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

1. A compound of formula (I)

wherein:

R1, R1′, R1″ and R1′″ are

independently of one another H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, (C 0 -C 8 )-alkylene-aryl, O—(C 0 -C 8 )-alkylene-aryl, S-aryl, N(R3)(R4), SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, CON(R5)(R6), N(R7)CO(R8), N(R9)SO 2 (R10), CO(R11), or (C(R12)(R13)) x —O(R14);

R3, R4, R5, R6, R7 and R9 are

independently of one another H or (C 1 -C 8 )-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 contains one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;

R8, R10 and R11 are

independently of one another H, (C 1 -C 8 )-alkyl, or aryl;

R12 and R13 are

independently of one another H, or (C 1 -C 8 )-alkyl;

R14 is H, (C 1 -C 6 )-alkyl, or aryl;

x is 0, 1, 2, 3, 4, 5, or 6;

R2 is H;

Y is C(R27)(R27′)C(R28)(R28′) or C(R29)=C(R29′);

R27, R27′, R28, R28′, R29 and R29′ are H;

X is S, O, or C(R30)=C(R30′);

R30 and R30′ are H;

A is a bond or a linker having 1 to 8 members, where the members are selected from the group consisting of O, S, SO 2 , 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 (C 1 -C 8 )-alkyl;

R32 and R33 are

independently of one another H, (C 1 -C 6 )-alkyl, OH, or O—(C 1 -C 6 )-alkyl;

B is N(R35)(R36), hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, or a 3 to 10-membered mono-, bi-, tri- or spirocyclic nonaromatic ring which contains 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, CF 3 , NO 2 , CN, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R37), CON(R38)(R39), hydroxy, COO(R40), N(R41)CO(C 1 -C 6 )-alkyl, N(R42)(R43), SO 2 CH 3 , SCF 3 or S—(C 1 -C 6 )-alkyl;

R35, R36, R37, R38, R39, R40, R41, R42 and R43 are

independently of one another H, or (C 1 -C 8 )-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 contains one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-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 substituents selected from the group consisting of F, OH, CF 3 , CN, OCF 3 , oxo, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, CO(R44), (C(R45)(R46)) o -R47, and CO(C(R45)(R46)) p -R48, where Q contains in total at least two N atoms;

or Q is selected from the group consisting of:

each of which is optionally substituted one or more times by F, OH, oxo, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, or hydroxy-(C 1 -C 4 )-alkyl;

R44 is H or (C 1 -C 8 )-alkyl;

R45 and R46 are

independently of one another H, (C 1 -C 8 )-alkyl, OH, (C 3 -C 8 )-cycloalkyl, or (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-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—(C 1 -C 8 )-alkyl, CON(R49)(R50), N(R51)CO(R52), N(R53)(R54), CO 2 (R55), SO 2 Me, 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, CF 3 , (C 1 -C 8 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, CO(R56), oxo, or OH;

R49, R50, R51, R52, R55 and R56 are

independently of one another H or (C 1 -C 8 )-alkyl,

or

R49 and R50

taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally contains one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;

R53 and R54 are

independently of one another H, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, CO(R57), (C(R58)(R59)) q -R60, CO(C(R61)(R62)) r -R63, or CO—O(C 1 -C 8 )-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 contains 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, CF 3 , O—(C 1 -C 8 )-alkyl, (C 1 -C 6 )-alkyl, CO(R64), oxo, OH, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, CON(R65)(R66), N(R67)CO(R68), N(R69)(R70), CO 2 (R71), or SO 2 (C 1 -C 6 )-alkyl;

R58 and R59 are

independently of one another H, (C 1 -C 6 )-alkyl, or OH;

R57, R61, R62, R64, R65, R66, R67, R68, R69, R70 and R71 are

independently of one another H or (C 1 -C 6 )-alkyl,

or

R69 and R70

taken together with the nitrogen atom to which they are bonded form a 5-6 membered ring which optionally contains one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-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—(C 1 -C 6 )-alkyl, CN, COO(R78), N(R74)CO(C 1 -C 6 )-alkyl, N(R76)(R77), CON(R72)(R73), SO 2 (C 1 -C 6 )-alkyl, or 3-12 membered mono-, bi- or spirocyclic ring which optionally contains 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, CF 3 , NO 2 , CN, OCF 3 , oxo, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 8 )-cycloalkyl, O—(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, O—(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, N(R76)(R77), COO(R78), SO 2 (C 1 -C 6 )-alkyl or COOH; and

R72, R73, R74, R76, R77 and R78 are

independently of one another H or (C 1 -C 8 )-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 contains one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;

or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein:

B is N(R35)(R36), hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 2 -C 8 )-alkenyl, (C 2 -C 8 )-alkynyl, or a 3 to 10-membered mono-, bi-, tri- or spirocyclic nonaromatic ring which contains 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, where the ring system is optionally substituted one or more times by F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R37), CON(R38)(R39), hydroxy, COO(R40), N(R41)CO(C 1 -C 6 )-alkyl, N(R42)(R43) or SO 2 CH 3 .

3. The compound according to claim 1 , wherein:

B is hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, or a 3 to 10-membered mono-, bi- or spirocyclic nonaromatic ring which contains 0 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, where the ring system is optionally substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R37), CON(R38)(R39), hydroxy, COO(R40), N(R41)CO(C 1 -C 6 )-alkyl, N(R42)(R43) or SO 2 CH 3 .

4. The compound according to claim 1 , wherein:

B is (C 1 -C 8 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, or a 3 to 10-membered mono-, bi- or spirocyclic nonaromatic ring which contains 0 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, where the ring system is optionally substituted by F, Cl, Br, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, CO(R37), hydroxy, COO(R40), N(R41)CO(C 1 -C 6 )-alkyl or SO 2 CH 3 .

5. The compound according to claim 1 , wherein:

R53 is H, (C 1 -C 8 )-alkyl, (C(R58)(R59)) q -R60, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, CO(C(R61)(R62)) r -R63, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, CO—(C 1 -C 6 )-alkyl, or CO—O(C 1 -C 8 )-alkyl, R54 is (C 1 -C 8 )-alkyl, (C(R58)(R59)) q -R60, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, CO(C(R61)(R62)) r -R63, (C 3 -C 8 )-alkenyl, or (C 3 -C 8 )-alkynyl,

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 contains 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, CF 3 , O—(C 1 -C 8 )-alkyl, (C 1 -C 6 )-alkyl, CO(R64), oxo, OH, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, CON(R65)(R66), N(R67)CO(R68), N(R69)(R70), CO 2 (R71), or SO 2 (C 1 -C 6 )-alkyl;

R45 is H or (C 1 -C 6 )-alkyl;

q and r are independently 0, 1, 2, 3 or 4; and

R60 and R63 are

independently of one another OH, F, O—(C 1 -C 6 )-alkyl, N(R74)CO(C 1 -C 6 )-alkyl, SO 2 (C 1 -C 6 )-alkyl, or 3-12 membered mono-, bi- or spirocyclic ring which optionally contains 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, CF 3 , NO 2 , CN, OCF 3 , oxo, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, N(R76)(R77) or SO 2 (C 1 -C 6 )-alkyl.

6. The compound according to claim 1 , wherein:

R53, R54 are independently of one another (C 1 -C 8 )-alkyl, (C(R58)(R59)) q -R60, or (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-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 contains 1 to 2 additional heteroatoms selected from the group consisting of N, O and S, and is optionally substituted one or more times by F, Cl, Br, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, CO(R64), oxo, OH, N(R67)CO(C 1 -C 6 )-alkyl or SO 2 (C 1 -C 6 )-alkyl.

7. The compound according to claim 1 , wherein:

R53 and R54 taken together with the nitrogen atom to which they are bonded form a 6 to 10-membered bi- or spirocyclic ring which optionally contains 1 to 2 additional heteroatoms selected from the group of N, O and S, and is optionally substituted one or more times by F, Cl, Br, CF 3 , (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, CO(R64), oxo, OH, N(R67)CO(C 1 -C 6 )-alkyl, or SO 2 (C 1 -C 6 )-alkyl;

or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein Q is

which is optionally substituted one or more times by F, OH, oxo, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, or hydroxy-(C 1 -C 4 )-alkyl;

or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein Q is

each of which is optionally substituted one or more times by F, OH, oxo, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, or hydroxy-(C 1 -C 4 )-alkyl;

or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , wherein Q is

each of which is optionally substituted one or more times by F, OH, oxo, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, or hydroxy-(C 1 -C 4 )-alkyl.

11. The compound according to claim 1 , wherein Q is

each of which is optionally substituted one or more times by F, OH, oxo, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl.

12. The compound according to claim 1 , wherein:

Y is C(R27)(R27′)C(R28)(R28′); and

R27, R27′, R28, and R28′ are H.

13. The compound according to claim 1 , wherein:

X is S or C(R30)=C(R30′), wherein R30 and R30′ are H.

14. The compound according to claim 1 , wherein:

X is C(R30)=C(R30′), wherein R30 and R30′ are H.

15. The compound according to claim 1 , wherein:

X is S or O;

or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 , wherein:

Y is C(R29)=C(R29′); and

R29 and R29′ are H;

or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 , which is a compound of formula Ia:

or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

18. The compound according to claim 1 , wherein:

Y is C(R29)=C(R29′); and

X is C(R30)=C(R30′);

or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

19. The compound according to claim 1 , wherein:

Y is C(R29)=C(R29′);

X is C(R30)=C(R30′);

Q is

R53 is H, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, or (C(R58)(R59)) q -R60;

or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

20. The compound according to claim 1 , wherein:

Y is C(R27)(R27′)C(R28)(R28′);

X is C(R30)=C(R30′);

Q is

R53 is (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl or (C(R58)(R59)) q -R60;

R58 and 59 are

independently of one another H or OH;

q and r are independently of one another 1, 2, 3 or 4; and

R60 and R63 are

independently of one another F, O—(C 1 -C 6 )-alkyl, N(R74)CO(C 1 -C 6 )-alkyl, SO 2 (C 1 -C 6 )-alkyl, or 3-12 membered mono-, bi- or spirocyclic ring which contains 0 to 3 additional heteroatoms selected from the group consisting of O and S, and the 3-12 membered ring is optionally substituted by F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , oxo, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl or SO 2 (C 1 -C 6 )-alkyl;

or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

21. The compound according to claim 1 , wherein:

R1, R1′, R1″ and R1′″ are independently of one another selected from H, F, Cl, methyl, O-methyl, and CO-methyl.

22. The compound according to claim 1 , wherein:

A is a bond or a linker having 1 to 6 members, where the members are selected from the group consisting of O, N(R31), CO, C(R32)(R33), C(R34)=C(R34′), and C≡C, resulting in a chemically reasonable radical.

23. The compound according to claim 1 , wherein:

A is selected from a bond, O, NH, CH(OH), CH 2 , CO, C≡C, HC═CH, CH 2 —O, CH(CH 3 )—O, CO—CH(CH 3 )—O, CO—NH, NH—CO, N(CH 3 )—CO, COCH 2 O, CH(OH)CH 2 O, O—CO—NH, C(OH)(CH 3 )—C≡C, and COCH 2 CH 2 O.

24. The compound according to claim 1 , wherein:

B is hydroxy-(C 1 -C 4 )-alkyl, (C 1 -C 8 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, or a monocyclic ring selected from the group consisting of

wherein the monocyclic ring is optionally substituted one or two times by F, CF 3 , CN, methyl, ethyl, methoxy, oxo, hydroxy, or SO 2 -methyl.

25. The compound according to claim 1 , wherein B-A is

wherein the tetrahydrofuranyl ring is optionally substituted one time by methyl or OH.

26. The compound according to claim 1 , wherein B-A is

or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition comprising the compound according to claim 1 , or pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one additional active ingredient that has a beneficial effect on a metabolic disturbance or a disorder associated therewith.

29. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one antidiabetic active ingredient.

30. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one lipid modulator.

31. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and at least one antiobesity active ingredient.