Phenyl-1,2,4-oxadiazolone derivatives, processes for their preparation and methods for their use as pharmaceuticals

1. A compound of formula I

wherein

B is C(R4)or N;

R1 is selected from the group consisting of H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, (C3-C7) cycloalkyl, SCH 3 and CN, wherein the alkyl and alkylene are optionally substituted one to five times by F;

R2, R3 and R4 are independently selected from the group consisting of:

H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, SCH 3 , and CN, wherein the alkyl and alkylene are optionally substituted one to five times by F; or

R2 and R3 together with the carbon atoms to which they are bonded form a (C6-C10) aryl or a (C5-C10) heteroaryl ring;

X is selected from the group consisting of O, S, S(O), S(O) 2 , O—CH 2 , S—CH 2 , CH 2 —O, and CH 2 —S;

one of U and V is N and the other is S or O;

W is a bond, (C1-C8) alkylene, or (C2-C8) alkenylene, wherein the alkylene and alkenylene are optionally mono-, di- or tri-substituted by OH or F;

Y is a bond, O, S, S(O), S(O) 2 , or N(R6);

R5 is selected from the group consisting of H, (C1-C8) alkyl, (C0-C4) alkylene-(C3-C13) cycloalkyl, (C0-C4) alkylene-(C6-C14) aryl, (C2-C8) alkenyl, (C0-C4) alkylene-(C3-C15) heterocycloalkyl, (C0-C4) alkylene-(C3-C15) heterocycloalkenyl, and (C0-C4) alkylene-(C5-C15) heteroaryl, wherein the alkyl and alkylene are optionally mono-, di- or tri-substituted by (C1-C4) alkyl or O—(C0-C4) alkylene-H, and are optionally substituted one to five times by F, and wherein the cycloalkyl, aryl, heterocycloalkyl, heterocycloalkenyl and heteroaryl are optionally mono-, di- or tri-substituted by F, Cl, Br, CF 3 , (C1-C4) alkyl or O—(C0-C4) alkylene-H;

R6 is selected from the group consisting of H, (C1-C8) alkyl and (C2-C8) alkenyl, wherein the alkyl and alkenyl are optionally mono-, di- or tri-substituted by F or O—(C0-C4)-alkylene-H, or

R5 and R6 together with the nitrogen atom to which they are bonded form a (C3-C9)-heterocycloalkyl, a (C3-C9)-heterocycloalkenyl or a (C5-C9)-heteroaryl, each of which can contain additionally 1 to 3 heteroatoms selected from N, O, and S, and each of which is optionally mono-, di- or tri-substituted by F, CF 3 , (C1-C4) alkyl, O—(C1-C4) alkyl, OH, CH 2 —OH, SO 2 -(C1-C4) alkyl, CO—(C1-C4) alkyl, CO—NH 2 , NH—CO—(C1-C4) alkyl, (C6-C14) aryl or (C5-C15) heteroaryl;

Z is a bond, (C1-C8) alkylene, (C2-C8) alkenylene, (C2-C8) alkylidene, or (C1-C6) alkylene-O—(C1-C6) alkyl;

A is selected from the group consisting of (C3-C13) cycloalkyl, (C4-C15) heterocycloalkyl, (C4-C15) heterocycloalkenyl and (C5-C15) heteroaryl ring;

R7 and R8 are independently selected from the group consisting of H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, SCF 3 , SF 5 , S(O) 2 CF 3 , O—(C6-C12) aryl, (C6-C12) aryl, and NO2, wherein the alkyl and alkylene are optionally mono-, di- or tri-substituted by F, and wherein the aryl is optionally mono-, di- or tri-substituted by halogen, (C1-C4) alkyl or O—(C1-C4) alkyl; and

R9 and R10 are independently selected from the group consisting of H, (C1-C6) alkyl, (C2-C6) alkenyl, (C0-C6) alkylene-(C6-C14) aryl, (C0-C6) alkylene-(C5-C15) heteroaryl, (C0-C6) alkylene-(C3-C8) cycloalkyl, and (C0-C6) alkylene-(C3-C8) cycloalkenyl, wherein the alkyl and alkylene are optionally mono-, di- or tri-substituted by F, and wherein the aryl and heteroaryl are optionally mono-, di- or tri-substituted by halogen, (C1-C4) alkyl or O—(C1-C4) alkyl;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

2. The compound according to claim 1 , wherein

R1 is selected from the group consisting of H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, and (C3-C7) cycloalkyl, wherein the alkyl and alkylene are optionally mono-, di- or tri-substituted by F;

R2 is H;

R3 is H or halogen;

R4 is H; or

R2 and R3 together with the carbon atoms to which they are bonded form a (C6) aryl or a (C5-C6) heteroaryl ring;

X is O or O—CH2;

W is a bond or (C1-C5) alkylene;

Y is a bond, O, or N(R6);

R5 is selected from the group consisting of H, (C1-C8) alkyl and (C0-C4) alkylene-(C6-C14) aryl;

R6 is H or (C1-C8) alkyl; or

R5 and R6 together with the nitrogen atom to which they are bonded form a (C3-C9)-heterocycloalkyl, which is optionally mono-substituted by CF 3 ;

Z is a bond, (C1-C4) alkylene or (C2-C4) alkenylene;

A is selected from the group consisting of (C3-C8) cycloalkyl, (C5-C6) heterocycloalkyl and (C5-C12) heteroaryl ring;

R7 is selected from the group consisting of H, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, S(O) 2 CF 3 , and (C6-C12) aryl, wherein the alkyl and alkylene are optionally mono-, di- or tri-substituted by F, and wherein the aryl is optionally mono-, di- or tri-substituted by halogen;

R8 is H;

R9 is selected from the group consisting of H, (C1-C6) alkyl, (C0-C6) alkylene-(C6-C14) aryl, and (C0-C6) alkylene-(C5-C15) heteroaryl, wherein the alkyl and alkylene are optionally mono-, di- or tri-substituted by F, and wherein the aryl is optionally mono-, di- or tri-substituted by halogen; and

R10 is H;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

3. The compound according to claim 1 , wherein

B is CH or N;

R1 is selected from the group consisting of H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, and (C3-C7) cycloalkyl, wherein the alkyl and alkylene are optionally mono-, di- or tri-substituted by F;

R2 and R4 are H;

R3 is H or F; or

R2 and R3 together with the carbon atoms to which they are bonded form a (C6)-aryl or a (C5-C6) heteroaryl;

X is O or OCH2;

V is N;

U is O, S;

W is a bond or (C1-C4) alkylene;

Y is a bond, O or N(R6);

R5 is selected from the group consisting of H, (C1-C8) alkyl, and (C0-C4) alkylene-(C6-C10) aryl, wherein the alkyl and alkylene are optionally mono-, di- or tri-substituted by F, (C1-C4) alkyl or O—(C0-C4) alkylene-H;

R6 is H or (C1-C4) alkyl; or

R5 and R6, together with the nitrogen atom to which they are bonded form a (C3-C6)-heterocycloalkyl, which can contain additionally 1 heteroatom selected from N and O, and the heterocycloalkyl is optionally mono- or disubstituted by F, CF3, CH3, OCH3 or phenyl;

Z is a bond, (C1-C4) alkylene or (C2-C4) alkenylene;

A is selected from the group consisting of (C5-C8) cycloalkyl, (C5-C10) heterocycloalkyl, (C5-C 10) heterocycloalkenyl and (C5-C10) heteroaryl ring;

R7 and R8 are independently selected from the group consisting of H, halogen, (C1-C8) alkyl, (C0-C4) alkylen-O—(C0-C4) alkylene-H, (C6-C12) aryl, and S(O ) 2 CF 3 , wherein the alkyl and alkylene are optionally mono-, di- or tri-substituted by F and aryl is substituted by halogen;

R9 selected from the group consisting of H, (C1-C4) alkyl, (C0-C4) alkylene-(C6-C10) aryl, and (C0-C4) alkylene-(C5-C6) heteroaryl, wherein the alkyl, alkylene, aryl and heteroaryl are unsubstituted oroptionally mono-, di- or tri-substituted by F; and

R10 is H;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

4. The compound according to claim 1 , wherein

B is C(R4);

R1 is selected from the group consisting of H, halogen, (C1-C8) alkyl, (C0-C4) alkylene-O—(C0-C4) alkylene-H, and (C3-C7) cycloalkyl, wherein the alkyl and alkylene are optionally mono, di- or trisubstituted by F;

R2 and R4 are H;

R3 is H, or F;

X is O, or S;

V is N;

U is O or S;

W is a bond, or (C1-C4) alkylene;

Y is a bond, O, or N(R6);

R5 is selected from the group consisting of H, (C1-C8) alkyl, (C0-C4) alkylene-(C3-C6) cycloalkyl, (C0-C4) alkylene-(C6-C10) aryl, (C0-C4) alkylene-(C4-C6) heterocycloalkyl, (C0-C4) alkylene-(C4-C6) heterocycloalkenyl, and (C0-C4) alkylene-(C5-C6) heteroaryl, wherein the alkyl and alkylene are optionally mono-, di- or tri-substituted by F, (C1—C4) alkyl or O—(C0-C4) alkylene-H, and wherein the cycloalkyl, aryl, heterocycloalkyl, heterocycloalkenyl and heteroaryl are mono-, di- or tri-substituted by F, CF 3 , (C1-C4) alkyl and O—(C0-C4) alkylene-H;

R6 is H, or (C1-C4) alkyl; or

R5 and R6 together with the nitrogen atom to which they are bonded form a (C3-C6)-heterocycloalkyl, a (C3-C6)-heterocycloalkenyl or a (C5-C6)-heteroaryl each of which can contain additionally 1 heteroatom selected from N and O, and each of which is optionally mono- or disubstituted by F, CF 3 , CH 3 , OCH 3 , phenyl or (C5-C6) heteroaryl;

Z is a bond, (C1-C4) alkylene, (C2-C4) alkylidene, or (C1-C4) alkylene-O—(C1-C4) alkyl;

A is (C5-C8) cycloalkyl, (C5-C10) heterocycloalkyl, (C5-C10) heterocycloalkenyl or (C5-C10) heteroaryl ring;

R7 and R8 are independently selected from the group consisting of H, halogen, (C1-C8) alkyl, (C0—C4) alkylen-O—(C0-C4) alkylene-H, and (C6-C12) aryl, wherein the alkyl and alkylene are optionally mono-, di- or tri-substituted by F, and wherein the aryl is substituted by halogen; and

R9 and R10 are independently selected from the group consisting of H, (C1-C4) alkyl, (C0-C4) alkylene-phenyl and (C0-C4) alkylene-(C5-C6) heteroaryl;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

5. The compound according to claim 1 ,

wherein R1 selected from the group consisting of H, F, Cl, CH 3 , OCH 3 , OCHF 2 , OCH 2 CF 3 and cyclopropyl;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

6. The compound according to claim 1 , wherein

R1 is OCH3, OCHF 2 or OCH 2 CF 3 ;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

7. The compound according to claim 1 , wherein

R1 is selected from the group consisting of H, F, Cl, CH 3 and cyclopropyl;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

8. The compound according to claim 1 , wherein

R2 and R3 are H;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

9. The compounds according to claim 1 , wherein X is O or O—CH2—;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

10. The compound according to claim 1 , wherein

V is N and U is O or S;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

11. The compound according to claim 1 , wherein

R5 and R6 together with the nitrogen atom to which they are bonded form a (C3-C7)-heterocycloalkyl, which may can contain 1 to 2 heteroatoms selected from the group consisting of N, O and S, wherein the heterocycloalkyl is optionally mono- or disubstituted by F, CF 3 , CH 3 , or OCH 3 ;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

12. The compound according to claim 1 ,

wherein Z is a bond;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

13. The compound according to claim 1 ,

wherein R7 is selected from the group consisting of H, F, CH 3 , CH 2 CH 3 , CF 3 , OCH 3 and phenyl; and

R8 is H;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

14. The compound according to claim 1 ,

wherein R9 is ethyl, CF 2 CH 2 CH 3 , CF 3 , CH 2 -phenyl, CH 2 -(4-fluoro-phenyl), or CH 3 pyridyl; and R10 is H;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

15. The compound according to claim 1 ,

wherein

A is cyclohexyl;

R7 is 4-CF 3 ;

R8 is H; and

R1 is O—CH 3 , O—CH 2 CF 3 or —O—CHF 2 ;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

16. The compound according to claim 1 , wherein

W is —CH2—;

Y is a bond; and

R5 is H;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

17. The compound according to claim 1 , wherein

B is C(R4);

R1 is selected from the group consisting of H, F, and Cl;

R2, R3 and R4 are H;

X is O or O—CH2;

V is N;

U is S;

W is —CH2—;

Y is a bond;

R5 is H;

Z is a bond;

A is pyridinyl or cyclohexyl;

R7 is CF 3 ;

R8 is H;

R9 is CH 2 —CH 3 , CF 3 , CF 2 —CH 2 —CH 3 , CH 2 ; 4-fluoro-phenyl, or CH 2 -pyridyl; and

R10 is H;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

18. The compound according to claim 1 , wherein

B is C(R4);

R1 is O—CH3, O—CH2CF3 or —O—CHF2;

R2 and R4 are H;

R3 is H or F;

X is O;

V is N;

U is O or S;

W is a bond or —CH2—;

Y is a bond or N(R6);

R5 is CH 3 ;

R6 is CH 3 ; or

R5 and R6 together with the nitrogen to which they are bonded form a piperidine ring which is substituted by CF 3 ;

Z is a bond;

A is cyclohexyl;

R7 is 4-CF3;

R8 is H;

R9 is H or ethyl; and

R10 is H;

or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

19. A pharmaceutical composition comprising the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof, and a pharmaceutically acceptable excipient.

20. A pharmaceutical composition comprising the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof, in combination with one or more additional active substances which are effective in the treatment of a metabolic disorder.

21. A pharmaceutical composition comprising the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof, in combination with one or more additional active substances which are effective in the treatment of diabetes.

22. A pharmaceutical composition comprising the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof, in combination with one or more additional active substances which are effective lipid modulators.

23. A pharmaceutical composition comprising the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof, in combination with one or more additional active substances which are effective in the treatment of fatty acid metabolism and glucose utilization disorders.

24. A pharmaceutical composition comprising the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof, in combination with one or more additional active substances which are effective in the treatment of a disorder which is the result or manifestation of insulin resistance.

25. A pharmaceutical composition comprising the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof, in combination with one or more additional active substances which are effective in the treatment of diabetes mellitus or a disorder which is the result or manifestation thereof.

26. A pharmaceutical composition comprising the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof, in combination with one or more additional active substances which are effective in the treatment of dyslipidemia or a disorder which is the result or manifestation thereof.

27. A method for treating metabolic syndrome, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

28. A method for treating demyelinating or a neurodegenerative disorder of central or peripheral nervous system, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

29. A method for treating a disorder of fatty acid metabolism or glucose utilization disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.

30. A method for treating a disorder that results from or is a manifestation thereof, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to claim 1 , or a stereoisomeric form thereof or a mixture in any ratio thereof, or a physiologically acceptable salt or a tautomer thereof.