Piperidine urea derivatives

Abstract

Compounds of the formula I ##STR00001##
in which R.sup.1-R.sup.3 have the meanings indicated in Claim 1,
are inhibitors of Tankyrase, and can be employed, inter alia, for the treatment of diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation.

Claims

1. A compound that is TABLE-US-00004 No. Name “A1” 4-benzoyl-piperidine-1-carboxylic acid methyl-m-tolyl-amide “A2” 4-benzoyl-piperidine-1-carboxylic acid methyl-p-tolyl-amide “A3” 4-benzoyl-piperidine-1-carboxylic acid (3-methoxy-phenyl)- methyl-amide “A4” 4-benzoyl-piperidine-1-carboxylic acid (4-methoxy-phenyl)- methyl-amide “A5” 4-(4-methyl-benzoyl)-piperidine-1-carboxylic acid (4- methoxy-phenyl)-methyl-amide “A6” 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid (4- methoxy-phenyl)-methyl-amide “A7” 4-(3-fluoro-benzoyl)-piperidine-1-carboxylic acid (4-methoxy- phenyl)-methyl-amide “A8” 4-(4-fluoro-benzoyl)-piperidine-1-carboxylic acid (4-methoxy- phenyl)-methyl-amide “A9” 4-(4-chloro-benzoyl)-piperidine-1-carboxylic acid (4- methoxy-phenyl)-methyl-amide “A10” 4-benzoyl-piperidine-1-carboxylic acid (3-cyano-phenyl)- methyl-amide “A11” 4-benzoyl-piperidine-1-carboxylic acid (4-cyano-phenyl)- methyl-amide “A12” 4-benzoyl-piperidine-1-carboxylic acid (3-fluoro-phenyl)- methyl-amide “A13” 4-benzoyl-piperidine-1-carboxylic acid (4-fluoro-phenyl)- methyl-amide “A14” 4-benzoyl-piperidine-1-carboxylic acid ethyl-(4-methoxy- phenyl)-amide “A15” 4-benzoyl-piperidine-1-carboxylic acid (2-hydroxy-ethyl)-(4- methoxy-phenyl)-amide “A16” (4-benzoyl-piperidin-1-yl)-(2,3-dihydro-indol-1-yl)-methanone “A17” (2,3-dihydro-indol-1-yl)-[4-(4-methyl-benzoyl)-piperidin-1-yl]- methanone “A18” (2,3-dihydro-indol-1-yl)-[4-(4-methoxy-benzoyl)-piperidin-1- yl]-methanone “A19” (2,3-dihydro-indol-1-yl)-[4-(3-fluoro-benzoyl)-piperidin-1-yl]- methanone “A20” (2,3-dihydro-indol-1-yl)-[4-(4-fluoro-benzoyl)-piperidin-1-yl]- methanone “A21” [4-(4-chloro-benzoyl)-piperidin-1-yl]-(2,3-dihydro-indol-1-yl)- methanone “A22” (4-benzoyl-piperidin-1-yl)-(3,4-dihydro-2H-quinolin-1-yl)- methanone “A23” 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide “A24” 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acid ethyl-(4-methoxy-phenyl)-amide “A25” 4-(3-methyl-benzoyl)-piperidine-1-carboxylic acid (4- methoxy-phenyl)-methyl-amide “A26” 4-(3-methyl-benzoyl)-piperidine-1-carboxylic acid ethyl-(4- methoxy-phenyl)-amide “A27” 4-(3-methoxy-benzoyl)-piperidine-1-carboxylic acid (4- methoxy-phenyl)-methyl-amide “A28” 4-(3-methoxy-benzoyl)-piperidine-1-carboxylic acid ethyl-(4- methoxy-phenyl)-amide “A29” 4-(3-fluoro-4-methoxy-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide “A30” 4-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}- piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl- amide “A31” 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid {4-[1-(2- methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-methyl-amide “A32” 4-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}- piperidine-1-carboxylic acid {4-[1-(2-methoxy-ethyl)-1H- pyrazol-4-yl]-phenyl}-methyl-amide “A33” 4-[4-(1-ethyl-1H-pyrazol-4-yl)-benzoyl]-piperidine-1- carboxylic acid (4-methoxy-phenyl)-methyl-amide “A34” 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid [4-(1- ethyl-1H-pyrazol-4-yl)-phenyl]-methyl-amide “A35” 4-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-benzoyl}- piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl- amide “A36” 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid methyl- {4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-phenyl}-amide “A37” 4-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-benzoyl}- piperidine-1-carboxylic acid methyl-{4-[1-(2-pyrrolidin-1-yl- ethyl)-1H-pyrazol-4-yl]-phenyl}-amide “A38” 4-(4-methanesulfonylamino-benzoyl)-piperidine-1-carboxylic acid methyl-phenyl-amide “A39” [(4-benzoyl-piperidine-1-carbonyl)-phenyl-amino]-acetic acid ethyl ester “A40” {[4-(4-methoxy-benzoyl)-piperidine-1-carbonyl]-phenyl- amino}-acetic acid ethyl ester “A41” N-ethyl-4-(3-fluoro-4-methoxy-benzoyl)-N-(4- methoxyphenyl)piperidine-1-carboxamide “A42” 4-(3-fluoro-4-methoxy-benzoyl)-N-(6-methoxy-3-pyridyl)-N- methyl-piperidine-1-carboxamide “A43” N-ethyl-N-(4-methoxyphenyl)-4-(6-methoxypyridine-3- carbonyl)piperidine-1-carboxamide “A44” 4-benzoyl-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1- carboxamide “A45” N-(6-methoxy-3-pyridyl)-N-methyl-4-(3- methylbenzoyl)piperidine-1-carboxamide “A46” N-(6-methoxy-3-pyridyl)-N-methyl-4-(4- methylbenzoyl)piperidine-1-carboxamide “A47” 4-(3-methoxybenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl- piperidine-1-carboxamide “A48” 4-[4-(1-ethylpyrazol-4-yl)benzoyl]-N-(6-methoxy-3-pyridyl)-N- methyl-piperidine-1-carboxamide “A49” 4-(4-methoxybenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl- piperidine-1-carboxamide “A50” 4-(3-fluorobenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl- piperidine-1-carboxamide “A51” 4-(4-fluorobenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl- piperidine-1-carboxamide “A52” 4-(4-methoxy-3-methyl-benzoyl)-N-(6-methoxy-3-pyridyl)-N- methyl-piperidine-1-carboxamide “A53” N-(4-methoxyphenyl)-4-(6-methoxypyridine-3-carbonyl)-N- methyl-piperidine-1-carboxamide “A54” 4-[4-(1-hydroxy-1-methyl-ethyl)benzoyl]-N-(4- methoxyphenyl)-N-methyl-piperidine-1-carboxamide “A55” N-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-4-(4- methoxybenzoyl)-N-methyl-piperidine-1-carboxamide “A56” 4-[4-(1-hydroxy-1-methyl-ethyl)benzoyl]-N-[4-(1-hydroxy-1- methyl-ethyl)phenyl]-N-methyl-piperidine-1-carboxamide “A57” 4-[4-(1-Ethyl-1H-pyrazol-4-yl)-benzoyl]-piperidine-1- carboxylic acid [4-(1-ethyl-1H-pyrazol-4-yl)-phenyl]-methyl- amide “A58” N-(4-cyanophenyl)-4-(4-methoxybenzoyl)-N-methyl- piperidine-1-carboxamide “A59” N-(4-cyanophenyl)-N-(2-hydroxyethyl)-4-(4- methoxybenzoyl)piperidine-1-carboxamide “A60” N-(6-cyano-3-pyridyl)-4-(4-methoxybenzoyl)-N-methyl- piperidine-1-carboxamide “A61” N-(4-cyanophenyl)-4-(3-fluoro-4-methoxy-benzoyl)-N- methyl-piperidine-1-carboxamide “A62” N-(4-cyanophenyl)-N-(2-hydroxyethyl)-4-(4-methoxy-3- methyl-benzoyl)piperidine-1-carboxamide “A63” N-(4-cyanophenyl)-4-(3-fluoro-4-methoxy-benzoyl)-N-(2- hydroxyethyl)piperidine-1-carboxamide “A64” N-(2-hydroxyethyl)-4-(4-methoxybenzoyl)-N-(4- methoxyphenyl)piperidine-1-carboxamide “A65” N-(2-hydroxyethyl)-4-(4-methoxy-3-methyl-benzoyl)-N-(4- methoxyphenyl)piperidine-1-carboxamide “A66” 4-(3-fluoro-4-methoxy-benzoyl)-N-(2-hydroxyethyl)-N-(4- methoxyphenyl)piperidine-1-carboxamide “A67” N-(2-hydroxyethyl)-4-(4-methoxy-3-methyl-benzoyl)-N-(6- methoxy-3-pyridyl)piperidine-1-carboxamide “A68” 4-(3-fluoro-4-methoxy-benzoyl)-N-(2-hydroxyethyl)-N-(6- methoxy-3-pyridyl)piperidine-1-carboxamide “A69” N-(2-hydroxyethyl)-4-(4-methoxybenzoyl)-N-(6-methoxy-3- pyridyl)piperidine-1-carboxamide “A70” 4-(4-methoxybenzoyl)-N-(6-methoxypyridazin-3-yl)-N- methyl-piperidine-1-carboxamide “A71” 4-(4-methoxybenzoyl)-N-(2-methoxypyrimidin-5-yl)-N- methyl-piperidine-1-carboxamide or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including mixtures thereof in all ratios.

2. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, including mixtures thereof in all ratios, and a pharmaceutically acceptable carrier, excipient or vehicle.

3. A medicament comprising at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, including mixtures thereof in all ratios, and at least one further medicament active ingredient.

4. A kit consisting of separate packs of (a) an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, solvate, salt or stereoisomer thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.

Description

EXAMPLES

phenyl(piperidin-4-yl)methanone

(1) ##STR00007##

(2) 1-acetyl piperidine-4-carboxylic acid (3.0 g, 0.018 mol) was added to thionyl chloride (10 mL, 0.143 mol) in small portions and stirred for 4 h at room temperature. The reaction was concentrated under vacuum and coevaporated with toluene (2×200 mL). The residue was dissolved (sparingly soluble) in 1,2-dichloroethane and added to the stirred suspension of anhydrous aluminum chloride in benzene (20 mL). The resulting mixture was refluxed for 2 h, poured into crushed ice and extracted with chloroform (2×200 mL). The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated to get the brown gum. The obtained gum was refluxed for 6 h with 6 N hydrochloric acid (60 mL). The reaction was cooled to room temperature and washed with diethyl ether (100 mL). The aqueous part was rendered basic with 10% sodium hydroxide and extracted with diethyl ether (2×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness. The residue was purified by column chromatography using silica gel (60-120) and petrol ether/ethyl acetate as gradient elution to afford the title compound; yield: 1.5 g (45%); LCMS (Method B): 190.3 (M+H), Rt: 2.01 min, purity: 85.3%;

(3) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.45-7.34 (m, 5H), 3.13 (s, 1H), 2.83 (s, 1H), 2.50-2.48 (m, 2H), 1.80-1.70 (m, 1H), 1.30-1.25 (m, 3H), 1.14-1.19 (m, 1H).

Example 1

4-benzoyl-piperidine-1-carboxylic acid methyl-m-tolyl-amide (“A1”)

(4) ##STR00008##

(5) To a suspension of phenyl(piperidin-4-yl)methanone (0.15 g, 0.79 mmol) in DCM (10 mL) was added diisopropylethylamine (0.30 g, 2.37 mmol) followed by triphosgene (0.23 g, 0.79 mmol) in drops at 0° C. After being stirred for 30 min, the reaction was cooled to 0° C. and methyl-m-tolyl-amine (0.093 g, 0.87 mmol) was added. The reaction mixture stirred for 16 h at room temperature. The reaction mixture was diluted with DCM (20 mL), washed with 10% sodium bicarbonate (50 mL), 1.5 N HCl (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated to dryness. The residue was purified by column chromatography using silica gel (60-120) and petrol ether/ethyl acetate as gradient elution to afford the title compound; yield: 58 mg (26%); LCMS (Method A): 337.2 (M+H), Rt. 4.93 min, purity 99.8% (254 nm); HPLC (Method A): Rt. 4.84 min, purity 99.8% (254 nm);

(6) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.94 (t, J=8.52 Hz, 2H), 7.61 (t, J=14.68 Hz, 1H), 7.50 (t, J=15.32 Hz, 2H), 7.22 (t, J=15.48 Hz, 1H), 6.93-6.89 (m, 3H), 3.74-3.71 (m, 2H), 3.55-3.49 (m, 1H), 3.06 (s, 3H), 2.79-2.73 (m, 2H), 2.28 (s, 3H), 1.61-1.58 (m, 2H), 1.33-1.24 (m, 2H).

Example 2

4-benzoyl-piperidine-1-carboxylic acid methyl-p-tolyl-amide (“A2”)

(7) ##STR00009##

(8) The compound is prepared analogously to example 1.

(9) Yield: 79 mg (35%); LCMS (Method A): 337.3 (M+H), Rt. 5.57 min, purity: 98.2% (254 nm); HPLC (Method A): Rt. 4.86 min, purity 97.8% (254 nm);

(10) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.92 (d, J=8.52 Hz, 2H), 7.63-7.61 (m, 1H), 7.52-7.48 (m, 2H), 7.15 (d, J=8.24 Hz, 2H), 6.99 (t, J=1.96 Hz, 2H), 3.70 (d, J=13.00 Hz, 2H), 3.53-3.48 (m, 1H), 3.04 (s, 3H), 2.76-2.70 (m, 2H), 2.26 (s, 3H), 1.60 (d, J=11.00 Hz, 2H), 1.32-1.22 (m, 2H).

Example 3

4-benzoyl-piperidine-1-carboxylic acid (3-methoxy-phenyl)-methyl-amide (“A3”)

(11) ##STR00010##

(12) The compound is prepared analogously to example 1.

(13) Yield: 56 mg (29%); LCMS (Method A): 367.0 (M+H), Rt. 4.73 min, purity 96% (254 nm); HPLC (Method A): Rt. 4.57 min, purity 98.5% (254 nm);

(14) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.96-7.94 (m, 2H), 7.62-7.57 (m, 1H), 7.51-7.47 (m, 2H), 7.29 (t, J=16.16 Hz, 1H), 6.76-6.71 (m, 3H), 3.88 (d, J=13.48 Hz, 2H), 3.81 (s, 3H), 3.56-3.49 (m, 1H), 3.19 (s, 3H), 2.85 (t, J=18.16 Hz, 2H), 1.70-1.68 (m, 2H), 1.52-1.48 (m, 2H).

Example 4

4-benzoyl-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide (“A4”)

(15) ##STR00011##

(16) The compound is prepared analogously to example 1.

(17) Yield: 28 mg (12%); LCMS (Method A): 353.2 (M+H), Rt. 4.47 min, purity 98.9% (254 nm); HPLC (Method A): Rt. 4.45 min, 99% (254 nm);

(18) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.93 (d, J=8.48 Hz, 2H), 7.61 (t, J=14.72 Hz, 1H), 7.50 (t, J=15.28 Hz, 2H), 7.07 (dd, J=8.88, Hz, 2H), 6.92 (dd, J=12.40 Hz, 2H), 3.73-3.69 (m, 5H), 3.52-3.45 (m, 1H), 3.01 (s, 3H), 2.73 (t, J=14.16 Hz, 2H), 1.58 (d, J=11.08 Hz, 2H), 1.30-1.20 (m, 2H).

Example 5

4-(4-methyl-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methylamide (“A5”)

(19) ##STR00012##

(20) The compound is prepared analogously to example 1.

(21) Yield: 132 mg (29%); LCMS (Method A): 367.3 (M+H), Rt. 4.80 min, purity 99.9% (254 nm); HPLC (Method A): Rt. 4.74 min, 99.8% (254 nm);

(22) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.79 (d, J=8.24 Hz, 2H), 7.27-7.23 (m, 2H), 7.08-7.04 (m, 2H), 6.89-6.85 (m, 2H), 3.87 (d, J=13.36 Hz, 2H), 3.80 (s, 3H), 3.26 (s, 1H), 3.18 (s, 3H), 2.78-2.72 (m, 2H), 2.40 (s, 3H), 1.68-1.66 (m, 2H).

Example 6

4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)methyl-amide (“A6”)

(23) ##STR00013##

(24) The compound is prepared analogously to example 1.

(25) Yield: 8 mg (16%); LCMS (Method A): 383.3 (M+H), Rt. 4.43 min, purity 99.7% (254 nm); HPLC (Method A): Rt. 4.42 min, 99.7% (254 nm);

(26) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.88 (dd, J=8.92 Hz, 2H), 7.06 (dd, J=9.00 Hz, 2H), 6.92 (dd, J=8.92 Hz, 2H), 6.87 (dd, J=8.96 Hz, 2H), 3.90-3.82 (m, 5H), 3.80 (s, 3H), 3.27-3.21 (m, 1H), 3.18 (s, 3H), 2.78-2.71 (m, 2H), 1.68-1.55 (m, 2H), 1.53-1.47 (m, 2H).

Example 7

4-(3-fluoro-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methylamide (“A7”)

(27) ##STR00014##

(28) The compound is prepared analogously to example 1.

(29) Yield: 77 mg (17%); LCMS (Method A): 371.3 (M+H), Rt. 4.59 min, purity 98.3% (254 nm); HPLC (Method A): Rt. 4.76 min, 98.2% (254 nm);

(30) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.67-7.65 (m, 1H), 7.58-7.55 (m, 1H), 7.46-7.41 (m, 1H), 7.27-7.23 (m, 1H), 7.09-7.04 (m, 2H), 6.90-6.86 (m, 2H), 3.89-3.86 (m, 2H), 3.81 (s, 3H), 3.26-3.20 (m, 4H), 2.79-2.72 (m, 2H), 1.70-1.64 (m, 2H), 1.55-1.45 (m, 2H).

Example 8

4-(4-fluoro-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methylamide (“A8”)

(31) ##STR00015##

(32) The compound is prepared analogously to example 1.

(33) Yield: 8 mg (16%); LCMS (Method A): 371.2 (M+H), Rt. 4.63 min, purity 99.6% (254 nm); HPLC (Method A): Rt. 4.60 min, 99.8% (254 nm);

(34) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.94-7.90 (m, 2H), 7.13 (t, J=8.64 Hz, 2H), 7.10 (d, J=2.04 Hz, 2H), 6.89-6.87 (m, 2H), 3.90-3.86 (m, 2H), 3.81 (s, 3H), 3.27-3.21 (m, 1H), 3.18 (s, 3H), 2.76 (t, J=14.44 Hz, 2H), 1.69-1.65 (m, 2H), 1.55-1.49 (m, 2H).

Example 9

4-(4-chloro-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methylamide (“A9”)

(35) ##STR00016##

(36) The compound is prepared analogously to example 1.

(37) Yield: 183 mg (16%); LCMS (Method A): 387.0 (M+H), Rt. 4.93 min, purity 99.5% (254 nm); HPLC (Method A): Rt. 4.90 min, 99.6% (254 nm);

(38) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.84-7.81 (m, 2H), 7.44-7.41 (m, 2H), 7.07-7.05 (m, 2H), 6.89-6.87 (m, 2H), 3.87 (t, J=13.32 Hz, 2H), 3.81 (s, 3H), 3.26-3.18 (m, 1H), 3.07 (s, 3H), 2.79-2.72 (m, 2H), 1.70-1.54 (m, 2H), 1.52-1.48 (m, 2H).

Example 10

4-benzoyl-piperidine-1-carboxylic acid (3-cyano-phenyl)-methyl-amide (“A10”)

(39) ##STR00017##

(40) The compound is prepared analogously to example 1.

(41) Yield: 4 mg (2%); LCMS (Method A): 405.2 (M+H), Rt. 4.76 min, purity 96.8% (254 nm); HPLC (Method A): Rt. 4.34 min, 94.9% (254 nm);

(42) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.98-7.96 (m, 2H), 7.62-7.44 (m, 7H), 3.85 (t, J=10.56 Hz, 2H), 3.61-3.56 (m, 1H), 3.24 (s, 3H), 2.95 (t, J=13.36 Hz, 2H), 1.78-1.58 (m, 2H), 1.57-1.41 (m, 2H).

Example 11

4-benzoyl-piperidine-1-carboxylic acid (4-cyano-phenyl)-methyl-amide (“A11”)

(43) ##STR00018##

(44) The compound is prepared analogously to example 1.

(45) Yield: 12 mg (5%); LCMS (Method A): 348.0 (M+H), Rt. 4.30 min, purity 98.6% (254 nm); HPLC (Method A): Rt. 4.46 min, 94.9% (254 nm);

(46) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.98-7.96 (m, 2H), 7.75-7.74 (m, 2H), 7.63 (t, J=13.48 Hz, 1H), 7.52 (t, J=15.20 Hz, 1H), 7.17-7.14 (m, 2H), 3.80-3.76 (m, 2H), 3.66-3.61 (m, 1H), 3.14 (s, 3H), 2.95 (t, J=12.52 Hz, 2H), 1.76-1.73 (m, 2H), 1.49-1.39 (m, 2H).

Example 12

4-benzoyl-piperidine-1-carboxylic acid (3-fluoro-phenyl)-methyl-amide (“A12”)

(47) ##STR00019##

(48) The compound is prepared analogously to example 1.

(49) Yield: 23 mg (10%); LCMS (Method A): 341.3 (M+H), RT. 4.68 min, purity 99% (254 nm); HPLC (Method B): Rt. 6.09 min, 94.7% (254 nm);

(50) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.91-7.89 (m, 2H), 7.57 (t, J=9.16 Hz, 1H), 7.46 (t, J=15.12 Hz, 2H), 7.32-7.27 (m, 1H), 6.90-6.88 (m, 1H), 6.85-6.79 (m, 2H), 3.91-3.86 (m, 2H), 3.36-3.32 (m, 1H), 3.24 (s, 3H), 2.87-2.80 (m, 2H), 1.78-1.74 (m, 2H), 1.66-1.63 (m, 1H), 1.62-1.56 (m, 2H).

Example 13

4-benzoyl-piperidine-1-carboxylic acid (4-fluoro-phenyl)-methyl-amide (“A13”)

(51) ##STR00020##

(52) The compound is prepared analogously to example 1.

(53) Yield: 26 mg (11%); LCMS (Method A): 341.2 (M+H), Rt. 4.70 min, purity 98.8% (254 nm); HPLC (Method A): Rt. 4.61 min, 98.6% (254 nm);

(54) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.94 (d, J=7.60 Hz, 2H), 7.61 (t, J=14.68 Hz, 1H), 7.50 (t, J=15.32 Hz, 2H), 7.19-7.17 (m, 4H), 3.71-3.68 (m, 2H), 3.55-3.49 (m, 1H), 3.05 (s, 3H), 2.76 (t, J=23.28 Hz, 2H), 1.62-1.59 (m, 2H), 1.32-1.22 (m, 2H).

Example 14

4-benzoyl-piperidine-1-carboxylic acid ethyl-(4-methoxy-phenyl)-amide (“A14”)

(55) ##STR00021##

(56) The compound is prepared analogously to example 1.

(57) Yield: 103 mg (42%); LCMS (Method A): 367.2 (M+H), Rt. 4.82 min, purity 100% (254 nm); HPLC (Method A): Rt. 4.75 min, 100% (254 nm);

(58) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.92 (d, J=7.44 Hz, 2H), 7.61 (t, J=14.72 Hz, 1H), 7.49 (t, J=15.40 Hz, 2H), 7.06 (d, J=1.96 Hz, 2H), 6.93 (d, J=3.32 Hz, 2H), 3.73 (s, 3H), 3.69-3.66 (m, 2H), 3.51-3.46 (m, 3H), 2.68 (t, J=23.16 Hz, 2H), 1.57-1.54 (m, 2H), 1.23-1.20 (m, 2H), 0.99-0.95 (m, 3H).

Example 15

4-benzoyl-piperidine-1-carboxylic acid (2-hydroxy-ethyl)-(4-methoxy-phenyl)amide (“A15”)

(59) ##STR00022##

(60) The compound is prepared analogously to example 1, purification via preparative HPLC; yield: 13 mg (17%); LCMS (Method A): 383.2 (M+H), Rt. 4.07 min, purity 98.2% (254 nm); HPLC (Method A): Rt. 4.04 min, 98% (254 nm)

(61) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.91-7.93 (m, 2H), 7.59-7.63 (m, 1H), 7.48-7.51 (m, 2H), 7.09 (dd, J=2.20, 6.74 Hz, 2H), 6.91 (dd, J=2.16, 6.78 Hz, 2H), 4.74 (t, J=5.20 Hz, 1H), 3.73 (s, 3H), 3.67-3.70 (m, 2H), 3.51-3.54 (m, 2H), 3.42 (q, J=12.16 Hz, 2H), 2.66-2.71 (m, 2H), 1.54-1.57 (m, 2H), 1.21-1.27 (m, 2H).

Example 16

(4-benzoyl-piperidin-1-yl)-(2,3-dihydro-indol-1-yl)-methanone (“A16”)

(62) ##STR00023##

(63) The compound is prepared analogously to example 1.

(64) Yield: 59 mg (26%); LCMS (Method A): 335.2 (M+H), Rt. 4.78 min, purity 98.5% (254 nm); HPLC (Method A): Rt. 4.74 min, 98.5% (254 nm);

(65) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.01 (d, J=8.48 Hz, 2H), 7.65 (t, J=14.72 Hz, 1H), 7.54 (t, J=15.16 Hz, 2H), 7.18 (d, J=7.20 Hz, 1H), 7.12 (t, J=15.24 Hz, 1H), 6.99 (d, J=7.88 Hz, 1H), 6.85 (t, J=14.56 Hz, 1H), 3.82 (t, J=16.56 Hz, 2H), 3.67-3.76 (m, 3H), 2.96-3.09 (m, 4H), 1.81 (d, J=11.20 Hz, 2H), 1.55-1.64 (m, 2H).

Example 17

(2,3-dihydro-indol-1-yl)-[4-(4-methyl-benzoyl)-piperidin-1-yl]-methanone (“A17”)

(66) ##STR00024##

(67) The compound is prepared analogously to example 1.

(68) Yield: 221 mg (52%); LCMS (Method A): 349.2 (M+H), Rt. 5.11 min, purity 98.6% (254 nm); HPLC (Method A): Rt. 5.05 min, 97.2% (254 nm);

(69) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.87 (d, J=8.24 Hz, 2H), 7.29 (d, J=8.04 Hz, 2H), 7.19-7.14 (m, 2H), 7.07-7.05 (m, 1H), 6.92-6.88 (m, 1H), 3.96-3.89 (m, 4H), 3.50-3.44 (m, 1H), 3.08-3.01 (m, 4H), 2.43 (s, 3H), 1.94-1.86 (m, 4H).

Example 18

(2,3-dihydro-indol-1-yl)-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-methanone (“A18”)

(70) ##STR00025##

(71) The compound is prepared analogously to example 1.

(72) Yield: 8 mg (16%); LCMS (Method A): 365.0 (M+H), Rt. 4.70 min, purity 99.9% (254 nm); HPLC (Method A): Rt. 4.71 min, 99.7% (254 nm);

(73) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.97 (d, J=8.92 Hz, 2H), 7.20-7.14 (m, 2H), 7.07 (d, J=7.92 Hz, 1H), 6.97 (d, J=11.76 Hz, 2H), 6.90 (d, J=14.72 Hz, 1H), 3.97-3.89 (m, 7H), 3.45 (t, J=14.36 Hz, 1H), 1.93-1.88 (m, 4H).

Example 19

(2,3-dihydro-indol-1-yl)-[4-(3-fluoro-benzoyl)-piperidin-1-yl]-methanone (“A19”)

(74) ##STR00026##

(75) The compound is prepared analogously to example 1.

(76) Yield: 60 mg (14%); LCMS (Method A): 353.2 (M+H), Rt. 5.01 min, purity 96.8% (254 nm); HPLC (Method A): Rt. 5.19 min, 96.9% (254 nm);

(77) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.75 (d, J=7.76 Hz, 1H), 7.67-7.63 (m, 1H), 7.51-7.46 (m, 1H), 7.32-7.28 (m, 1H), 7.20-7.14 (m, 2H), 7.06 (d, J=7.92 Hz, 1H), 6.91 (t, J=14.72 Hz, 1H), 3.97-3.90 (m, 4H), 3.50-3.41 (m, 1H), 3.09-3.02 (m, 4H), 1.96-1.87 (m, 4H).

Example 20

(2,3-dihydro-indol-1-yl)-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-methanone (“A20”)

(78) ##STR00027##

(79) The compound is prepared analogously to example 1.

(80) Yield: 8 mg (16%); LCMS (Method A): 353.2 (M+H), Rt. 4.93 min, purity 98.9% (254 nm); HPLC (Method A): Rt. 5.19 min, 96.9% (254 nm);

(81) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.03-7.99 (m, 2H), 7.20-7.15 (m, 4H), 7.06 (d, J=7.88 Hz, 2H), 6.93-6.89 (m, 1H), 3.97-3.90 (m, 4H), 3.47-3.43 (m, 1H), 3.08-3.02 (m, 4H), 1.93-1.88 (m, 4H).

Example 21

[4-(4-chloro-benzoyl)-piperidin-1-yl]-(2,3-dihydro-indol-1-yl)-methanone (“A21”)

(82) ##STR00028##

(83) The compound is prepared analogously to example 1.

(84) Yield: 108 mg (26%); LCMS (Method A): 369.0 (M+H), Rt. 5.18 min, purity 98% (254 nm); HPLC (Method A): Rt. 5.19 min, 96.9% (254 nm);

(85) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.92-7.90 (m, 2H), 7.49-7.46 (m, 2H), 7.27-7.14 (m, 2H), 7.06 (d, J=7.84 Hz, 1H), 6.93-6.89 (m, 1H), 3.97-3.89 (m, 4H), 3.50-3.42 (m, 1H), 3.08-3.01 (m, 4H), 1.93-1.61 (m, 4H).

Example 22

(4-benzoyl-piperidin-1-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone (“A22”)

(86) ##STR00029##

(87) The compound is prepared analogously to example 1.

(88) Yield: 8 mg (16%); LCMS (Method A): 349.2 (M+H), Rt. 4.85 min, purity 97.3% (254 nm); HPLC (Method A): Rt. 4.84 min, 97.6% (254 nm);

(89) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.98 (t, J=8.52 Hz, 2H), 7.64 (t, J=13.64 Hz, 1H), 7.53 (t, J=15.20 Hz, 2H), 7.08-7.04 (m, 2H), 6.92 (d, J=7.92 Hz, 1H), 6.87-6.83 (m, 1H), 3.77 (d, J=13.16 Hz, 2H), 3.64-3.54 (m, 1H), 3.47-3.44 (m, 2H), 2.99-2.92 (m, 2H), 2.73-2.66 (m, 2H), 1.88-1.83 (m, 2H), 1.76-1.73 (m, 2H), 1.54-1.44 (m, 2H).

Example 23

Synthesis of 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide (“A23”)

23.1 piperidine-1,4-dicarboxylic acid mono-tert-butyl ester

(90) ##STR00030##

(91) To a solution of piperidine-4-carboxylic acid (20.00 g, 150.20 mmol) in water (200 mL) was added sodium hydroxide (18.21 g, 450.61 mmol) followed by BOC anhydride (38.34 ml, 165.23 mmol) at 0° C. dropwise. The reaction mixture was stirred at room temperature for 16 h and acidified with 10% citric acid. The solids precipitated out were collected by filtration, washed with water (100 mL) and dried under suction; yield: 25.0 g (72%), colorless solid (crude product);

(92) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 3.82 (d, J=13.0 Hz, 2H), 2.90-2.75 (m, 2H), 2.42-2.35 (m, 1H), 1.77 (dd, J=3.1, 13.3 Hz, 2H), 1.41 (s, 9H), 1.40-1.35 (m, 2H);

(93) LC/MS (Method A): 130.2 (M+H; BOC-cleaved mass), Rt. 3.29 min, purity 99%.

23.2 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester

(94) ##STR00031##

(95) To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (25.00 g, 107.72 mmol) in DMF (250 mL) were added N,N-diisopropyl ethylamine (57.01 mL, 323.16 mmol), 1-hydroxybenzotriazole hydrate (1.67 g, 10.77 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (25.03 g, 129.27 mmol) followed by the addition of O,N-dimethyl-hydroxylamine hydrochloride (11.68 g, 118.49 mmol) in small portions at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. After completion of the reaction the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with 10% sodium bicarbonate (2×200 mL), 0.5 N HCl (2×100 mL), water (200 mL) and brine (200 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum; yield: 24.0 g (81%), colorless liquid (crude product);

(96) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 4.15-4.09 (m, 2H), 3.70 (s, 3H), 3.17 (s, 3H), 2.79-2.72 (m, 3H), 1.72-1.60 (m, 4H), 1.44 (s, 9H);

(97) LC/MS (Method A): 173.2 (M+H; BOC-cleaved mass), Rt. 3.54 min, purity 99%.

23.3 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester

(98) ##STR00032##

(99) Iodine (0.93 mg) and 5 mL of 4-bromo-2-methyl anisole (5.96 g, 29.06 mmol) dissolved in THF (40 mL) were added to a suspension of magnesium turnings (0.72 g, 29.06 mmol) in dry THF (40 mL) under nitrogen atmosphere. The mixture was stirred at room temperature for 15 min and then warmed up to 50° C. The mixture was cooled to room temperature and remaining solution of 4-Bromo-2-methyl anisole in THF was added dropwise during a period of 20 min. The mixture was stirred for additional 2 h at room temperature to complete dissolution of magnesium. This grignard reagent solution was added dropwise to a solution of 4-(Methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (4.00 g, 14.53 mmol) in THF (40.00 mL) at −78° C. The reaction mixture was allowed to stir at room temperature for 15 h. Then it was cooled to 0° C., quenched by saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with 10% sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The crude material was purified by flash chromatography using silica gel (230-400) and petrol ether/ethyl acetate (0-30%) as a gradient elution; yield: 1.50 g (30%);

(100) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.82 (dd, J=2.2, 8.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 4.17 (d, J=13.0 Hz, 2H), 3.90 (s, 3H), 3.41-3.34 (m, 1H), 2.93-2.86 (m, 2H), 2.26 (s, 3H), 1.83-1.80 (m, 2H), 1.76-1.65 (m, 2H), 1.45 (s, 9H);

(101) LC/MS (Method A): 234.3 (M+H; BOC-cleaved mass), Rt. 5.31 min, purity 99%.

23.4 (4-methoxy-3-methyl-phenyl)-piperidin-4-yl-methanone hydrochloride

(102) ##STR00033##

(103) A solution of 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.50 g, 4.36 mmol) in dioxane/HCl (3M, 14.53 ml, 43.60 mmol) was stirred at room temperature for 6 h under nitrogen atmosphere. The solvent was evaporated to dryness under reduced pressure to afford the title compound; yield: 1.10 g (92% crude product);

(104) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.25 (brs, 1H), 8.92 (brs, 1H), 7.90 (dd, J=2.2, 8.6 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 3.87 (s, 3H), 3.75-3.67 (m, 1H), 3.29-3.25 (m, 2H), 3.06-2.97 (m, 2H), 2.19 (s, 3H), 1.89-1.86 (m, 2H), 1.81-1.78 (m, 2H);

(105) LC/MS (Method A): 234.3 (M+H), Rt. 2.65 min, purity 98%.

23.5 4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide (“A23”)

(106) ##STR00034##

(107) To a solution 4-methoxy-N-methyl aniline (0.28 g, 2.01 mmol) in DCM (10 mL) was added ethyl-diisopropyl-amine (1.61 mL, 9.15 mmol) followed by triphosgene (0.66 g, 2.20 mmol) at 0° C. under nitrogen atmosphere. After being stirred for 1 h at 0° C., (4-methoxy-3-methyl-phenyl)-piperidin-4-yl-methanone hydrochloride (0.50 g, 1.83 mmol) was added and stirred at room temperature for 16 h. The reaction was diluted with DCM (100 mL), washed with water (100 mL), 10% sodium bicarbonate (2×100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The crude material was purified by flash column using silica gel (230-400) and petrol ether/ethyl acetate (0-40%) as eluent; yield: 60 mg (8%);

(108) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.82 (dd, J=2.1, 8.6 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.06 (dd, J=2.2, 6.8 Hz, 2H), 7.00 (d, J=8.6 Hz, 1H), 6.91 (dd, J=2.1, 6.8 Hz, 2H), 3.84 (s, 3H), 3.74-3.69 (m, 5H), 3.46-3.40 (m, 1H), 3.01 (s, 3H), 2.73-2.67 (m, 2H), 2.16 (s, 3H), 1.55-1.52 (m, 2H), 1.29-1.19 (m, 2H);

(109) LC/MS (Method A): 397 (M+H), Rt. 4.76 min, purity 100%.

Example 24

4-(4-methoxy-3-methyl-benzoyl)-piperidine-1-carboxylic acid ethyl-(4-methoxy-phenyl)-amide (“A24”)

(110) ##STR00035##

(111) The compound is prepared analogously to example 22 from ethyl-(4-methoxy-phenyl)-amine (0.31 g, 2.01 mmol), ethyl-diisopropyl-amine (1.61 ml, 9.15 mmol), triphosgene (0.66 g, 2.20 mmol) and (4-methoxy-3-methyl-phenyl)piperidin-4-yl-methanone hydrochloride (0.50 g, 1.83 mmol) in DCM (10 mL); Purification: preparative HPLC; yield: 40 mg (5%);

(112) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.81 (dd, J=2.2, 8.6 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.05-6.99 (m, 3H), 6.94-6.90 (m, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 3.69-3.66 (m, 2H), 3.51-3.41 (m, 3H), 2.67 (t, J=12.5 Hz, 2H), 2.16 (s, 3H), 1.52-1.50 (m, 2H), 1.26-1.16 (m, 2H), 0.97 (t, J=6.96 Hz, 3H);

(113) LC/MS (Method A): 411 (M+H), Rt. 5.06 min, purity 100%.

Example 25

25.1 piperidin-4-yl-m-tolyl-methanone hydrochloride

(114) ##STR00036##

(115) The compound is prepared analogously to example 23.1.-23.4.

(116) Yield: 2.80 g (95% crude product);

(117) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.27 (brs, 1H), 8.98 (brs, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.48-7.40 (m, 2H), 3.79-3.71 (m, 1H), 3.27 (d, J=12.6 Hz, 2H), 3.06-2.97 (m, 2H), 2.38 (s, 3H), 1.92-1.89 (m, 2H), 1.81-1.74 (m, 2H);

(118) LC/MS (Method A): 204.3 (M+H), Rt. 2.48 min, purity 100%.

25.2 4-(3-methyl-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)methyl-amide (“A25”)

(119) ##STR00037##

(120) Preparation as described for example 22 from 4-methoxy-N-methyl aniline (0.32 g, 2.27 mmol), ethyl-diisopropyl-amine (1.82 ml, 10.33 mmol), triphosgene (0.75 g, 2.48 mmol) and piperidin-4-yl-m-tolyl-methanone hydrochloride (0.50 g, 2.07 mmol) in DCM (10 mL).

(121) Purification: Flash column chromatography using silica gel (230-400) and petrol ether/ethyl acetate (0-30%) as eluent; yield: 100 mg (13%);

(122) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.73-7.71 (m, 2H), 7.43-7.35 (m, 2H), 7.06 (dd, J=2.2, 6.8 Hz, 2H), 6.91 (dd, J=2.2, 6.8 Hz, 2H), 3.73-3.69 (m, 5H), 3.50-3.44 (m, 1H), 3.01 (s, 3H), 2.71 (t, J=12.2 Hz, 2H), 2.35 (s, 3H), 1.57 (d, J=11.1 Hz, 2H), 1.29-1.19 (m, 2H);

(123) LC/MS (Method A): 367 (M+H), Rt. 4.76 min, purity 97%.

Example 26

4-(3-methyl-benzoyl)-piperidine-1-carboxylic acid ethyl-(4-methoxy-phenyl)amide (“A26”)

(124) ##STR00038##

(125) The compound is prepared analogously to example 22 from ethyl-(4-methoxy-phenyl)-amine (0.35 g, 2.27 mmol), ethyl-diisopropyl-amine (1.82 ml, 10.33 mmol), triphosgene (0.75 g, 2.48 mmol) and piperidin-4-yl-m-tolyl-methanone hydrochloride (0.50 g, 2.07 mmol) in DCM (10 mL).

(126) Purification: Flash column chromatography using silica gel (230-400) and petrol ether/ethyl acetate (0-30%) as eluent; yield: 30 mg (4%);

(127) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.72-7.70 (m, 2H), 7.43-7.35 (m, 2H), 7.04 (dd, J=2.2, 6.7 Hz, 2H), 6.92 (dd, J=2.2, 6.7 Hz, 2H), 3.73 (s, 3H), 3.69-3.66 (m, 2H), 3.51-3.42 (m, 3H), 2.67 (t, J=12.4 Hz, 2H), 2.35 (s, 3H), 1.56-1.53 (m, 2H), 1.26-1.17 (m, 2H), 0.97 (t, J=6.92 Hz, 3H); LC/MS (Method A): 381.2 (M+H), %; Rt. 5.05 min, purity 97%.

Example 27

4-(3-methoxy-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)methyl-amide (“A27”)

(128) ##STR00039##

(129) The compound is prepared analogously to example 22 from 4-methoxy-N-methyl aniline (0.30 g, 2.15 mmol), ethyl-diisopropyl-amine (1.72 ml, 9.76 mmol), triphosgene (0.71 g, 2.34 mmol) and (3-methoxy-phenyl)-piperidin-4-yl-methanone hydrochloride (0.50 g, 1.95 mmol) in DCM (10 mL).

(130) Purification: Flash column chromatography using silica gel (230-400) and petrol ether/ethyl acetate (0-40%) as eluent; yield: 160 mg (21%);

(131) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.53 (d, J=7.7 Hz, 1H), 7.43-7.38 (m, 2H), 7.18 (dd, J=2.6, 8.1 Hz, 1H), 7.06 (dd, J=2.1, 6.7 Hz, 2H), 6.91 (dd, J=2.2, 6.8 Hz, 2H), 3.79 (s, 3H), 3.73-3.68 (m, 5H), 3.52-3.45 (m, 1H), 3.01 (s, 3H), 2.72 (t, J=12.2 Hz, 2H), 1.58-1.56 (m, 2H), 1.29-1.19 (m, 2H). LC/MS (Method A): 383.2 (M+H), Rt. 4.52 min, 100%.

Example 28

4-(3-methoxy-benzoyl)-piperidine-1-carboxylic acid ethyl-(4-methoxy-phenyl)amide (“A28”)

(132) ##STR00040##

(133) The compound is prepared analogously to example 22 from ethyl-(4-methoxy-phenyl)-amine (0.33 g, 2.15 mmol), ethyl-diisopropyl-amine (1.72 ml, 9.76 mmol), triphosgene (0.71 g, 2.34 mmol) and (3-methoxy-phenyl)-piperidin-4-yl-methanone hydrochloride (0.50 g, 1.95 mmol) in DCM (10 mL).

(134) Purification: preparative HPLC; yield: 17 mg (22%);

(135) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.52 (d, J=7.7 Hz, 1H), 7.43-7.37 (m, 2H), 7.18 (dd, J=2.5, 8.1 Hz, 1H), 7.04 (dd, J=2.1, 6.8 Hz, 2H), 6.92 (dd, J=2.1, 6.9 Hz, 2H), 3.78 (s, 3H), 3.73 (s, 3H), 3.67 (d, J=13.1 Hz, 2H), 3.51-3.43 (m, 3H), 2.71-2.65 (m, 2H), 1.56-1.53 (m, 2H), 1.26-1.16 (m, 2H), 0.99-0.97 (m, 3H);

(136) LC/MS (Method A): 397 (M+H), Rt. 4.81 min, purity 99%.

Example 29

4-(3-fluoro-4-methoxy-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide (“A29”)

(137) ##STR00041##

(138) The compound is prepared analogously to example 22 from 4-methoxy-N-methyl aniline (0.28 g, 1.97 mmol), ethyl-diisopropyl-amine (1.57 ml, 8.93 mmol), triphosgene (0.65 g, 2.14 mmol) and (3-fluoro-4-methoxy-phenyl)piperidin-4-yl-methanone hydrochloride (0.50 g, 1.79 mmol) in DCM (10 mL).

(139) Purification: Flash column chromatography using silica gel (230-400) and petrol ether/ethyl acetate (0-40%) as eluent; yield: 250 mg (34%);

(140) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.82-7.73 (m, 2H), 7.25 (t, J=8.6 Hz, 1H), 7.06 (dd, J=2.2, 6.8 Hz, 2H), 6.91 (dd, J=2.2, 6.8 Hz, 2H), 3.90 (s, 3H), 3.73-3.68 (m, 5H), 3.49-3.40 (m, 1H), 3.01 (s, 3H), 2.71 (t, J=12.2 Hz, 2H), 1.55 (d, J=11.1 Hz, 2H), 1.25-1.22 (m, 2H);

(141) LC/MS (Method A): 401.2 (M+H), Rt. 4.55 min, purity 97%.

Example 30

Synthesis of 4-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide (“A30”)

30.1 (4-bromo-phenyl)-piperidin-4-yl-methanone

(142) ##STR00042##

(143) A mixture of 1-acetyl-piperidine-4-carboxylic acid (10.00 g, 57.24 mmol) and thionyl chloride (20.85 g, 171.73 mmol) was stirred at room temperature for 6 h under nitrogen atmosphere. Thionyl chloride was removed under reduced pressure and the residue was co-distilled with DCM (2×200 mL). This acid chloride was then added dropwise to a suspension of bromobenzene (27.24 g, 171.73 mmol) and anhydrous aluminum chloride (9.25 g, 68.69 mmol) in DCE (200 mL) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h, quenched to ice and extracted with DCM (2×200 mL). The organic layer was washed with water (2×200 mL), brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting black residue was taken in 6M HCl (200 mL), refluxed for 12 h and concentrated to half of its original volume. The aqueous part was basified with 10% sodium bicarbonate and extracted with DCM (2×200 mL), washed with water (2×200 mL), brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The crude material was purified by column chromatography using silica gel (60-120) and DCM/methanol as gradient elution; yield: 3.50 g (21%);

(144) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.95-7.92 (m, 2H), 7.78-7.74 (m, 2H), 3.71-3.68 (m, 1H), 3.25-3.22 (m, 2H), 2.98-2.92 (m, 2H), 1.90-1.87 (m, 2H), 1.76-1.70 (m, 2H);

(145) LC/MS (Method A): 268/270 (M+H), Rt. 2.73 min, purity 93%.

30.2 4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)methyl-amide

(146) ##STR00043##

(147) The compound is prepared analogously to example 22 from 4-methoxy-N-methyl aniline (0.81 g, 5.78 mmol), ethyl-diisopropyl-amine (4.62 ml, 26.28 mmol), triphosgene (1.91 g, 6.31 mmol) and (4-bromo-phenyl)-piperidin-4-yl-methanone (1.50 g, 5.26 mmol) in DCM (30 mL).

(148) Purification: Flash column chromatography using silica gel (230-400) and petrol ether/ethyl acetate (0-30%) as eluent; yield: 1.10 g (46%);

(149) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.75 (dd, J=1.9, 6.7 Hz, 2H), 7.59 (dd, J=2.0, 6.7 Hz, 2H), 7.06 (dd, J=2.2, 6.7 Hz, 2H), 6.87 (dd, J=2.3, 6.7 Hz, 2H), 3.89-3.85 (m, 2H), 3.80 (s, 3H), 3.23-3.21 (m, 1H), 3.18 (s, 3H), 2.78-2.71 (m, 2H), 1.68-1.64 (m, 2H), 1.51-1.47 (m, 2H), 1.28-1.24 (m, 2H);

(150) LC/MS (Method A): 431/433 (M+H), Rt. 4.99 min, purity 94%.

30.3 4-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide (“A30”)

(151) ##STR00044##

(152) A solution of 4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide (100.0 mg, 0.22 mmol), 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (93.5 mg, 0.24 mmol) and cesium carbonate (216 mg, 0.66 mmol) in dioxane (2 mL)/water (0.20 mL) was degassed for 5 min. 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (18.43 mg, 0.02 mmol) was then added and refluxed for 16 h under nitrogen atmosphere. The reaction was cooled to room temperature and filtered through celite. The filtrate was evaporated under vacuum. The residue was dissolved in ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The crude material was purified by preparative HPLC; yield: 69 mg (62%);

(153) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.29 (s, 1H), 8.00 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.07 (dd, J=2.0, 6.9 Hz, 2H), 6.92 (dd, J=2.0, 6.9 Hz, 2H), 4.27 (t, J=5.2 Hz, 2H), 3.73-3.69 (m, 7H), 3.55-3.45 (m, 1H), 3.22 (s, 3H), 3.01 (s, 3H), 2.72 (t, J=12.08 Hz, 2H), 1.59-1.56 (m, 2H), 1.31-1.21 (m, 2H);

(154) LC/MS (Method A): 477.2 (M+H), Rt. 4.2 min, purity 93%.

Example 31

31.1 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid (4-bromo-phenyl)methyl-amide

(155) ##STR00045##

(156) The compound is prepared analogously to example 22 from (4-bromo-phenyl)methyl-aniline (1.96 g, 10.22 mmol), ethyl-diisopropyl-amine (6.06 g, 46.43 mmol), triphosgene (3.37 g, 11.14 mmol) and (4-methoxy-phenyl)-piperidin-4-yl-methanone hydrochloride (2.50 g, 9.29 mmol) in DCM (50 mL). Purification: Flash column chromatography using silica gel (230-400) and petrol ether/ethyl acetate (0-40%) as eluent; yield: 1.70 g (41%);

(157) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.89 (dd, J=2.0, 9.3 Hz, 2H), 7.45 (dd, J=2.0, 6.8 Hz, 2H), 6.99 (dd, J=2.1, 6.8 Hz, 2H), 6.93 (d, J=8.9 Hz, 2H), 3.89 (s, 3H), 3.87-3.84 (m, 2H), 3.32-3.25 (m, 1H), 3.21 (s, 3H), 2.83-2.76 (m, 2H), 1.74-1.69 (m, 2H), 1.64-1.53 (m, 3H);

(158) LC/MS (Method A): 430/432 (M+H), Rt. 4.98 min, purity 98%.

31.2 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid {4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-methyl-amide (“A31”)

(159) ##STR00046##

(160) The compound is prepared analogously to example 29 from 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid (4-bromo-phenyl)-methyl-amide (100.0 mg, 0.23 mmol), 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (96.4 mg; 0.25 mmol), cesium carbonate (222.8 mg, 0.68 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1.90 mg) in dioxane/water.

(161) Purification: preparative HPLC; yield: 14 mg (13%);

(162) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.12 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.85 (s, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 7.00 (d, J=8.9 Hz, 2H), 4.25 (t, J=5.2 Hz, 2H), 3.81 (s, 3H), 3.75-3.68 (m, 4H), 3.49-3.42 (m, 1H), 3.23 (s, 3H), 3.08 (s, 3H), 2.76 (t, J=12.12 Hz, 2H), 1.59-1.56 (m, 2H), 1.36-1.27 (m, 2H);

(163) LC/MS (Method A): 477.2 (M+H), Rt. 4.16 min, purity 95%.

Example 32

32.1 4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid (4-bromo-phenyl)methyl-amide

(164) ##STR00047##

(165) The compound is prepared analogously to example 22 from (4-bromo-phenyl)methyl-aniline (1.11 g, 5.78 mmol), ethyl-diisopropyl-amine (4.62 ml, 26.28 mmol), triphosgene (1.91 g, 6.31 mmol) and (4-bromo-phenyl)-piperidin-4-yl-methanone (1.50 g, 5.26 mmol) in DCM (30 mL).

(166) Purification: Flash column chromatography using silica gel (230-400) and petrol ether/ethyl acetate (0-30%) as eluent; yield: 1.20 g (45%);

(167) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.76 (dd, J=1.9, 6.7 Hz, 2H), 7.60 (dd, J=2.0, 6.7 Hz, 2H), 7.45 (dd, J=2.1, 6.7 Hz, 2H), 6.99 (dd, J=2.2, 6.7 Hz, 2H), 3.87-3.82 (m, 2H), 3.27-3.25 (m, 1H), 3.21 (s, 3H), 2.82-2.75 (m, 2H), 1.73-1.69 (m, 2H), 1.59-1.54 (m, 2H);

(168) LC/MS (Method A): 480/482 (M+H), Rt. 5.52 min, purity 95%.

32.2 4-{4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylic acid {4-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-methyl-amide (“A32”)

(169) ##STR00048##

(170) The compound is prepared analogously to example 29 from 4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid (4-bromo-phenyl)-methyl-amide (100.0 mg, 0.20 mmol), 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (169.6 mg, 0.44 mmol), cesium carbonate (391.9 mg, 1.19 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (3.3 mg) in dioxane/water.

(171) Purification: preparative HPLC; yield: 21 mg (17%);

(172) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.29 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.92 (dd, J=8.4 Hz, 2H), 7.86 (s, 1H), 7.68 (dd, J=8.3 Hz, 2H), 7.55 (dd, J=8.5 Hz, 2H), 7.10 (dd, J=8.5 Hz, 2H), 4.26 (q, J=5.4 Hz, 4H), 3.76-3.69 (m, 6H), 3.54-3.49 (m, 1H), 3.23 (s, 3H), 3.22 (s, 3H), 3.09 (s, 3H), 2.78 (t, J=12.08 Hz, 2H), 1.63-1.60 (m, 2H), 1.38-1.28 (m, 2H);

(173) LC/MS (Method A): 571.3 (M+H), Rt. 3.96 min, purity 93%.

Example 33

4-[4-(1-ethyl-1H-pyrazol-4-yl)-benzoyl]-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide (“A33”)

(174) ##STR00049##

(175) The compound is prepared analogously to example 29 from 4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide (150.0 mg; 0.33 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (139.3 mg, 0.39 mmol), cesium carbonate (324.2 mg, 0.99 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (27.6 mg, 0.03 mmol) in dioxane/water.

(176) Purification: Column chromatography using silica gel (230-400) and DCM/methanol as gradient elution; yield: 19 mg (12%),

(177) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.33 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.68 (d, J=8.2 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 4.15 (t, J=7.2 Hz, 2H), 3.73-3.70 (m, 5H), 3.51-3.46 (m, 1H), 3.01 (s, 3H), 2.75-2.69 (m, 2H), 1.59-1.56 (m, 2H), 1.39 (t, J=7.36 Hz, 3H), 1.31-1.24 (m, 2H);

(178) LC/MS (Method A): 447.3 (M+H), Rt. 4.38 min, purity 96%.

Example 34

4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid [4-(1-ethyl-1H-pyrazol-4-yl)-phenyl]-methyl-amide (“A34”)

(179) ##STR00050##

(180) The compound is prepared analogously to example 29 from 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid (4-bromo-phenyl)-methyl-amide (150.0 mg, 0.34 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (143.6 mg, 0.41 mmol), cesium carbonate (334.1 mg, 1.02 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (28.5 mg, 0.03 mmol) in dioxane/water.

(181) Purification: Column chromatography using silica gel (230-400) and DCM/methanol as gradient elution; yield: 52 mg (32%);

(182) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.15 (s, 1H), 7.92 (d, J=8.7 Hz, 2H), 7.83 (s, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.10 (d, J=8.3 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 4.13 (q, J=7.3 Hz, 2H), 3.81 (s, 3H), 3.75-3.72 (m, 2H), 3.49-3.46 (m, 1H), 3.08 (s, 3H), 2.79-2.73 (m, 2H), 1.59-1.56 (m, 2H), 1.39 (t, J=7.28 Hz, 3H), 1.36-1.32 (m, 2H);

(183) LC/MS (Method A): 447.3 (M+H), Rt. 4.31 min, purity 96%.

Example 35

4-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide (“A35”)

(184) ##STR00051##

(185) The compound is prepared analogously to example 29 from 4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-phenyl)-methyl-amide (150.0 mg, 0.33 mmol), 1-(2-pyrrolidin-1-yl-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (118.0 mg, 0.39 mmol), cesium carbonate (324.2 mg, 0.99 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (27.6 mg, 0.03 mmol) in dioxane/water. Purification: preparative HPLC; yield: 16 mg (9%);

(186) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.33 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.2 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 4.22 (t, J=6.4 Hz, 2H), 3.73-3.70 (m, 5H), 3.55-3.45 (m, 1H), 3.01 (s, 3H), 2.83 (t, J=6.60 Hz, 2H), 2.76-2.66 (m, 2H), 2.49-2.45 (m, 4H), 1.65-1.63 (m, 4H), 1.59-1.56 (m, 2H), 1.30-1.22 (m, 2H);

(187) LC/MS (Method A): 516 (M+H), Rt. 3.48 min, purity 97%.

Example 36

4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid methyl-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-phenyl}-amide (“A36”)

(188) ##STR00052##

(189) The compound is prepared analogously to example 29 from 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid (4-bromo-phenyl)-methyl-amide (150.0 mg, 0.34 mmol), 1-(2-pyrrolidin-1-yl-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (121.6 mg, 0.41 mmol), cesium carbonate (334.1 mg, 1.02 mmol) and 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (28.5 mg, 0.03 mmol) in dioxane/water.

(190) Purification: Column chromatography using silica gel (230-400) and DCM/methanol as gradient elution; yield: 30 mg (16%);

(191) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.16 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.84 (s, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 4.20 (t, J=6.5 Hz, 2H), 3.81 (s, 3H), 3.75-3.72 (m, 2H), 3.50-3.43 (m, 1H), 3.08 (s, 3H), 2.84 (t, J=6.44 Hz, 2H), 2.79-2.73 (m, 2H), 2.49-2.45 (m, 4H), 1.65-1.57 (m, 6H), 1.36-1.29 (m, 2H);

(192) LC/MS (Method A): 516.3 (M+H), Rt. 3.46 min, purity 95%.

Example 37

4-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-benzoyl}-piperidine-1-carboxylic acid methyl-{4-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-phenyl}-amide (“A37”)

(193) ##STR00053##

(194) The compound is prepared analogously to example 29 from 4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid (4-bromo-phenyl)-methyl-amide (100.0 mg, 0.20 mmol), 1-(2-pyrrolidin-1-yl-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (130.8 mg, 0.44 mmol), cesium carbonate (391.9 mg, 1.19 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (33.4 mg, 0.04 mmol) in dioxane/water. Purification: preparative HPLC; yield: 6 mg (5%);

(195) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.33 (s, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.84 (s, 1H), 7.67 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 4.21 (dd, J=6.4, 12.9 Hz, 4H), 3.76-3.73 (m, 2H), 3.54-3.48 (m, 1H), 3.08 (s, 3H), 2.84-2.75 (m, 6H), 2.49-2.44 (m, 8H), 1.65-1.60 (m, 10H), 1.36-1.31 (m, 2H);

(196) LC/MS (Method A): 649.3 (M+H), Rt. 2.84 min, purity 95%.

(197) The following compounds are prepared analogously

4-(4-methanesulfonylamino-benzoyl)-piperidine-1-carboxylic acid methyl-phenyl-amide (“A38”)

(198) ##STR00054##

[(4-benzoyl-piperidine-1-carbonyl)-phenyl-amino]-acetic acid ethyl ester (“A39”)

(199) ##STR00055##

{[4-(4-methoxy-benzoyl)-piperidine-1-carbonyl]-phenyl-amino}-acetic acid ethyl ester (“A40”)

(200) ##STR00056##

N-ethyl-4-(3-fluoro-4-methoxy-benzoyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide (“A41”)

(201) ##STR00057##

4-(3-fluoro-4-methoxy-benzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide (“A42”)

(202) ##STR00058##

(203) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.98 (t, J=0.32 Hz, 1H), 7.83-7.80 (m, 1H), 7.76 (dd, J=2.08, 12.32 Hz, 1H), 7.57 (dd, J=2.88, 8.80 Hz, 1H), 7.26 (t, J=8.60 Hz, 1H), 6.82 (d, J=8.88 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.67 (d, J=13.12 Hz, 2H), 3.51-3.45 (m, 1H), 3.04 (s, 3H), 2.79-2.72 (m, 2H), 1.58 (d, J=10.96 Hz, 2H), 1.30-1.20 (m, 2H); LC/MS (Method A): 402 (M+H), Rt. 3.80 min;

N-ethyl-N-(4-methoxyphenyl)-4-(6-methoxypyridine-3-carbonyl)piperidine-1-carboxamide (“A43”)

(204) ##STR00059##

(205) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.81 (d, J=2.04 Hz, 1H), 8.15 (dd, J=2.48, 8.78 Hz, 1H), 7.04 (dd, J=2.40, 6.74 Hz, 2H), 6.93-6.88 (m, 3H), 3.91 (s, 3H), 3.73 (s, 3H), 3.69-3.65 (m, 1H), 3.50-3.40 (m, 1H), 3.48 (t, J=7.04 Hz, 2H), 3.40-3.30 (m, 1H), 2.66 (q, J=6.52 Hz, 2H), 1.56-1.53 (m, 2H), 1.27-1.17 (m, 2H), 0.97 (t, J=7.00 Hz, 3H).

(206) LC/MS (Method A): 398 (M+H), Rt. 4.36 min;

4-benzoyl-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide (“A44”)

(207) ##STR00060##

(208) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.98 (t, J=0.40 Hz, 1H), 7.94-7.92 (m, 2H), 7.64-7.55 (m, 2H), 7.52-7.48 (m, 2H), 6.82 (dd, J=0.44, 8.86 Hz, 1H), 3.82 (s, 3H), 3.73-3.64 (m, 2H), 3.56-3.31 (m, 1H), 3.04 (s, 3H), 2.80-2.73 (m, 2H), 1.61 (d, J=10.84 Hz, 2H), 1.32-1.21 (m, 2H); LC/MS (Method A): 354 (M+H), Rt. 3.84 min;

N-(6-methoxy-3-pyridyl)-N-methyl-4-(3-methylbenzoyl)piperidine-1-carboxamide (“A45”)

(209) ##STR00061##

(210) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.99 (d, J=2.68 Hz, 1H), 7.73 (d, J=7.28 Hz, 2H), 7.57 (dd, J=2.84, 8.84 Hz, 1H), 7.44-7.38 (m, 2H), 6.83 (d, J=8.76 Hz, 1H), 3.82 (s, 3H), 3.67 (d, J=12.84 Hz, 2H), 3.51 (s, 1H), 3.04 (s, 3H), 2.76 (t, J=10.96 Hz, 2H), 2.35 (s, 3H), 1.60 (d, J=10.88 Hz, 2H), 1.26 (q, J=3.92 Hz, 2H);

(211) LC/MS (Method A): 368 (M+H), Rt. 4.21 min;

N-(6-methoxy-3-pyridyl)-N-methyl-4-(4-methylbenzoyl)piperidine-1-carboxamide (“A46”)

(212) ##STR00062##

(213) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.98 (d, J=2.76 Hz, 1H), 7.84 (d, J=8.20 Hz, 2H), 7.57 (dd, J=2.84, 8.80 Hz, 1H), 7.30 (d, J=8.16 Hz, 2H), 6.82 (d, J=8.80 Hz, 1H), 3.82 (s, 3H), 3.67 (d, J=13.12 Hz, 2H), 3.51-3.46 (m, 1H), 3.04 (s, 3H), 2.77 (t, J=1.32 Hz, 2H), 2.35 (s, 3H), 1.59 (d, J=11.16 Hz, 2H), 1.31-1.20 (m, 2H); LC/MS (Method A): 368 (M+H), Rt. 4.18 min;

4-(3-methoxybenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide (“A47”)

(214) ##STR00063##

(215) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.98 (d, J=2.76 Hz, 1H), 7.58-7.53 (m, 2H), 7.44-7.39 (m, 2H), 7.20-7.18 (m, 1H), 6.82 (d, J=8.76 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.79-3.65 (m, 2H), 3.54-3.49 (m, 1H), 3.04 (s, 3H), 2.79-2.74 (m, 2H), 1.60 (d, J=10.96 Hz, 2H), 1.31-1.21 (m, 2H);

(216) LC/MS (Method A): 384 (M+H), Rt. 3.96 min;

4-[4-(1-ethylpyrazol-4-yl)benzoyl]-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide (“A48”)

(217) ##STR00064##

(218) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.34 (s, 1H), 7.99 (t, J=0.40 Hz, 2H), 7.92 (d, J=8.48 Hz, 2H), 7.69 (s, 2H), 7.58 (dd, J=2.84, 8.82 Hz, 1H), 6.83 (d, J=8.88 Hz, 1H), 4.15 (q, J=7.28 Hz, 2H), 3.83 (s, 3H), 3.68 (d, J=13.00 Hz, 2H), 3.55-3.49 (m, 1H), 3.05 (s, 3H), 2.77 (t, J=10.84 Hz, 2H), 1.61 (d, J=10.80 Hz, 2H), 1.40 (t, J=7.28 Hz, 3H), 1.33-1.23 (m, 2H); LC/MS (Method A): 448 (M+H), Rt. 3.81 min;

4-(4-methoxybenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide (“A49”)

(219) ##STR00065##

(220) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.98 (d, J=2.56 Hz, 1H), 7.92 (dd, J=1.96, 6.96 Hz, 2H), 7.57 (dd, J=2.88, 8.82 Hz, 1H), 7.01 (dd, J=1.88, 7.02 Hz, 2H), 6.83 (d, J=8.64 Hz, 1H), 3.82 (s, 6H), 3.37 (d, J=16.7 Hz, 2H), 3.66-3.43 (m, 1H), 3.04 (s, 3H), 2.78-2.73 (m, 2H), 1.58 (d, J=11.04 Hz, 2H), 1.31-1.21 (m, 2H); LC/MS (Method A): 384 (M+H), Rt. 3.71 min;

4-(3-fluorobenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide (“A50”)

(221) ##STR00066##

(222) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.99 (d, J=2.80 Hz, 1H), 7.79 (d, J=7.68 Hz, 1H), 7.72 (d, J=9.72 Hz, 1H), 7.59-7.54 (m, 2H), 7.50-7.46 (m, 1H), 6.83 (d, J=8.80 Hz, 1H), 3.82 (s, 3H), 3.69 (t, J=13.16 Hz, 2H), 3.55-3.50 (m, 1H), 3.04 (s, 3H), 2.76 (t, J=11.40 Hz, 2H), 1.62 (d, J=11.20 Hz, 2H), 1.30-1.20 (m, 2H); LC/MS (Method A): 372 (M+H), Rt. 4.04 min;

4-(4-fluorobenzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide (“A51”)

(223) ##STR00067##

(224) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.05-7.98 (m, 3H), 7.57 (dd, J=2.84, 8.80 Hz, 1H), 7.35-7.31 (m, 2H), 6.83 (d, J=8.80 Hz, 1H), 3.82 (s, 3H), 3.67 (d, J=13.16 Hz, 2H), 3.54-3.48 (m, 1H), 3.04 (s, 3H), 2.78-2.73 (m, 2H), 1.60 (d, J=11.20 Hz, 2H), 1.31-1.22 (m, 2H); LC/MS (Method A): 372 (M+H), Rt. 3.99 min;

4-(4-methoxy-3-methyl-benzoyl)-N-(6-methoxy-3-pyridyl)-N-methyl-piperidine-1-carboxamide (“A52”)

(225) ##STR00068##

(226) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.98 (d, J=2.36 Hz, 1H), 7.82 (dd, J=2.20, 8.60 Hz, 1H), 7.74 (d, J=1.52 Hz, 1H), 7.58-7.55 (m, 1H), 7.01 (d, J=8.68 Hz, 1H), 6.82 (dd, J=0.40, 8.84 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.67 (d, J=13.20 Hz, 2H), 3.49-3.41 (m, 1H), 3.04 (s, 3H), 2.75 (t, J=10.76 Hz, 2H), 2.16 (s, 3H), 1.57 (d, J=10.84 Hz, 2H), 1.31-1.16 (m, 2H); LC/MS (Method A): 398 (M+H), Rt. 4.25 min;

N-(4-methoxyphenyl)-4-(6-methoxypyridine-3-carbonyl)-N-methyl-piperidine-1-carboxamide (“A53”)

(227) ##STR00069##

(228) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.82 (d, J=2.08 Hz, 1H), 8.16 (dd, J=2.48, 8.76 Hz, 1H), 7.06 (dd, J=2.28, 6.70 Hz, 2H), 6.92-6.89 (m, 3H), 3.91 (s, 3H), 3.72-3.68 (m, 5H), 3.68-3.41 (m, 1H), 3.01 (s, 3H), 2.73-2.65 (m, 2H), 1.58-1.55 (m, 2H), 1.30-1.20 (m, 2H); LC/MS (Method A): 384 (M+H), Rt. 4.04 min;

4-[4-(1-Ethyl-1H-pyrazol-4-yl)-benzoyl]-piperidine-1-carboxylic acid [4-(1-ethyl-1H-pyrazol-4-yl)-phenyl]-methyl-amide (“A57”)

(229) ##STR00070##

(230) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.33 (s, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.83 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H), 7.13-7.09 (m, 2H), 4.17-4.10 (m, 4H), 3.76-3.73 (m, 2H), 3.54-3.48 (m, 1H), 3.08 (s, 3H), 2.81-2.75 (m, 2H), 1.62-1.60 (m, 2H), 1.41-1.37 (m, 6H), 1.34-1.28 (m, 2H); LC/MS (Method A): 511 (M+H), Rt. 4.25 min;

N-(4-cyanophenyl)-4-(4-methoxybenzoyl)-N-methyl-piperidine-1-carboxamide (“A58”)

(231) ##STR00071##

N-(4-cyanophenyl)-N-(2-hydroxyethyl)-4-(4-methoxybenzoyl)piperidine-1-carboxamide (“A59”)

(232) ##STR00072##

N-(6-cyano-3-pyridyl)-4-(4-methoxybenzoyl)-N-methyl-piperidine-1-carboxamide (“A60”)

(233) ##STR00073##

N-(4-cyanophenyl)-4-(3-fluoro-4-methoxy-benzoyl)-N-methyl-piperidine-1-carboxamide (“A61”)

(234) ##STR00074##

N-(4-cyanophenyl)-N-(2-hydroxyethyl)-4-(4-methoxy-3-methyl-benzoyl)piperidine-1-carboxamide (“A62”)

(235) ##STR00075##

N-(4-cyanophenyl)-4-(3-fluoro-4-methoxy-benzoyl)-N-(2-hydroxyethyl)piperidine-1-carboxamide (“A63”)

(236) ##STR00076##

N-(2-hydroxyethyl)-4-(4-methoxybenzoyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide (“A64”)

(237) ##STR00077##

N-(2-hydroxyethyl)-4-(4-methoxy-3-methyl-benzoyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide (“A65”)

(238) ##STR00078##

4-(3-fluoro-4-methoxy-benzoyl)-N-(2-hydroxyethyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide (“A66”)

(239) ##STR00079##

N-(2-hydroxyethyl)-4-(4-methoxy-3-methyl-benzoyl)-N-(6-methoxy-3-pyridyl)piperidine-1-carboxamide (“A67”)

(240) ##STR00080##

4-(3-fluoro-4-methoxy-benzoyl)-N-(2-hydroxyethyl)-N-(6-methoxy-3-pyridyl)piperidine-1-carboxamide (“A68”)

(241) ##STR00081##

N-(2-hydroxyethyl)-4-(4-methoxybenzoyl)-N-(6-methoxy-3-pyridyl)piperidine-1-carboxamide (“A69”)

(242) ##STR00082##

4-(4-methoxybenzoyl)-N-(6-methoxypyridazin-3-yl)-N-methyl-piperidine-1-carboxamide (“A70”)

(243) ##STR00083##

4-(4-methoxybenzoyl)-N-(2-methoxypyrimidin-5-yl)-N-methyl-piperidine-1-carboxamide (“A71”)

(244) ##STR00084##

Synthesis of 4-[4-(1-hydroxy-1-methyl-ethyl)benzoyl]-N-(4-methoxyphenyl)-N-methyl-piperidine-1-carboxamide (“A54”)

(245) ##STR00085##

(246) The following compounds are prepared analogously:

N-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-4-(4-methoxybenzoyl)-N-methyl-piperidine-1-carboxamide (“A55”)

(247) ##STR00086##

4-[4-(1-hydroxy-1-methyl-ethyl)benzoyl]-N-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-N-methyl-piperidine-1-carboxamide (“A56”)

(248) ##STR00087##
Pharmacological Data

(249) TABLE-US-00001 TABLE 1 Inhibition of tankyrases of compounds of the formula I IC.sub.50 IC.sub.50 TNKS1 TNKS2 Compound enzyme enzyme No. assay assay “A1” B B “A2” B B “A3” B B “A4” B B “A5” A B “A6” A B “A7” B B “A8” B B “A9” A B “A10” B C “A11” B B “A12” B B “A13” B B “A14” A B “A15” B B “A16” B B “A17” B B “A18” B B “A19” B B “A20” B B “A21” B B “A22” C C “A23” A B “A24” A B “A25” A B “A26” A B “A27” A B “A28” A A “A29” B “A38” A B “A39” “A40” A B “A41” “A42” A B “A43” “A44” “A45” B B “A46” B B “A47” B B “A48” “A49” A B “A50” B B “A51” B B IC.sub.50: <0.3 μM = A 0.3-3 μM = B 3-50 μM = C

(250) TABLE-US-00002 TABLE 2 Inhibition of tankyrases of compounds of the formula I EC.sub.50 [M] Compound TNKS No. cellular assay “A1” B “A2” B “A3” B “A4” B “A5” A “A6” A “A7” B “A8” A “A9” B “A10” C “A11” B “A12” B “A13” B “A14” A “A15” B “A16” C “A17” B “A18” B “A19” C “A20” C “A21” C “A22” C “A23” A “A24” A “A25” A “A26” A “A27” A “A28” A “A29” A “A30” A “A31” A “A32” A “A33” A “A34” A “A35” A “A36” A “A37” B “A38” B “A39” B “A40” A “A42” A “A43” A “A44” B “A45” A “A46” B “A47” B “A48” B “A49” A “A50” B “A51” B “A52” A “A53” B “A57” A EC.sub.50: <0.3 μM = A 0.3-3 μM = B 3-50 μM = C

(251) The compounds shown in Table 2 are particularly preferred compounds according to the invention.

(252) TABLE-US-00003 TABLE 3 Inhibition of tankyrases of some representative compounds of the formula I IC.sub.50 [M] IC.sub.50 [M] Compound IC.sub.50 [M] TNKS1 TNKS2 No. PARP ELISA ELISA “A1” C A A “A2” C A A “A3” A A “A4” C A A “A5” C A A “A6” C A A “A7” C A A “A8” C A A “A9” A A “A10” B A “A11” A A “A12” A A “A13” C A A “A14” C A A “A15” C A A “A16” C A A “A17” C A A “A18” C A A “A19” A A “A20” A A “A21” B A “A22” B B “A23” A A “A24” C A A “A25” C A A “A26” C A A “A27” C A A “A28” C A A “A29” C A A “A30” C A A “A31” C A A “A32” C A A “A33” C A A “A34” C A A “A35” C A A “A36” C A A “A37” A A “A38” C A A “A39” C A A “A40” C A A “A42” A A “A43” A A “A44” A A “A45” A A “A46” A A “A47” A A “A48” A A “A49” A A “A50” A A “A51” A A “A52” A A “A53” A A “A57” A A IC.sub.50: <0.3 μM = A 0.3-3 μM = B 3-50 μM = C

(253) The compounds shown in Table 3 are particularly preferred compounds according to the invention.

(254) The following examples relate to medicaments:

Example A: Injection Vials

(255) 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

(256) 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

(257) 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

(258) 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

Example E: Tablets

(259) 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

(260) 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

(261) 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

(262) 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.