Novel azacyclyl-substituted aryldihydroisoquinolinones, process for their preparation and their use as medicaments

A compound of formula (I)

• wherein:
• R1, R1′, R1″ and R1′″ are
• independently of one another H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R3)(R4), SO2—CH3, COOH, COO—(C1-C6)-alkyl, CON(R5)(R6), N(R7)CO(R8), N(R9)SO2(R10), CO(R11), or (C(R12)(R13))x-O(R14);
• R3, R4, R5, R6, R7 and R9 are
• independently of one another H or (C1-C8)-alkyl,
• or
• R3 and R4, or R5 and R6
• independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C1-C6)-alkyl, oxygen and sulfur;
• R8, R10 and R11 are
• independently of one another H, (C1-C8)-alkyl, or aryl;
• R12 and R13 are
• independently of one another H, or (C1-C8)-alkyl;
• R14 is H, (C1-C6)-alkyl, or aryl;
• x is 0, 1, 2, 3, 4, 5, or 6;
• R2 is H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R15)(R16), SO2—CH3, COOH, COO—(C1-C6)-alkyl, CON(R17)(R18), N(R19)CO(R20), N(R21)SO2(R22), CO(R23), or (C(R24)(R25)))-O(R26);
• R15, R16, R17, R18, R19 and R21 are
• independently of one another H or (C1-C8)-alkyl,
• or
• R15 and R16, or R17 and R18
• independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C1-C6)-alkyl, oxygen and sulfur;
• R20, R22 and R23 are
• independently of one another H, (C1-C8)-alkyl, or aryl;
• R24 and R25 are
• independently of one another H or (C1-C8)-alkyl;
• R26 is H, (C1-C6)-alkyl, or aryl;
• x′ is 0, 1, 2, 3, 4, 5, or 6;
• Y is C(R27)(R27′)C(R28)(R28′), or C(R29)=C(R29′);
• R27, R27′, R28, R28′, R29 and R29′ are
• independently of one another H, F, Cl, Br, CN, (C1-C8)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl;
• X is S, O, or C(R30)=C(R30′);
• R30 and R30′ are
• independently of one another H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R15)(R16), SO2—CH3, COOH, COO—(C1-C6)-alkyl, CON(R17)(R18), N(R19)CO(R20), N(R21)SO2(R22), CO(R23), or (C(R24)(R25))x′-O(R26);
• A is a bond or a linker having 1 to 8 members, where the members are selected from the group consisting of O, S, SO2, N(R31), CO, C(R32)(R33), C(R34)=C(R34′), cyclopropylene, and C≡C, resulting in a chemically reasonable radical;
• R31, R34 and R34′ are
• independently of one another H or (C1-C8)-alkyl;
• R32 and R33 are
• independently of one another H, (C1-C6)-alkyl, OH, or O—(C1-C6)-alkyl;
• B is N(R35)(R36), hydroxy-(C1-C4)-alkyl, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, or a 3 to 10-membered mono-, bi-, tri- or spirocyclic nonaromatic ring which comprises 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and the ring system is optionally substituted one or more times by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, oxo, CO(R37), CON(R38)(R39), hydroxy, COO(R40), N(R41)CO(C1-C6)-alkyl, N(R42)(R43), SO2CH3, SCF3 or S—(C1-C6)-alkyl;
• R35, R36, R37, R38, R39, R40, R41, R42 and R43 are
• independently of one another H, or (C1-C8)-alkyl;
• or
• R38 and R39, or R42 and R43
• independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C1-C6)-alkyl, oxygen and sulfur;
• Q is mono-, bi-, tri- or spirocyclic saturated or partly unsaturated ring structure having one nitrogen atom and 0-3 additional heteroatoms selected from the group consisting of N, O and S, where the ring of the structure may be spiro-linked, fused or bridged, and where the ring system is optionally substituted one or more times by F, OH, CF3, CN, OCF3, oxo, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, CO(R44), (C(R45)(R46))o-R47, or CO(C(R45)(R46))p-R48, where Q comprises in total at least two N atoms;
• R44 is H or (C1-C8)-alkyl;
• R45 and R46 are
• independently of one another H, (C1-C8)-alkyl, OH, (C3-C8)-cycloalkyl, or (C1-C4)-alkoxy-(C1-C4)-alkyl;
• o and p are independently of one another 0, 1, 2, 3, 4, 5 or 6;
• R47 and R48 are
• independently of one another OH, F, O—(C0-C8)-alkyl, CON(R49)(R50), N(R51)CO(R52), N(R53)(R54), CO2(R55), SO2Me, CN, or a 3-10 membered ring system having 0 to 3 heteroatoms selected from the group of N, O and S, which may be substituted by one or more of the following substituents:
• F, Cl, Br, CF3, (C1-C8)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, CO(R56), oxo, or OH;
• R49, R50, R51, R52, R55 and R56 are
• independently of one another H or (C1-C8)-alkyl,
• or
• R49 and R50
• taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C1-C6)-alkyl, oxygen and sulfur;
• R53 and R54 are
• independently of one another H, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, CO(R57), (C(R58)(R59))q-R60, CO(C(R61)(R62))rR63, or CO—O(C1-C8)-alkyl, or
• R53 and R54 taken together with the nitrogen atom to which they are bonded form a 4 to 10-membered mono-, bi- or spirocyclic ring which optionally comprises 1 to 3 additional heteroatoms selected from the group consisting of N, O and S, and is optionally substituted one or more times by F, Cl, Br, CF3, O—(C1-C8)-alkyl, (C1-C6)-alkyl, CO(R64), oxo, OH, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, CON(R65)(R66), N(R67)CO(R68), N(R69)(R70), CO2(R71), or SO2(C1-C6)-alkyl;
• R58 and R59 are
• independently of one another H, (C1-C6)-alkyl, or OH;
• R57, R61, R62, R64, R65, R66, R67, R68, R69, R70 and R71 are
• independently of one another H or (C1-C6)-alkyl,
• or
• R69 and R70
• taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C1-C6)-alkyl, oxygen and sulfur;
• q and r are independently of one another 0, 1, 2, 3, 4, 5 or 6;
• R60 and R63 are
• independently of one another OH, F, O—(C1-C6)-alkyl, CN, COO(R78), N(R74)CO(C1-C6)-alkyl, N(R76)(R77), CON(R72)(R73), SO2(C1-C6)-alkyl, or 3-12 membered mono-, bi- or spirocyclic ring which optionally comprises one or more heteroatoms selected from the group consisting of N, O and S, and the 3-12 membered ring is optionally substituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, oxo, O—(C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O—(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, N(R76)(R77), COO(R78), SO2(C1-C6)-alkyl or COOH;
• and
• R72, R73, R74, R76, R77 and R78 are
• independently of one another H or (C1-C8)-alkyl,
• or
• R72 and R73, or R76 and R77
• independently of one another taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally comprises one additional heteroatom selected from the group consisting of NH, N—(C1-C6)-alkyl, oxygen and sulfur;
• or an isomer, hydrate, solvate or pharmaceutically acceptable salt thereof.