Thiazoles as inhibitors of 11B-hydroxysteroid dehydrogenase

Abstract

Provided herein are compounds of the formula (I):

Description

Claims

1. A compound of the formula (I):

2. The compound according to claim 1, wherein: R1 is 5 to 8-membered cycloalkyl or phenyl, unsubstituted or mono-, bi-, or tri-substituted independently with halogen, lower alkyl, halo-lower-alkyl, phenyl, —OCH3, —O(CH2)nCH3, —(CH2)nOH, —OH, —NH2, —OCF3, —O(CH2)n-phenyl, —SCH3, —NHSO2CH3, thiophene, morpholine, —C(O)CH3, —N(CH3)2 or —NO2; andone of R2 or R3 is H or branched or unbranched lower alkyl, and the other is C4-C10 alkyl, —CH2-phenyl, mono-, bi- or tri-cyclic 5- to 10-membered carbocyclic ring unsubstituted or mono- or bi-substituted with lower alkyl, hydroxy, or oxo, or bicyclic partially unsaturated 9- or 10-membered ring.

3. The compound according to claim 1, wherein: R1 is 5- or 6-membered saturated, partially unsaturated, or aryl ring, which is connected by a ring carbon atom and which has from 1 to 3 hetero ring atoms selected from the group consisting of sulfur, nitrogen and oxygen, unsubstituted or substituted with halogen, lower alkoxy, or lower alkyl; andone of R2 or R3 is H or branched or unbranched lower alkyl, and the other is C4-C10 alkyl, —CH2-phenyl, mono-, bi- or tri-cyclic 5- to 10-membered carbocyclic ring unsubstituted or mono- or bi-substituted with lower alkyl, hydroxy, or oxo, or bicyclic partially unsaturated 9- or 10-membered ring.

4. The compound according to claim 1, wherein: R1 is 9- or 10-membered bicyclic unsaturated or partially unsaturated ring which is connected by a ring carbon and which has from 1 to 3 hetero ring atoms selected from the group consisting of sulfur, nitrogen and oxygen, unsubstituted or mono-, bi- or tri-substituted with halogen or lower alkyl; andone of R2 or R3 is H or branched or unbranched lower alkyl, and the other is C4-C10 alkyl, —CH2-phenyl, mono-, bi- or tri-cyclic 5- to 10-membered carbocyclic ring unsubstituted or mono- or bi-substituted with lower alkyl, hydroxy, or oxo, or bicyclic partially unsaturated 9- or 10-membered ring.

5. The compound according to claim 1, wherein: R1 is 5 to 8-membered cycloalkyl or phenyl, unsubstituted or mono-, bi-, or tri-substituted independently with halogen, lower alkyl, halo-lower-alkyl, phenyl, —OCH3, —O(CH2)nCH3, —(CH2)nOH, —OH, —NH2, —OCF3, —O(CH2)n-phenyl, —SCH3, —NHSO2CH3, thiophene, morpholine, —C(O)CH3, —N(CH3)2 or —NO2; andR2 and R3, together with the N atom to which they are attached, form a saturated or partially unsaturated 6- to 8-membered monocyclic or 7- to 10-membered bicyclic ring, which contains the N atom to which R2 and R3 are attached, and optionally another hetero atom which is selected from O and S, unsubstituted or mono- or bi-substituted with branched or unbranched lower alkyl, halogen, hydroxy, hydroxy-alkyl, pyridine, carboxy, phenyl, oxo, —CH2-phenyl or 5- to 10-membered cycloalkyl.

6. The compound according to claim 1, wherein: R1 is 5- or 6-membered saturated, partially unsaturated, or aryl ring, which is connected by a ring carbon atom and which has from 1 to 3 hetero ring atoms selected from the group consisting of sulfur, nitrogen and oxygen, unsubstituted or substituted with halogen, lower alkoxy, or lower alkyl; andR2 and R3, together with the N atom to which they are attached, form a saturated or partially unsaturated 6- to 8-membered monocyclic or 7- to 10-membered bicyclic ring, which contains the N atom to which R2 and R3 are attached, and optionally another hetero atom which is selected from O and S, unsubstituted or mono- or bi-substituted with branched or unbranched lower alkyl, halogen, hydroxy, hydroxy-alkyl, pyridine, carboxy, phenyl, oxo, —CH2-phenyl or 5- to 10-membered cycloalkyl.

7. The compound according to claim 1, wherein: R1 is 9- or 10-membered bicyclic unsaturated or partially unsaturated ring which is connected by a ring carbon and which has from 1 to 3 hetero ring atoms selected from the group consisting of sulfur, nitrogen and oxygen, unsubstituted or mono-, bi- or tri-substituted with halogen or lower alkyl; andR2 and R3, together with the N atom to which they are attached, form a saturated or partially unsaturated 6- to 8-membered monocyclic or 7- to 10-membered bicyclic ring, which contains the N atom to which R2 and R3 are attached, and optionally another hetero atom which is selected from O and S, unsubstituted or mono- or bi-substituted with branched or unbranched lower alkyl, halogen, hydroxy, hydroxy-alkyl, pyridine, carboxy, phenyl, oxo, —CH2-phenyl or 5- to 10-membered cycloalkyl.

8. The compound according to claim 1, wherein R1 is phenyl.

9. The compound according to claim 1, wherein R1 is phenyl mono- or bi-substituted with halogen, alkyl, lower alkoxy, —SCH3 or —C(O)CH3.

10. The compound according to claim 1, wherein one of R2 or R3 is H and the other is a mono-, bi- or tri-cyclic 5- to 10-membered ring, unsubstituted or mono- or bi-substituted with lower alkyl or hydroxy.

11. The compound according to claim 1, wherein R2 and R3, together with the N atom to which they are attached, form an unsubstituted 6- to 8-membered monocyclic or an unsubstituted 7- to 10-membered bicyclic ring, which contains the N atom to which R1 and R2 are attached, and optionally another hetero atom which is selected from O and S.

12. The compound according to claim 1, wherein said compound is azocan-1-yl-[2-(2,3-dichloro-phenyl)-thiazol-4-yl]-methanone.

13. The compound according to claim 1, wherein said compound is [2-(3-chloro-phenyl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone.

14. The compound according to claim 1, wherein said compound is [2-(3-methylsulfanyl-phenyl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone.

15. The compound according to claim 1, wherein said compound is (2-phenyl-thiazol-4-yl)-((1R,5R)-3,3,5-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-methanone.

16. The compound according to claim 1, wherein said compound is 1-{2-[4-(2-isopropyl-pyrrolidine-1-carbonyl)-thiazol-2-yl]-phenyl}-ethanone.

17. The compound according to claim 1, wherein said compound is 2-(2-acetyl-phenyl)-thiazole-4-carboxylic acid cyclooctylamide.

18. The compound according to claim 1, wherein said compound is 2-(2-acetyl-phenyl)-thiazole-4-carboxylic acid adamantan-2-ylamide.

19. The compound according to claim 1, wherein said compound is 1-{2-[4-((1R,5R)-3,3,5-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-thiazol-2-yl]-phenyl}-ethanone.

20. The compound according to claim 1, wherein said compound is 2-(2-acetyl-phenyl)-thiazole-4-carboxylic acid ((1R,2R,3R,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide.

21. The compound according to claim 1, wherein said compound is [2-(2-fluoro-6-methoxy-phenyl)-thiazol-4-yl]-((1R,5R)-3,3,5-trimethyl-6-aza-bicyclo[3.2.1 ]oct-6-yl)-methanone.

22. The compound according to claim 1, wherein said compound is 2-o-tolyl-thiazole-4-carboxylic acid adamantan-2-ylamide.

23. The compound according to claim 1, wherein said compound is 2-(2-Acetyl-phenyl)-thiazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide.

24. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to formula (I):

25. A method for treating a metabolic disease or disorder, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to formula (I):

26. The method according to claim 25, wherein said metabolic disease or disorder is type II diabetes mellitus or metabolic syndrome.