Hexafluoroisopropanol substituted cyclohexane derivatives

1. A compound of formula (I)

wherein

R 1 is hydrogen, lower-alkyl, fluoro-lower-alkyl, lower-alkyl-carbonyl, fluoro-lower-alkyl-carbonyl, aryl-lower-alkyl, cycloalkyl-lower-alkyl, cycloalkyl-carbonyl or cycloalkyl-lower-alkyl-carbonyl;

R 2 is hydrogen or lower-alkyl;

R 3 is lower-alkyl, aryl-lower-alkyl, heterocyclyl-lower-alkyl or lower-alkoxy-carbonyl, or, if X is not a single bond, or, if X is a single bond and m is not 0, R 3 can also be hydroxy;

R 4 is aryl or heterocyclyl;

X is a single bond, SO 2 , CO, C(O)O or C(O)N(R 5 );

R 5 is hydrogen, lower-alkyl, aryl, heterocyclyl, aryl-lower-alkyl or heterocyclyl-lower-alkyl;

m is 0, 1, 2 or 3;

n is 0 or 1;

and pharmaceutically acceptable salts and esters thereof.

2. The compound according to claim 1 , having the formula (IA)

wherein R 1 , R 2 , R 3 , R 4 , X, m and n are as defined in claim 1 ,

and pharmaceutically acceptable salts and esters thereof.

3. The compound according to claim 1 , wherein R 1 is hydrogen, lower-alkyl, fluoro-lower-alkyl, lower-alkyl-carbonyl, fluoro-lower-alkyl-carbonyl, aryl-lower-alkyl, cycloalkyl-lower-alkyl or cycloalkyl-carbonyl.

4. The compound according to claim 1 , wherein R 1 is fluoro-lower-alkyl, aryl-lower-alkyl or cycloalkyl-lower-alkyl.

5. The compound according to claim 1 , wherein R 1 is 2,2,2-trifluoroethyl, benzyl or cyclopropylmethyl.

6. The compound according to claim 1 , wherein n is 1, R 2 is hydrogen or lower-alkyl, and R 3 is lower-alkyl, aryl-lower-alkyl or lower-alkoxy-carbonyl, or, if X is not a single bond, or, if X is a single bond and m is not 0, R 3 can also be hydroxy.

7. The compound according to claim 6 , wherein R 2 is lower-alkyl.

8. The compound according to claim 7 , wherein R 2 is methyl.

9. The compound according to claim 6 wherein R 3 is lower-alkyl.

10. The compound according to claim 9 , wherein R 3 is methyl.

11. The compound according to claim 1 , wherein R 4 is aryl or a heterocyclyl selected from the group consisting of thiazolyl, imidazolyl and pyrazolyl, which thiazolyl, imidazolyl or pyrazolyl is optionally substituted with 1 to 3 substituents independently selected from the group of lower-alkyl and halogen.

12. The compound according to claim 1 , wherein R 4 is aryl.

13. The compound according to claim 1 , wherein R 4 is phenyl.

14. The compound according to claim 1 , wherein m is 0 or 1.

15. The compound according to claim 1 , wherein m is 0.

16. The compound according to claim 15 , wherein n is 0.

17. The compound according to claim 1 , wherein X is a single bond, SO 2 , CO or C(O)O.

18. The compound according to claim 1 , wherein X is SO 2 .

19. The compound according to claim 1 , selected from the group consisting of

trans N-(2,2,2-Trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide,

trans N-[4-(2,2,2-Trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide,

trans N-Benzyl-2,2,2-trifluoro-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-acetamide,

trans Phenyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexylamino]-acetic acid ethyl ester,

trans N-Benzyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-acetamide,

trans N-Benzyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide,

trans 2,4-Dimethyl-thiazole-5-sulfonic acid [4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans 1,2-Dimethyl-1H-imidazole-4-sulfonic acid [4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans 1,2-Dimethyl-1H-imidazole-4-sulfonic acid (2,2,2-trifluoro-ethyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans 1,2-Dimethyl-1H-imidazole-4-sulfonic acid ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans 4-Methyl-2-propyl-thiazole-5-sulfonic acid ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans 2,4-Dimethyl-thiazole-5-sulfonic acid (2,2,2-trifluoro-ethyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans 2,4-Dimethyl-thiazole-5-sulfonic acid cyclopropylmethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans 2,4-Dimethyl-thiazole-5-sulfonic acid ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans N-Cyclopropylmethyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide,

trans N-Ethyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide,

trans 5-Chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid (2,2,2-trifluoro-ethyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans 5-Chloro-1,4-dimethyl-1H-pyrazole-3-sulfonic acid [4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans 2-[4-(Benzyl-ethyl-amino)-cyclohexyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,

trans 2-[4-(Benzyl-propyl-amino)-cyclohexyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,

trans 2-[4-(Benzyl-cyclopropylmethyl-amino)-cyclohexyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol,

trans N-Benzyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-propionamide,

trans Cyclopropanecarboxylic acid benzyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans N-Cyclopropylmethyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzamide,

trans N-Cyclopropylmethyl-2-phenyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-acetamide,

trans Cyclopropylmethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-carbamic acid phenyl ester,

trans Cyclopropylmethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-carbamic acid benzyl ester,

(rac) trans 2-{4-[cyclopropylmethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-cyclohexyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol,

trans Benzyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-sulfonamide,

trans Benzyl-N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-sulfonamide,

(rac) trans 1-Phenyl-ethanesulfonic acid (2,2,2-trifluoro-ethyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

trans 2-Phenyl-propane-2-sulfonic acid (2,2,2-trifluoro-ethyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

(rac) trans 1,2-diphenyl-ethanesulfonic acid (2,2,2-trifluoro-ethyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

(rac) trans 3-(2-Phenyl-2-{(2,2,2-trifluoro-ethyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-sulfamoyl}-ethyl)-benzoic acid methyl ester, and

cis N-Ethyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide,

and pharmaceutically acceptable salts and esters thereof.

20. The compound according to claim 1 , selected from the group consisting of

trans N-(2,2,2-Trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide,

trans N-Benzyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide,

trans N-Cyclopropylmethyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide,

trans Benzyl-N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-sulfonamide, and

trans 2-Phenyl-propane-2-sulfonic acid (2,2,2-trifluoro-ethyl)-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide,

and pharmaceutically acceptable salts and esters thereof.

21. A process for the manufacture of compounds of formula (I) as defined in claim 1 , comprising the steps of

a) reacting a compound of formula (II)

with a compound LG—R 1 ,

wherein R 1 , R 2 , R 3 , R 4 , X, m and n are as defined in any of claims 1 - 20 , A is hydrogen or a protecting group and LG is a leaving group,

or

b) reacting a compound of formula (III)

with a compound LG—X—(CH 2 ) m —(CR 2 R 3 ) n —R 4 ,

wherein R 1 , R 2 , R 3 , R 4 , X, m and n are as defined in any of claims 1 - 20 , A is hydrogen or a protecting group, LG is a leaving group,

and removing the protecting group A.

22. A pharmaceutical composition, comprising a therapeutically defective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier and/or adjuvant.