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

摘要

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.;

主权项

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, (C1-C6)-alkyl-, (C1-C6)-alkyl-O— and (C1-C6)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; X is (C6-C10)-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, (C1-C6)-alkyl-, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S—, (C1-C6)-alkyl-C(O)— and (C1-C6)-alkyl-SO2—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; R1 is R5-C(═O)— or (C1-C6)-alkyl-SO2—; R2 is H, (C1-C6)-alkyl- or (C3-C6)-cycloalkyl-; R3 is H or (C1-C4)-alkyl-; R4 is H or (C1-C4)-alkyl-; or R3 and R4 together form a (C2-C3)-alkylene bridge; R5 is H, (C1-C6)-alkyl-, (C3-C6)-cycloalkyl-, (C1-C6)-alkyl-O—, (C1-C6)-alkyl-S—, (C1 -C6)-alkyl-O—(C1-C6)-alkyl-, HO—(C1-C6)-alkyl-, (C3-C6)-cycloalkyl-(C1-C6)-alkyl-, (C6-C10)-aryl-, (C6-C10)-aryl-(C1-C6)-alkyl-, R7R6N—, heteroaryl, heteroaryl-(C1-C6)-alkyl-or aliphatic heterocycle,
wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, andwherein 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, (C1-C6)-alkyl-O— and (C1-C6)-alkyl-, andwherein the heteroaryl residues are five- or six-membered ring systems comprising 1-3 heteroatoms selected from the group N, O and S, andwherein the aryl and heteroaryl are optionally substituted with 1-3 groups selected independently from F, Cl, Br, CF3, (C1-C6)-alkyl-, (C1-C6)-alkyl-O—, CN, (C1-C2)-alkyl-SO2—; R6 is H, (C1-C6)-alkyl- or (C3-C6)-cycloalkyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy or (C1-C6)-alkyl-O—, and wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine; and R7 is H or (C1-C6)-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.