Piperidinyl-propanone derivatives

Abstract

Compounds of the formula I ##STR00001##
in which X, Q, R.sup.1 and R.sup.2 have the meanings indicated in Claim 1, are inhibitors of pyruvate dehydrogenase kinase (PDHK), and can be employed, inter alia, for the treatment of diseases such as cancer.

Claims

1. A compound of the formula I ##STR00054## in which X denotes NH or O, Q denotes C(CH.sub.3).sub.2 or 1,1-cyclopropylene, R.sup.1 denotes H, A, Cyc, Ar or Het, R.sup.2 denotes H or CH.sub.3, R.sup.3 denotes H or A′, Ar denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, NO.sub.2, CN, A, OR.sup.3, S(O).sub.mR.sup.3, N(R.sup.3).sub.2, COA, COOR.sup.3, CON(R.sup.3).sub.2, SO.sub.2N(R.sup.3).sub.2, NR.sup.3COR.sup.3, NR.sup.3SO.sub.2A and/or NR.sup.3CON(R.sup.3).sub.2, Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono- or disubstituted by Hal, NO.sub.2, CN, A, OR.sup.3, S(O).sub.mR.sup.3, N(R.sup.3).sub.2, COA, COOR.sup.3, CON(R.sup.3).sub.2, SO.sub.2N(R.sup.3).sub.2, NR.sup.3COR.sup.3, NR.sup.3SO.sub.2A and/or NR.sup.3CON(R.sup.3).sub.2, A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH- and/or CH.sub.2-groups may be replaced by N-, O- and/or S-atoms and/or wherein 1-7 H-atoms may be replaced by R.sup.4, R.sup.4 denotes F, Cl or OH, A′ denotes unbranched or branched alkyl with 1-6 C-atoms, wherein 1-5 H-atoms may be replaced by F, Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms, which is unsubstituted or monosubstituted by OH, Hal denotes F, Cl, Br or I, m denotes 0, 1 or 2, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

2. A compound according to claim 1 in which R.sup.1 denotes A, Cyc, Ar or Het, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

3. A compound according to claim 1, in which R.sup.3 denotes H or CH.sub.3, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

4. A compound according to claim 1, in which Ar denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, A and/or OR.sup.3, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

5. A compound according to claim 1, in which Het denotes pyrimidyl, pyridyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, triazolyl, oxadiazolyl or thiadiazolyl, each of which is unsubstituted or mono- or disubstituted by Hal, A, CN and/or OR.sup.3, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

6. A compound according to claim 1, in which Het denotes pyrimidyl, pyridyl, pyridazinyl or pyrazinyl, each of which is unsubstituted or mono- or disubstituted by A and/or OR.sup.3, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

7. A compound according to claim 1, in which A denotes unbranched or branched alkyl with 1-6 C-atoms, wherein 1-5 H-atoms may be replaced by F, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

8. A compound according to claim 1, in which Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

9. A compound according to claim 1 in which X denotes NH or O, Q denotes C(CH.sub.3).sub.2 or 1,1-cyclopropylene, R.sup.1 denotes A, Cyc, Ar or Het, R.sup.2 denotes H or CH.sub.3, R.sup.3 denotes H or CH.sub.3, Ar denotes phenyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, A and/or OR.sup.3, Het denotes pyrimidyl, pyridyl, pyridazinyl or pyrazinyl, each of which is unsubstituted or mono- or disubstituted by A and/or OR.sup.3, A denotes unbranched or branched alkyl with 1-6 C-atoms, wherein 1-5 H-atoms may be replaced by F, Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms, Hal denotes F, Cl, Br or I, and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

10. A compound according to claim 1, that is: TABLE-US-00003 No. Name “A1” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-phenyl-1H- [1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A2” (R)-3,3,3-Trifluoro-1-{4-{1-[5-(4-fluorophenyl)-4H-[1,2,4]triazol-3- yl]-cyclopropyl}-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A3” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-methyl-1-(5-phenyl-4H- [1,2,4]triazol-3-yl)-ethyl]-piperidin-1-yl}-propan-1-one “A4” (R)-1-{4-[1-(5-Cyclohexyl-4H-[1,2,4]triazol-3-yl)-1-methyl-ethyl]- piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A5” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-phenyl- [1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A6” (R)-3,3,3-Trifluoro-1-{4-{1-[5-(4-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]- cyclopropyl}-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A7” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-methyl- [1,3,4]oxadizaol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A8” (R)-1-{4-[1-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}- 3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A9” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-methyl-1-(5-phenyl- [1,3,4]oxadiazol-2-yl)-ethyl]-piperidin-1-yl}-propan-1-one “A10” (R)-1-{4-[1-(5-Cyclohexyl-[1,3,4]oxadiazol-2-yl)-1-methyl-ethyl]- piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A11” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-phenyl-1H- [1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A12” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-phenyl- [1,3,4]oxadizaol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A13” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3R,4R)-3-methyl-4-[1-(5-phenyl-4H- [1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A14” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3S,4S)-3-methyl-4-[1- (5-phenyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A15” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(S)-3-methyl-4-[1-(5-phenyl- [1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A16” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(R)-3-methyl-4-[1-(5-phenyl- [1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A17” (R)-3,3,3-Trifluoro-1-(4-{1-[5-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]- cyclopropyl}-3-methyl-piperidin-1-yl)-2-hydroxy-2-methyl-propan-1-one “A18” (R)-3,3,3-Trifluoro-1-((3R,4R)-4-{1-[5-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]- cyclopropyl}-3-methyl-piperidin-1-yl)-2-hydroxy-2-methyl-propan-1-one “A19” (R)-3,3,3-Trifluoro-1-((3S,4S)-4-{1-[5-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]- cyclopropyl}-3-methyl-piperidin-1-yl)-2-hydroxy-2-methyl-propan-1-one “A20” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-p-tolyl-4H-[1,2,4] triazol-3-yl}-cyclopropyl]-piperidin-1-yl}-propan-1-one “A21” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3R,4R)-3-methyl-4-[1-(5-p-tolyl-4H- [1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A22” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3S,4S)-3-methyl-4-[1-(5-p-tolyl-4H- [1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl)-propan-1-one “A23” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-p-tolyl-[1,3,4]oxadiazol- 2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A24” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3R,4R)-3-methyl-4-[1-(5-p-tolyl- [1,3,4]oxadiazo1-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A25” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3S,4S)-3-methyl-4-[1-(5-p-tolyl- [1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one “A26” (R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-yl]- cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one “A27” (R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(4-methoxy-phenyl)-4H- [1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one “A28” (R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(4-methoxy-phenyl)-4H- [1,2,4]trizaol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one “A29” (R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(4-methoxy-phenyl)- [1,3,4]oxadizaol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one “A30” (R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]- cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one “A31” (R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]- cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one “A32” (R)-1-(4-{1-[5-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}- 3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A33” (R)-1-((3R,4R)-4-{1-[5-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}- 3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A34” (R)-1-((3S,4S)-4-{1-[5-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}- 3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A35” (R)-1-(4-{1-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}- 3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A36” (R)-1-((3R,4R)-4-{1-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}- 3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A37” (R)-1-((3S,4S)-4-{1-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}- 3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A38” (R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(6-methoxy-pyridin-3-yl)-4H- [1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one “A39” (R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(6-methoxy-pyridin-3-yl)-4H- [1,2,4]triazol-3-yl]cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one “A40” (R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(6-methoxy-pyridin-3-yl)-4H- [1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one “A41” (R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(6-methoxy-pyridin-3-yl)- [1,3,4]oxadizaol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one “A42” (R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(6-methoxy-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]- cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one “A43” (R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(6-methoxy-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]- cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

11. A process for the preparation of a compound of the formula I according to claim 1 and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, wherein X denotes NH, wherein a compound of the formula II ##STR00055## in which Q denotes C(CH.sub.3).sub.2 or 1,1-cyclopropylene, R.sup.2 denotes H or CH.sub.3, is reacted with a compound of the formula III
R.sup.1—C(═NH)OCH.sub.3  III in which R.sup.1 denotes H, A, Cyc, Ar or Het, and/or a base or acid of the formula I is converted into one of its salts.

12. A pharmaceutical composition comprising at least one compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios, and optionally a pharmaceutically acceptable carrier, excipient or vehicle.

13. A method for treating cancer or diabetes comprising administering a compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

14. A method for treating cancer comprising administering a pharmaceutical composition according to claim 12.

15. A pharmaceutical composition comprising at least one compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios, and at least one further active ingredient.

16. A set (kit) consisting of separate packs of (a) an effective amount of a compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, tautomer and or stereoisomer thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further active ingredient.

17. A method of inhibiting PDHK comprising administering a compound of the formula I according to claim 1 and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

Description

EXAMPLE 1

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-phenyl-1H-[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A1”)

(1) ##STR00004##
Reaction Scheme:

(2) ##STR00005##

1.1 1-Pyridin-4-yl-cyclopropanecarboxylic acid ethyl ester

(3) Pyridin-4-yl-acetic acid ethyl ester (2.00 g; 12.107 mmol) was dissolved in DMF (30.0 mL), lithium bis(trimethylsilyl)amide (1 M in THF; 18.16 mL; 18.161 mmol) was added and the mixture was stirred at 25 twice for 30 min. 1,2-Dibromoethane (1.25 mL; 14.529 mmol) was added and the mixture was stirred at 25° C. for 1 h. Lithium bis(trimethylsilyl)amide (1 M in THF; 18.16 mL; 18.161 mmol was added and the mixture stirred for another 1 h. The mixture was quenched under ice cooling with acetic acid (4 ml) and evaporated. The residue was partitioned between NH.sub.4Cl solution and dichloromethane. The organic phase was separated and the water layer extracted twice with dichloromethane. The combined organic phases were dried over MgSO.sub.4 and evaporated under reduced pressure. The residue was purified by RP-flash chromatography (Isco Companion). Yield: 1.90 g (82%) brown solid; HPLC/MS, Rt: 0.94 min; (M+H) 192.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6/TFA) δ 8.96-8.84 (m, 2H), 8.17-8.08 (m, 2H), 4.14 (q, J=7.1 Hz, 1H), 1.81-1.77 (m, 1H), 1.56-1.48 (m, 1H), 1.17 (t, J=7.1 Hz, 3H).

1.2 1-Piperidin-4-yl-cyclopropanecarboxylic acid ethyl ester hydrochloride

(4) Compound 1.1 (3.39 g; 17.728 mmol) was dissolved in ethanol (200.0 mL) and concentrated HCl (1.92 mL; 19.500 mmol) and hydrogenated over Platin(IV)-oxid hydrate at room temperature and normal pressure for 14 h. The reaction mixture was filtered and evaporated under reduced pressure. Yield: 4.14 g (100%) colorless solid; HPLC/MS, Rt: 0.34 min; (M+H) 198.2.

1.3 1-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-cyclopropanecarboxylic acid ethyl ester

(5) Compound 1.2 (1.75 g; 7.487 mmol), (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (1.21 g; 7.487 mmol) and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (2.93 g; 7.487 mmol) were dissolved in dry DMF (40.0 mL). N-Ethyldiisopropylamine (5.14 mL; 29.948 mmol) was added and the mixture was stirred at room temperature for 5 h. The mixture was evaporated to dryness and the residue purified by RP-flash chromatography (CombiFlash RF 200). Yield: 2.53 g (100%) brown oil; HPLC/MS, Rt: 2.15 min; (M+H) 338.2.

1.4 1-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-cyclopropanecarboxylic acid

(6) Compound 1.3 (2.53 g; 6.238 mmol) was dissolved in ethanol (50.0 mL) and sodium hydroxide solution (2 N; 50.0 mL) was added. The mixture was stirred at 25° C. for 2 d. The mixture was concentrated under reduced pressure, acidified with HCOOH to pH 4 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. Yield: 1.93 g (100%) orange oil; HPLC/MS, Rt: 1.72 min; (M+H) 310.1.

1.5 N′-{1-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-cyclopropanecarbonyl}-hydrazinecarboxylic acid tert-butyl ester

(7) Compound 1.4 (1.10 g; 3.557 mmol) and (tert-butoxy)carbohydrazide (0.56 g; 4.268 mmol) were dissolved in dry DMF (5.0 mL) and the mixture was cooled in an ice bath. [Dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (1.76 g; 4.624 mmol) and subsequently N-ethyldiisopropylamine (1.82 mL; 10.670 mmol) were added, cooling was removed and the mixture was stirred for 20 h at 25° C.

(8) The reaction mixture was evaporated and the residue subjected to RP-flash chromatography (Isco Companion). Yield: 1.10 g (73%) colourless solid; HPLC/MS, Rt: 1.78 min; (M+H-t-Bu) 368.1.

1.6 1-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-cyclopropanecarboxylic acid hydrazide hydrochloride

(9) Compound 1.5 (1.10 g; 2.598 mmol) was dissolved in HCl solution (4.0 M in dioxane; 50.0 mL) and stirred at 25° C. for 20 h. The mixture was evaporated under reduced pressure. The residue was dissolved in acetonitrile (2 mL) and MTB-ether (50 mL) was added. The precipitate was collected by suction filtration and dried for 20 h at 25° C. Yield: 0.93 g (99%) off-white solid; HPLC/MS, Rt: 1.22 min; (M+H) 324.2.

1.7 (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-phenyl-1H-[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one

(10) Compound 1.6 (100.0 mg; 0.278 mmol) and methyl benzenecarboxyimidate, hydrochloride (71.6 mg; 0.417 mmol) were dissolved in dry ethanol (2.0 mL) and N-ethyldiisopropylamine (0.25 mL; 1.470 mmol) was added. The mixture was heated to 80° C. and stirred at this temperature for 2 d. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was purified using preparative HPLC. The combined fractions were lyophilized. Yield: 42.0 mg (37%) colourless solid; HPLC/MS, Rt: 1.87 min; (M+H) 409.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.72 (s, br, 1H), 8.01-7.89 (m, 2H), 7.51-7.35 (m, 3H), 6.97 (s, 1H), 4.96-4.29 (m, 2H), 3.03-2.53 (m, 2H), 1.81-1.62 (m, 3H), 1.51 (s, 3H), 1.48-1.21 (m, 2H), 1.03-0.95 (m, 2H), 0.95-0.78 (m, 2H).

EXAMPLE 2

(R)-3,3,3-Trifluoro-1-{4-{1-[5-(4-fluorophenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one (“A2”)

(11) ##STR00006##

(12) Preparation as described for example 1. Yield: 169 mg (36%) colorless solid; HPLC/MS, Rt: 1.99 min; (M+H) 427.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.24-13.35 (m, 1H), 8.25-7.71 (m, 2H), 7.56-7.11 (m, 2H), 6.97 (s, 1H), 5.16-4.23 (m, 2H), 3.08-2.42 (m, 2H), 1.88-1.08 (m, 8H), 1.12-0.67 (m, 4H).

EXAMPLE 3

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-methyl-1-(5-phenyl-4H-[1,2,4]triazol-3-yl)-ethyl]-piperidin-1-yl}-propan-1-one (“A3”)

(13) ##STR00007##
Reaction Scheme:

(14) ##STR00008##

3.1 2-Methyl-2-pyridin-4-yl-propionic acid ethyl ester

(15) Pyridin-4-yl-acetic acid ethyl ester (3.00 g; 17.616 mmol) was dissolved in dry DMF (40.0 mL) under nitrogen atmosphere, treated with lithium bis(trimethyl-silyl)amide (1 M in THF; 22.02 mL; 22.020 mmol) at room temperature and the mixture was stirred for 30 min. The reaction mixture was cooled in an ice bath, treated with iodomethane (1.68 mL; 26.424 mmol), gradually warmed to room temperature and stirred for 1 h. Further lithium bis(trimethylsilyl)amide (1 M in THF; 22.02 mL; 22.020 mmol) and dry DMF (15 mL) was added and the mixture stirred for 30 min after which another portion of iodomethane (1.68 mL; 26.424 mmol) was added under cooling. The resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlashRF 200). Yield: 2.95 g (86%) colorless oil; HPLC/MS, Rt: 1.18 min; (M+H) 194.2

3.2 2-Methyl-2-pyridin-4-yl-propionic acid

(16) Compound 3.1 (3.61 g; 18.663 mmol) was dissolved in ethanol (55.0 mL), sodium hydroxide solution (2 N; 50.0 mL) was added and the mixture was stirred at 20° C. for 20 h. Ethanol was removed by evaporation and the aqueous residue was neutralized under ice cooling using hydrochloric acid (pH˜7). The mixture was concentrated to dryness, the colourless residue triturated three times with dichloromethane/methanol, and the combined filtrates were evaporated to dryness. Yield: 2.63 g (85%) colourless solid; HPLC/MS, Rt: 0.43 min; (M+H) 166.1.

3.3N′-(2-Methyl-2-pyridin-4-yl-propionyl)-hydrazinecarboxylic acid tert-butyl ester

(17) Compound 3.2 (1.85 g; 11.199 mmol) and (tert-butoxy)carbohydrazide (1.64 g; 12.319 mmol) were dissolved in dry DMF (35.0 mL) and the mixture was cooled in an ice bath. [Dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (5.05 g; 12.879 mmol) and N-ethyldiisopropylamine (5.83 mL; 33.598 mmol) were added, cooling was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the residue purified by RP-flash chromatography (CombiFlashRF 200). Yield: 2.74 g (88%) light yellow oil; HPLC/MS, Rt: 0.34/1.04 min; (M+H) 280.2.

3.4 2-Methyl-2-pyridin-4-yl-propionic acid hydrazide hydrochloride

(18) HCl solution (1N, 16.0 mL) was added to compound 3.3 (2.09 g; 7.482 mmol) and the mixture stirred at room temperature. After 10 min a colorless suspension was formed which was stirred over night at ambient temperature. The reaction mixture was lyophilisated and the product used in the next step without further purification.

3.5 4-[1-Methyl-1-(5-phenyl-1H-[1,2,4]triazol-3-yl)-ethyl]-pyridine

(19) Compound 3.4 (744.0 mg; 3.450 mmol) and methyl benzimidate hydrochloride (888.0 mg; 5.174 mmol) were dissolved in ethanol (14.0 mL). N-Ethyldiisopropylamine (1.76 mL; 10.349 mmol) was added and the mixture was heated to 80° C. overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue purified by flash chromatography (CombiFlashRF 200). Yield: 657 mg (72%) colourless solid; HPLC/MS, Rt: 1.23 min; (M+H)

3.6 4-[1-Methyl-1-(5-phenyl-4H-[1,2,4]triazol-3-yl)-ethyl]-piperidine hydrochloride

(20) Compound 3.5 (485.0 mg; 1.835 mmol) was dissolved in ethanol (10.0 mL) and conc. HCl (0.34 mL; 3.511 mmol) and hydrogenated over Pd—C(5%) at room temperature and normal pressure for 48 h. The reaction mixture was filtered and evaporated under reduced pressure. Yield: 532 mg (94%) yellow oil; HPLC/MS, Rt: 1.25 min; (M+H) 271.2.

3.7 (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-methyl-1-(5-phenyl-4H-[1,2,4]triazol-3-yl)-ethyl]-piperidin-1-yl}-propan-1-one

(21) (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic acid (255.0 mg; 1.612 mmol) was dissolved in dichloromethane (10.0 mL). 1-Chloro-N,N,2-trimethyl-1-propenylamine (213 μl; 1.612 mmol) was added and the colorless solution was stirred at room temperature for 90 min. This solution was slowly added to a solution of compound 3.6 (430.0 mg; 1.401 mmol) and triethylamine (583 μl; 4.204 mmol) in dichloromethane (10.0 ml) and the reaction mixture was stirred at room temperature for 90 min. The reaction mixture was diluted with water and saturated aqueous NaHCO.sub.3-solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by RP-flash chromatography (CombiFlashRF 200) and freeze-dried. Yield: 118 mg (20%) colorless solid; HPLC/MS, Rt: 1.98 min; (M+H) 411.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.1-13.46 (m, 1H), 8.05-7.92 (m, 2H), 7.58-7.32 (m, 3H), 6.96 (s, 1H), 4.91-4.28 (m, 2H), 3.03-2.70 (m, 1H), 1.95-1.79 (m, 1H), 1.61-1.42 (m, 5H), 1.32 (s, 6H), 1.28-0.96 (m, 3H).

EXAMPLE 4

(R)-1-{4-[1-(5-Cyclohexyl-4H-[1,2,4]triazol-3-yl)-1-methyl-ethyl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one (“A4”)

(22) ##STR00009##
Reaction Scheme:

(23) ##STR00010##

4.1 4-[1-(5-Cyclohexyl-4H-[1,2,4]triazol-3-yl)-1-methyl-ethyl]-piperidine

(24) Compound 3.5 (97.0 mg; 0.367 mmol) was dissolved in ethanol (10.0 mL) and hydrogenated over Platin(IV)-oxid hydrate at room temperature and normal pressure for 35 h. The reaction mixture was filtered and evaporated under reduced pressure. Yield: 98 mg (97%) red-brown oil; HPLC/MS, Rt: 1.28 min; (M+H) 277.4.

4.2 (R)-1-{4-[1-(5-Cyclohexyl-4H-[1,2,4]triazol-3-yl)-1-methyl-ethyl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one

(25) Preparation as described for example 3 (step 3.7). Yield: 3 mg (2%) colorless solid; HPLC/MS, Rt: 1.78 min; (M+H) 417.3.

EXAMPLE 5

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A5”)

(26) ##STR00011##
Reaction Scheme:

(27) ##STR00012##

5.1 4-(1-Ethoxycarbonyl-cyclopropyl)-piperidine-1-carboxylic acid tert-butyl ester

(28) To a solution of compound 1.2 (4.14 g; 17.712 mmol) in water (60.0 mL) sodium bicarbonate (4.51 g; 53.137 mmol) and di-tert-butyldicarbonate (3.83 mL; 17.712 mmol), dissolved in 1,4-dioxane (110.0 mL), were added and the mixture stirred for 2 h at room temperature. The suspension was concentrated under reduced pressure, diluted with water (60 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlashRF 200). Yield: 3.92 g (74%) colorless solid; HPLC/MS, Rt: 2.57 min; (M+H-BOC) 198.2.

5.2 4-(1-Carboxy-cyclopropyl)-piperidine-1-carboxylic acid tert-butyl ester

(29) Compound 5.1 (3.46 g; 11.630 mmol) was dissolved in ethanol (75.0 mL), treated with sodium hydroxide solution (2 N; 75.0 ml; 150.000 mmol) and the solution stirred for 4 d. The mixture was concentrated under reduced pressure, acidified with formic acid (˜pH4) and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and evaporated under reduced pressure. Yield: 3.12 g (100%) yellow solid; used in the next step without further purification.

5.3 4-[1-(N′-Benzoyl-hydrazinocarbonyl)-cyclopropyl]-piperidine-1-carboxylic acid tert-butyl ester

(30) Compound 5.2 (433.2 mg; 1.608 mmol) and benzoic acid hydrazide (210.0 mg; 1.608 mmol) were dissolved in dry DMF (6.00 ml; 47,978 äq.). [Dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (HATU) (703.2 mg; 1.849 mmol) and subsequently N-ethyldiisopropylamine (0.82 mL; 4.825 mmol) were added and the yellow solution was stirred at room temperature for 1 d. The reaction mixture was evaporated to dryness and the residue purified by RP-flash chromatography (CombiFlashRF 200).

(31) Yield: 318 mg (51%) light yellow solid; HPLC/MS, Rt: 1.97 min; (M+H) 288.2.

5.4 4-[1-(5-Phenyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidine-1-carboxylic acid tert-butyl ester

(32) A mixture of compound 5.3 (114.8 mg; 0.296 mmol) and Burgess reagent (423.4 mg; 1.777 mmol) dissolved in dry THF (1.50 mL) was heated in a CEM microwave reactor for 20 min at 130° C. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlashRF 200). Yield: 108 mg (99%) yellow oil; HPLC/MS, Rt: 2.57 min; (M+H-t-Bu) 314.1.

5.5 4-[1-(5-Phenyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidine hydrochloride

(33) Hydrogen chloride solution (4.0 M in dioxane; 5.0 mL) was added to compound 5.4 (384.0 mg; 1.039 mmol), dissolved in dioxane (5.0 mL), and stirred for 14 h at ambient temperature. The reaction was concentrated in vacuo and the residue used in the next step without further purification. Yield: 317 mg (100%) beige solid.

5.6 (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one

(34) Compound 5.5 (127.0 mg; 0.415 mmol), (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (65.6 mg; 0.415 mmol) and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (HATU) (157.9 mg; 0.415 mmol) were dissolved in dry DMF (5.0 mL) and N-ethyldiisopropylamine (283.0 μL; 1.665 mmol) was added. The reaction mixture was stirred at room temperature for 6 h. The mixture was evaporated to dryness and the residue purified by RP-flash chromatography (CombiFlashRF 200). Yield: 149 mg (87%) colorless solid; HPLC/MS, Rt: 2.19 min; (M+H) 410.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.97-7.91 (m, 2H), 7.64-7.54 (m, 3H), 7.01 (s, 1H), 4.89-4.40 (m, 2H), 3.06-2.81 (m, 1H), 2.65-2.50 (m, 1H), 1.85-1.67 (m, 3H), 1.64-1.39 (m, 5H), 1.28-1.21 (m, 2H), 1.12-1.03 (m, 2H).

EXAMPLE 6

(35) (R)-3,3,3-Trifluoro-1-{4-{1-[5-(4-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one (“A6”)

(36) ##STR00013##

(37) Preparation as described for example 5. Yield: 166 mg (59%) colorless solid; HPLC/MS, Rt: 2.23 min; (M+H) 428.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.04-7.97 (m, 2H), 7.46-7.38 (m, 2H), 7.01 (s, 1H), 4.93-4.35 (m, 2H), 3.06-2.83 (m, 1H), 2.64-2.44 (m, 1H), 1.84-1.67 (m, 2H), 1.64-1.38 (m, 6H), 1.29-1.19 (m, 2H), 1.13-1.02 (m, 2H).

(38) The following compounds were prepared analogously:

EXAMPLE 7

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-methyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A7”)

(39) ##STR00014##

(40) Yield: 114 mg (52%) colorless solid; HPLC/MS, Rt: 1.73 min; (M+H) 348.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.99 (s, 1H), 5.27-3.99 (m, 4H), 3.06-2.70 (m, 1H), 2.41 (s, 3H), 1.79-1.31 (m, 7H), 1.15-0.45 (m, 4H).

EXAMPLE 8

(R)-1-{4-[1-(5-tert-Butyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one (“A8”)

(41) ##STR00015##

(42) Yield: 266 mg (93%) colorless solid; HPLC/MS, Rt: 2.12 min; (M+H) 390.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.00 (s, 1H), 4.91-4.36 (m, 2H), 3.02-2.78 (m, 1H), 1.78-1.64 (m, 2H), 1.64-1.34 (m, 7H), 1.30 (s, 9H), 1.13-1.06 (m, 2H), 1.03-0.96 (m, 2H).

EXAMPLES 9 AND 10

Preparation of (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-methyl-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-ethyl]-piperidin-1-yl}-propan-1-one (“A9”)

(43) ##STR00016##

And (R)-1-{4-[1-(5-Cyclohexyl-[1,3,4]oxadiazol-2-yl)-1-methyl-ethyl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one (“A10”)

(44) ##STR00017##
Reaction Scheme:

(45) ##STR00018##

9.1 4-[1-Methyl-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-ethyl]-pyridine

(46) Compound 3.2 (500.0 mg; 3.027 mmol), benzohydrazide (412.1 mg; 3.027 mmol) and 2-chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium chloride (511.7 mg; 3.027 mmol) were suspended in dichloromethane (20.0 mL). Triethylamine (1.70 mL; 12.107 mmol) was added and the reaction mixture stirred at room temperature for 14 h. Further 2-chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium chloride (511.7 mg; 3.027 mmol) and triethylamine (848 μl; 6.054 mmol) was added and the reaction was stirred at room temperature for 48 h. The reaction mixture was diluted with saturated aqueous NaHCO.sub.3-solution and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlashRF 200). Yield: 130 mg (16%) orange oil; HPLC/MS, Rt: 1.48 min; (M+H) 266.1.

9.2 4-[1-Methyl-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-ethyl]-piperidine hydrochloride and 4-[1-(5-Cyclohexyl-[1,3,4]oxadiazol-2-yl)-1-methyl-ethyl]-piperidine hydrochloride

(47) Compound 9.1 (120.0 mg; 0.452 mmol) was dissolved in ethanol (10.0 mL) and 1 M HCl (0.5 mL; 0.5 mmol) and hydrogenated over platin(IV)-oxid hydrate at room temperature and normal pressure for 2 h. The reaction mixture was filtered and evaporated under reduced pressure. The residue, which contained approximately a 1/1 mixture of the title compounds, was used in the next step without further purification.

9.3 (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-methyl-1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-ethyl]-piperidin-1-yl}-propan-1-one and (R)-1-{4-[1-(5-Cyclohexyl-[1,3,4]oxadiazol-2-yl)-1-methyl-ethyl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one

(48) Preparation and work-up as described for example 3 (step 3.7). The compounds were separated by preparative HPLC. The combined fractions were evaporated to dryness. The residue was dissolved in acetonitrile, diluted with water and lyophilized.

(49) “A9”: 31 mg (33%) colorless solid; LC/MS, Rt: 2.19 min; (M+H) 412.2; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.02-7.97 (m, 2H), 7.65-7.57 (m, 3H), 6.98 (s, 1H), 4.87-4.68 (m, 1H), 4.54-4.36 (m, 1H), 3.01-2.81 (m, 1H), 2.59-2.45 (m, 1H), 1.99-1.90 (m, 1H), 1.66-1.55 (m, 2H), 1.48 (s, 3H), 1.39 (s, 6H), 1.32-1.06 (m, 2H).

(50) “A10”: 48 mg (51%) colorless solid; LC/MS, Rt: 2.31 min; (M+H) 418.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.00 (s, 1H), 4.86-4.65 (m, 1H), 4.54-4.33 (m, 1H), 2.96-2.79 (m, 2H), 2.01-1.92 (m, 2H), 1.87-1.76 (m, 1H), 1.75-1.67 (m, 2H), 1.67-1.59 (m, 1H), 1.58-1.44 (m, 7H), 1.43-1.34 (m, 2H), 1.34-0.98 (m, 10H).

EXAMPLE 11

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-phenyl-1H-[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one, Mixture of Diastereomers (“A11”)

(51) ##STR00019##
Reaction Scheme:

(52) ##STR00020##

11.1 (3-Methyl-pyridin-4-yl)-acetic acid ethyl ester

(53) 3,4-Dimethylpyridine (2.30 mL; 20.499 mmol) was dissolved in THF (10.0 mL), lithium bis(trimethylsilyl)amide (20% solution in THF; 61.50 mL; 61.496 mmol) was added at room temperature under nitrogen atmosphere and the mixture was stirred for 30 min. Diethyl carbonate (3.23 mL; 26,648 mmol) was added and the mixture was stirred at room temperature for 1 h. A saturated solution of NH.sub.4Cl (50 mL) was added and the aqueous mixture was extracted with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered, and evaporated to dryness. The residue was purified by RP-flash chromatography (Isco Companion). Yield: 1.40 g (38%) yellow oil; Rt: 1.44 min; (M+H) 180.1.

11.2 1-(3-Methyl-pyridin-4-yl)-cyclopropanecarboxylic acid ethyl ester

(54) Compound 11.1 (1.40 g; 7.810) was dissolved in dry DMF (10.0 mL), lithium bis(trimethylsilyl)amide (1 M in THF; 9.37 mL; 9.370 mmol) was added at room temperature and the mixture was stirred for 30 min. 1,2-Dibromoethane (942.5 μl; 10.940 mmol) was added and the mixture was stirred at room temperature for 1 h. Further lithium bis(trimethylsilyl)amide (1 M in THF; 9.37 mL; 9.370 mmol) was added and the mixture stirred for 1 h. The mixture was quenched under ice cooling with acetic acid (4 mL) and evaporated to dryness. The residue was partitioned between NH.sub.4Cl solution and dichloromethane. The organic phase was separated and the water phase extracted with dichloromethane. The combined organic phases were dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by RP-flash chromatography (Isco Companion). Yield: 590 mg (37%) yellow oil;

(55) Rt: 1.63 min; (M+H) 206.1.

11.3 1-(3-Methyl-piperidin-4-yl)-cyclopropanecarboxylic acid ethyl ester hydrochloride

(56) Hydrogenation of compound 11.2 (590.0 g; 2.875 mmol) was performed and worked-up as described for compound 1.2. Yield: 676 mg (95%) oil. The product was used in the next step without further purification.

11.4 1-[3-Methyl-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-cyclopropanecarboxylic acid ethyl ester

(57) Acylation of compound 11.3 (676.0 mg; 2.728 mmol) was performed as described for compound 1.3. The crude product was purified by RP-flash chromatography. Yield: 727 mg (76%) oil; Rt: 2.18 min; (M+H) 352.2.

11.5 1-[3-Methyl-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-cyclopropanecarboxylic acid

(58) Compound 11.4 (727.0 mg; 1.721 mmol) was saponified as described for compound 1.3. Yield: 510 mg (92%) oil; Rt: 1.71 min; (M+H) 324.2. The product was used in the next step without further purification.

11.6 N′-{1-[3-Methyl-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-cyclopropanecarbonyl}-hydrazinecarboxylic acid tert-butyl ester

(59) Preparation of the title compound using compound 11.5 (510.0 mg; 1.577 mmol) was performed as described for compound 1.5 and purified by RP-flash chromatography (Isco Companion). Yield: 402 mg (58%) solid; Rt: 1.79 min; (M+H-t-Bu) 382.2.

11.7 1-[3-Methyl-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-cyclopropanecarboxylic acid hydrazide hydrochloride

(60) Boc-cleavage was performed with compound 11.6 (402.0 mg; 0.919 mmol) as described for compound 1.5 (step 1.6). Yield: 343 mg (100%) oil; Rt: 1.27 min; (M+H) 382.2. The product was used in the next step without further purification.

11.8 (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-phenyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one

(61) Compound 11.7 (306.0 mg; 0.819 mmol) and methyl benzenecarboxyimidate hydrochloride (215.0 mg; 1.228 mmol) were dissolved in dry ethanol (3.3 mL). N-Ethyldiisopropylamine (0.42 mL; 2.456 mmol) was added and the mixture was heated at 85° C. for 15 h. The reaction was concentrated under reduced pressure and the residue purified by RP-flash chromatography (CombiFlashRF 200). Yield: 81 mg (23%) colorless solid; Rt: 1.99 min; (M+H) 423.2.

EXAMPLE 12

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one, Mixture of Diastereomers (“A12”)

(62) ##STR00021##
Reaction Scheme:

(63) ##STR00022##

(64) Compound 11.7 (343.0 mg; 0.918 mmol) and methyl benzenecarboxyimidate hydrochloride (236.2 mg; 1.376 mmol) were dissolved in dry ethanol (2.0 mL). N-Ethyldiisopropylamine (0.31 mL; 1.835 mmol) was added, the mixture was heated to 80° C. and stirred at this temperature for 44 h. The reaction was cooled to room temperature and evaporated under reduced pressure. The residue was purified by preparative HPLC. Yield: 152 mg (39%) solid; 2.20 min; (M+H) 424.2.

EXAMPLES 13 AND 14

Preparation of (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3R,4R)-3-methyl-4-[1-(5-phenyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A13”)

(65) ##STR00023##

And (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3S,4S)-3-methyl-4-[1-(5-phenyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A14”)

(66) ##STR00024##

(67) The preparative separation of the diastereomers of example 11 was performed by SFC (column: ChiralPak AD-H; eluent: CO.sub.2:methanol—85:15). The combined fractions were evaporated to dryness. The oily residue was dissolved in acetonitrile, diluted with water and lyophilized.

(68) “A13”: 29.5 mg colorless solid; LC/MS, Rt: 2.00 min; (M+H) 423.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 13.54 (s, 1H), 8.04-7.87 (m, 2H), 7.56-7.32 (m, 3H), 6.66 (s, 1H), 4.81-4.63 (m, 1H), 4.44-4.24 (m, 1H), 2.98-2.76 (m, 2H), 2.44-2.36 (m, 1H), 2.16-2.01 (m, 1H), 1.65-1.49 (m, 4H), 1.49-1.36 (m, 1H), 1.31-1.17 (m, 1H), 1.00-0.88 (m, 2H), 0.83 (d, J=7.0 Hz, 3H), 0.75-0.67 (m, 1H).

(69) “A14”: 26 mg colorless solid; LC/MS, Rt: 1.99 min; (M+H) 423.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 13.52 (s, 1H), 8.04-7.87 (m, 2H), 7.55-7.32 (m, 3H), 6.65 (s, 1H), 4.80-4.63 (m, 1H), 4.44-4.30 (m, 1H), 2.96-2.77 (m, 2H), 2.43-2.28 (m, 1H), 2.17-1.93 (m, 1H), 1.67-1.46 (m, 4H), 1.46-1.34 (m, 1H), 1.34-1.13 (m, 1H), 1.06-0.86 (m, 2H), 0.82 (d, J=7.0 Hz, 3H), 0.76-0.58 (m, 1H).

EXAMPLES 15 AND 16

Preparation of (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(S)-3-methyl-4-[1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A15”)

(70) ##STR00025##

And (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(R)-3-methyl-4-[1-(5-phenyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A16”)

(71) ##STR00026##

(72) The preparative separation of the diastereomers of example 12 was performed by SFC (column: ChiralPak AD-H; eluent: CO.sub.2:methanol—86:14). The combined fractions were evaporated to dryness. The oily residue was dissolved in acetonitrile, diluted with water and lyophilized.

(73) “A15”: 58 mg colorless solid; LC/MS, Rt: 2.21 min; (M+H) 424.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 8.00-7.92 (m, 2H), 7.64-7.53 (m, 3H), 6.68 (s, 1H), 4.79-4.69 (m, 1H), 4.41-4.32 (m, 1H), 2.96-2.82 (m, 2H), 2.29-2.22 (m, 1H), 2.22-2.13 (m, 1H), 1.75-1.62 (m, 1H), 1.56 (s, 3H), 1.54-1.47 (m, 1H), 1.34-1.25 (m, 1H), 1.16-1.05 (m, 3H), 0.83 (d, J=7.0 Hz, 3H).

(74) “A16”: 62 mg colorless solid; LC/MS, Rt: 2.20 min; (M+H) 424.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 8.00-7.93 (m, 2H), 7.64-7.55 (m, 3H), 6.69 (s, 1H), 4.80-4.71 (m, 1H), 4.45-4.38 (m, 1H), 2.94-2.83 (m, 2H), 2.25-2.12 (m, 2H), 1.75-1.63 (m, 1H), 1.58-1.47 (m, 4H), 1.32-1.25 (m, 1H), 1.14-1.06 (m, 3H), 0.83 (d, J=7.0 Hz, 3H).

(75) The following compounds were prepared analogously:

EXAMPLE 17

(R)-3,3,3-Trifluoro-1-(4-{1-[5-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-hydroxy-2-methyl-propan-1-one (“A17”), Mixture of Diastereomers

(76) ##STR00027##

(77) Yield: 110 mg (41%) colourless solid; LC/MS, Rt: 2.07 min; (M+H) 441.2

Preparation of (R)-3,3,3-Trifluoro-1-((3R,4R)-4-{1-[5-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-hydroxy-2-methyl-propan-1-one (“A18”)

(78) ##STR00028##

And (R)-3,3,3-Trifluoro-1-((3S,4S)-4-{1-[5-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-hydroxy-2-methyl-propan-1-one (“A19”)

(79) ##STR00029##

(80) The preparative separation of the diastereomers of example 17 was performed by SFC (column: ChiralPak AD-H; eluent: CO.sub.2:methanol—90:10). The combined fractions were evaporated to dryness. The oily residue was dissolved in acetonitrile, diluted with water and lyophilized.

(81) “A18”: 25.5 mg colorless solid; LC/MS, Rt: 2.08 min; (M+H) 441.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 13.51 (s, 1H), 8.13-7.93 (m, 2H), 7.38-7.16 (m, 2H), 6.68 (s, 1H), 4.74 (d, J=13.8 Hz, 1H), 4.34 (d, J=13.0 Hz, 1H), 2.97-2.79 (m, 2H), 2.40 (dt, J=12.2, 3.9 Hz, 1H), 2.17-2.00 (m, 1H), 1.71-1.50 (m, 4H), 1.50-1.39 (m, 1H), 1.39-1.20 (m, 1H), 1.06-0.77 (m, 5H), 0.77-0.62 (m, 1H).

(82) “A19”: 26 mg colorless solid; LC/MS, Rt: 2.07 min; (M+H) 441.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 13.56 (s, 1H), 8.13-7.91 (m, 2H), 7.40-7.16 (m, 2H), 6.67 (s, 1H), 4.74 (d, J=13.2 Hz, 1H), 4.39 (d, J=13.1 Hz, 1H), 2.98-2.74 (m, 2H), 2.38 (dt, J=12.4, 4.0 Hz, 1H), 2.18-1.96 (m, 1H), 1.67-1.48 (m, 4H), 1.47-1.36 (m, 1H), 1.33-1.19 (m, 1H), 1.05-0.88 (m, 2H), 0.84 (d, J=7.0 Hz, 3H), 0.78-0.55 (m, 1H).

EXAMPLE 20

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-p-tolyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A20”), Mixture of Diastereomers

(83) ##STR00030##

(84) Yield: 52 mg (20%) beige oil; LC/MS, Rt: 2.10 min; (M+H) 437.3.

Preparation of (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3R,4R)-3-methyl-4-[1-(5-p-tolyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A21”)

(85) ##STR00031##

And (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3S,4S)-3-methyl-4-[1-(5-p-tolyl-4H-[1,2,4]triazol-3-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A22”)

(86) ##STR00032##

(87) The preparative separation of the diastereomers of example 20 was performed by SFC (column: ChiralPak AD-H; eluent: CO.sub.2:methanol (containing 0.5% diethylamine)—80:20). The combined fractions were evaporated to dryness. The oily residue was dissolved in acetonitrile, diluted with water and lyophilized.

(88) “A21”: 18 mg colorless solid; LC/MS, Rt: 2.09 min; (M+H) 437.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 13.33 (s, br, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 6.62 (s, 1H), 4.69 (d, J=13.0 Hz, 1H), 4.30 (d, J=12.8 Hz, 1H), 2.94-2.75 (m, 2H), 2.42-2.28 (m, 4H), 2.13-1.98 (m, 1H), 1.62-1.46 (m, 4H), 1.44-1.34 (m, 1H), 1.29-1.16 (m, 1H), 0.95-0.84 (m, 2H), 0.80 (d, J=7.0 Hz, 3H), 0.73-0.59 (m, 1H).

(89) “A22”: 18 mg colorless solid; LC/MS, Rt: 2.08 min; (M+H) 437.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 13.44 (s, br, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 6.62 (s, 1H), 4.69 (d, J=12.5 Hz, 1H), 4.34 (d, J=12.8 Hz, 1H), 2.91-2.76 (m, 2H), 2.41-2.27 (m, 4H), 2.12-1.97 (m, 1H), 1.59-1.44 (m, 4H), 1.43-1.33 (m, 1H), 1.29-1.15 (m, 1H), 0.98-0.84 (m, 2H), 0.80 (d, J=7.0 Hz, 3H), 0.71-0.60 (m, 1H).

EXAMPLE 23

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{3-methyl-4-[1-(5-p-tolyl-[1,3,4]oxa-diazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A23”), Mixture of Diastereomers

(90) ##STR00033##

(91) Yield: 144 mg (52%) beige oil; LC/MS, Rt: 2.35 min; (M+H) 438.2.

Preparation of (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3R,4R)-3-methyl-4-[1-(5-p-tolyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A24”)

(92) ##STR00034##

And (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{(3S,4S)-3-methyl-4-[1-(5-p-tolyl-[1,3,4]oxadiazol-2-yl)-cyclopropyl]-piperidin-1-yl}-propan-1-one (“A25”)

(93) ##STR00035##

(94) The preparative separation of the diastereomers of example 23 was performed by SFC (column: ChiralPak AD-H; eluent: CO.sub.2:ethanol—80:20). The combined fractions were evaporated to dryness. The oily residue was dissolved in acetonitrile, diluted with water and lyophilized.

(95) “A24”: 45 mg colorless solid; LC/MS, Rt: 2.34 min; (M+H) 438.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 7.83 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 6.66 (s, 1H), 4.72 (d, J=12.6 Hz, 1H), 4.34 (d, J=12.9 Hz, 1H), 2.94-2.76 (m, 2H), 2.39 (s, 3H), 2.22 (dt, J=12.4, 3.8 Hz, 1H), 2.18-2.10 (m, 1H), 1.66 (qd, J=12.6, 4.3 Hz, 1H), 1.58-1.44 (m, 4H), 1.33-1.21 (m, 1H), 1.14-1.01 (m, 3H), 0.81 (d, J=7.0 Hz, 3H).

(96) “A25”: 45 mg colorless solid; LC/MS, Rt: 2.33 min; (M+H) 438.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 7.83 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 6.67 (s, 1H), 4.73 (d, J=12.8 Hz, 1H), 4.39 (d, J=13.0 Hz, 1H), 2.92-2.79 (m, 2H), 2.39 (s, 3H), 2.23-2.10 (m, 2H), 1.66 (qd, J=12.6, 4.4 Hz, 1H), 1.57-1.44 (m, 4H), 1.31-1.20 (m, 1H), 1.14-1.02 (m, 3H), 0.81 (d, J=6.9 Hz, 3H).

EXAMPLE 26

(R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A26”), Mixture of Diastereomers

(97) ##STR00036##

(98) Yield: 60 mg (21%) beige oil; LC/MS, Rt: 1.96 min; (M+H) 453.2

Preparation of (R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A27”)

(99) ##STR00037##

And (R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A28”)

(100) ##STR00038##

(101) The preparative separation of the diastereomers of example 26 was performed by SFC (column: Luc Cellulose-2; eluent: CO.sub.2:ethanol (containing 0.5% diethylamine)—85:15). The combined fractions were evaporated to dryness. The oily residue was dissolved in acetonitrile, diluted with water and lyophilized.

(102) “A27”: 21 mg colorless solid; LC/MS, Rt: 1.97 min; (M+H) 453.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 13.38 (s, br, 1H), 7.90 (d, J=8.9 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.66 (s, 1H), 4.72 (d, J=12.5 Hz, 1H), 4.32 (dt, J=12.8, 2.1 Hz, 1H), 3.83 (s, 3H), 2.97-2.77 (m, 2H), 2.38 (dt, J=12.3, 3.8 Hz, 1H), 2.16-2.04 (m, 1H), 1.64-1.48 (m, 4H), 1.42 (dq, J=12.8, 2.9 Hz, 1H), 1.26-1.15 (m, 1H), 0.96-0.86 (m, 2H), 0.82 (d, J=7.0 Hz, 3H), 0.74-0.61 (m, 1H).

(103) “A28”: 21 mg colorless solid; LC/MS, Rt: 1.96 min; (M+H) 453.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 13.39 (s, br, 1H), 7.90 (d, J=8.9 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.65 (s, 1H), 4.72 (d, J=11.8 Hz, 1H), 4.37 (d, J=12.9 Hz, 1H), 3.83 (s, 3H), 2.95-2.79 (m, 2H), 2.37 (dt, J=12.4, 3.8 Hz, 1H), 2.15-2.02 (m, 1H), 1.62-1.47 (m, 4H), 1.45-1.37 (m, 1H), 1.32-1.18 (m, 1H), 0.96-0.86 (m, 2H), 0.83 (d, J=7.0 Hz, 3H), 0.74-0.64 (m, 1H).

EXAMPLE 29

(R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A29”), Mixture of Diastereomers

(104) ##STR00039##

(105) Yield: 108 mg (39%) beige oil; LC/MS, Rt: 2.22 min; (M+H) 454.2

Preparation of (R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A30”)

(106) ##STR00040##

And (R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A31”)

(107) ##STR00041##

(108) The preparative separation of the diastereomers of example 29 was performed by SFC (column: ChiralPak AD-H; eluent: CO.sub.2:ethanol—75:25). The combined fractions were evaporated to dryness. The oily residue was dissolved in acetonitrile, diluted with water and lyophilized.

(109) “A30”: 34 mg colorless solid; LC/MS, Rt: 2.23 min; (M+H) 454.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 7.90 (d, J=8.9 Hz, 2H), 7.13 (d, J=8.9 Hz, 2H), 6.69 (s, 1H), 4.75 (d, J=12.4 Hz, 1H), 4.37 (dt, J=13.0, 2.2 Hz, 1H), 3.87 (s, 3H), 2.96-2.82 (m, 2H), 2.24 (dt, J=12.4, 3.8 Hz, 1H), 2.20-2.11 (m, 1H), 1.68 (qd, J=12.6, 4.2 Hz, 1H), 1.57 (s, 3H), 1.51 (dq, J=12.8, 3.3 Hz, 1H), 1.32-1.24 (m, 1H), 1.16-1.03 (m, 3H), 0.83 (d, J=7.0 Hz, 3H).

(110) “A31”: 35.5 mg colorless solid; LC/MS, Rt: 2.22 min; (M+H) 454.2; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 7.90 (d, J=8.9 Hz, 2H), 7.13 (d, J=8.9 Hz, 2H), 6.70 (s, 1H), 4.75 (d, J=12.6 Hz, 1H), 4.42 (d, J=13.0 Hz, 1H), 3.87 (s, 3H), 2.96-2.81 (m, 2H), 2.26-2.11 (m, 2H), 1.68 (qd, J=12.5, 4.4 Hz, 1H), 1.55 (s, 3H), 1.54-1.46 (m, 1H), 1.30-1.23 (m, 1H), 1.15-1.02 (m, 3H), 0.83 (d, J=6.9 Hz, 3H).

EXAMPLE 32

(R)-1-(4-{1-[5-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one (“A32”), Mixture of Diastereomers

(111) ##STR00042##

(112) Yield: 68 mg (25%) beige oil; LC/MS, Rt: 2.21 min; (M+H) 457.2/459.1

Preparation of (R)-1-((3R,4R)-4-{1-[5-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one (“A33”)

(113) ##STR00043##

And (R)-1-((3S,4S)-4-{1-[5-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one (“A34”)

(114) ##STR00044##

(115) The preparative separation of the diastereomers of example 32 was performed by SFC (column: ChiralPak AD-H; eluent: CO.sub.2:methanol (containing 0.5% diethylamine)—85:15). The combined fractions were evaporated to dryness. The oily residue was dissolved in acetonitrile, diluted with water and lyophilized.

(116) “A33”: 20 mg colorless solid; LC/MS, Rt: 2.21 min; (M+H) 457.2/459.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 12.82 (s, br, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H), 6.66 (s, 1H), 4.72 (d, J=13.4 Hz, 1H), 4.32 (d, J=12.8 Hz, 1H), 2.90 (t, J=13.0 Hz, 1H), 2.84 (d, J=12.2 Hz, 1H), 2.38 (dt, J=12.2, 3.9 Hz, 1H), 2.09-2.00 (m, 1H), 1.62-1.48 (m, 4H), 1.48-1.39 (m, 1H), 1.30-1.21 (m, 1H), 0.99-0.90 (m, 2H), 0.82 (d, J=7.0 Hz, 3H), 0.76-0.65 (m, 1H).

(117) “A34”: 21 mg colorless solid; LC/MS, Rt: 2.21 min; (M+H) 457.2/459.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 13.28 (s, br, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H), 6.66 (s, 1H), 4.72 (d, J=12.2 Hz, 1H), 4.37 (d, J=13.0 Hz, 1H), 2.95-2.76 (m, 2H), 2.37 (dt, J=12.3, 3.8 Hz, 1H), 2.11-1.97 (m, 1H), 1.65-1.46 (m, 4H), 1.46-1.36 (m, 1H), 1.32-1.20 (m, 1H), 0.99-0.88 (m, 2H), 0.82 (d, J=7.0 Hz, 3H), 0.75-0.65 (m, 1H).

EXAMPLE 35

(R)-1-(4-{1-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one (“A35”), Mixture of Diastereomers

(118) ##STR00045##

(119) Yield: 170 mg (58%) beige oil; LC/MS, Rt: 2.39 min; (M+H) 458.1/460.1.

Preparation of (R)-1-((3R,4R)-4-{1-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one (“A36”)

(120) ##STR00046##

And (R)-1-((3S,4S)-4-{1-[5-(4-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one (“A37”)

(121) ##STR00047##

(122) The preparative separation of the diastereomers of example 35 was performed by SFC (column: ChiralPak AD-H; eluent: CO.sub.2:ethanol—75:25). The combined fractions were evaporated to dryness. The oily residue was dissolved in acetonitrile, diluted with water and lyophilized.

(123) “A36”: 53 mg colorless solid; LC/MS, Rt: 2.40 min; (M+H) 458.1/460.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 8.03-7.94 (m, 2H), 7.68-7.60 (m, 2H), 6.69 (s, 1H), 4.75 (d, J=12.4 Hz, 1H), 4.37 (d, J=12.9 Hz, 1H), 2.96-2.81 (m, 2H), 2.27 (dt, J=12.5, 3.9 Hz, 1H), 2.23-2.13 (m, 1H), 1.68 (qd, J=12.6, 4.3 Hz, 1H), 1.61-1.55 (m, 3H), 1.55-1.45 (m, 1H), 1.40-1.25 (m, 1H), 1.18-1.02 (m, 3H), 0.83 (d, J=7.0 Hz, 3H).

(124) “A37”: 54.5 mg colorless solid; LC/MS, Rt: 2.39 min; (M+H) 458.1/460.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6, 90° C.) δ 8.04-7.93 (m, 2H), 7.70-7.57 (m, 2H), 6.70 (s, 1H), 4.75 (d, J=12.4 Hz, 1H), 4.42 (d, J=13.1 Hz, 1H), 2.96-2.83 (m, 2H), 2.24 (dt, J=12.5, 3.8 Hz, 1H), 2.21-2.12 (m, 1H), 1.67 (qd, J=12.6, 4.2 Hz, 1H), 1.55 (s, 3H), 1.53-1.45 (m, 1H), 1.34-1.25 (m, 1H), 1.16-1.06 (m, 3H), 0.84 (d, J=7.0 Hz, 3H).

EXAMPLE 38

(R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A38”), Mixture of Diastereomers

(125) ##STR00048##

(126) Yield: 103 mg (29%) beige oil; LC/MS, Rt: 1.91 min; (M+H) 454.2 Preparation of (R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A39”)

(127) ##STR00049##

And (R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(6-methoxy-pyridin-3-yl)-4H-[1,2,4]triazol-3-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A40”)

(128) ##STR00050##

(129) The preparative separation of the diastereomers of example 38 was performed by SFC (column: ChiralPak AD-H; eluent: CO.sub.2:methanol (containing 0.5% diethylamine)—65:35). The combined fractions were evaporated to dryness. The oily residue was dissolved in acetonitrile, diluted with water and lyophilized.

(130) “A39”: 40 mg colorless solid; LC/MS, Rt: 1.90 min; (M+H) 454.2; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 13.54 (s, br, 1H), 8.77-8.70 (m, 1H), 8.19 (dd, J=8.6, 2.0 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J=8.6 Hz, 1H), 4.94-4.18 (m, 2H), 3.91 (s, 3H), 2.97 (s, 1H), 2.77-2.62 (m, 1H), 2.48-2.37 (m, 1H), 1.97 (s, 1H), 1.54 (s, 3H), 1.49-1.37 (m, 2H), 1.30-1.23 (m, 1H), 1.00-0.91 (m, 2H), 0.77 (s, 3H), 0.60 (d, J=10.5 Hz, 1H).

(131) “A40”: 30 mg colorless solid; LC/MS, Rt: 1.90 min; (M+H) 454.2; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 13.66 (s, br, 1H), 8.78-8.68 (m, 1H), 8.19 (dd, J=8.6, 2.4 Hz, 1H), 6.98 (s, 1H), 6.92 (d, J=8.7 Hz, 1H), 4.97-4.15 (m, 2H), 3.91 (s, 3H), 3.17-2.84 (m, 1H), 2.75-2.63 (m, 1H), 2.44 (d, J=11.3 Hz, 1H), 2.03-1.90 (m, 1H), 1.51 (s, 3H), 1.50-1.32 (m, 2H), 1.32-1.22 (m, 1H), 0.98-0.71 (m, 5H), 0.64-0.56 (m, 1H).

EXAMPLE 41

(R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{1-[5-(6-methoxy-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A41”), Mixture of Diastereomers

(132) ##STR00051##

(133) Yield: 101 mg (29%) beige oil; LC/MS, Rt: 2.16 min; (M+H) 455.2 Preparation of (R)-3,3,3-Trifluoro-2-hydroxy-1-((3R,4R)-4-{1-[5-(6-methoxy-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A42”)

(134) ##STR00052##

And (R)-3,3,3-Trifluoro-2-hydroxy-1-((3S,4S)-4-{1-[5-(6-methoxy-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-cyclopropyl}-3-methyl-piperidin-1-yl)-2-methyl-propan-1-one (“A43”)

(135) ##STR00053##

(136) The preparative separation of the diastereomers of example 41 was performed by SFC (column: ChiralPak AD-H; eluent: CO.sub.2:ethanol—80:20). The combined fractions were evaporated to dryness. The oily residue was dissolved in acetonitrile, diluted with water and lyophilized.

(137) “A42”: 32.5 mg colorless solid; LC/MS, Rt: 2.16 min; (M+H) 455.2; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.81-8.77 (m, 1H), 8.23 (dd, J=8.7, 2.4 Hz, 1H), 7.14-6.98 (m, 2H), 5.01-4.19 (m, 2H), 3.96 (s, 3H), 3.10-2.66 (m, 2H), 2.33 (s, 1H), 2.20-2.11 (m, 1H), 1.59 (s, 1H), 1.54 (s, 3H), 1.46 (d, J=11.4 Hz, 1H), 1.37-1.28 (m, 1H), 1.17-1.06 (m, 2H), 1.06-0.98 (m, 1H), 0.84-0.70 (m, 3H).

(138) “A43”: 32 mg colorless solid; LC/MS, Rt: 2.15 min; (M+H) 455.2; .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.78 (d, J=1.8 Hz, 1H), 8.23 (dd, J=8.7, 2.3 Hz, 1H), 7.07-6.93 (m, 2H), 4.96-4.17 (m, 2H), 3.96 (s, 3H), 3.19-2.55 (m, 2H), 2.29 (d, J=11.9 Hz, 1H), 2.21-2.09 (m, 1H), 1.74-1.54 (m, 1H), 1.52 (s, 3H), 1.50-1.39 (m, 1H), 1.36-1.29 (m, 1H), 1.15-0.98 (m, 3H), 0.96-0.68 (m, 3H).

(139) Pharmacological Data

(140) TABLE-US-00002 TABLE 1 Inhibition of PDHK of some representative compounds of the formula I Binding IC.sub.50 PDHK2 (ITC) IC.sub.50 Compound (enzyme assay) KD (cell data) No. [M] [M] [M] “A1” 5.90E−07   1.10E−07   3.00E−06 “A2” 4.90E−β7   1.80E−07   2.00E−06 “A3” 3.20E−07   9.80E−08   3.30E−06 “A4” 1.40E−06   2.90E−07   3.90E−06 “A5” 4.40E−07   2.00E−07   1.50E−06 “A6” 5.00E−07   2.70E−07   2.00E−06 “A7” 3.50E−06   8.50E−07 >3.00E−05 “A8” 2.40E−06   6.50E−07   8.70E−06 “A9” 7.20E−07   5.00E−08   6.50E−07 “A10” 4.00E−07   1.20E−07   2.00E−06 “A11” 3.70E−07   8.30E−09   1.20E−07 “A12” 2.70E−07   8.70E−09   5.60E−08 “A13” 6.60E−06 “A14” 1.30E−07 <2.00E−09   1.90E−08 “A15” 1.10E−05   7.30E−06 “A16” 1.50E−07   4.90E−09   3.50E−08 “A17” “A18” 2.60E−06 “A19” 7.50E−08   4.20E−09   2.80E−08 “A20” “A21” 4.90E−06 “A22” 9.00E−08   2.60E−09   1.60E−08 “A23” “A24” 7.30E−06 “A25” 1.00E−07   4.10E−09   3.00E−08 “A26” “A27” 1.30E−05 “A28” 8.80E−08   2.50E−09   1.20E−08 “A29” “A30” 1.90E−06 “A31” 1.80E−07   3.60E−09   1.70E−08 “A32” “A33” 1.80E−05 “A34” 1.80E−07   2.80E−09   1.90E−08 “A35” “A36” 8.20E−06 “A37” 1.30E−07   2.40E−09   2.50E−08 “A38” “A39” 6.00E−06 “A40” 9.10E−08   6.50E−09   2.50E−08 “A41” “A42” 2-90E−05 “A43” 1.00E−07   3.80E−09   1.60E−08 IC.sub.50 [M] e.g.: 5.90E−07 = 5.90 × 10.sup.−7

(141) The compounds shown in Table 1 are particularly preferred compounds according to the invention.

(142) The following examples relate to medicaments:

Example A: Injection Vials

(143) A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

Example B: Suppositories

(144) A mixture of 20 g of an active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: Solution

(145) A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH.sub.2PO.sub.4.2H.sub.2O, 28.48 g of Na.sub.2HPO.sub.4.12H.sub.2O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment

(146) 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

Example E: Tablets

(147) A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in a conventional manner to give tablets in such a way that each tablet contains 10 mg of active ingredient.

Example F: Dragees

(148) Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: Capsules

(149) 2 kg of active ingredient of the formula I are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.

Example H: Ampoules

(150) A solution of 1 kg of active ingredient of the formula I in 60 l of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.