7-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof

12:

• A method of treatment of heart failure, coronary heart disease, atrial and ventricular arrhythmia, renal failure and nephropathy, comprising administering a compound of formula (I),
• wherein
• X is halogen,
• R1 is hydrogen,
• or
• is —NR4R5,
• wherein
• R4 is hydrogen, methyl, (C2-C4)-alkyl or (C3-C6)-cycloalkyl,
• wherein (C2-C4)-alkyl is optionally substituted by hydroxyl or up to trisubstituted by fluorine:
• and
• R5 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered saturated heterocyclyl or (C1-C4)-alkylsulfonyl,
• wherein (C1-C6)-alkyl, (C3-C6)-cycloalkyl and 3- to 6-membered saturated heterocyclyl are optionally up to trisubstituted, identically or differently, by methyl, difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy or cyano, and additionally up to tetrasubstituted by fluorine,
• or
• R4 and R5 together with the nitrogen atom to which they are bonded form a saturated or partially unsaturated, 3- to 6-membered monocyclic or 6- to 10-membered bicyclic heterocycle which optionally contains one or two further, identical or different heteroatoms selected from the group consisting of N, O, S, SO and SO2 as ring members,
• wherein the 3- to 6-membered monocyclic and the 6- to 10-membered bicyclic heterocycle are optionally substituted by 1 to 5 substituents independently selected from the group consisting of (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl, oxo, (C1-C3)-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, (C1-C3)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C3)-alkylaminocarbonyloxy, —NHC(═O)R14A, —CH2NHC(═O)R14B, and —OC(═O)R15, and additionally up to tetrasubstituted by fluorine,
• wherein (C1-C4)-alkyl is optionally mono- or disubstituted, identically or differently, by hydroxyl or (C1-C3)-alkoxy, and up to tetrasubstituted by fluorine,
• R14A and R14B are independently (C1-C3)-alkyl or cyclopropyl,
• and wherein
• R15 is (C1-C4)-alkyl,
• R2 is a group of the formula
• wherein
• * marks the point of attachment to the nitrogen atom of the amide moiety,
• R6A is hydrogen or (C1-C4)-alkyl,
• R6B is hydrogen, (C1-C4)-alkyl, cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl or trifluoromethoxymethyl,
• R7 is (C1-C6)-alkyl or (C3-C5)-cycloalkyl which is up to tetrasubstituted by fluorine,
• wherein (C1-C6)-alkyl is optionally substituted by amino, hydroxy, or (C1-C6)alkoxy and up to pentasubstituted by fluorine,
• wherein (C1-C6)-alkoxy is optionally up to pentasubstituted by fluorine,
• L1 is a bond or a group of the formula —C(R8AR8)—(C(R9AR9B))m—,
• wherein
• m is 0 or 1,
• R8A is hydrogen or methyl,
• R8B is hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl,
• R9A and R9B are independently hydrogen or methyl,
• Ar2 is phenyl,
• wherein phenyl is optionally mono- to trisubstituted, identically or differently, by fluorine, chlorine, (C1-C3)-alkyl, difluoromethoxymethyl, trifluoromethoxymethyl or trifluoromethyl,
• or
• Ar2 is a 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle which optionally contains one or two further identical or different heteroatoms selected from the group consisting of N and O as ring members,
• wherein the 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle is optionally up to trisubstituted by identical or different substituents from the group consisting of (C1-C3)-alkyl, trifluoromethyl and (C1-C4)alkoxycarbonyl and furthermore up to tetrasubstituted by fluorine,
• Ar1 is a group of the formula
• wherein
• *** marks the point of attachment to the nitrogen atom,
• R3A is fluorine, chlorine, trifluoromethyl or methyl,
• R3B is hydrogen or fluorine,
• and
• R3C is hydrogen, fluorine, chlorine or methyl:
• or
• Ar1 is a pyridine ring which is attached via a ring carbon atom,
• wherein the pyridine ring is optionally mono- or disubstituted by fluorine, chlorine, cyano, methyl or trifluoromethyl,
• or an N-oxide, a salt, a solvate, a salt of the N-oxide, a solvate of the N-oxide, or a solvate of the salt thereof.

15:

• A method for treatment of heart failure, coronary heart disease, atrial and ventricular arrhythmia, renal failure and nephropathy, comprising administering a pharmaceutical combination comprising a compound of formula (I),
• wherein
• X is halogen,
• R1 is hydrogen,
• or
• is —NR4R5,
• wherein
• R4 is hydrogen, methyl, (C2-C4)-alkyl or (C3-C6)-cycloalkyl,
• wherein (C2-C4)-alkyl is optionally substituted by hydroxyl or up to trisubstituted by fluorine:
• and
• R5 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered saturated heterocyclyl or (C1-C4)-alkylsulfonyl,
• wherein (C1-C6)-alkyl, (C3-C6)-cycloalkyl and 3- to 6-membered saturated heterocyclyl are optionally up to trisubstituted, identically or differently, by methyl, difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy or cyano, and additionally up to tetrasubstituted by fluorine,
• or
• R4 and R5 together with the nitrogen atom to which they are bonded form a saturated or partially unsaturated, 3- to 6-membered monocyclic or 6- to 10-membered bicyclic heterocycle which optionally contains one or two further, identical or different heteroatoms selected from the group consisting of N, O, S, SO and SO2 as ring members,
• wherein the 3- to 6-membered monocyclic and the 6- to 10-membered bicyclic heterocycle are optionally substituted by 1 to 5 substituents independently selected from the group consisting of (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl, oxo, (C1-C3)-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, (C1-C3)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C3)-alkylaminocarbonyloxy, —NHC(═O)R14A, —CH2NHC(═O)R14B, and —OC(═O)R15, and additionally up to tetrasubstituted by fluorine,
• wherein (C1-C4)-alkyl is optionally mono- or disubstituted, identically or differently, by hydroxyl or (C1-C3)-alkoxy, and up to tetrasubstituted by fluorine,
• R14A and R14B are independently (C1-C3)-alkyl or cyclopropyl,
• and wherein
• R15 is (C1-C4)-alkyl,
• R2 is a group of the formula
• wherein
• * marks the point of attachment to the nitrogen atom of the amide moiety,
• R6A is hydrogen or (C1-C4)-alkyl,
• R6B is hydrogen, (C1-C4)-alkyl, cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl or trifluoromethoxymethyl,
• R7 is (C1-C6)-alkyl or (C3-C5)-cycloalkyl which is up to tetrasubstituted by fluorine,
• wherein (C1-C6)-alkyl is optionally substituted by amino, hydroxy, or (C1-C6)alkoxy and up to pentasubstituted by fluorine,
• wherein (C1-C6)-alkoxy is optionally up to pentasubstituted by fluorine,
• L1 is a bond or a group of the formula —C(R8AR8B)—(C(R9AR9B))m—,
• wherein
• m is 0 or 1,
• R8A is hydrogen or methyl,
• R8B is hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl,
• R9A and R9B are independently hydrogen or methyl,
• Ar2 is phenyl,
• wherein phenyl is optionally mono- to trisubstituted, identically or differently, by fluorine, chlorine, (C1-C3)-alkyl, difluoromethoxymethyl, trifluoromethoxymethyl or trifluoromethyl,
• or
• Ar2 is a 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle which optionally contains one or two further identical or different heteroatoms selected from the group consisting of N and O as ring members,
• wherein the 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle is optionally up to trisubstituted by identical or different substituents from the group consisting of (C1-C3)-alkyl, trifluoromethyl and (C1-C4)alkoxycarbonyl and furthermore up to tetrasubstituted by fluorine,
• Ar1 is a group of the formula
• wherein
• *** marks the point of attachment to the nitrogen atom,
• R3A is fluorine, chlorine, trifluoromethyl or methyl,
• R3B is hydrogen or fluorine,
• and
• R3C is hydrogen, fluorine, chlorine or methyl:
• or
• Ar1 is a pyridine ring which is attached via a ring carbon atom,
• wherein the pyridine ring is optionally mono- or disubstituted by fluorine, chlorine, cyano, methyl or trifluoromethyl,
• or an N-oxide, a salt, a solvate, a salt of the N-oxide, a solvate of the N-oxide, or a solvate of the salt thereof,
• in combination with one or more further active ingredients selected from the group consisting of active hypotensive ingredients, active antiarrhythmic ingredients, vasopressin receptor antagonists, PDE 5 inhibitors, platelet aggregation inhibitors, sGC activators and sGC stimulators.

16:

• A method of treatment of heart failure, coronary heart disease, atrial and ventricular arrhythmia, renal failure and nephropathy, comprising administering a pharmaceutical composition comprising a compound of formula (I),
• wherein
• X is halogen,
• R1 is hydrogen,
• or
• is —NR4R5,
• wherein
• R4 is hydrogen, methyl, (C2-C4)-alkyl or (C3-C6)-cycloalkyl,
• wherein (C2-C4)-alkyl is optionally substituted by hydroxyl or up to trisubstituted by fluorine;
• and
• R5 is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered saturated heterocyclyl or (C1-C4)-alkylsulfonyl,
• wherein (C1-C6)-alkyl, (C3-C6)-cycloalkyl and 3- to 6-membered saturated heterocyclyl are optionally up to trisubstituted, identically or differently, by methyl, difluoromethyl, trifluoromethyl, hydroxyl, hydroxycarbonyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy or cyano, and additionally up to tetrasubstituted by fluorine,
• or
• R4 and R5 together with the nitrogen atom to which they are bonded form a saturated or partially unsaturated, 3- to 6-membered monocyclic or 6- to 10-membered bicyclic heterocycle which optionally contains one or two further, identical or different heteroatoms selected from the group consisting of N, O, S, SO and SO2 as ring members,
• wherein the 3- to 6-membered monocyclic and the 6- to 10-membered bicyclic heterocycle are optionally substituted by 1 to 5 substituents independently selected from the group consisting of (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxycarbonyl, oxo, (C1-C3)-alkoxy, difluoromethoxy, trifluoromethoxy, cyano, (C1-C3)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C3)-alkylaminocarbonyloxy, —NHC(═O)R14A, —CH2NHC(═O)R14B, and —OC(═O)R15, and additionally up to tetrasubstituted by fluorine,
• wherein (C1-C4)-alkyl is optionally mono- or disubstituted, identically or differently, by hydroxyl or (C1-C3)-alkoxy, and up to tetrasubstituted by fluorine,
• R14A and R14B are independently (C1-C3)-alkyl or cyclopropyl,
• and wherein
• R15 is (C1-C4)-alkyl,
• R2 is a group of the formula
• wherein
• * marks the point of attachment to the nitrogen atom of the amide moiety,
• R6A is hydrogen or (C1-C4)-alkyl,
• R6B is hydrogen, (C1-C4)-alkyl, cyclopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl or trifluoromethoxymethyl,
• R7 is (C1-C6)-alkyl or (C3-C5)-cycloalkyl which is up to tetrasubstituted by fluorine,
• wherein (C1-C6)-alkyl is optionally substituted by amino, hydroxy, or (C1-C6)alkoxy and up to pentasubstituted by fluorine,
• wherein (C1-C6)-alkoxy is optionally up to pentasubstituted by fluorine,
• L1 is a bond or a group of the formula —C(R8AR8B)—(C(R9AR9B))m—,
• wherein
• m is 0 or 1,
• R8A is hydrogen or methyl,
• R8B is hydrogen, methyl, trifluoromethyl, pentafluoroethyl or trifluoromethoxymethyl,
• R9A and R9B are independently hydrogen or methyl,
• Ar2 is phenyl,
• wherein phenyl is optionally mono- to trisubstituted, identically or differently, by fluorine, chlorine, (C1-C3)-alkyl, difluoromethoxymethyl, trifluoromethoxymethyl or trifluoromethyl,
• or
• Ar2 is a 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle which optionally contains one or two further identical or different heteroatoms selected from the group consisting of N and O as ring members,
• wherein the 5- to 10-membered monocyclic, bicyclic or tricyclic carbocycle or heterocycle is optionally up to trisubstituted by identical or different substituents from the group consisting of (C1-C3)-alkyl, trifluoromethyl and (C1-C4)alkoxycarbonyl and furthermore up to tetrasubstituted by fluorine,
• Ar1 is a group of the formula
• wherein
• *** marks the point of attachment to the nitrogen atom,
• R3A is fluorine, chlorine, trifluoromethyl or methyl,
• R3B is hydrogen or fluorine,
• and
• R3C is hydrogen, fluorine, chlorine or methyl;
• or
• Ar1 is a pyridine ring which is attached via a ring carbon atom,
• wherein the pyridine ring is optionally mono- or disubstituted by fluorine, chlorine, cyano, methyl or trifluoromethyl,
• or an N-oxide, a salt, a solvate, a salt of the N-oxide, a solvate of the N-oxide, or a solvate of the salt thereof,
• in combination with an inert, non-toxic, pharmaceutically suitable excipient.