Thienomethylpiperazine derivatives as inhibitors of soluble epoxide hydrolase

Abstract

The present invention relates to compounds of the formula (I), wherein R1, R2, R3, R4 and X have the meanings indicated in the claims. The compounds of formula I are valuable pharmacologically active compounds. They are highly potent and selective soluble epoxide hydrolase inhibitors and are suitable, for example, for the therapy and prophylaxis of renal failure, diabetic nephropathy, type 2 diabetes mellitus, cardiovascular diseases, inflammatory diseases or could show beneficial effects in pain, dyslipidemia, atherosclerosis wound healing and stroke. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them. ##STR00001##

Claims

1. A compound selected from the group consisting of: 5-[4-((R)-2-Hydroxy-3-methyl-butyryl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 5-[4-(2-Hydroxy-propionyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide; 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3-carbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 4-chloro-2-fluoro-benzylamide; 5-[4-(1-Amino-cyclopropanecarbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide; 5-[4-(2,6-Dimethyl-pyridin-4-yl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide; 5-[4-(3,5-Dimethyl-1H-pyrazole-4-carbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 5-[4-(3,6-Difluoro-pyridine-2-carbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; and 2-[4-(2-Dimethylamino-propionyl)-piperazin-1-ylmethyl]-thiazole-5-carboxylic acid 2,4-dichloro-benzylamide, or a stereoisomeric form thereof, or a physiologically tolerable salt of any of the foregoing.

2. A pharmaceutical composition comprising at least one compound of claim 1, a stereoisomeric form thereof or a mixture of stereoisomeric forms thereof in any ratio, or a physiologically tolerable salt of any of the foregoing, and a pharmaceutically acceptable carrier.

Description

EXAMPLES

(1) The prepared compounds were in general characterized by spectroscopic data and chromatographic data, in particular mass spectra and HPLC retention times (Rt; in min) which were obtained by combined analytical HPLC/MS characterization (LC/MS), and/or nuclear magnetic resonance (NMR) spectra. Unless specified otherwise, 1H-NMR spectra were recorded at 500 MHz in D6-dimethyl sulfoxide as solvent at RT or 300 MHz in CDCl.sub.3 as solvent at RT. In the NMR characterization, the chemical shift 6 (in ppm), the number of hydrogen atoms (H) and the multiplicity (s: singlet, d: doublet, t: triplet, m: multiplet) of the peaks are given. In the MS characterization, in general the detected mass number (m/z) of the peak of the molecular ion (M), for example (M+), or of a related ion such as the ion (M+1), for example (M+1+), i.e. the protonated molecular ion [M+H]+ (MH+), or the ion (M−1), for example (M−1).sup.−, i.e. the deprotonated molecular ion [M−H].sup.−, which was formed depending on the ionization used, is given. The particulars of the LC/MS s used are as follows. Unless specified otherwise, the MS ionization was electrospray ionization ES+LC/MS spectra were recorded according to the following methods:

(2) Method 1: column: Waters UPLC BEH C18, 2.1×50 mm; 1.7 μM solvent: H.sub.2O+0.1% TFA:ACN+0.08% TFA (flow 0.9 ml/min) gradient: 95:5 (0 min) to 5:95 (1.1 min) to 5:95 (1.7 min) to 95:5 (1.8 min) to 95:5 (2 min)

(3) Method 2: column: Waters UPLC BEH C18, 2.1×50 mm; 1.7 μM solvent: H.sub.2O+0.05% TFA:ACN+0.035% TFA (flow 0.9 ml/min) gradient: 95:5 (0 min) to 5:95 (1.1 min) to 5:95 (1.7 min) to 95:5 (1.8 min) to 95:5 (2 min)

(4) Method 3: column: Waters UPLC BEH C18 2.1×50 mm; 1.7 μM, solvent: H.sub.2O+0.05% TFA:ACN+0.035% TFA (flow 0.9 ml/min) gradient: 98:2 (0 min) to 5:95 (2.6 min) to 95:5 (2.7 min) to 95:5 (3 min)

(5) Method 4: column: Waters XBridge C18, 4.6×50 mm; 2.5 μM solvent: H.sub.2O+0.1% TFA:ACN+0.1% FA (flow 1.3 ml/min) gradient: 97:3 (0 min) to 40:60 (3.5 min) to 2:98 (4 min) to 2:98 (5 min) to 97:3 (5.2 min) to 97:3 (6.5 min)

(6) Method 5: column: Luna C18, 10×2.0 mm; 3 μM solvent: H.sub.2O+0.05% TFA:ACN (flow 1.1 ml/min) gradient: 99:1 (0 min) to 93:7 (1.0 min) to 5:95 (1.8 min) to 99:1 (1.85 min)]

(7) Method 6: column: Waters UPLC BEH C18, 2.1×50 mm; 1.7 μM solvent: H.sub.2O+0.05% TFA:ACN+0.035% TFA (flow 0.9 ml/min) gradient: 98:2 (0 min) to 5:95 (2 min) to 5:95 (2.6 min) to 95:5 (2.7 min) to 95:5 (3 min)
List of Abbreviations ACN acetonitrile BSA Bis(trimethylsilyl)acetamide Boc tert-butyloxycarbonyl DMAP 4-(Dimethylamino)-pyridine DMF dimethylformamide EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide e.g. for example EtOAc ethyl acetate HOBt 1-Hydroxybenzotriazole HPLC high performance liquid chromatography Hünig's base N,N-Diisopropylethylamine MeOH methanol MS mass spectra NMM 4-Methylmorpholine NMR nuclear magnetic resonance PG protecting group RP-HPLC reversed phase high performance liquid chromatography RT room temperature (20° C. to 25° C.) SFC supercritical fluid chromatography TBS tert-butyldimethylsilyl TBAF tetrabutylammoniumflouride THF tetrahydrofuran TFA trifluoroacetic acid TOTU O-(Cyano(ethoxycarbonyl)methylenamino)-1, 1,3,3-tetramethyluronium tetrafluoroborate

Synthesis Intermediates

Intermediate 1: 5-Piperazin-1-ylmethyl-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide hydrochloride

(8) ##STR00010##

(9) To a solution of 4-(5-Carboxy-thiophen-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (4 g, 13.0 mmol), HOBt (1.9 gr, 14.3 mmol), 2-trifluoromethoxybenzylamine (2.7 g, 13.6 mmol) and NMM (3.9 g, 38.9 mmol) in DMF (20 ml), ECD*HCl was added (2.6 gr, 13.6 mmol). The mixture was stirred at RT, until conversion to product was observed (about 3 h). Then it was diluted with EtOAc and washed with water. The organic layer was then washed with diluted HCl (2×) and then with brine. The organic layer was dried over MgSO4 and the solvent was evaporated to give 4-[5-(2-trifluoromethoxy-benzylcarbamoyl)-thiophen-2-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester. The crude material was stirred at RT in 4 M HCl in dioxane (20 mL) for 2 hr. The formed solid was filtered off and dried, to give 5-piperazin-1-ylmethyl-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide (5.4 gr, 96%). 1H NMR (DMSO, 500 MHz) δ ppm 9.3-9.0 (m, 3H), 7.68 (d, 1H), 7.47-7.32 (m, 4H), 7.36 (bs, 1H), 4.53 (d, 2H), 4.3 (bm, 2H), 3.8-3.5 (m, broad, 4H), 3.3 (m, 2H), 3.1 (m, 2H). LC/MS (Method 2); Rt=1.37 min; detected mass: m/z=400.1 ([M+H]+).

Intermediate 2: 5-Piperazin-1-ylmethyl-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide hydrochloride

(10) ##STR00011##

(11) Synthesized in the same way as intermediate 1 but starting from 4-(5-Carboxy-thiophen-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester and 2-4-dichlororobenzylamide.

(12) 1H NMR (DMSO, 500 MHz) δ ppm 9.8 (bs, 2H), 9.51 (bs, 1H), 7.87 (bs, 1H), 7.60 (bs, 1H), 7.4 (m, 2H), 7.33 (d, 1H), 4.54 (bs, 2H), 4.48 (d, 2H), 3.7 (m, broad, 4H), 3.4-3.1 (bm, 4H). LC/MS (Method 4): Rt=2.94 min; detected mass: m/z=384.16 ([M+H]+).

Intermediate 3: 5-Piperazin-1-ylmethyl-thiophene-2-carboxylic acid 2-trifluoromethyl-benzylamide

(13) ##STR00012##

(14) The intermediate was synthesized in the same way as intermediate 1 but starting from 4-(5-Carboxy-thiophen-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester and 2-trifluoromethylbenzylamine.

(15) 1H NMR (DMSO, 500 MHz) δ ppm 9.08 (t, 1H), 8.5 (bs, 2H), 7.73 (m, 2H), 7.68 (m, 1H), 7.49 (m, 2H), 7.06 (m, 1H), 4.52 (m, 2H), 3.79 (s, 2H), 3.1 (bs, 4H), 2.58 (bm, 4H). LC/MS (Method 4): Rt=1.25 min; detected mass: m/z=384.05 ([M+H]+).

Intermediate 4: 5-piperazin-1-ylmethyl-thiophene-2-carboxylic acid (3-methyl-butyl)-amide Hydrochloride

(16) ##STR00013##

(17) To a solution of 4-(5-Carboxy-thiophen-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (4 g, 13.0 mmol), HOBt (1.9 gr, 14.3 mmol), 3-Methyl-butylamine (1.18 g, 13.6 mmol) and NMM (3.9 g, 38.9 mmol) in DMF (20 ml), ECD*HCl was added (2.6 gr, 13.6 mmol). The mixture was stirred at RT, until conversion to product was observed (about 3 h). The received mixture was diluted with EtOAc and washed with water. The organic layer was then washed with diluted HCl (2×) and then with brine. The organic layer was dried over MgSO4 and the solvent was evaporated to give the above-identified intermediate (3.7 gr). The crude material was stirred at RT in 4 M HCl in dioxane (20 mL) for 2 hr. The formed solid was filtered off and dried to give 5-piperazin-1-ylmethyl-thiophene-2-carboxylic acid (3-methyl-butyl)-amide (Intermediate 4) as hydrochloride salt (3.18 gr, 74%). 1H NMR (DMSO, 500 MHz) δ ppm 9.5 (bs, 2H), 8.52 (bs, 1H), 7.7 (d, 1H), 7.33 (bs, 1H), 4.5 (bs, 2H), 3.65 (m, 2H), 3.38 (m, 4H), 3.22 (m, 4H), 1.59 (m, 1H), 1.40 (m, 2H), 0.9 (d, 6H). LC/MS (Method 4): Rt=2.43 min; detected mass: m/z=296.24 ([M+H]+).

Intermediate 5: 5-Piperazin-1-ylmethyl-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide hydrochloride

(18) ##STR00014##

(19) Synthesized in the same way as intermediate 1 but starting from 4-(5-Carboxy-thiophen-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester and C-(2-Methoxy-pyridin-4-yl)-methylamine.

(20) 1H NMR (DMSO, 400 MHz) δ ppm 9.25 (bm, 2H), 8.11 (d, 1H), 7.80 (d, 1H), 7.32 (bs, 1H), 6.90 (d, 1H), 6.19 (s, 1H), 4.43 (d, 2H), 4.34 (bs, 2H), 3.82 (s, 3H), 3.32 (bs, 4H), 3.17 (bs, 4H). LC/MS (Method 4): Rt=0.73 min; detected mass: m/z=347.1 ([M+H]+).

Intermediate 6: 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3-carbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid hydrochloride

(21) ##STR00015##

(22) 46 mL of 5N HCl were added to solid 4-(5-Carboxy-thiophen-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (15.2 g, 46.4 mmol) at RT. The mixture was warmed at 50° C. for about 1 hour and the initial suspension turns into a clear solution. After 1 hour and 45 min, LC/MS showed full conversion to the above-identified intermediate. The pH of the resulting solution was adjusted to pH 6.8 by addition of a 32% aqueous solution of NaOH under cooling in an ice bath. The resulting light yellow solution was concentrated under reduced pressure. Then toluene was added (50 mL) and the mixture evaporated (2×). After addition of heptane (50 mL) the mixture was also evaporated (2×) and the crude material used in the following step without further purification. The resulting solid contains 5-Piperazin-1-ylmethyl-thiophene-2-carboxylic acid in about. 43% purity and NaCl.

(23) The previous solid (22.4 gr, 43% purity, 42.5 mmol) was suspended in MeCN (150 mL) under Argon and BSA (25.98 g, 127.7 mmol) was added. The mixture was heated for 1 h at 82° C. until formation of a yellow solution. The mixture was left to cool down and at 43° C., isodehydroacetic acid chloride (prepared in situ from the corresponding acid and thionyl chloride, using standard procedures) (7.94 gr, 42.5 mmol) was added. The mixture was again warmed at 82° C. After 1 h, the reaction mixture was allowed to cool down and at 40° C., NaCl was filtered off and washed with MeCN. The solvent was then evaporated and the residue was taken up in 125 mL of water. The formed suspension was filtered off and the mother liquor was acidified with 5.2 g of 32% aq. HCl until pH 1.4 was reached. The water was evaporated and the residue suspended in toluene and evaporated (2×50 mL) and then suspended in heptane and evaporated (2×50 mL). The crude material was then warmed at 58° C. in acetone (235 ml) containing 2 mL of water (2 mL) for 1 h and the formed crystals were collected at 43° C. and washed with acetone. The product was again recrystallized in about 150 mL of a acetone: water (3:1) mixture to give d 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3-carbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid hydrochloride (Intermediate 6) as a creme solid. (7.4 gr, 24%). 1H NMR (D.sub.2O, 400 MHz) δ ppm 7.71 (d, 1H), 7.32 (d, 1H), 6.28 (s, 1H), 4.57 (s, 2H), 3.9-3.2 (m, 8H), 2.2 (s, 3H), 2.0 (s, 3H). LC/MS (Method 5); Rt=3.60 min; detected mass: m/z=377.43 ([M+H]+).

Intermediate 7: 5-Formyl-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide

(24) ##STR00016##

(25) To a suspension of 5-Formyl-2-thiophenecarboxylic acid (2 g, 12.81 mmol) in 50 ml dichloromethane at 0° C., 1-Chlor-N,N,2-trimethylpropinylamin (1.88 g, 14.1 mmol) was added. The mixture was stirred 5 min at 000° C. and then was allowed to reach RT and stirred at this temperature for 15 min. To the obtained clear solution, a solution of 2,4-dichlorobenzylamine (2.5 g, 14.1 mmol) and triethylamine (19.2 mmol) in 10 ml dichloromethane were added and the reaction was stirred at RT overnight. The mixture was diluted with dichloromethane and washed with aqueous HCl (0.25 M). The organic layer was dried, filtered off and concentrated under reduced pressure. The obtained residue-5-Formyl-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide (Intermediate 7)-(3.3 g, 82%) was used in the next step without further purification. 1H NMR (DMSO-d6, 500 MHz) δ ppm 9.9 (s, 1H), 9.41 (t, 1H), 8.07 (d, 1H), 7.98 (d, 1H), 7.53 (s, 1H), 7.49-7.35 (m, 2H), 4.52 (d, 2H). LC/MS (Method 2) Rt=1.73 min; detected mass: m/z=360.12 ([M+H]+).

Intermediate 8: 5-Formyl-thiophene-2-carboxylic acid 4-methoxy-2-trifluoromethoxy-benzylamide

(26) ##STR00017##

(27) To a solution of 5-Formyl-2-thiophenecarboxylic acid (100 mg, 0.64 mmol) and (4-methoxy-2-(trifluoromethoxy)phenyl)methanamine (141 mg, 0.64 mmol) in 4 ml DMF, HOBt (117 mg, 196 mmol) and 4-methylmorpholine (196 mg, 1.9 mmol) were added. Then 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg, 0.83 mmol) was added and the mixture stirred at RT over night. The resulting solution was filtered, 0.1 mL TFA was added and purified by HPLC to give 5-Formyl-thiophene-2-carboxylic acid 4-methoxy-2-trifluoromethoxy-benzylamide (Intermediate 8)-(78 mg, 26%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 9.9 (s, 1H), 9.28 (t, 1H), 8.05 (d, 1H), 7.91 (d, 1H), 7.40 (dd, 1H), 6.99 (dd, 1H), 6.90 (s, 1H), 4.48 (d, 2H) 3.80 (s, 3H). LC/MS (Method 3); Rt=1.88 min; detected mass: m/z=314.10 ([M+H]+).

Intermediate 9: 5-Formyl-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide

(28) ##STR00018##

(29) To a suspension of 5-Formyl-2-thiophenecarboxylic acid (2 g, 12.8 mmol) in 50 ml dichloromethane at 0° C., 1-Chlor-N,N,2-trimthylpropinylamin (1.8 g, 14.1 mmol) was added. The mixture was stirred 5 min at 000° C. and then was allowed to reach RT and stirred at this temperature for 15 min. To the obtained clear solution, a solution of 2,4-dichlorobenzylamine (2.69 g, 14.1 mmol) and diisorpopylethylamine (14.1 mmol) in 10 ml dichloromethane were added and the reaction was stirred at RT overnight. The mixture was diluted with dichloromethane and washed with aq. HCl (0.25 M). The organic layer was dried, filtered off and concentrated under reduced pressure to give the desired compound 5-Formyl-thiophene-2-carboxylic acid 2-trifluoromethoxybenzylamide (Intermediate 93.5 gr, 86%), which was used in the next step without further purification. 1H NMR (DMSO-d6, 500 MHz) δ ppm 9.9 (s, 1H), 9.39 (t, 1H), 8.06 (d, 1H), 7.95 (d, 1H), 7.5-7.3 (m, 4H), 4.52 (d, 2H). LC/MS (Method 3); Rt=1.86 min; detected mass: m/z=330.03 ([M+H]+).

Intermediate 10: 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3-carbonyl)-piperazin-1-ylmethyl]-4-methyl-thiophene-2-carboxylic acid

(30) ##STR00019##

(31) To a solution of isodehydracetic acid (2 g, 7.22 mmol) in dioxane (5 mL) at 0° C., 1-chloro-N,N,2-trimethylpropynylamine was added in portions (1.33 g, 7.9 mmol). The mixture was stirred 1 h at RT and was added slowly to a suspension of 4-methyl-5-(piperazin-1-ylmethyl)thiophene-2-carboxylic acid (commercially available or easily prepared from known commercial starting materials) and sodium bicarbonate (1.5 gr, 2.5 mmol) in dioxan (10 ml). The mixture was allowed to stir overnight at RT and then the solvent was evaporated. 10 mL of pyridine was added and 1 mL of water and the mixture stirred for 4 h at RT. Toluene was added, the mixture evaporated and the residue purified by HPLC to give 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3-carbonyl)-piperazin-1-ylmethyl]-4-methyl-thiophene-2-carboxylic acid (intermediate 10) as a white solid (1.68 g, 60%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 7.54 (s, 1H), 7.28 (s, 1H), 6.12 (s, 1H), 4.5 (bs, 2H), 3.5 (bm, 8H), 2.22 (s, 3H), 2.12 (s, 3H), 2.0 (s, 3H).

Intermediate 11: 5-[4-(2-Hydroxy-propionyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid hydrochloride

(32) ##STR00020##

(33) To a solution of 4-(5-Carboxy-thiophen-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (9.8 g, 30.0 mmol) in dichloromethane (300 mL) at 0° C., oxalyl chloride was added (10.3 ml, 120 mmol). The mixture was stirred at this temperature for 30 min and then quenched with MeOH (100 mL). The solvent was evaporated and the resulting residue taken up in dichloromethane (200 mL) and trifluoroacetic acid was added (50 mL) and the mixture stirred at RT overnight. The solvent was evaporated and the resulting solid suspended in boiling THF. After cooling down to RT the resulting solid was filtered off and washed with diisopropylether to give 5-Piperazin-1-ylmethyl-thiophene-2-carboxylic acid methyl ester as the trifluoroacetate salt (8.8 g, 78%).

(34) To a solution of 5-Piperazin-1-ylmethyl-thiophene-2-carboxylic acid methyl ester trifluoroacetate salt (6.9 g, 24.9 mmol) and sodium-2-(tert-Butyl-dimethyl-silanyloxy)-propionate (6.77 g, 29.92 mmol)-prepared from methyl lactate and tert butyldiemthylchlorosilane using standard procedures- and triethylamine (10.6 ml, 74.8 mmol) in THF (200 mL) at RT, TOTU (9.8 g, 29.92 mmol) was added and the mixture stirred at RT overnight. EtOAc was added (200 mL) and the organic layer was washed with water (2 times) and concentrated under reduced pressure to give an oil (6.9 g, 65%). LC/MS (Method 6); Rt=4.11 min; detected mass: m/z=427.29 ([M+H]+).

(35) The above obtained oil (4.8 g, 11.25 mmol) was dissolved in MeOH (25 ml) and then 1M NaOH was added (15 ml). The mixture was stirred at RT overnight and the solvent was evaporated. The resulting oil was suspended in toluol and after evaporation (2 times) sodium 5-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-propionyl]-piperazin-1-ylmethyl}-thiophene-2-carboxylate as a white solid (4.7 g, 96%) was prepared. LC/MS (Method 3); Rt=1.57 min; detected mass: m/z=413.3 ([M+H]+).

(36) A solution of sodium 5-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-propionyl]-piperazin-1-ylmethyl}-thiophene-2-carboxylate (40 mg, 0.097 mmol) in 5M HCl in isopropanol (4 mL) was stirred at RT overnight. The solvent was evaporated and the residue purified by supercritical fluid chromatography to give 5-[4-(2-Hydroxy-propionyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid hydrochloride as an oil (35 mg; 100%): 1H NMR (DMSO-d6, 400 MHz) δ ppm 9.12 (s, 1H), 9.39 (t, 1H), 8.06 (d, 1H), 7.95 (d, 1H), 7.5-7.3 (m, 4H), 4.52 (d, 2H). LC/MS (Method 2); Rt=0.43 min; detected mass: m/z=299.17 ([M+H]+).

Intermediate 12: 2-Piperazin-1-ylmethyl-thiazole-5-carboxylic acid 2,4-dichloro-benzylamide dihydrochloride

(37) ##STR00021##

Step 1

Synthesis of 4-(5-Ethoxycarbonyl-thiazol-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester

(38) A mixture of 2-Bromomethyl-thiazole-5-carboxylic acid methyl ester [U.S. Pat. No. 6,162,808 A1 page 14] (17.5 g, 70 mmol), tert-butyl 1-piperazinecarboxylate (13.03 g, 70 mmol), K.sub.2CO.sub.3 (19.35 g, 140 mmol) and NaI (2.09, 14 mmol) in dry acetonitrile (576 mL) was stirred at reflux under nitrogen atmosphere for 1 h. After cooling down, the solvent was removed under reduced pressure and the residue was suspended in dichloromethane (0.5 L). The solid was removed by filtration, washed with dichloromethane and the filtrate was concentrated to dryness. The crude reaction product was purified by flash column chromatography (SiO2, c-Hex/AcOEt) to give 18 g of 4-(5-Ethoxycarbonyl-thiazol-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (72%). 1H NMR (CDCl3, 500 MHz) δ 8.27 (s, 1H), 4.34 (dd, 2H), 3.83 (s, 2H), 3.46 (m, 4H), 2.54 (m, 4H), 1.44 (s, 9H), 1.36 (t, 3H). MS-(ESI) 356.13/357.13 [M+]

Step 2

(39) To a solution of 4-(5-Ethoxycarbonyl-thiazol-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (4.0 gr, 11.25 mmol) in EtOH (40 mL), 3.4 mL of a 5M NaOH solution in water were added. The mixture was allowed to stir at RT overnight and then the solvent was evaporated. 50 mL of water were added and the solution was acidified by adding 5M aqueous HCl (3.7 mL). The resulting suspension was cooled for 1 h in an ice bath and then filtered off. The solid was washed with water and dried with ethyl ether and used in the following amide coupling without further purification.

(40) To a solution of the previous solid (3.4 g, 10.6 mmol), 2,4-dichlorobenzylamine (1.96 g, 11.3 mmol), N-Methyl morpholine (2.6 gr, 26.5 mmol) and HOBt (1.6 gr, 11.66 mmol) in DMF (63 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.8 gr, 11.66 mmol) were added. The mixture was stirred at RT overnight and then DMF was evaporated under reduced pressure. The crude material was diluted in EtOAc and washed with water and saturated NaHCO.sub.3 solution. The organic layer was dried, filtered off and evaporated to give crude 4-[5-(2,4-Dichloro-benzylcarbamoyl)-thiazol-2-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (5.4 g). The residue was dissolved in dioxane (30 mL) and then 40 mL of 4M HCl in dioxane were added. The mixture was allowed to stir at RT overnight and the resulting solid was filtered off and washed with dioxane and diisopropylether.

(41) 2-Piperazin-1-ylmethyl-thiazole-5-carboxylic acid 2,4-dichloro-benzylamide dihydrochloride (Intermediate 12) (4.85 g, 88%) was obtained as a colorless solid in about 90% purity.

(42) .sup.1H NMR (DMSO-d6, 400 MHz) δ 9.36 (bs, 1H), 9.20 (bs, 2H), 8.49 (s, 1H), 7.52 (s, 1H), 7.40 (m, 2H), 4.5 (d, 2H), 4.25 (bs, 2H), 3.22 (bs, 4H), 3.04 (bs, 4H). LC/MS (Method 3): Rt=1.29 min; detected mass: m/z=385.18 ([M+H]+).

(43) General Procedure for the Coupling of Intermediates II (1-5 and 12):

(44) ##STR00022##

(45) Method 1

(46) A reaction vessel was filled with a solution containing the corresponding carboxylic acid (0.13 mmol). Then 0.75 ml of a stock solution containing HOBt*H2O (0.13 mmol), N-methylmorpholine (1 mmol) and DMAP (0.01 mmol) were added and the mixture was stirred at RT until the acid had dissolved. Subsequently a solution of the corresponding intermediate (1-5) in 1 ml of DMF was added, followed by EDC (neat, 0.13 mmol). The tube was closed with a screw cap and shaken over night at 40° C. 0.1 ml TFA was added and the volume was adjusted to 2.2 ml with DMF. The solution was filtered and submitted to prep. RP-HPLC purification.

(47) Method 2:

(48) General Procedure for the Coupling of Intermediates IV (6, 10, 11)

(49) ##STR00023##

(50) Method 1: Amide Coupling

(51) To a solution of the corresponding thiophen-2-carboxylic acid intermediate (IV) (14.85 mmol) in DMF (100 mL), HOBt x H2O (17.55 mmol) and N-methyl morpholine (81 mmol) were added. Then EDC (17.55 mmol) was added and the mixture was stirred for 40 minutes at RT to form the active ester. The volume was adjusted to 135 ml with DMF.

(52) The corresponding amine (0.15 mmol) was weighed into a reaction tube and 1 ml of the above stock solution (containing about 0.11 mmol of the active ester) was added, the tube was closed with a screw cap and shaken at RT overnight. The mixture was diluted with 15 ml ethyl acetate and washed twice with 5 ml 5% NaHCO3 (aq) each, then dried by passage through a XTR Chroma bond column, and evaporated. The residue was submitted to SFC purification.

(53) Method 2: Via Acid Chloride

(54) Step 1: In a round bottom flask was introduced the corresponding thiophene-2-carboxylic acid (IV) (4.3 mmol) and suspended in dry CH.sub.2Cl.sub.2 (50 mL). The flask was fitted with a dropping funnel and an Argon bubbler, purged with Argon, and then cooled in an ice bath. Then 1-chloro-2,2,N-trimethylpropenylamine (7.1 mmol) in dry CH2Cl2 (5 mL) was added drop wise during 30 min with stirring. The reaction was allowed to stir for 3 h at RT until conversion of the acid to acid chloride was observed by LCMS. If the conversion was not complete additional amount 1-chloro-2,2,N-trimethylpropenylamine was added and further stirring at RT was done until complete conversion was achieved. The resulting solution was used in the next step without further treatment.

(55) Step 2: In a reaction flask was introduced a solution of the corresponding amine (0.15 mmol) in THF (1 mL). Then diisopropylethylamine (0.5 mmol) was added followed by the corresponding amount of the solution generated in step 1 (containing 0.11 mmol of acid chloride). The reaction was purged with Ar and stirred overnight at RT. Then, the solvent was evaporated, a mixture of DMF and TFA was added (19:1 2 mL) and the products purified by HPLC.

(56) General Procedures for the Reductive Aminations of Intermediates VI (7-9)

(57) ##STR00024##

(58) Method 1:

(59) To a reaction vessel containing the corresponding amine VII (0.16 mmol), NaOAc (0.18 mmol) was added (+0.18 mmol for hydrochlorides per HCl), followed by the corresponding thiophenealdehyde or thiazolaldehyde VI (0.15 mmol) in 2 ml of THF, 0.4 ml glacial acetic acid, and finally 0.3 mmol polymer-bound cyanoborohydride. The tube was closed with a screw cap and shaken at RT overnight. The resin was filtered off and washed with 2×2 ml THF. The filtrate was diluted with 5 ml toluene and evaporated. The residue was dissolved in 15 ml ethyl acetate and washed with 2×5 ml 10% NaHCO3 (aqua), then dried by passage through an XTR Chroma bond column. The column was washed with 2 ml ethyl acetate. The filtrate was evaporated, the residue was dissolved in 2 ml DMF, filtered, and submitted to SFC to give the desired compound.

(60) Method 2:

(61) To a solution of the corresponding amine (VII) (0.41 mmol) and the corresponding 5-Formyl-thiophene-2-carboxylic amide (VI) (0.32 mmol), THF (6 mL) was added followed by glacial acetic acid (0.8 mL) and polymer-bound cyanoborohydride (0.64 mmol). The reaction tube was closed with a screw cap and shaken at RT overnight. The resin was filtered off and washed with 2×4 ml THF. The filtrate was diluted with 10 ml toluene and evaporated. The residue was dissolved in 4 ml DMF, filtered, and submitted to HPLC purification.

(62) ##STR00025##

(63) Method 3—Two Step Procedure:

(64) Step 1: In a round bottom flask was introduced 5-formylthiophene-2-carboxylic acid (6.45 mmol) and suspended in 20 mL of dry CH2Cl2. The flask was fitted with a dropping funnel and an Argon bubbler, purged with Argon, and then cooled in an ice bath. Then 1-chloro-2,2,N-trimethylpropenylamine (7.75 mmol) in dry CH2Cl2 (5 mL) was added drop wise with stirring. The reaction was allowed to warm to RT and stirred for a further 30 minutes after all solids had dissolved. The solution was again cooled in an ice bath and a mixture of 6.75 mmol of the benzyl amine and 7.1 mmol diisopropyl ethyl amine in 5 ml dry THF was added drop wise with stirring. After the addition was complete the solution was allowed to warm to RT and stirred for another hour at this temperature. The solution was diluted with THF to a volume of 86 ml and used in the next step without further treatment.

(65) Step 2:

(66) In a reaction tube was introduced the corresponding piperazine (0.16 mmol). Then NaOAc (0-18 mmol, +0.18 mmol for hydrochlorides per HCl) was added, followed by 2 ml of the solution from step 1 (containing ca. 0.15 mmol of the corresponding intermediate VI), glacial acetic acid (0.4 ml), and finally polymer-bound cyanoborohydride (0.3 mmol). The tube was closed with a screw cap and shaken at RT overnight. The resin was filtered off and washed with 2×2 ml THF. The filtrate was diluted with 5 ml toluene and evaporated. The residue was dissolved in 15 ml ethyl acetate and washed with 2×5 ml 10% aqueous NaHCO3, then dried by passage through an XTR Chroma bond column. The column was washed with 2 ml ethyl acetate. The filtrate was evaporated and the residue was dissolved in 2 ml DMF, filtered, and submitted to SFC purification.

(67) The following examples illustrate the invention.

Example 30: 5-[4-((R)-2-Hydroxy-3-methyl-butyryl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide

(68) ##STR00026##

(69) To (R)-(+)-2-Hydroxy-3-methylbutyric acid (15 mg, 0.13 mmol), a solution containing HOBt*H.sub.2O (0.13 mmol), N-methylmorpholine and 0.01 mmol DMAP in 0.75 ml DMF was added and the mixture was stirred at RT until the acid had dissolved. Then 5-piperazin-1-ylmethyl-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide (Intermediate 5) (42 mg, 0.11 mmol) in 1 ml DMF was added, followed by 0.13 mmol EDC (neat). The tube was closed with a screw cap and shaken over night at 40° C. 0.1 ml TFA was added and the volume was adjusted to 2.2 ml with DMF. The solution was filtered and submitted to SFC purification to give the title compound as a colorless film (17 mg, 30%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 9.02 (t, 1H), 8.1 (d, 1H), 7.66 (d, 1H), 7.02 (d, 1H), 6.90 (d, 1H), 6.68 (s, 1H), 4.6 (bs, 1H), 4.41 (d, 2H), 4.03 (d, 1H), 3.82 (s, 3H), 3.7 (s, 2H), 3.6-3.4 (m, 4H), 2.45-2.3 (m, 4H), 1.89 (m, 1H), 0.88 (d, 3H), 0.78 (d, 3H). LC/MS (Method 3); Rt=1.26 min; detected mass: m/z=447.20 ([M+H]+).

Example 54: 5-[4-(2-Hydroxy-propionyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide, trifluoroacetate

(70) ##STR00027##

(71) A solution containing HOBt*H.sub.2O (0.13 mmol), N-methylmorpholine (0.26 mmol) and 0.01 mmol DMAP in 0.75 ml DMF was added to a reaction vessel containing lactic acid (12 mg, 0.13 mmol) and the mixture was stirred at RT until the acid had dissolved. Then 5-piperazin-1-ylmethyl-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide hydrochloride (intermediate 1) (42 mg, 0.11 mmol) in 1 ml DMF was added, followed by 0.13 mmol EDC (neat). The tube was closed with a screw cap and shaken over night at 40° C. 0.1 ml TFA was added and the volume was adjusted to 2.2 ml with DMF. The solution was filtered and submitted to preparative RP-HPLC purification to give the title compound as a colorless film (42 mg, 65%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 9.14 (bs, 1H), 7.8 (s, 1H), 7.49-7.36 (m, 4H), 7.26 (bs, 1H), 4.51 (d, 2H), 4.5 (bs, 2H), 3.8-3.3 (m, 6H), 3.0 (m, 2H), 1.19 (2, 3H), 0.88 (d, 3H), 0.78 (d, 3H). LC/MS (Method 3); Rt=1.00 min; detected mass: m/z=472.22 ([M+H]+).

Example 60: 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3-carbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 4-chloro-2-fluoro-benzylamide

(72) ##STR00028##

(73) To a solution containing 5-[4-(2,4-dimethyl-6-oxo-6H-pyran-3-carbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid hydrochloride (intermediate 6) (45 mg, 0.11 mmol), HOBt*H.sub.2O (0.13 mmol), N-methylmorpholine (0.55 mmol) in 1 mL DMF, EDC (0.13 mmol) was added and the mixture was stirred at RT for 40 min. Then 4-chloro-2-fluoro-benzylamine (0.15 mmol) was added and the mixture stirred at RT over night. The mixture was diluted with 15 ml ethyl acetate and washed twice with 5 ml 5% NaHCO.sub.3 (aq) each, then dried by passage through a XTR Chromabond column, and evaporated. The residue was submitted to SFC purification to give the title compound as colorless oil (14 mg, 25%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 8.99 (t, 1H), 7.8 (s, 1H), 7.49-7.36 (m, 4H), 7.26 (bs, 1H), 4.51 (d, 2H), 4.5 (bs, 2H), 3.8-3.3 (m, 6H), 3.0 (m, 2H), 1.19 (2, 3H), 0.88 (d, 3H), 0.78 (d, 3H). LC/MS (Method 1); Rt=1.07 min; detected mass: m/z=518.12 ([M+H]+).

Example 115: 5-[4-(1-Amino-cyclopropanecarbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide, trifluoroacetate

(74) ##STR00029##

(75) To a solution of 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid (114 mg, 0.57 mmol), ethyl cyanoglioxylate-2-oxyma (81 mg, 0.57 mmol), DMAP (2 mg, 0.017 mmol) and 5-piperazin-1-ylmethyl-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide hydrochloride (intermediate 1) (200 mg, 0.47 mmol) in 4 ml DMF, 4 methylmorpholine (0.12 mL, 1.04 mmol) was added, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg, 0.57 mmol). The mixture was stirred at RT over night. The resulting solution was extracted with EtOAc and a saturated solution of sodium bicarbonate. The phases were separated and the organic layer concentrated under reduced pressure and redissolved in 2 mL DMF. 0.1 ml TFA was added and the volume was adjusted to 2.2 ml with DMF. The solution was filtered and submitted to preparative RP-HPLC purification to give (1-{4-[5-(2-trifluoromethoxy-benzylcarbamoyl)-thiophen-2-ylmethyl]-piperazine-1-carbonyl}-cyclopropyl)-carbamic acid tert-butyl ester as a white solid (232 mg, 83%).

(76) To a solution of (1-{4-[5-(2-Trifluoromethoxy-benzylcarbamoyl)-thiophen-2-ylmethyl]-piperazine-1-carbonyl}-cyclopropyl)-carbamic acid tert-butyl ester (190 mg, 3.26 mmol) in dichloromethane (2.5 mL) at 0° C., 2.5 mL of trifluoroacetic acid were added and the mixture stirred at RT for 2 h. Then the solvent was evaporated to get 5-[4-(1-Amino-cyclopropanecarbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide trifluoroacetate as a white solid (194 mg, 100%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 9.17 (t, 1H), 8.7 (bs, 2H), 7.8 (d, 1H), 7.49-7.36 (m, 4H), 7.26 (bs, 1H), 4.51 (d, 2H), 4.5 (bs, 2H), 3.8-3.3 (m, 6H), 3.0 (m, 2H), 1.2 (bs, 2H). LC/MS (Method 4); Rt=2.50 min; detected mass: m/z=483.32 ([M+H]+).

Example 120: 5-[4-(2,6-Dimethyl-pyridin-4-yl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide

(77) ##STR00030##

(78) Step 2:

(79) 0.16 mmol of the 1-(2,6-Dimethyl-pyridin-4-yl)-piperazine was weighed into a reaction tube. 0.18 mmol NaOAc was added, followed by a solution of 5-formyl-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide (intermediate 7) (0.15 mmol) in 2 mL of THF. Then 0.4 ml glacial acetic acid and finally polymer-bound cyanoborohydride (0.3 mmol) were added and shaken at RT over night. The resin was filtered off and washed with 2×2 ml THF. The filtrate was diluted with 5 ml toluene and evaporated. The residue was dissolved in 15 ml ethyl acetate and washed with 2×5 ml 10% NaHCO.sub.3(aq), dried by passage through an XTR Chromabond column. The column was washed with 2 ml ethyl acetate. The received filtrate was evaporated, the residue was dissolved in 2 ml DMF, filtered, and submitted to SFC purification to give the 5-[4-(2,6-Dimethyl-pyridin-4-yl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide (5.6 mg, 8%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 9.0 (t, 1H), 7.7 (d, 1H), 7.62 (s, 1H), 7.44 (dd, 1H), 7.37 (dd, 1H), 7.02 (d, 1H), 6.5 (bs, 2H), 4.49 (d, 2H), 3.7 (s, 2H), 3.3 (bs, 4H), 2.5 (bs, 4H), 2.29 (s, 6H). LC/MS (Method 4); Rt=1.51 min; detected mass: m/z=491.24 ([M+2H]+; 489.25 ([M]+).).

Example 139: 5-[4-(3,5-Dimethyl-1H-pyrazole-4-carbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide trifluoroacetate

(80) ##STR00031##

(81) To a solution of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid (18 mg, 0.13 mmol), HOBt*H.sub.2O (0.13 mmol), N-Methylmorpholine (1 mmol), 4-Dimethylaminopyridine (0.01 mmol) in 0.75 mL of DMF, a solution of intermediate 5 (0.11 mmol in 1 mL DMF) was added followed by EDC (neat, 0.13 mmol). The tube was closed with a screw cap and shaken over night at 40° C. 0.1 ml TFA was added and the volume was adjusted to 2.2 ml with DMF. The solution was filtered and submitted to preparative RP-HPLC purification to give 5-[4-(3,5-Dimethyl-1H-pyrazole-4-carbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide trifluoroacetate as a colorless film (33 mg, 52%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 9.22 (t, 1H), 8.1 (d, 1H), 7.80 (d, 1H), 7.30 (bs, 1H), 6.90 (d, 1H), 6.69 (s, 1H), 4.6 (bs, 2H), 4.40 (bs, 2H), 4.3-3.7 (broad signal, 4H), 3.7 (s, 3H), 3.5-3.0 (broad signal, 4H), 2.13 (s, 6H). LC/MS (Method 3); Rt=1.15 min; detected mass: m/z=469.31 ([M+H]+)

Example 149: 5-[4-(3,6-Difluoro-pyridine-2-carbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide

(82) ##STR00032##

(83) To a solution of 3,6-difluoro-pyridine-2-carboxylic acid (20 mg, 0.13 mmol), HOBt*H.sub.2O (0.13 mmol), N-methylmorpholine (1 mmol), 4-dimethylaminopyridine (0.01 mmol) in 0.75 mL of DMF, a solution of intermediate 5 (0.11 mmol in 1 mL DMF) was added followed by EDC (neat, 0.13 mmol). The tube was closed with a screw cap and shaken over night at 40° C. 0.1 ml TFA was added and the volume was adjusted to 2.2 ml with DMF. The solution was filtered and submitted to preparative RP-HPLC purification. The resulting product obtained after freeze drying was redissolved in DMF and submitted to SFC purification to give 5-[4-(3,6-Difluoro-pyridine-2-carbonyl)-piperazin-1-ylmethyl]-thiophene-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide as a colorless film (19 mg, 35%). 1H NMR (DMSO-d6, 500 MHz) δ ppm 9.01 (t, 1H), 8.08 (m, 2H), 7.56 (d, 1H), 7.40 (m, 1H), 7.02 (d, 1H), 6.90 (d, 1H), 6.57 (s, 1H), 4.39 (d, 2H), 3.82 (s, 3H), 3.75 (s, 2H), 3.62 (m, 2H), 3.25 (m, 4H). LC/MS (Method 3); Rt=1.33 min; detected mass: m/z=488.23 ([M+H]+)

Example 177: 2-[4-(2-Dimethylamino-propionyl)-piperazin-1-ylmethyl]-thiazole-5-carboxylic acid 2,4-dichloro-benzylamide

(84) ##STR00033##

(85) To a solution of 2-dimethylamino-propionic acid (15 mg, 0.13 mmol), intermediate 12 (50 mg, 0.11 mmol), HOBt (18 mg, 0.13 mmol) and N-methylmorpholine (101 mg, 1.0 mmol) in DMF (2 mL), EDC was added (20 mg, 0.13 mmol). The reaction vessel was closed with a screw cap and the reaction stirred at 40° C. over night. The reaction mixture was diluted with 15 ml ethyl acetate and washed twice with 5 ml 5% NaHCO.sub.3 each. The organic phase was dried by passage through an XTR Chromabond column, and evaporated. The residue was dissolved in 2 ml DMF and submitted to SFC purification to give 2-[4-(2-Dimethylamino-propionyl)-piperazin-1-ylmethyl]-thiazole-5-carboxylic acid 2,4-dichloro-benzylamide (24 mg, 45%). 1H NMR (DMSO-d6, 400 MHz) δ 9.29 (t, 1H), 8.33 (s, 1H), 7.62 (s, 1H), 7.4 (dd, 2H), 4.5 (d, 2H), 3.82 (s, 2H), 3.7-3.5 (m, 4H), 3.4 (m, 2H). 2.5 (m, 2H), 2.42 (m, 1H), 2.14 (s, 6H), 1.01 (d, 3H). LC/MS (Method 3): Rt=1.21 min; detected mass: m/z=484.21 ([M+H]+).

(86) According to the previous examples the following compounds were prepared in close analogy.

(87) In case of trifluoroacetic acid salts formed by the procedure described above, the free base could be isolated via following procedure: The respective trifluoroacetic acid salt was partitioned between an organic solvent (dichloromethane, tert.-butyl methyl ether or ethyl acetate) and saturated aqueous sodium carbonate solution and stirred for 30 min. The organic layer was separated, washed with water, dried over magnesium sulfate, filtered and evaporated to give free base.

(88) TABLE-US-00001 Mass R.sub.t (from Starting (from LC/MS) LC/MS No compound Chemical name LC/MS) (min) Method 1 Inter- 5-[4-((R)-2-Hydroxy-propionyl)-piperazin- 472.28 2.88 4 mediate 1 1-ylmethyl]-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide; Trifluoroacetate 2 Inter- 5-[4-(3,5-Dimethyl-isoxazole-4-carbonyl)- 507.14 0.99 2 mediate 2 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 3 Inter- 5-{4-[2-(2-Chloro-phenyl)-acetyl]- 536.2 1.02 2 mediate 3 piperazin-1-ylmethyl}-thiophene-2- carboxylic acid 2-trifluoromethyl- benzylamide; Trifluoroacetate 4 Inter- 5-[4-(Pyridine-3-carbonyl)-piperazin-1- 489.23 0.89 2 mediate 3 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethyl-benzylamide; Trifluoroacetate 5 Inter- 5-[4-((1R,2R)-2-Phenyl-cyclopropane- 440.14 1.12 2 mediate 4 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid (3-methyl- butyl)-amide 6 Inter- 5-[4-(Bicyclo[4.2.0]octa-1(6),2,4-triene-7- 514.22 1.01 2 mediate 3 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2-trifluoro- methyl-benzylamide; Trifluoroacetate 7 Inter- 5-[4-(2-Methoxy-pyridine-3-carbonyl)- 519.11 0.98 2 mediate 2 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 8 Inter- 5-[4-(Pyrazolo[1,5-a]pyridine-3-carbonyl)- 528.14 0.95 2 mediate 2 piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide; Trifluoroacetate 9 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 564.25 1.1 2 mediate 6 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 4-methoxy- 2-trifluoromethyl-benzylamide 10 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 460.28 1.06 2 mediate 6 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid (3,3- dimethyl-butyl)-amide 11 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 566.1 1.05 2 mediate 6 carbonyl)-piperazin-1-ylmethyl]-thiophene-2- carboxylic acid [3-(5-methyl-3-trifluoro- methyl-pyrazol-1-yl)-propyl]-amide 12 Inter- 5-[4-(5-Bromo-3-methyl-benzofuran-2- 532.07 1.23 1 mediate 4 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid (3-methyl- butyl)-amide; Trifluoroacetate 13 Inter- 5-[4-(2-Difluoromethyl-2H-pyrazole-3- 440.14 1.05 1 mediate 4 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid (3-methyl- butyl)-amide; Trifluoroacetate 14 Inter- 2-{4-[5-(2,4-Dichloro-benzylcarbamoyl)- 518.2 1.52 3 mediate 7 thiophen-2-ylmethyl]-piperazin-1-yl}-N- methyl-nicotinamide; Trifluoroacetate 15 Inter- 5-[4-(Imidazo[1,2-a]pyridine-6-carbonyl)- 528.24 0.8 2 mediate 3 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethyl- benzylamide; Trifluoroacetate 16 Inter- 5-[4-(Pyridine-2-carbonyl)-piperazin-1- 489.23 0.91 2 mediate 3 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethyl-benzylamide; Trifluoroacetate 17 Inter- 5-[4-(2-Phenoxy-acetyl)-piperazin-1- 518.22 1 2 mediate 3 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethyl-benzylamide; Trifluoroacetate 18 Inter- 5-[4-(4-Bromo-thiophene-3-carbonyl)- 572.11 1.01 2 mediate 3 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethyl- benzylamide; Trifluoroacetate 19 Inter- 5-[4-(Pyrrolidine-1-carbonyl)-piperazin-1- 497.26 1.04 2 mediate 1 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide 20 Inter- 5-[4-(2-Hydroxy-propionyl)-piperazin-1- 456.3 1.33 3 mediate 2 ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide; Trifluoroacetate 21 Inter- 5-[4-(4-Hydroxy-6-methoxymethyl- 522.19 1.6 3 mediate 7 pyrimidin-2-yl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 22 Inter- 5-[4-(6-Hydroxy-pyridazin-3-yl)-piperazin-1- 524.25 1.5 3 mediate 8 ylmethyl]-thiophene-2-carboxylic acid 4- methoxy-2-trifluoromethoxy-benzylamide; Trifluoroacetate 23 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 506.11 1.08 2 mediate 6 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid (indan-1- ylmethyl)-amide 24 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 564.07 1.14 2 mediate 10 carbonyl)-piperazin-1-ylmethyl]-4-methyl- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide 25 Inter- 5-[4-(5-tert-Butyl-2-methyl-2H-pyrazole-3- 548.28 1.06 2 mediate 3 carbonyl)-piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethyl-benzyl- amide; Trifluoroacetate 26 Inter- 5-(3′,6′-Dimethyl-2,3,5,6-tetrahydro- 506.3 1.62 3 mediate 9 [1,2′]bipyrazinyl-4-ylmethyl)-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide 27 Inter- 5-(4-Cyclobutyl-piperazin-1-ylmethyl)- 438.22 1.6 3 mediate 7 thiophene-2-carboxylic acid 2,4-dichloro- benzylamide 28 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 474.53 1.48 3 mediate 10 carbonyl)-piperazin-1-ylmethyl]-4-methyl- thiophene-2-carboxylic acid (3,3- dimethyl-butyl)-amide; Trifluoroacetate 29 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 538.26 1.36 3 mediate 10 carbonyl)-piperazin-1-ylmethyl]-4-methyl- thiophene-2-carboxylic acid (2,3-dihydro- benzo[1,4]dioxin-5-ylmethyl)-amide; Trifluoroacetate 31 Inter- 5-{4-[2-(3-Trifluoromethyl-phenyl)- 570.26 1.06 2 mediate 3 acetyl]-piperazin-1-ylmethyl}-thiophene- 2-carboxylic acid 2-trifluoromethyl- benzylamide; Trifluoroacetate 32 Inter- 5-[4-(2-Hydroxy-propionyl)-piperazin-1- 502.2 1.38 3 mediate 11 ylmethyl]-thiophene-2-carboxylic acid 4- methoxy-2-trifluoromethoxy-benzylamide 33 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 534.06 1.09 2 mediate 6 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 4- trifluoromethyl-benzylamide 34 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 497.07 0.89 2 mediate 6 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid (2-methoxy- pyridin-4-ylmethyl)-amide 35 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 550.13 3.33 4 mediate 6 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide 36 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 534.06 1.08 2 mediate 6 carbonyl)-piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethyl-benzyl- amide; Trifluoroacetate 37 Inter- 5-[4-(1-Hydroxy-cyclopropanecarbonyl)- 484.23 1.02 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 38 Inter- 5-(4-Cyclopentyl-3-oxo-piperazin-1- 482.28 1.9 3 mediate 9 ylmethyl)-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide 39 Inter- 5-(6′-Methyl-2,3,5,6-tetrahydro- 490.29 1.62 3 mediate 9 [1,2′]bipyrazinyl-4-ylmethyl)-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide 40 Inter- 5-[4-(2,2-Dimethyl-5-oxo-tetrahydro- 487.29 1.25 3 mediate 5 furan-3-carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid (2-methoxy- pyridin-4-ylmethyl)-amide 41 Inter- 5-[4-((2S,3R)-3-Hydroxy-2-methylamino- 515.21 1.25 3 mediate 1 butyryl)-piperazin-1-ylmethyl]-thiophene- 2-carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 42 Inter- 5-[4-(2-Phenoxy-acetyl)-piperazin-1- 518.17 1.03 2 mediate 2 ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide; Trifluoroacetate 43 Inter- 5-[4-(2-Chloro-4-fluoro-benzoyl)- 540.1 1.08 2 mediate 2 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 44 Inter- 5-[4-(1-Methyl-5-oxo-pyrrolidine-3-carbonyl)- 525.27 1 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide; Trifluoroacetate 45 Inter- 5-[4-(Isoquinoline-1-carbonyl)-piperazin- 539.25 1 2 mediate 3 1-ylmethyl]-thiophene-2-carboxylic acid 2-trifluoromethyl-benzylamide; Trifluoroacetate 46 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 534.06 1.08 2 mediate 3 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2-trifluoro- methyl-benzylamide; Trifluoroacetate 47 Inter- 5-(3-Oxo-4-thiazol-2-yl-piperazin-1- 497.16 1.94 3 mediate 9 ylmethyl)-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 48 Inter- 5-[4-(2-Amino-3-fluoro-propionyl)- 473.14 1.27 3 mediate 2 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 49 Inter- 5-[4-(Morpholine-3-carbonyl)-piperazin- 513.2 1.25 3 mediate 1 1-ylmethyl]-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide; Trifluoroacetate 50 Inter- 5-[4-(6-Hydroxy-pyridazin-3-yl)- 478.16 1.48 3 mediate 7 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 51 Inter- 5-[4-(1-Methyl-1H-pyrrole-2-carbonyl)- 491.21 0.95 2 mediate 3 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethyl- benzylamide; Trifluoroacetate 52 Inter- 5-[4-(4-Bromo-2-methyl-2H-pyrazole-3- 570.15 1.02 2 mediate 3 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2-trifluoro- methyl-benzylamide; Trifluoroacetate 53 Inter- 5-[4-(2-Ethoxy-benzoyl)-piperazin-1- 532.24 1.01 2 mediate 3 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethyl-benzylamide; Trifluoroacetate 55 Inter- 5-[4-(Tetrahydro-furan-3-carbonyl)- 498.25 1.02 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 56 Inter- 5-[3-Oxo-4-(2,2,2-trifluoro-ethyl)- 526.19 1.91 3 mediate 8 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 4-methoxy-2-trifluoro- methoxy-benzylamide; Trifluoroacetate 57 Inter- 5-[4-(2-Methoxy-pyridine-3-carbonyl)- 519.22 0.95 2 mediate 3 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethyl- benzylamide; Trifluoroacetate 58 Inter- 5-[4-(1-Phenyl-cyclopropanecarbonyl)- 528.19 1.05 2 mediate 2 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2,4-dichloro-benzyl- amide; Trifluoroacetate 59 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 534.03 3.4 4 mediate 2 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2,4-dichloro- benzylamide 61 Inter- 5-[4-(2-Hydroxy-propionyl)-piperazin-1- 447.2 1.15 3 mediate 11 ylmethyl]-thiophene-2-carboxylic acid 2- chloro-4-cyano-benzylamide 62 Inter- 5-(2,2-Dimethyl-3-oxo-piperazin-1- 442.21 1.76 3 mediate 9 ylmethyl)-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 63 Inter- 5-[4-(2-Phenyl-propionyl)-piperazin-1- 516.22 1.04 2 mediate 2 ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide; Trifluoroacetate 64 Inter- 5-[4-(2-Chloro-4-fluoro-benzoyl)- 540.17 1.05 2 mediate 3 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethyl- benzylamide; Trifluoroacetate 65 Inter- 5-[4-(Isoquinoline-1-carbonyl)-piperazin- 539.19 1.03 2 mediate 2 1-ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide; Trifluoroacetate 66 Inter- 5-[4-(2-Oxo-1,2-dihydro-pyridine-3- 521.25 0.99 2 mediate 1 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 67 Inter- 5-[4-(3,6-Dimethoxy-pyridine-2- 565.28 1.1 2 mediate 1 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 68 Inter- 5-[4-(1-Methoxymethyl- 512.26 1.05 2 mediate 1 cyclopropanecarbonyl)-piperazin-1- ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 69 Inter- 5-{4-[2-(2-Chloro-phenyl)-acetyl]- 536.13 1.05 2 mediate 2 piperazin-1-ylmethyl}-thiophene-2- carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 70 Inter- 5-[4-(Bicyclo[4.2.0]octa-1(6),2,4-triene-7- 514.13 1.04 2 mediate 2 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 71 Inter- 5-[4-((1R,2R)-2-Phenyl- 528.19 1.05 2 mediate 2 cyclopropanecarbonyl)-piperazin-1- ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide; Trifluoroacetate 72 Inter- 5-[4-(6-Methyl-pyridine-2-carbonyl)- 519.26 1.07 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 73 Inter- 5-(2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4- 478.27 1.57 3 mediate 9 ylmethyl)-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide 74 Inter- 2-{4-[5-(4-Methoxy-2-trifluoromethoxy- 564.3 1.56 3 mediate 8 benzylcarbamoyl)-thiophen-2-ylmethyl]- piperazin-1-yl}-N-methyl-nicotinamide; Trifluoroacetate 75 Inter- 5-[4-(1-Phenyl-cyclopropanecarbonyl)- 528.29 1.02 2 mediate 3 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethyl- benzylamide; Trifluoroacetate 76 Inter- 5-[4-((1R,2R)-2-Phenyl- 528.28 1.03 2 mediate 3 cyclopropanecarbonyl)-piperazin-1- ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethyl-benzylamide; Trifluoroacetate 77 Inter- 5-[4-(Pyridine-2-carbonyl)-piperazin-1- 489.12 0.94 2 mediate 2 ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide; Trifluoroacetate 78 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 498.12 0.9 2 mediate 6 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid (2-propyl- 2H-pyrazol-3-ylmethyl)-amide 79 Inter- 5-[4-(3-Hydroxy-6-methyl-pyridine-2- 535.15 3.11 4 mediate 1 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 80 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 525.22 1.02 2 mediate 6 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2-chloro-4- cyano-benzylamide 81 Inter- 5-[4-(2,6-Dichloro-benzoyl)-piperazin-1- 556.15 1.08 2 mediate 3 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethyl-benzylamide; Trifluoroacetate 82 Inter- 5-[4-(3-Hydroxy-pyridine-2-carbonyl)- 521.24 1.03 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 83 Inter- 5-{4-[2-(2-Methoxy-ethoxy)-acetyl]- 516.27 1.03 2 mediate 1 piperazin-1-ylmethyl}-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 84 Inter- 5-(4-Cyclopentyl-3-oxo-piperazin-1- 466.24 4.25 4 mediate 7 ylmethyl)-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide 85 Inter- 5-[4-(1,1-Dioxo-tetrahydro-1lambda6- 518.22 1.5 3 mediate 9 thiophen-3-yl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 86 Inter- 5-[4-((S)-5,5-Dimethyl-pyrrolidine-2- 525.25 1.32 3 mediate 1 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 87 Inter- 5-[4-(5-Hydroxymethyl-pyridin-2-yl)- 507.23 1.48 3 mediate 9 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 88 Inter- 5-[4-(3,5-Dimethyl-isoxazole-4-carbonyl)- 507.21 0.96 2 mediate 3 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethyl- benzylamide; Trifluoroacetate 89 Inter- 5-[4-(Pyridine-3-carbonyl)-piperazin-1- 489.15 0.92 2 mediate 23 ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide; Trifluoroacetate 90 Inter- 5-[4-(5-Ethyl-isoxazole-4-carbonyl)- 507.13 1.01 2 mediate 2 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 91 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 534 1.1 2 mediate 2 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2,3-dichloro- benzylamide 92 Inter- 5-[4-(3-Hydroxy-butyryl)-piperazin-1- 486.25 1 2 mediate 6 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 93 Inter- 5-[4-((R)-2-Methoxy-propionyl)-piperazin- 486.25 1.04 2 mediate 1 1-ylmethyl]-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide; Trifluoroacetate 94 Inter- 5-[4-((1R,2S)-2-Hydroxy- 512.28 1.04 2 mediate 1 cyclopentanecarbonyl)-piperazin-1- ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 95 Inter- 5-[4-(2-Hydroxy-2-methyl-butyryl)- 500.28 1.05 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 96 Inter- 5-[4-((R)-2-Hydroxy-butyryl)-piperazin-1- 486.25 1.03 2 mediate 1 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 97 Inter- 5-[4-(3-Methoxy-pyridine-2-carbonyl)- 535.27 1.05 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 98 Inter- 5-[4-(2-Phenyl-propionyl)-piperazin-1- 516.25 1.01 2 mediate 3 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethyl-benzylamide; Trifluoroacetate 99 Inter- 5-[4-(4-Bromo-2-ethyl-5-methyl-2H- 510.15 1.16 2 mediate 4 pyrazole-3-carbonyl)-piperazin-1- ylmethyl]-thiophene-2-carboxylic acid (3- methyl-butyl)-amide 100 Inter- 5-{4-[2-(3-Trifluoromethyl-phenyl)- 570.18 1.08 2 mediate 2 acetyl]-piperazin-1-ylmethyl}-thiophene- 2-carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 101 Inter- 5-[4-((R)-2-Hydroxy-3-methyl-butyryl)- 500.29 1.07 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 102 Inter- 5-[4-(5-Oxo-pyrrolidine-2-carbonyl)- 511.17 1.33 3 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 103 Inter- 5-[4-((S)-5,5-Dimethyl-thiazolidine-4- 527.17 1.49 3 mediate 2 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 104 Inter- 5-(5,6-Dihydro-8H-[1,2,4]triazolo[4,3- 468.23 1.56 3 mediate 8 a]pyrazin-7-ylmethyl)-thiophene-2- carboxylic acid 4-methoxy-2- trifluoromethoxy-benzylamide; Trifluoroacetate 105 Inter- 5-[4-(3-Methyl-pyridin-2-yl)-3-oxo- 489.18 1.85 3 mediate 7 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 106 Inter- 5-[4-(3-Hydroxy-propionyl)-piperazin-1- 472.23 0.98 2 mediate 1 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 107 Inter- 5-[4-(4-Oxo-1,4-dihydro-pyrimidine-5- 522.22 0.98 2 mediate 1 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 108 Inter- 5-[4-(1-Methyl-6-oxo-1,6-dihydro- 492.17 3.07 4 mediate 2 pyridazin-4-yl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2,4-dichloro- benzylamide 109 Inter- 5-[4-(1-Amino-cyclopropanecarbonyl)- 467.21 1.4 3 mediate 2 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 110 Inter- 5-[4-((S)-5,5-Dimethyl-thiazolidine-4- 543.23 1.47 3 mediate 1 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 111 Inter- 5-[3-Oxo-4-(2,2,2-trifluoro-ethyl)- 496.17 1.9 3 mediate 9 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 112 Inter- 5-[4-(3-Methyl-pyridin-2-yl)-3-oxo- 505.24 1.81 3 mediate 9 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 113 Inter- 5-[4-(1-Methyl-1H-imidazol-2-yl)- 510.26 1.44 3 mediate 8 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 4-methoxy-2- trifluoromethoxy-benzylamide; Trifluoroacetate 114 Inter- 5-(6-Oxo-hexahydro-pyrrolo[1,2- 438.18 1.58 3 mediate 7 a]pyrazin-2-ylmethyl)-thiophene-2- carboxylic acid 2,4-dichloro-benzylamide 116 Inter- 5-[4-(3-Methoxy-propionyl)-piperazin-1- 486.25 1.02 2 mediate 1 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 117 Inter- 5-[4-(5-Ethyl-isoxazole-4-carbonyl)- 507.21 0.98 2 mediate 3 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethyl- benzylamide; Trifluoroacetate 118 Inter- 5-[4-(2-Ethoxy-benzoyl)-piperazin-1- 444.14 1.09 2 mediate 4 ylmethyl]-thiophene-2-carboxylic acid (3- methyl-butyl)-amide 119 Inter- 5-[4-(2-Fluoro-benzoyl)-piperazin-1- 506.18 1 2 mediate 3 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethyl-benzylamide; Trifluoroacetate 121 Inter- 5-[4-(Pyridine-2-carbonyl)-piperazin-1- 505.22 1.05 2 mediate 1 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 122 Inter- 5-[4-(3,5-Dimethyl-isoxazole-4-carbonyl)- 523.25 1.1 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 123 Inter- 5-[4-(2-Hydroxy-2-methyl-propionyl)- 486.25 1.01 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 124 Inter- 5-(4-Pyridin-2-yl-piperazin-1-ylmethyl)- 507.26 1.57 3 mediate 8 thiophene-2-carboxylic acid 4-methoxy- 2-trifluoromethoxy-benzylamide; Trifluoroacetate 125 Inter- 5-[4-(2-Hydroxy-ethyl)-piperazin-1- 444.25 1.5 3 mediate 9 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 126 Inter- 5-[4-(3-Methyl-pyridin-2-yl)-3-oxo- 535.28 1.82 3 mediate 8 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 4-methoxy-2- trifluoromethoxy-benzylamide; Trifluoroacetate 127 Inter- 5-[4-(4-Methyl-pyridin-2-yl)-piperazin-1- 521.29 1.57 3 mediate 8 ylmethyl]-thiophene-2-carboxylic acid 4- methoxy-2-trifluoromethoxy- benzylamide; Trifluoroacetate 128 Inter- 5-[4-(3-Hydroxy-3-methyl-butyryl)- 500.27 1.03 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 129 Inter- 5-[4-(3,6-Difluoro-pyridine-2-carbonyl)- 541.24 1.12 2 mediate 8 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 130 Inter- 5-[4-(1-Methyl-1H-pyrrole-2-carbonyl)- 491.14 0.98 2 mediate 2 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 131 Inter- 5-[4-(2-Fluoro-benzoyl)-piperazin-1- 506.14 1.03 2 mediate 2 ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide; Trifluoroacetate 132 Inter- 5-[4-(6-Hydroxy-pyridine-2-carbonyl)- 521.24 1.02 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 133 Inter- 5-[4-(4-Amino-tetrahydro-pyran-4- 511.17 1.28 3 mediate 2 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 134 Inter- 5-(4-Methyl-3-oxo-piperazin-1-ylmethyl)- 458.2 1.69 3 mediate 8 thiophene-2-carboxylic acid 4-methoxy- 2-trifluoromethoxy-benzylamide; Trifluoroacetate 135 Inter- N-Methyl-2-{4-[5-(2-trifluoromethoxy- 534.28 1.53 3 mediate 9 benzylcarbamoyl)-thiophen-2-ylmethyl]- piperazin-1-yl}-nicotinamide; Trifluoroacetate 136 Inter- 5-[4-(6-Hydroxy-pyridazin-3-yl)- 494.21 1.46 3 mediate 9 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 137 Inter- 5-[4-(3-Methylsulfanyl-propionyl)- 502.22 1.07 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 138 Inter- 5-[4-(2-Dimethylamino-propionyl)- 499.28 0.95 2 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 140 Inter- 5-[4-(4-Methoxy-butyryl)-piperazin-1- 500.27 1.04 2 mediate 1 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide 141 Inter- 5-(4-Cyclopropanecarbonyl-piperazin-1- 468.18 3.13 4 mediate 1 ylmethyl)-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 142 Inter- 5-(4-[1,3,4]Thiadiazol-2-yl-piperazin-1 - 484.19 1.57 3 mediate 9 ylmethyl)-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 143 Inter- 5-[4-(1-Amino-cyclobutanecarbonyl)- 497.19 1.26 3 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 144 Inter- 5-[4-(2-Amino-3-fluoro-propionyl)- 489.18 1.24 3 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 145 Inter- 5-[4-(4-Amino-tetrahydro-pyran-4- 527.21 1.25 3 mediate 1 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 146 Inter- 5-[4-(5-Hydroxymethyl-pyridin-2-yl)- 537.28 1.52 3 mediate 8 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 4-methoxy-2- trifluoromethoxy-benzylamide; Trifluoroacetate 147 Inter- 5-[4-([1,4]Dioxane-2-carbonyl)-piperazin- 514.26 1.03 2 mediate 10 1-ylmethyl]-thiophene-2-carboxylic acid 2-trifluoromethoxy-benzylamide; Trifluoroacetate 148 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 564.07 1.14 2 mediate 6 carbonyl)-piperazin-1-ylmethyl]-4-methyl- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide 150 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 532.07 1.04 2 mediate 3 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- difluoromethoxy-benzylamide 151 Inter- 5-[4-(Pyrazolo[1,5-a]pyridine-3- 528.24 0.92 2 mediate 3 carbonyl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- trifluoromethyl-benzylamide; Trifluoroacetate 152 Inter- 5-[4-(5-Methyl-thiophene-2-carbonyl)- 508.18 1 2 mediate 3 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethyl- benzylamide; Trifluoroacetate 153 Inter- 5-[4-((1R,2R)-2-Phenyl- 528.19 1.05 2 mediate 2 cyclopropanecarbonyl)-piperazin-1- ylmethyl]-thiophene-2-carboxylic acid 2,4-dichloro-benzylamide; Trifluoroacetate 154 Inter- 5-[4-(5-Methyl-thiophene-2-carbonyl)- 508.09 1.03 2 mediate 2 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2,4-dichloro- benzylamide; Trifluoroacetate 155 Inter- 5-[4-(2-Hydroxy-propionyl)-piperazin-1- 472.22 1.01 2 mediate 1 ylmethyl]-thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 156 Inter- 5-{4-[2-(2-Oxo-oxazolidin-3-yl)-acetyl]- 527.25 1.01 2 mediate 1 piperazin-1-ylmethyl}-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 157 Inter- 5-[4-(1-Amino-cyclohexanecarbonyl)- 525.24 1.31 3 mediate 1 piperazin-1-ylmethyl]-thiophene-2- carboxylic acid 2-trifluoromethoxy- benzylamide; Trifluoroacetate 158 Inter- 5-[4-(4-Hydroxy-6-methoxymethyl- 538.27 1.56 3 mediate 1 pyrimidin-2-yl)-piperazin-1-ylmethyl]- thiophene-2-carboxylic acid 2- trifluoromethoxy-benzylamide; Trifluoroacetate 159 Inter- 5-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 474.53 1.48 3 mediate 10 carbonyl)-piperazin-1-ylmethyl]-4-methyl- thiophene-2-carboxylic acid (3,3- dimethyl-butyl)-amide; Trifluoroacetate 160 Inter- 2-[4-(3,5-Dimethyl-isoxazole-4-carbonyl)- 508.14 3.85 4 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 161 Inter- 2-[4-(2,2-Dimethyl-5-oxo-tetrahydro- 525.17 3.71 4 mediate 12 furan-3-carbonyl)-piperazin-1-ylmethyl]- thiazole-5-carboxylic acid 2,4-dichloro- benzylamide 162 Inter- 2-[4-(2,4-Dimethyl-6-oxo-6H-pyran-3- 535.16 1.65 3 mediate 12 carbonyl)-piperazin-1-ylmethyl]-thiazole- 5-carboxylic acid 2,4-dichloro- benzylamide 163 Inter- 2-[4-(3-Hydroxy-propionyl)-piperazin-1- 457.19 1.41 3 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 164 Inter- 2-[4-(3-Methylsulfanyl-propionyl)- 487.09 3.66 4 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 165 Inter- 2-{4-[2-(3,5-Dimethyl-isoxazol-4-yl)- 522.13 3.64 4 mediate 12 acetyl]-piperazin-1-ylmethyl}-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 166 Inter- 2-[4-(4-Methoxy-butyryl)-piperazin-1- 485.21 1.56 3 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 167 Inter- 2-[4-(2-Hydroxy-2-methyl-butyryl)- 485.18 3.43 4 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 168 Inter- 2-{4-[2-(2-Oxo-pyrrolidin-1-yl)-acetyl]- 510.19 1.49 3 mediate 12 piperazin-1-ylmethyl}-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 169 Inter- 2-{4-[2-(2-Oxo-pyrrolidin-1-yl)-propionyl]- 524.18 3.4 4 mediate 12 piperazin-1-ylmethyl}-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 170 Inter- 2-[4-([1,4]Dioxane-2-carbonyl)-piperazin- 499.17 1.54 3 mediate 12 1 -ylmethyl]-thiazole-5-carboxylic acid 2,4-dichloro-benzylamide 171 Inter- 2-(4-Cyclopropanecarbonyl-piperazin-1- 453.17 1.58 3 mediate 12 ylmethyl)-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 172 Inter- 2-[4-(2-Hydroxy-2-methyl-propionyl)- 471.15 1.49 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 173 Inter- 2-[4-(3-Methoxy-propionyl)-piperazin-1- 471.15 1.52 3 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 174 Inter- 2-[4-(6-Methyl-pyridine-2-carbonyl)- 504.18 1.63 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 175 Inter- 2-[4-(6-Hydroxy-pyridine-2-carbonyl)- 506.18 1.52 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 176 Inter- 2-[4-(3-Hydroxy-2,2-dimethyl-propionyl)- 485.19 1.54 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 178 Inter- 2-[4-(2-Oxo-1,2-dihydro-pyridine-3- 506.13 1.42 3 mediate 12 carbonyl)-piperazin-1-ylmethyl]-thiazole- 5-carboxylic acid 2,4-dichloro- benzylamide 179 Inter- 2-[4-((R)-2-Hydroxy-butyryl)-piperazin-1- 471.19 3.47 4 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 180 Inter- 2-[4-(3,6-Difluoro-pyridine-2-carbonyl)- 526.15 1.71 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 181 Inter- 2-[4-(2-Hydroxy-acetyl)-piperazin-1- 443.13 1.44 3 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 182 Inter- 2-[4-(Tetrahydro-furan-2-carbonyl)- 483.19 1.56 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 183 Inter- 2-[4-(Tetrahydro-furan-3-carbonyl)- 483.16 1.53 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 184 Inter- 2-[4-((S)-1-Methyl-pyrrolidine-2- 496.22 1.33 3 mediate 12 carbonyl)-piperazin-1-ylmethyl]-thiazole- 5-carboxylic acid 2,4-dichloro- benzylamide 185 Inter- 2-[4-(3-Hydroxy-3-methyl-butyryl)- 485.19 1.54 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 186 Inter- 2-[4-(Pyridine-2-carbonyl)-piperazin-1- 490.16 1.58 3 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 187 Inter- 2-[4-(3-Hydroxy-pyridine-2-carbonyl)- 506.16 1.55 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 188 Inter- 2-{4-[2-(2-Methoxy-ethoxy)-acetyl]- 501.15 3.36 4 mediate 12 piperazin-1-ylmethyl}-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 189 Inter- 2-[4-(2-Hydroxy-propionyl)-piperazin-1- 457.13 1.49 3 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 190 Inter- 2-[4-(1-Methyl-piperidine-4-carbonyl)- 510.23 1.28 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 191 Inter- 2-[4-((S)-2-Hydroxy-butyryl)-piperazin-1- 471.19 1.57 3 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 192 Inter- 2-[4-(2-Methoxy-acetyl)-piperazin-1- 457.17 1.51 3 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 193 Inter- 2-{4-[2-(2-Oxo-oxazolidin-3-yl)-acetyl]- 512.18 1.49 3 mediate 12 piperazin-1-ylmethyl}-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 194 Inter- 2-[4-(3-Methyl-pyridine-2-carbonyl)- 504.18 3.68 4 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 195 Inter- 2-[4-(2-Cyano-acetyl)-piperazin-1- 452.14 1.56 3 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 196 Inter- 2-[4-(3-Methoxy-pyridine-2-carbonyl)- 520.2 1.59 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 197 Inter- 2-[4-(1-Methyl-5-oxo-pyrrolidine-3- 510.18 1.48 3 mediate 12 carbonyl)-piperazin-1-ylmethyl]-thiazole- 5-carboxylic acid 2,4-dichloro- benzylamide 198 Inter- 2-[4-((R)-2-Hydroxy-3-methyl-butyryl)- 485.19 1.66 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 199 Inter- 2-[4-(3-Dimethylamino-propionyl)- 484.21 1.28 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 200 Inter- 2-[4-(1-Amino-cyclopropanecarbonyl)- 468.19 1.31 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 201 Inter- 2-[4-(1-Hydroxy-cyclopropanecarbonyl)- 469.18 1.48 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 202 Inter- 2-[4-(6-Methoxy-pyridine-2-carbonyl)- 520.19 1.71 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 203 Inter- 2-[4-(2-Oxo-imidazolidine-4-carbonyl)- 497.17 1.43 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 204 Inter- 2-[4-((R)-2-Methoxy-propionyl)-piperazin- 471.19 3.48 4 mediate 12 1-ylmethyl]-thiazole-5-carboxylic acid 2,4-dichloro-benzylamide 205 Inter- 2-[4-(1-Methoxymethyl- 497.19 3.53 4 mediate 12 cyclopropanecarbonyl)-piperazin-1- ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 206 Inter- 2-[4-(3,5-Dimethyl-1H-pyrazole-4- 507.19 1.51 3 mediate 12 carbonyl)-piperazin-1-ylmethyl]-thiazole- 5-carboxylic acid 2,4-dichloro- benzylamide 207 Inter- 2-[4-(2-Methoxy-2-methyl-propionyl)- 485.18 3.7 4 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 208 Inter- 2-[4-(Oxetane-2-carbonyl)-piperazin-1- 469.18 1.52 3 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 209 Inter- 2-[4-(3-Hydroxy-cyclopentanecarbonyl)- 497.23 1.47 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 210 Inter- 2-{4-[2-((S)-4-Hydroxy-2-oxo-pyrrolidin- 526.2 1.41 3 mediate 12 1-yl)-acetyl]-piperazin-1-ylmethyl}- thiazole-5-carboxylic acid 2,4-dichloro- benzylamide 211 Inter- 2-{4-[2-(3-Hydroxy-pyrrolidin-1-yl)- 512.22 1.29 3 mediate 12 acetyl]-piperazin-1-ylmethyl}-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 206 Inter- 2-[4-(3,5-Dimethyl-1H-pyrazole-4- 507.19 1.51 3 mediate 12 carbonyl)-piperazin-1-ylmethyl]-thiazole- 5-carboxylic acid 2,4-dichloro- benzylamide 207 Inter- 2-[4-(2-Methoxy-2-methyl-propionyl)- 485.18 3.7 4 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 208 Inter- 2-[4-(Oxetane-2-carbonyl)-piperazin-1- 469.18 1.52 3 mediate 12 ylmethyl]-thiazole-5-carboxylic acid 2,4- dichloro-benzylamide 209 Inter- 2-[4-(3-Hydroxy-cyclopentanecarbonyl)- 497.23 1.47 3 mediate 12 piperazin-1-ylmethyl]-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide 210 Inter- 2-{4-[2-((S)-4-Hydroxy-2-oxo-pyrrolidin- 526.2 1.41 3 mediate 12 1-yl)-acetyl]-piperazin-1-ylmethyl}- thiazole-5-carboxylic acid 2,4-dichloro- benzylamide 211 Inter- 2-{4-[2-(3-Hydroxy-pyrrolidin-1-yl)- 512.22 1.29 3 mediate 12 acetyl]-piperazin-1-ylmethyl}-thiazole-5- carboxylic acid 2,4-dichloro-benzylamide

(89) Pharmacological Testing:

(90) The ability of the compounds of the formula I to inhibit soluble epoxide hydrolase can be determined as follows:

(91) Compounds were tested in a biochemical screening assay using recombinant sEH purified from Sf9 insect cells and an artificial substrate, (3-phenyl-oxiranyl)-acetic acid cyano-(6-methoxy-naphtalen-2-yl)-methyl ester, Phome. The biochemical assay was performed in analogy to a fluorometric described in the literature (P. D. Jones et al., Anal. Biochem. 2005, 343, 66-75). The assay principle bases on the sEH-catalyzed hydrolysis of an artificial α-cyano-ester substrate. O-deacetylation liberates a cyanohydrin intermediate that rapidly decomposes to the highly fluorescent 6-methoxy-2-naphtaldehyde. To discriminate sample autofluorescence, the assay was carried out as a kinetic measurement with two time points. The first measurement is performed immediately before addition of the substrate and the 15 second measurement is done after completion of the assay. The assay format is either in 96- or in 384-well format.

(92) Details of the assay using a 96-well plate format are described below. 40 μl recombinant sEH enzyme and 5 μl test compound are pre-incubated for 15 minutes at 30° C. Following pre-incubation, the reaction is started by addition of 5 μl Phome. The assay mixture containing 2 nM final sEH concentration, test compound ranging in a concentration from 0.0001-10 μM and 5 μM Phome is incubated for 60 minutes at 30° C.

(93) Fluorescence is measured with any suitable detector for instance a TECAN Safire or Tecan Ultra at 340 nm emission and 465 nm extinction. % inhibition of recombinant sEH activity is used for calculation of corresponding IC50 values as illustrated and described in the examples.

(94) The NCBI gene bank reference sequence with the accession number NM_001979 for EPHX2/sEH was applied for recombinant protein production:

(95) The following commercially available materials have been used: Incubation reagent: 25 mM Hepes (Sigma-Aldrich, Cat. No H-3375), 0.01% bovine albumin (Sigma-Aldrich Cat. No PA9205) Substrate: 3-Phenyl-oxiranyl)-acetic acid cyano-(6-methoxy-naphtalen-2-yl)-methyl ester, Phome (Biozol Cat. No 10003134) Microtiter plates: 96-well plates (Greiner Cat. No 655180; Costar Cat. No 3915)

(96) The results for inhibition of soluble epoxide hydrolase are shown in Table 1.

(97) TABLE-US-00002 TABLE 1 Example sEH IC.sub.50 (μM) 1 0.000122 2 0.000502 3 0.000407 4 0.000168 5 0.000432 6 0.000528 7 0.000524 8 0.000512 9 0.00306 10 0.00294 11 0.00295 12 0.0254 13 0.00298 14 0.00293 15 0.000604 16 0.000534 17 0.000699 18 0.000678 19 0.000695 20 0.000539 21 0.0029 22 0.0028 23 0.00275 24 0.00187 25 0.00276 26 0.00275 27 0.000803 28 0.000803 29 0.000803 30 0.000803 31 0.000758 32 0.000756 33 0.000906 34 0.000906 35 0.000916 36 0.000906 37 0.000929 38 0.000803 39 0.00275 40 0.00275 41 0.00275 42 0.0027 43 0.00274 44 0.00272 45 0.00267 46 0.000906 47 0.00269 48 0.00269 49 0.00268 50 0.00267 51 0.000994 52 0.000955 53 0.00102 54 0.000976 55 0.00105 56 0.00101 57 0.00113 58 0.00117 59 0.00115 60 0.0011 61 0.00118 62 0.00114 63 0.00121 64 0.00125 65 0.00119 66 0.00125 67 0.00121 68 0.00119 69 0.00261 70 0.00262 71 0.00256 72 0.00259 73 0.00259 74 0.00266 75 0.00255 76 0.00253 77 0.00249 78 0.00254 79 0.00254 80 0.00253 81 0.00236 82 0.00237 83 0.00237 84 0.00235 85 0.00244 86 0.00238 87 0.00241 88 0.00144 89 0.0014 90 0.00143 91 0.00142 92 0.00139 93 0.00131 94 0.0015 95 0.00151 96 0.00157 97 0.0016 98 0.00152 99 0.00153 100 0.0023 101 0.00228 102 0.00233 103 0.00232 104 0.00233 105 0.00233 106 0.00218 107 0.00226 108 0.00215 109 0.00216 110 0.00216 111 0.00223 112 0.00164 113 0.00167 114 0.00167 115 0.00164 116 0.0016 117 0.00164 118 0.00172 119 0.00168 120 0.0053 121 0.00168 122 0.00174 123 0.00169 124 0.00169 125 0.00168 126 0.00175 127 0.00173 128 0.00173 129 0.00173 130 0.00173 131 0.00213 132 0.00209 133 0.00214 134 0.00215 135 0.00214 136 0.00213 137 0.00176 138 0.00627 139 0.00285 140 0.00181 141 0.00186 142 0.00182 143 0.00185 144 0.00179 145 0.00188 146 0.00194 147 0.00196 148 0.00187 149 0.0082 150 0.00187 151 0.00197 152 0.00207 153 0.00256 154 0.00205 155 0.00199 156 0.002 157 0.00208 158 0.00204 159 0.00080 160 0.00141 161 0.00611 162 0.0122 163 0.0252 164 0.0114 165 0.00961 166 0.0213 167 0.0122 168 0.0779 169 0.00876 170 0.018 171 0.0158 172 0.0108 173 0.0334 174 0.0148 175 0.0204 176 0.0134 177 0.0911 178 0.0586 179 0.0241 180 0.00846 181 0.0521 182 0.0184 183 0.0188 184 0.115 185 0.0138 186 0.0337 187 0.0832 188 0.0159 189 0.0289 190 >1 191 0.014 192 0.0353 193 0.0152 194 0.032 195 0.0736 196 0.0364 197 0.0495 198 0.0133 199 0.208 200 0.00257 201 0.00637 202 0.0133 203 0.0363 204 0.0188 205 0.0057 206 0.00524 207 0.00631 208 0.00967 209 0.00349 210 0.0524 211 0.0909

(98) These data show that compounds of formula I exhibit a highly potent and selective sEH inhibitory activity.