Adamantyl-pyrazole carboxamides as inhibitors of 11B-hydroxysteroid dehydrogenase

Abstract

Provided herein are compounds of the formula (I):

Description

Claims

1. A compound of formula (I):

2. The compound according to claim 1, wherein: R2 is unsubstituted adamantane; andR3 is lower alkyl, branched or unbranched, halogen, halo-lower alkyl, 3- to 8-membered heteroaryl having 1-3 heteroatoms selected from N, O and S, which may be unsubstituted or substituted with halogen or lower alkyl, —NH(CH2)nOH, —NH(CH2)nOCH3, —NHCH(CH3)2, —NH(CH2)nCH3OH, —NH(CH3)(CH2)nOCH3, —NH(CH3)(CH2)nOH, —NCH2CH(CH3)OH, —NH(CH2)nO(CH2)nCH3, —N(CH2CH3)2, —(CH2)nOH, —(CH2)nO(CH2)nCH3, or a 3- to 8-membered monocyclic heterocycle with 1-3 hetero atoms selected from N, O and S, which may be unsubstituted or substituted with lower alkyl, hydroxy, hydroxy phenyl, —(CH2)n-phenyl, —(CH2)nOH or halogen.

3. The compound according to claim 1, wherein: R2 is adamantane substituted with hydroxy, halogen, amino, acetylamino or methane sulfonylamino; andR3 is lower alkyl, branched or unbranched, halogen, halo-lower alkyl, 3- to 8-membered heteroaryl having 1-3 heteroatoms selected from N, O and S, which may be unsubstituted or substituted with halogen or lower alkyl, —NH(CH2)nOH, —NH(CH2)nOCH3, —NHCH(CH3)2, —NH(CH2)nCH3OH, —NH(CH3)(CH2)nOCH3, —NH(CH3)(CH2)nOH, —NCH2CH(CH3)OH, —NH(CH2)nO(CH2)nCH3, —N(CH2CH3)2, —(CH2)nOH, —(CH2)nO(CH2)nCH3, or a 3- to 8-membered monocyclic heterocycle with 1-3 hetero atoms selected from N, O and S, which may be unsubstituted or substituted with lower alkyl, hydroxy, hydroxy phenyl, —(CH2)n-phenyl, —(CH2)nOH or halogen.

4. The compound according to claim 1, wherein: R2 is unsubstituted adamantane; andR4 is lower alkyl, branched or unbranched, —(CH2)m-(C3-C5)cycloalkyl, unsubstituted or substituted with hydroxy or lower alkyl, halo-alkyl, hydroxyalkyl, —(CH2)nO(CH2)nCH3, —(CH2)nO(CH2)pO(CH2)nCH3, —(CH2)nOC(CH3)3 or —CH(CH3)2(CH2)nOH;

5. The compound according to claim 1, wherein: R2 is adamantane substituted with hydroxy, halogen, amino, acetylamino or methane sulfonylamino; andR4 is lower alkyl, branched or unbranched, —(CH2)m-(C3-C5)cycloalkyl, unsubstituted or substituted with hydroxy or lower alkyl, halo-alkyl, hydroxyalkyl, —(CH2)nO(CH2)nCH3, —(CH2)nO(CH2)pO(CH2)nCH3, —(CH2)nOC(CH3)3 or —CH(CH3)2(CH2)nOH;

6. The compound according to claim 1, wherein R2 is trans-hydroxy adamantane.

7. The compound according to claim 1, wherein R3 is a trifluoromethyl group.

8. The compound according to claim 1, wherein R3 is a pyrazole, triazole, piperidine, pyrrolidine, hydroxymethyl piperidine, benzylpiperazine, hydroxypyrrolidine, tert-butyl pyrrolidine, hydroxyethyl piperazine, hydroxypiperidine or thiomorpholine group.

9. The compound according to claim 1, wherein R4 is a cyclopropyl, tert-butyl, —CH(CH3)2CH2OH, methyl, —CF3 or —(CH2)nCF3 group, wherein n is 1 or 2.

10. The compound according to claim 1, wherein R5 is a trifluoromethyl group.

11. The compound according to claim 1, wherein said compound is trans-2′-tert-butyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide.

12. The compound according to claim 1, wherein said compound is 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide.

13. The compound according to claim 1, wherein said compound is trans-1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide.

14. The compound according to claim 1, wherein said compound is 2′-methyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid adamantan-2-ylamide.

15. The compound according to claim 1, wherein said compound is 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide.

16. The compound according to claim 1, wherein said compound is trans-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide.

17. The compound according to claim 1, wherein said compound is cis-1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide.

18. The compound according to claim 1, wherein said compound is trans-2′-methyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide.

19. The compound according to claim 1, wherein said compound is 1-cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide.

20. The compound according to claim 1, wherein said compound is 2′-tert-butyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid adamantan-2-ylamide.

21. The compound according to claim 1, wherein said compound is 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide.

22. The compound according to claim 1, wherein said compound is selected from the group consisting of: trans-1-tert-Butyl-5-chloro-1H-pyrazole-4-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide;trans-2′-tert-Butyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide;trans-2′-tert-Butyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-methanesulfonylamino-adamantan-2-yl)-amide;trans-1-tert-Butyl-5-ethoxymethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-1-tert-Butyl-5-methoxymethyl-1H-pyrazole-4-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide;trans-1-tert-Butyl-5-(5-methyl-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide;trans-1-tert-Butyl-5-(5-chloro-isoxazol-3-yl)-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-2′-Cyclohexyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-2′-Cyclohexyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide;trans-2′-(Tetrahydro-pyran-4-yl)-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-2′-Cyclopentyl-2′H-[1,3′ ]bipyrazolyl-4′-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-2′-Cyclopentyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide;trans-2′-(cis-4-Hydroxy-cyclohexyl)-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-1-(cis-4-Hydroxy-cyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-1-(trans-4-Hydroxy-cyclohexyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-2′-(2-Methoxyethyl)-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-hydroxy-adamantan-2-yl-amide;trans-1-(2-Methoxyethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-2′-(2-Methoxyethyl)-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid(5-acetylamino-adamantan-2-yl-amide;trans-2′-(3-Methoxypropyl)-2′H-[1,3′ ]bipyrazolyl-4-′carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-2′-(3-Methoxypropyl)-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide;trans-1-Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-5-Chloro 1-cyclopropyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-2′-Cyclopropyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-4-Chloro-2′-cyclopropyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-1-Cyclopropylmethyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-1-(2-Hydroxy-1,1-dimethyl-ethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-1-tert-Butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-1-Cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-1-Cyclobutyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide;trans-5-Chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide;trans-2′-Cyclobutyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide;trans-2′-tert-Butyl-4-methyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-2′-tert-Butyl-4-chloro-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide;trans-2′-tert-Butyl-4-chloro-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide; andtrans-4-Chloro-2′-cyclobutyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (5-acetylamino-adamantan-2-yl)-amide.

23. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

24. A method of treating a metabolic disorder, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 to a patient in need thereof.