 -C 2 )-alkyl-O—, CN methyl-SO 2 —;

or R5 is R7R6N—, wherein
R6 is H, (C 1 -C 4 )-alkyl-, cyclopropyl,
wherein one hydrogen atom of the alkyl group may be replaced by an OH, methoxy or ethoxy residue; and
R7 is H, methyl-, ethyl;

or R5 is heteroaryl, heteroaryl-(C 1 -C 6 )-alkyl-,
wherein the heteroaryl residues are selected from the group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl, and
wherein the heteroaryl residues are optionally substituted with 1 or 2 groups selected independently from F, Cl, Br, CF 3 , (C 1 -C 4 )-alkyl-, (C 1 -C 4 )-alkyl-O—, CN,(C 1 -C 2 )-alkyl-SO 2 —;

or R5 is morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl and tetrahydrofuranyl, tetrahydropyranyl, each optionally substit

Assignees

• Sanofi Sa

Inventors

• Bialy Laurent
• Lorenz Katrin
• Wirth Klaus
• Steinmeyer Klaus
• Hessler Gerhard
• Pernerstorfer Josef
• Brendel Joachim

Classifications

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P11/16

  Central respiratory analeptics · CPC title