Amino alcohol-substituted arylthienopyrimidinones, process for their preparation and their use as medicaments

1. A compound of formula I

wherein:

D is N, or C(R 1″ );

R 1 , R 1′ , R 1′″ are independently of one another H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (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 1 -C 8 )-alkylene-(C 3 -C 8 )-cycloalkyl, 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), (C(R12)(R13)) x -O(R14), or (C 2 -C 6 )-alkynyl-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 comprises 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, or (C 1 -C 8 )-alkyl;

R12 and R13 are independently of one another H, or (C 1 -C 8 )-alkyl;

R14, and R14′ are

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

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

R 2 is 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 2 -C 6 )-alkynyl, aryl which is optionally substituted with F, Cl, Br, O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, CO(C 1 -C 6 )-alkyl;

R 27 is H, or (C 1 -C 6 )-alkyl;

X is S or O;

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;

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 H, 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 optionally comprises 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein 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, and the ring system may be linked to A by ═C(R43′);

R35, R36, R37, R38, R39, R40, R41, R42, R43, 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 comprises one additional heteroatom selected from the group consisting of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;

L is a bond, or (C 1 -C 3 )-alkylene;

Q is a group selected from

is independently of one another H, (C(C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, CO—(C 1 -C 6 )-alkyl, CO(R57), (C(R58)(R59)) q -R60, CO(C(R61)(R62)), R63, CO(C(R61)(R62)) r N(R76)(R77), or CO—(CH 2 ) o ′—O—(C 1 -C 6 )-alkyl,

o′ is 0, 1, 2, 3, 4, 5 or 6;

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 comprises 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 a 3-12 membered mono-, bi- or spirocyclic ring which optionally comprises one or more heteroatoms 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, 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 comprises one additional heteroatom selected from the group of NH, N—(C 1 -C 6 )-alkyl, oxygen and sulfur;

provided that when L is (C 1 -C 3 )-alkylene, then B is not, a cycloalkyl radical, an alk-2-en-1-yl radical or a cycloalk-2-en-1-yl radical, and A does not contain the moiety C(R34)=C(R34′);

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein:

B is H, 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 optionally comprises 0 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein 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 , and the ring system may be linked to A by ═C(R43′);

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein:

B is H, 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-, tri- or spirocyclic nonaromatic ring which optionally comprises 0 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, wherein 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 ; and the ring system may be linked to A by ═C(R43′);

or a pharmaceutically acceptable salt thereof.

4. 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 optionally comprises 0 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, where the ring system is optionally substituted by F, Cl, 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, N(R41)CO(C 1 -C 6 )-alkyl, or SO 2 CH 3 ;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 , wherein:

Q is a group selected from

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein:

R 53′ is

independently of one another (C 1 -C 6 )-alkyl, (C(R58)(R59)) q —R60, or (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl,

R60 is OH, F, CN, O—(C 1 -C 6 )-alkyl, N(R74)CO(C 1 -C 6 )-alkyl, SO 2 (C 1 -C 6 )-alkyl, or a 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, CF 3 , NO 2 , CN, OCF 3 , oxo, O—(C 1 -C 6 )-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, N(R76)(R77) or SO 2 (C 1 -C 6 )-alkyl;

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , wherein O-L-Q is:

R 53′ is H, (C 1 -C 6 )-alkyl, (C(R58)(R59)) q -R60, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 3 -C 8 )-alkenyl, (C 3 -C 8 )-alkynyl, CO—(C 1 -C 6 )-alkyl, CO—(CH 2 ) o ′, —O—(C 1 -C 6 )-alkyl, or CO(C(R61)(R62)) r N(R76)(R77);

o′, q, and r are independently of one another 0, 1, 2, 3 or 4; and

R60 is OH, F, O—(C 1 -C 6 )-alkyl, N(R74)CO(C 1 -C 6 )-alkyl, SO 2 (C 1 -C 6 )-alkyl, or 3-7 membered monocyclic ring which may comprise one or two heteroatoms from the group of N, O and S, and the 3-7 membered ring further substituents selected from the group consisting of F, Cl, OH, CF 3 , CN, oxo, O—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, (C 1 -C 6 )-alkyl and SO 2 (C 1 -C 6 )-alkyl;

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 , wherein:

R 27 is H;

or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 , wherein:

A is a bond or a linker having 1 to 4 members, where the members are selected from the group consisting of O, SO 2 , N(R31), CO, C(R32)(R33), C(R34)=(R34′), and C≡C, provided that the linker has no CO—O or O—CO groups;

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 , wherein:

A is a bond or a linker selected from O, CH 2 , CH(OH), CO, CH 2 —CH 2 , O—CH 2 , CH═CH—, C(CH 3 )═CH, CH(OH)—CH 2 , CH 2 —CH(OH), C((CH 3 ) 2 )—CH 2 —CH 2 , C≡C, NH—CO, N(CH 3 )CO, O—CH 2 —CH 2 , CH 2 —O—CH 2 , C≡C—CH 2 , —O—CH═CH—, C((OH)(CH 3 ))—C≡C, C((CH 3 ) 2 )—C≡C, O—CH 2 —C≡C, or CO—N(CH 3 )—CH 2 ;

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 , wherein:

R1, R 1′ , R 1″ , and R 1′″ are

independently of one another H, F, Cl, OH, O—(C 1 -C 6 )-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, (C 1 -C 3 )-alkylene-(C 3 -C 6 )-cycloalkyl, CO—(C 1 -C 6 )-alkyl, (C(R12)(R13)) x —O(R14), or (C 2 -C 6 )-alkynyl-O(R14′);

R12 and R13 are

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

R14 and R14′ are

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

x is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

15. 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 7 membered monocyclic nonaromatic ring, which optionally comprises 0 to 3 heteroatoms from the group consisting of N, O and S, and wherein the 3-7 membered ring is optionally substituted by F, Cl, (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, oxo, or hydroxyl;

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 , wherein:

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

and wherein each of the ring system is optionally substituted by F, Cl, (C 1 -C 6 )-alkyl, O—(C 1 -C 8 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, oxo, or hydroxyl;

or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 , wherein:

R 2 is H;

or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1 , which is a compound of formula Ic

wherein:

A′ is a bond or a linker having 1 to 5 members, where the members are selected from the group consisting of O, S, SO 2 , N(R31), CO, and (C(R32)(R33);

R31 is H or (C 1 -C 8 )-alkyl; and

R32 and R33 are

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

or a pharmaceutically acceptable salt thereof.

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

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

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

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

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