Heterocyclicalkyl derivative compounds as selective histone deacetylase inhibitors and pharmaceutical compositions comprising the same

Abstract

The present invention relates to novel heterocyclicalkyl derivatives having histone deacetylase (HDAC) inhibitory activity, optical isomers thereof or pharmaceutically acceptable salts thereof, the use thereof for the preparation of medicaments, pharmaceutical compositions containing the same, a method for treating diseases using the composition, and methods for preparing the novel heterocyclicalkyl derivatives. The novel heterocyclicalkyl derivatives according to the present invention are selective histone deacetylase (HDAC) inhibitors, and may be effectively used for the treatment of histone deacetylase-mediated diseases, such as cell proliferative diseases, inflammatory diseases, autosomal dominant diseases, genetic metabolic diseases, autoimmune diseases, acute/chronic neurological disease, hypertrophy, heart failure, ocular diseases, or neurodegenerative diseases.

Claims

1. A compound represented by the following formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof: ##STR00131## wherein, X is a heterocyclic alkyl selected from the group consisting of ##STR00132## wherein when X is ##STR00133## Z and W are each independently CH or N, at least one of Z and W is N, and R.sub.3 and R.sub.4 are each independently —H or —C.sub.1-C.sub.4 alkyl, wherein when X is ##STR00134## R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are each independently —H or —C.sub.1-C.sub.4 alkyl; Y is C or N; each of A and B is independently —C.sub.1-C.sub.4 alkyl, —C.sub.6-C.sub.10 aryl, —C.sub.3-C.sub.12 heteroaryl, —C.sub.3-C.sub.10 cycloalkyl, —C.sub.2-C.sub.10 heterocycloalkyl, or —C.sub.3-C.sub.10 cycloalkenyl, wherein one or more hydrogen atoms of the —C.sub.1-C.sub.4 alkyl is optionally substituted with —OH or halogen, and each —C.sub.6-C.sub.10 aryl, —C.sub.3-C.sub.12 heteroaryl, —C.sub.3-C.sub.10 cycloalkyl, —C.sub.2-C.sub.10 heterocycloalkyl and —C.sub.3-C.sub.10 cycloalkenyl is independently optionally substituted with —OH, —C.sub.1-C.sub.4 alkyl, —OC.sub.1-C.sub.4 alkyl, —CF.sub.3 or halogen; Q is C═O or SO.sub.2; R.sub.1 is —H or —C.sub.1-C.sub.4 alkyl; R.sub.2 is —H, —OH, —C.sub.1-C.sub.4 alkyl, —C.sub.1-C.sub.4 alkylhydroxy, halogen or null provided that when Y is C, R.sub.2 is —H, —OH, —C.sub.1-C.sub.4 alkyl, —C.sub.1-C.sub.4 alkylhydroxy, or halogen and when Y is N, R.sub.2 is null; and n is 1, 2, 3, or 4.

2. The compound represented by formula I, optical isomer thereof or pharmaceutically acceptable salt thereof according to claim 1, wherein X is a heterocyclic alkyl selected from the group consisting of ##STR00135## wherein when X is ##STR00136## Z and W are each independently CH or N, at least one of Z and W is N, and R.sub.3 and R.sub.4 are each independently —H or —C.sub.1-C.sub.4 alkyl, wherein when X is ##STR00137## R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each independently —H or —C.sub.1-C.sub.4 alkyl; Y is C or N; each of A and B is independently —C.sub.1-C.sub.4 alkyl, —C.sub.6-C.sub.10 aryl, —C.sub.3-C.sub.12 heteroaryl, —C.sub.3-C.sub.10 cycloalkyl, —C.sub.2-C.sub.10 heterocycloalkyl, or —C.sub.3-C.sub.10 cycloalkenyl, wherein one or more hydrogen atoms of the —C.sub.1-C.sub.4 alkyl is optionally substituted with —OH or halogen, and each —C.sub.6-C.sub.10 and —C.sub.3-C.sub.12 heteroaryl is independently optionally substituted with —OH, —C.sub.1-C.sub.4 alkyl, —OC.sub.1-C.sub.4 alkyl, —CF.sub.3 or halogen; Q is C═O or SO.sub.2; R.sub.1 is —H or —C.sub.1-C.sub.4 alkyl; R.sub.2 is —H, —OH, halogen or null, provided that when Y is C, R.sub.2 is —H, —OH, or halogen, and when Y is N, R.sub.2 is null; and n is 1, 2, 3, or 4.

3. The compound represented by formula I, optical isomer thereof or pharmaceutically acceptable salt thereof according to claim 2, wherein X is ##STR00138## wherein each Z and W is independently CH or N, at least one of Z and W is N, and each of R.sub.3 and R.sub.4 is independently —H or C.sub.1-C.sub.4 alkyl; Y is C or N; each of A and B is independently —C.sub.1-C.sub.4 alkyl, —C.sub.6-C.sub.10 aryl or —C.sub.3-C.sub.12 heteroaryl, wherein one or more hydrogen atoms of the —C.sub.1-C.sub.4 alkyl is optionally substituted with —OH or halogen, and each C.sub.6-C.sub.10 aryl and C.sub.3-C.sub.12 heteroaryl is independently optionally substituted with —OH, —C.sub.1-C.sub.4 alkyl, —OC.sub.1-C.sub.4 alkyl, —CF.sub.3 or halogen; Q is C═O; R.sub.1 is —H or —C.sub.1-C.sub.4 alkyl; R.sub.2 is —H, —OH, halogen or null provided that when Y is C, R.sub.2 is —H, —OH or halogen, and when Y is N, R.sub.2 is null; and n is 3.

4. The compound represented by formula I, optical isomer thereof or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by formula I is selected from the group consisting of compounds described in the following table: TABLE-US-00005 Compound Structure 1102 1124 1188 1189 1190 1209 1210 1213 1221 1222 1223 1224 1240 1241 1243 1256 1257 1316 1317 1647 1648 1649 1719 1726 1734 1763 1764

5. The compound represented by formula I, optical isomer thereof or pharmaceutically acceptable salt thereof according to claim 4, wherein the compound represented by formula I is selected from the group consisting of compounds described in the following table: TABLE-US-00006 Compound Structure 1102 1124 1188 1209

6. A pharmaceutical composition for treating histone deacetylase-mediated disease, comprising, as an active ingredient, the compound represented by formula I, optical isomer thereof or pharmaceutically acceptable salt thereof according to claim 1, wherein the histone deacetylase-mediated disease is cell proliferative disease, inflammatory disease, autosomal dominant disease, genetic metabolic disease, autoimmune disease, acute/chronic neurological disease, hypertrophy, heart failure, ocular disease, or neurodegenerative disease.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 shows the results of analyzing the effect of compound 1102 on the alleviation of arthritis in adjuvant-induced arthritis models.

MODE FOR THE INVENTION

(2) Hereinafter, preferred examples will be presented to assist in the understanding of the present invention. However, these examples are provided only for a better understanding of the present invention and are not intended to limit the scope of the present invention.

(3) The reagents and solvents mentioned below were purchased from Sigma-Aldrich and TCI unless otherwise specified, and HPLC was performed using Waters e2695. As silica gel for column chromatography, silica gel (230-400 mesh) from Merck was used.

(4) .sup.1H-NMR data were measured using Bruker 400 MHz, and mass spectra were obtained using Agilent 1100 series.

EXAMPLE 1

Synthesis of Compound 1102

Step 1: Synthesis of methyl 7-(4-benzhydrylpiperazine-1-carboxamido)heptanoate (formula 1-3)

(5) ##STR00044##

(6) 1-benzhydrylpiperazine (0.200 g, 0.793 mmol), methyl 7-aminoheptanoate (0.151 g, 0.951 mmol), triphosgene (0.118 g, 0.396 mmol) and DIPEA (0.415 mL, 2.378 mmol) were dissolved in methylene chloride (5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Waters, C.sub.18; 1%-formic acid (methanoic acid) aqueous solution/acetonitrile=from 100% to 20%) and concentrated by passage through an SPE cartridge (PL-HCO.sub.3 resin), thereby obtaining the desired compound of formula 1-3 (0.075 g, 21.6%) as alight yellow oil.

Step 2: Synthesis of 4-benzhydryl-N-(7-(hydroxyamino)-7-oxoheptyl)piperazine-1-carboxamide (Compound 1102)

(7) ##STR00045##

(8) The compound of formula 1-3 (0.075 g, 0.171 mmol) prepared in step 1, hydroxylamine (50.00% aqueous solution, 0.210 mL, 3.428 mmol) and potassium hydroxide (0.096 g, 1.714 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium bicarbonate (20 mL) to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water, and dried, thereby obtaining the desired compound 1102 (0.047 g, 62.5%) as a yellow solid.

(9) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.39 (brs, 1H), 7.42 (d, 4H, J=7.2 Hz), 7.29 (t, 4H, J=7.5 Hz), 7.18 (t, 2H, J=7.3 Hz), 6.40 (t, 1H, J=5.3 Hz), 4.28 (s, 1H), 3.27 (s, 4H), 2.98-2.93 (m, 2H), 2.08 (s, 4H), 1.89 (t, 2H, J=7.3 Hz), 1.44-1.43 (m, 2H), 1.34-1.33 (m, 2H), 1.20 (s, 4H); MS (ESI) m/z 439.6 (M.sup.++H).

EXAMPLE 2

Synthesis of Compound 1124

Step 1: Synthesis of 4-nitrophenyl 4-(hydroxydiphenylmethyl)piperidine-1-carboxylate (formula 7-3)

(10) ##STR00046##

(11) Diphenyl(piperidin-4-yl)methanol (0.100 g, 0.374 mmol) and triethylamine (0.104 mL, 0.748 mmol) were dissolved in methylene chloride (5 mL) at 0° C., and 4-nitrophenyl chloroformate (0.083 g, 0.411 mmol) was added to the solution, followed by stirring at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Sift, 4 g cartridge; ethyl acetate/hexane=from 0% to 20%) and concentrated, thereby obtaining the desired compound of formula 7-3 (0.152 g, 94.0%) as a colorless oil.

Step 2: Synthesis of methyl 7-(4-(hydroxydiphenylmethyl)piperidine-1-carboxamido)heptanoate (Formula 7-4)

(12) ##STR00047##

(13) The compound of formula 7-3 (0.152 g, 0.351 mmol) prepared in step 1, methyl 7-aminoheptanoate hydrochloride (0.280 g, 1.757 mmol) and potassium carbonate (0.097 g, 0.703 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and the solution was stirred at 100° C. for 17 hours. Then, the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 10% to 40%) and concentrated, thereby obtaining the compound of formula 7-4 (0.075 g, 39.4%) as an orange oil.

Step 3: N-(7-(hydroxyamino)-7-oxoheptyl)-4-(hydroxydiphenylmethyl)piperidine-1-carboxamide (Compound 1124)

(14) ##STR00048##

(15) The compound of formula 7-4 (0.075 g, 0.166 mmol) prepared in step 2, hydroxylamine (50.00% aqueous solution, 0.203 mL, 3.314 mmol) and potassium hydroxide (0.093 g, 1.657 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and water was added to the concentrate, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The precipitated solid was filtered, washed with hexane, and dried to afford the desired compound 1124 (0.007 g, 9.3%) as a white solid.

(16) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.36 (brs, 1H), 7.52 (d, 4H, J=7.6 Hz), 7.27 (t, 4H, J=7.7 Hz), 7.13 (t, 2H, J=7.3 Hz), 6.30 (t, 1H, J=5.3 Hz), 5.32 (brs, 1H), 3.94 (d, 2H, J=13.4 Hz), 2.99-2.94 (m, 2H), 2.67-2.58 (m, 3H), 1.91 (t, 2H, J=7.4 Hz), 1.48-1.46 (m, 2H), 1.35-1.34 (m, 2H), 1.30-1.25 (m, 6H).

EXAMPLE 3

Synthesis of Compound 1188

Step 1: Synthesis of (3S,5R)-1-benzhydryl-3,5-dimethylpiperazine (Compound 4-3)

(17) ##STR00049##

(18) (2R,6S)-2,6-dimethylpiperazine (1.000 g, 8.757 mmol), (chloromethylene)dibenzene (3.550 g, 17.515 mmol) and potassium carbonate (6.052 g, 43.787 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and water was added to the concentrate, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Sift, 12 g cartridge; methanol/methylene chloride=from 0% to 10%) and concentrated to afford the desired compound of formula 4-3 (0.798 g, 32.5%) as a white solid.

Step 2: Synthesis of methyl 7-((2S,6R)-4-benzhydryl-2,6-dimethylpiperazine-1-carboxamido)heptanoate (Formula 4-4)

(19) ##STR00050##

(20) Triphosgene (0.159 g, 0.535 mmol) and diisopropylamine (0.561 mL, 3.210 mmol) were dissolved in methylene chloride (5 mL) at 0° C., and methyl 7-aminoheptanoate hydrochloride (0.251 g, 1.284 mmol) was added to the solution, followed by stirring at the same temperature. The compound of formula 4-3 (0.300 g, 1.070 mmol) prepared in step 1 was added to the reaction mixture, followed by stirring at the same temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 30%) and concentrated to afford the desired compound of formula 4-4 (0.212 g, 42.6%) as a white solid.

Step 3: Synthesis of (2S,6R)-4-benzhydryl-N-(7-(hydroxyamino)-7-oxoheptyl)-2,6-dimethylpiperazine-1-carboxyamide (Compound 1188)

(21) ##STR00051##

(22) The compound of formula 4-4 (0.100 g, 0.215 mmol) prepared in step 2, hydroxylamine (50.00% aqueous solution, 0.263 mL, 4.295 mmol) and potassium hydroxide (0.121 g, 2.148 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium bicarbonate (30 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water and dried to afford the desired compound 1188 (0.099 g, 98.8%) as a white solid.

(23) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.51 (d, 4H, J=7.5 Hz), 7.30 (t, 4H, J=7.6 Hz), 7.19 (t, 2H, J=7.3 Hz), 6.23 (t, 1H, J=5.3 Hz), 4.23 (s, 1H), 3.94 (brs, 2H), 3.03-2.98 (m, 2H), 2.60 (d, 2H, J=10.9 Hz), 1.96-1.90 (m, 4H), 1.46-1.45 (m, 2H), 1.38-1.36 (m, 2H), 1.26-1.22 (m, 10H).

EXAMPLE 4

Synthesis of Compound 1189

Step 1: Synthesis of tert-butyl (R)-4-benzhydryl-2-methylpiperazine-1-carboxylate (Formula 4-5)

(24) ##STR00052##

(25) (R)-tert-butyl 2-methylpiperazine-1-carboxylate (1.000 g, 4.993 mmol), (chloromethylene)dibenzene (2.024 g, 9.986 mmol) and potassium carbonate (3.450 g, 24.965 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the solution was stirred at 80° C. for 17 hours and then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and water was added to the concentrate, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 10%) and concentrated to afford the desired compound of formula 4-5 (0.813 g, 44.4%) as a white solid.

Step 2: Synthesis of (R)-1-benzhydryl-3-methylpiperazine (Formula 4-6)

(26) ##STR00053##

(27) The compound of formula 4-5 (0.813 g, 2.218 mmol) prepared in step 1 was dissolved in methylene chloride (10 mL) at room temperature and hydrochloric acid (4.00 M dioxane solution, 5.546 mL, 22.183 mmol) was added to the solution, followed by stirring at the same temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The desired compound of formula 4-6 (0.590 g, 99.8%) was obtained as a white solid without additional purification.

Step 3: Synthesis of methyl (R)-7-(4-benzhydryl-2-methylpiperazine-1-carboxamido)heptanoate (Formula 4-7)

(28) ##STR00054##

(29) Triphosgene (0.167 g, 0.563 mmol) and DIPEA (1.180 mL, 6.757 mmol) were dissolved in methylene chloride (5 mL) at 0° C., and methyl 7-aminoheptanoate hydrochloride (0.264 g, 1.351 mmol) was added to the solution, followed by stirring at the same temperature. The compound of formula 4-6 (0.300 g, 1.126 mmol) was added to the reaction mixture, followed by stirring at the same temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 30%) and concentrated. Then, the concentrate was purified again by chromatography (Waters, C.sub.18; 1%-formic acid (methanoic acid) aqueous solution/acetonitrile=from 75% to 5%) and concentrated by passage through an SPE cartridge (PL-HCO.sub.3 resin) to afford the desired compound of formula 4-7 (0.106 g, 20.8%).

Step 4: Synthesis of (R)-4-benzhydryl-N-(7-(hydroxyamino)-7-oxoheptyl)-2-methylpiperazine-1-carboxamide (Compound 1189)

(30) ##STR00055##

(31) The compound of formula 4-7 (0.100 g, 0.221 mmol) prepared in step 3, hydroxylamine (50.00% aqueous solution, 0.271 mL, 4.429 mmol) and potassium hydroxide (0.124 g, 2.214 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and an aqueous solution of sodium bicarbonate (30 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water and dried to afford the desired compound 1189 (0.099 g, 98.8%) as a white solid.

(32) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.42 (brs, 2H), 7.45 (t, 4H, J=6.3 Hz), 7.30 (t, 4H, J=7.6 Hz), 7.19 (t, 2H, J=6.8 Hz), 6.36-6.34 (m, 1H), 4.23 (s, 1H), 4.04 (brs, 1H), 3.62 (d, 1H, J=12.4 Hz), 3.01-2.93 (m, 3H), 2.67 (d, 1H, J=9.6 Hz), 2.60 (d, 1H, J=10.8 Hz), 1.95 (dd, 1H, J=11.0, 3.0 Hz), 1.88 (t, 2H, J=7.3 Hz), 1.78 (t, 1H, J=10.1 Hz), 1.44-1.43 (m, 2H), 1.36-1.35 (m, 2H), 1.20-1.18 (m, 7H).

EXAMPLE 5

Synthesis of Compound 1190

Step 1: Synthesis of tert-butyl (S)-4-benzhydryl-2-methylpiperazine-1-carboxylate (Formula 4-5)

(33) ##STR00056##

(34) (S)-tert-butyl 2-methylpiperazine-1-carboxylate (1.000 g, 4.993 mmol), (chloromethylene)dibenzene (2.024 g, 9.986 mmol) and potassium carbonate (3.450 g, 24.965 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the solution was stirred at 80° C. for 17 hours, and then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and water was added to the concentrate, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 10%) and concentrated to afford the desired compound of formula 4-5 (0.742 g, 40.5%) as a white solid.

Step 2: Synthesis of(S)-1-benzhydryl-3-methylpiperazine (Formula 4-6)

(35) ##STR00057##

(36) The compound of formula 4-5 (0.742 g, 2.025 mmol) prepared in step 1 was dissolved in methylene chloride (10 mL) at room temperature, and hydrochloric acid (4.00 M dioxane solution, 5.061 mL, 20.246 mmol) was added to the solution, followed by stirring at the same temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The product (0.530 g, 98.3%, white solid) was used without additional purification.

Step 3: Synthesis of methyl (S)-7-(4-benzhydryl-2-methylpiperazine-1-carboxamido)heptanoate (Formula 4-7)

(37) ##STR00058##

(38) Triphosgene (0.111 g, 0.375 mmol) and DIPEA (0.582 g, 4.505 mmol) were dissolved in methylene chloride (5 mL) at 0° C., and methyl 7-aminoheptanoate hydrochloride (0.176 g, 0.901 mmol) was added to the solution, followed by stirring at the same temperature. The compound of formula 4-6 (0.200 g, 0.751 mmol) prepared in step 2 was added to the reaction mixture, followed by stirring at the same temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 30%) and concentrated to afford the desired compound of 4-7 (0.213 g, 62.8%) as a light yellow oil.

Step 4: Synthesis of (S)-4-benzhydryl-N-(7-(hydroxyamino)-7-oxoheptyl)-2-methylpiperazine-1-carboxamide (Compound 1190)

(39) ##STR00059##

(40) The compound of formula 4-7 (0.100 g, 0.221 mmol) prepared in step 3, hydroxylamine (50.00% aqueous solution, 0.271 mL, 4.429 mmol) and potassium hydroxide (0.124 g, 2.214 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and an aqueous solution of sodium bicarbonate (30 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water and dried to afford the desired compound 1190 (0.093 g, 92.8%) as a light orange solid.

(41) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.43 (brs, 2H), 7.45 (t, 4H, J=6.3 Hz), 7.30 (t, 4H, J=7.6 Hz), 6.35 (t, 1H, J=5.5 Hz), 4.23 (s, 1H), 4.04 (brs, 1H), 3.62 (d, 1H, J=12.6 Hz), 3.03-2.92 (m, 3H), 2.67 (d, 1H, J=10.6 Hz), 2.60 (d, 1H, J=11.2 Hz), 1.95 (dd, 1H, J=11.1, 3.1 Hz), 1.88 (t, 2H, J=7.4 Hz), 1.80-1.75 (m, 1H), 1.45-1.43 (m, 2H), 1.36-1.34 (m, 2H), 1.20-1.18 (m, 7H).

EXAMPLE 6

Synthesis of Compound 1209

Step 1: Synthesis of ethyl 1-benzhydrylpiperidine-4-carboxylate (Formula 5-2)

(42) ##STR00060##

(43) Ethyl piperidine-4-carboxylate (3.000 g, 19.083 mmol), (chloromethylene)dibenzene (5.802 g, 28.624 mmol) and potassium carbonate (13.187 g, 95.414 mmol) were dissolved in N,N-dimethylformamide (50 mL), and the solution was stirred at room temperature for 17 hours, and then stirred at 80° C. for 3 hours. Then, the solution was cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and water was added to the concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 40 g cartridge; ethyl acetate/hexane=from 0% to 15%) and concentrated to afford the desired compound of formula 5-2 (1.410 g, 22.8%) as a colorless oil.

Step 2: Synthesis of 1-benzhydrylpiperidine-4-carboxylic acid (Formula 5-3)

(44) ##STR00061##

(45) The compound of formula 5-2 (1.410 g, 4.360 mmol) prepared in step 1 and LiOH (0.209 g, 8.719 mmol) were dissolved in methanol (10 mL)/water (5 mL) at room temperature, and the solution was stirred at 60° C. for 17 hours, and then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and then neutralized with an aqueous solution of 1 N hydrochloric acid and concentrated under reduced pressure to remove the solvent. The product (1.300 g, 101.0%, white solid) was used without additional purification.

Step 3: Synthesis of methyl 7-(1-benzhydrylpiperidine-4-carboxamido)heptanoate (Formula 5-4)

(46) ##STR00062##

(47) The compound of formula 5-3 (1.500 g, 5.078 mmol) prepared in step 2, methyl 7-aminoheptanoate hydrochloride (1.988 g, 10.156 mmol), EDC (1.947 g, 10.156 mmol), HBOt (1.372 g, 10.156 mmol) and diisopropylamine (4.435 mL, 25.391 mmol) were dissolved in methylene chloride (30 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 40 g cartridge; ethyl acetate/hexane=from 0% to 40%) and concentrated to afford the desired compound of formula 5-4 (1.810 g, 81.6%) as a colorless oil.

Step 4: Synthesis of 1-benzhydryl-N-(7-(hydroxyamino)-7-oxoheptyl)piperidine-4-carboxamide (Compound 1209)

(48) ##STR00063##

(49) The compound of formula 5-4 (1.000 g, 2.290 mmol) prepared in step 3, hydroxylamine (50.00% aqueous solution, 2.802 mL, 45.809 mmol) and potassium hydroxide (1.285 g, 22.904 mmol) were dissolved in methanol (15 mL) at 0° C., and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium bicarbonate was added to the concentrate, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure.

(50) The desired compound 1209 (1.000 g, 99.8%) was obtained as a light orange solid without additional purification.

(51) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.71 (t, 1H, J=5.4 Hz), 7.40 (d, 4H, J=7.3 Hz), 7.27 (t, 4H, J=7.5 Hz), 7.16 (t, 2H, J=7.3 Hz), 4.25 (s, 1H), 2.98 (q, 2H, J=6.4 Hz), 2.79 (d, 2H, J=11.0 Hz), 2.09˜2.02 (m, 1H), 1.89 (t, 2H, J=7.3 Hz), 1.77 (t, 2H, J=9.8 Hz), 1.66˜1.59 (m, 4H), 1.45˜1.39 (m, 2H), 1.34˜1.32 (m, 2H), 1.29˜1.27 (m, 4H); MS (ESI) m/z 438.2 (M.sup.++H).

EXAMPLE 7

Synthesis of Compound 1210

Step 1: Synthesis of 1-((1H-imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (Formula 8-3)

(52) ##STR00064##

(53) 1,1′-sulfonylbis(1H-imidazole) (5.000 g, 25.227 mmol) and methyl trifluoromethanesulfonate (2.855 mL, 25.227 mmol) were dissolved in methylene chloride (100 mL) at room temperature, and the solution was stirred at the same temperature for 3 hours. The precipitated solid was filtered and dried to afford the desired compound of formula 8-3 (5.160 g, 45.3%) as a light yellow oil.

Step 2: Synthesis of (1-((1H-imidazol-1-yl)sulfonyl)piperidin-4-yl)diphenylmethanol (Formula 8-4)

(54) ##STR00065##

(55) Diphenyl(piperidin-4-yl)methanol (1.000 g, 3.740 mmol) and the compound of formula 8-3 (2.033 g, 5.610 mmol) prepared in step 1 were dissolved in acetonitrile (20 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography (Sift, 12 g cartridge; ethyl acetate/hexane=from 0% to 40%) and concentrated to afford the desired compound of formula 8-4 (0.487 g, 32.8%) as a white solid.

(56) Step 3: (1-((3-methyl-1H-3-ium-imidazol-1-yl)sulfonyl)piperidin-4-yl)diphenylmethanol trifluoromethanesulfonate (formula 8-5)

(57) ##STR00066##

(58) The compound of formula 8-4 (0.487 g, 1.225 mmol) prepared in step 2 and methyl trifluoromethanesulfonate (0.146 mL, 1.286 mmol) were dissolved in methylene chloride (10 mL) at 0° C., and the solution was stirred at room temperature for 2 hours. The precipitated solid was filtered, washed with methylene chloride and dried to afford the desired compound of formula 8-5 (0.670 g, 97.4%) as a white solid.

Step 4: Synthesis of methyl 7-((4-(hydroxydiphenylmethyl)piperidine)-1-sulfonamido)hepatanoate (Formula 8-6)

(59) ##STR00067##

(60) The compound of formula 8-5 (0.504 g, 0.897 mmol) prepared in step 3 and methyl 7-aminoheptanoate hydrochloride (0.228 g, 1.167 mmol) were dissolved in acetonitrile (3 mL) at 80° C., and the solution was stirred at the same temperature for 12 hours, and then cooled to room temperature to terminate the reaction. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Sift, 12 g cartridge; ethyl acetate/hexane=from 10% to 60%) and concentrated to afford the desired compound of formula 8-6 (0.147 g, 33.5%) as a white solid.

Step 5: Synthesis of N-hydroxy-7-((4-(hydroxydiphenylmethyl)piperidine)-1-sulfonamido)heptanamide (Compound 1210)

(61) ##STR00068##

(62) The compound of formula 8-6 (0.150 g, 0.307 mmol) prepared in step 4, potassium hydroxide (0.172 g, 3.070 mmol) and hydroxylamine (50.00% solution, 0.188 mL, 3.070 mmol) were dissolved in methanol (1 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The desired compound 1210 (0.067 g, 44.6%) was obtained as a white solid and used without additional purification.

(63) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.34 (s, 1H), 8.68 (s, 1H), 7.52 (d, 4H, J=7.4 Hz), 7.26 (t, 4H, J=7.6 Hz), 7.12 (m, 3H), 3.46 (m, 2H), 2.82 (m, 2H), 2.63 (m, 3H), 1.93 (t, 2H, J=7.3 Hz), 1.48-1.22 (m, 13H); MS (ESI) m/z 490.6 (M.sup.++H).

EXAMPLE 8

Synthesis of Compound 1213

Step 1: Synthesis of methyl 7-(4-benzhydryl-N-methylpiperizine-1-carboxamido)heptanoate (Formula 1-4)

(64) ##STR00069##

(65) Methyl 7-(4-benzhydrylpiperazine-1-carboxamido)heptanoate (0.100 g, 0.229 mmol) and sodium hydride (60.00%, 0.046 g, 1.143 mmol) were dissolved in N,N-dimethylformamide (3 mL) at 0° C., and iodomethane (0.071 mL, 1.143 mmol) was added to the solution, followed by stirring at the same temperature for 10 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Sift, 4 g cartridge; ethyl acetate/hexane=from 10% to 40%) and concentrated to afford the desired compound of formula 1-4 (0.097 g, 94.0%) as a colorless oil.

Step 2: Synthesis of 4-benzhydryl-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylpiperazine-1-carboxamide (Compound 1213)

(66) ##STR00070##

(67) The compound of formula 1-4 (0.097 g, 0.215 mmol) prepared in step 1, hydroxylamine (50.00% aqueous solution, 0.263 mL, 4.296 mmol) and potassium hydroxide (0.121 g, 2.148 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The desired compound 1213 (0.010 g, 10.3%) was obtained as a white solid without additional purification.

(68) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.44 (d, 4H, J=7.4 Hz), 7.27 (t, 4H, J=7.5 Hz), 7.17 (t, 2H, J=7.3 Hz), 4.26 (s, 1H), 3.24-3.22 (m, 4H), 3.17 (t, 2H, J=7.2 Hz), 2.81 (s, 3H), 2.41-2.38 (m, 4H), 2.07 (t, 2H, J=7.4 Hz), 1.62-1.52 (m, 4H), 1.33-1.24 (m, 4H); MS (ESI) m/z 453.4 (M.sup.++H).

EXAMPLE 9

Synthesis of Compound 1221

Step 1: Synthesis of N,N-diphenylpiperidine-4-amine hydrochloride (Formula 6-4)

(69) ##STR00071##

(70) Tert-butyl 4-(diphenylamino)piperidine-1-carboxylate (1.000 g, 2.837 mmol) was dissolved in methylene chloride (10 mL) at room temperature, and hydrochloric acid (4.00 M 1,4-dioxane solution, 3.546 mL, 14.185 mmol) was added to the solution, followed by stirring at the same temperature for 17 hours. The precipitated solid was filtered, washed with methylene chloride and dried to afford the desired compound of formula 6-4 (0.800 g, 97.6%) as a white solid.

Step 2: Synthesis of N,N-diphenylpiperidine-4-amine (Formula 6-5)

(71) ##STR00072##

(72) The compound of formula 6-4 (0.600 g, 2.077 mmol) prepared in step 1 was dissolved in water (5 mL) at room temperature, and a saturated aqueous solution of sodium bicarbonate (50 mL) was added to the solution, followed by stirring at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The product (0.496 g, 94.6%, colorless oil) was used without additional purification.

Step 3: Synthesis of methyl 7-(4-(diphenylamino)piperidine-1-carboxamido)heptanoate (Formula 6-6)

(73) ##STR00073##

(74) The compound of formula 6-5 (0.100 g, 0.396 mmol) prepared in step 2, methyl 7-aminoheptanoate hydrochloride (0.078 g, 0.396 mmol), triphosgene (0.059 g, 0.198 mmol) and DIPEA (0.415 mL, 2.378 mmol) were dissolved in methylene chloride (3 mL) at 0° C., and the solution was stirred at the same temperature for 1 hour. Then, a saturated aqueous solution of sodium bicarbonate (50 mL) was added to the reaction mixture at 0° C., followed by stirring for 10 minutes. After completion of the reaction, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Sift, 4 g cartridge; ethyl acetate/hexane=from 10% to 60%) and concentrated to afford the desired compound of formula 6-6 (0.096 g, 55.4%) as a light yellow oil.

Step 4: Synthesis of 4-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)piperidine-1-carboxamide (Compound 1221)

(75) ##STR00074##

(76) The compound of formula 6-6 (0.096 g, 0.219 mmol) prepared in step 3, hydroxylamine (50.00% aqueous solution, 0.268 mL, 4.388 mmol) and potassium hydroxide (0.123 g, 2.194 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium bicarbonate (20 mL) and methylene chloride (5 mL) were added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water and dried to afford the desired compound 1221 (0.076 g, 79.0%) as a white solid.

(77) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.27 (t, 4H, J=7.8 Hz), 6.97 (t, 2H, J=7.2 Hz), 6.79 (d, 4H, J=7.8 Hz), 6.35 (t, 1H, J=5.4 Hz), 4.10-4.04 (m, 1H), 3.97 (d, 2H, J=13.1 Hz), 2.90 (q, 2H, J=6.4 Hz), 2.78 (t, 2H, J=12.5 Hz), 1.90 (t, 2H, J=7.3 Hz), 1.84 (d, 2H, J=12.5 Hz), 1.46-1.39 (m, 2H), 1.31-1.27 (m, 2H), 1.17-1.10 (m, 4H), 1.08-1.01 (m, 2H).

EXAMPLE 10

Synthesis of Compound 1222

Step 1: Synthesis of di(pyridin-2-yl)methanol (Formula 3-2)

(78) ##STR00075##

(79) Di(pyridin-2-yl)methanone (2.000 g, 10.858 mmol) was dissolved in methanol (20 mL) at 0° C., and NaBH.sub.4 (0.452 g, 11.944 mmol) was added to the solution, followed by stirring at the same temperature for 1 hour. Then, a saturated aqueous solution of sodium bicarbonate (10 mL) was added to the reaction mixture at 0° C., followed by stirring for 10 minutes. After completion of the reaction, water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The desired compound of formula 3-2 (2.000 g, 98.9%) was obtained as a red oil and used without additional purification.

Step 2: Synthesis of di(pyridin-2-yl)methylmethanesulfonate (Formula 3-3)

(80) ##STR00076##

(81) The compound of formula 3-2 (1.000 g, 5.370 mmol) prepared in step 1, methanesulfonyl chloride (0.623 mL, 8.055 mmol) and triethylamine (2.246 mL, 16.111 mmol) were dissolved in methylene chloride (10 mL) at 0° C., and the solution was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 30%) and concentrated to afford the desired compound of formula 3-3 (0.670 g, 47.2%) as a pink solid.

Step 3: Synthesis of methyl 7-(4-(di(pyridin-2-yl)methyl)piperazine-1-carboxamido)heptanoate (Formula 3-4)

(82) ##STR00077##

(83) The compound of formula 3-3 (0.258 g, 0.975 mmol) prepared in step 2, the compound of formula 2-5 (0.200 g, 0.650 mmol) and potassium carbonate (0.449 g, 3.249 mmol) were dissolved in N,N-dimethylformamide (4 mL) at room temperature, and the solution was stirred at 80° C. for 17 hours and then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and water was added to the concentrate, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 4 g cartridge; methanol/methylene chloride=from 0% to 10%) and concentrated to afford the desired compound of formula 3-4 (0.255 g, 89.3%) as an orange oil.

Step 4: Synthesis of 4-(di(pyridin-2-yl)methyl)-N-(7-(hydroxyamino)-7-oxoheptyppiperazine-1-carboxamide (Compound 1222)

(84) ##STR00078##

(85) The compound of formula 3-4 (0.255 g, 0.580 mmol) prepared in step 3, hydroxylamine (50.00% aqueous solution, 0.710 mL, 11.603 mmol) and potassium hydroxide (0.326 g, 5.801 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified by column chromatography (Waters, C.sub.18; 1%-formic acid (methanoic acid) aqueous solution/acetonitrile aqueous solution=from 70% to 5%) and concentrated by passage through an SPE cartridge (PL-HCO.sub.3 resin), thereby obtaining the desired compound 1222 (0.051 g, 20.0%) as a white solid.

(86) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.46 (dt, 2H, J=4.8, 0.8 Hz), 7.77 (td, 2H, J=7.7, 1.7 Hz), 7.62 (d, 2H, J=7.8 Hz), 7.25-7.22 (m, 2H), 6.40 (t, 1H, J=5.2 Hz), 4.64 (s, 1H), 3.28-3.27 (m, 4H), 2.96 (q, 2H, J=6.6 Hz), 2.25 (t, 4H, J=4.7 Hz), 1.92 (t, 2H, J=7.3 Hz), 1.48-1.43 (m, 2H), 1.35-1.33 (m, 2H), 1.21-1.20 (m, 4H).

EXAMPLE 11

Synthesis of Compound 1223

Step 1: Synthesis of tert-butyl 4-((7-methoxy-7-oxoheptyl)carbamoyl)piperazine-1-carboxylate (Formula 2-2)

(87) ##STR00079##

(88) Triphosgene (4.780 g, 16.107 mmol) and diisopropylamine (16.879 mL, 96.644 mmol) were dissolved in methylene chloride (100 mL) at 0° C., and methyl 7-aminoheptanoate hydrochloride (6.304 g, 32.215 mmol) was added to the solution, followed by stirring at the same temperature. Tert-butyl piperazine-1-carboxylate (6.000 g, 32.215 mmol) was added to the reaction mixture, followed by stirring at the same time for 1 hour. Then, a saturated aqueous solution of sodium bicarbonate (100 mL) was added to the reaction mixture at 0° C., followed by stirring for 10 minutes. After completion of the reaction, water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 80 g cartridge; methanol/methylene chloride=from 0% to 5%) and concentrated to afford the desired compound of formula 2-2 (3.430 g, 28.7%) as a light yellow oil.

Step 2: Synthesis of methyl 7-(piperazine-1-carboxamido)heptanoate hydrochloride (Formula 2-5)

(89) ##STR00080##

(90) The compound of formula 2-2 (3.430 g, 9.233 mmol) prepared in step 1 was dissolved in methylene chloride (50 mL) at room temperature, and hydrochloric acid (4.00M dioxane solution, 11.542 mL, 46.167 mmol) was added to the solution, followed by stirring at the same temperature for 17 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and ethyl acetate (50 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with ethyl acetate and dried to afford the desired compound of formula 2-5 (2.300 g, 80.9%) as a white solid.

Step 3: Synthesis of 4,4′-(chloromethylene)bis(fluorobenzene) (Formula 2-4)

(91) ##STR00081##

(92) Bis(4-fluorophenyl)methanol (5.000 g, 22.706 mmol) was dissolved in methylene chloride (50 mL), and the solution was stirred at room temperature for 4 hours, and thionyl chloride (1.812 mL, 24.976 mmol) was added thereto. Then, the solution was stirred at 40° C. for 2 hours, and then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent. As the product, the desired compound of formula 2-4 (5.350 g, 98.7%) was obtained as an orange oil and used without additional purification.

Step 4: Synthesis of methyl 7-(4-(bis(4-fluorophenyl)methyl)piperazine-1-carboxamido)heptanoate (Formula 2-6)

(93) ##STR00082##

(94) The compound of formula 2-4 (0.233 g, 0.975 mmol) prepared in step 3, methyl 7-(piperazine-1-carboxamido)heptanoate hydrochloride (0.200 g, 0.650 mmol) and potassium carbonate (0.449 g, 3.249 mmol) were dissolved in N,N-dimethylformamide (4 mL) at room temperature, and the solution was stirred at 80° C. for 17 hours, and then cooled to room temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and water was added to the concentrate, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 4 g cartridge; methanol/methylene chloride=from 0% to 10%) and concentrated to afford the desired compound of formula 2-6 (0.101 g, 32.8%) as a light brown oil.

Step 5: Synthesis of 4-(bis(4-fluorophenyl)methyl)-N-(7-(hydroxyamino)-7-oxoheptyppiperazine-1-carboxamide (Compound 1223)

(95) ##STR00083##

(96) The compound of formula 2-6 (0.101 g, 0.213 mmol) prepared in step 4, hydroxylamine (50.00% aqueous solution, 0.261 mL, 4.266 mmol) and potassium hydroxide (0.120 g, 2.133 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified by column chromatography (Waters, C.sub.18; 1%-formic acid (methanoic acid) aqueous solution/acetonitrile=from 70% to 5%) and concentrated by passage through an SPE cartridge (PL-HCO.sub.3 resin) to afford the desired compound 1223 (0.002 g, 2.0%) as a white solid.

(97) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.48-7.44 (m, 4H), 7.04 (t, 4H, J=8.8 Hz), 6.44 (t, 1H, J=5.3 Hz), 4.31 (s, 1H), 3.39 (t, 4H, J=5.0 Hz), 3.16-3.12 (m, 2H), 2.36 (t, 4H, J=5.0 Hz), 2.09 (t, 2H, J=7.4 Hz), 1.64-1.61 (m, 2H), 1.51-1.48 (m, 2H), 1.35-1.33 (m, 4H); MS (ESI) m/z 475.3 (M.sup.++H).

EXAMPLE 12

Synthesis of Compound 1224

Step 1: Synthesis of 4,4′-(chloromethylene)bis(chlorobenzene) (Formula 2-4)

(98) ##STR00084##

(99) Bis(4-chlorophenyl)methanol (10.000 g, 39.507 mmol) was dissolved in methylene chloride (100 mL) at 0° C., and thionyl chloride (3.153 mL, 43.458 mmol) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The desired compound of formula 2-4 (10.700 g, 99.7%) was obtained as a white solid without additional purification.

Step 2: Synthesis of methyl 7-(4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxamido)heptanoate (Formula 2-6)

(100) ##STR00085##

(101) The compound of formula 2-4 (0.265 g, 0.975 mmol) prepared in step 1, the compound of formula 2-5 (0.200 g, 0.650 mmol) and potassium carbonate (0.449 g, 3.249 mmol) were dissolved in N,N-dimethylformamide (4 mL) at room temperature, and the solution was stirred at 80° C. for 17 hours, and then cooled to temperature to terminate the reaction. The reaction mixture was concentrated under reduced pressure to remove the solvent, and water was added to the concentrate, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 4 g cartridge; methanol/methylene chloride=from 0% to 10%) and concentrated to afford the desired compound of formula 2-6 (0.271 g, 82.4%) as a light yellow oil.

Step 3: Synthesis of 4-(bis(4-chlorophenyl)methyl)-N-(7-(hydroxyamino)-7-oxoheptyppiperazine-1-carboxamide (Compound 1224)

(102) ##STR00086##

(103) The compound of formula 2-6 (0.271 g, 0.535 mmol) prepared in step 2, hydroxylamine (50.00% aqueous solution, 0.655 mL, 10.702 mmol) and potassium hydroxide (0.300 g, 5.351 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified by column chromatography (Waters, C.sub.18; 1%-formic acid (methanoic acid) aqueous solution/acetonitrile=from 70% to 5%) and concentrated by passage through an SPE cartridge (PL-HCO.sub.3 resin) to afford the desired compound 1224 (0.035 g, 12.9%) as a white solid.

(104) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.34 (brs, 1H), 8.69 (brs, 1H), 7.43 (d, 4H, J=8.6 Hz), 7.37 (d, 4H, J=8.4 Hz), 6.41 (t, 1H, J=5.3 Hz), 4.40 (s, 1H), 3.28-3.27 (m, 4H), 2.96 (q, 2H, J=6.4 Hz), 2.22-2.21 (m, 4H), 1.92 (t, 2H, J=7.4 Hz), 1.48-1.44 (m, 2H), 1.37-1.35 (m, 2H), 1.24-1.21 (m, 4H); MS (ESI) m/z 507.4 (M.sup.++H).

EXAMPLE 13

Synthesis of Compound 1240

Step 1: Synthesis of methyl 8-(4-benzhydrylpiperazine-1-carboxyamido)octanoate (Formula 1-3)

(105) ##STR00087##

(106) Triphosgene (0.118 g, 0.396 mmol) and diisopropylamine (0.830 mL, 4.755 mmol) were dissolved in methylene chloride (5 mL) at 0° C., and methyl 8-aminoctanoate hydrochloride (0.166 g, 0.793 mmol) was added to the solution, followed by stirring for 1 hour. A starting material (0.200 g, 0.793 mmol) was added to the reaction mixture, followed by stirring at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=from 10% to 70%) and concentrated to afford the desired compound of formula 1-3 (0.158 g, 44.1%) as a light yellow solid.

Step 2: Synthesis of 4-benzhydryl-N-(8-(hydroxyamino)-8-oxoethyl)piperazine-1-carboxamide (Compound 1240)

(107) ##STR00088##

(108) The compound of formula 1-3 (0.158 g, 0.350 mmol) prepared in step 1, hydroxylamine (50.00% aqueous solution, 0.428 mL, 6.997 mmol) and potassium hydroxide (0.196 g, 3.499 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium bicarbonate (20 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water and dried to afford the desired compound 1240 (0.074 g, 46.7%) as a white solid.

(109) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.49 (brs, 2H), 7.43 (d, 4H, J=7.5 Hz), 7.30 (t, 4H, J=7.6 Hz), 7.19 (t, 2H, J=7.3 Hz), 6.42 (t, 1H, J=5.2 Hz), 4.29 (s, 1H), 3.28-3.27 (m, 4H), 2.97 (q, 2H, J=6.4 Hz), 2.23-2.22 (m, 4H), 1.90 (t, 2H, J=7.3 Hz), 1.47-1.44 (m, 2H), 1.37-1.34 (m, 2H), 1.22 (brs, 4H); MS (ESI) m/z 453.6 (M.sup.++H).

EXAMPLE 14

Synthesis of Compound 1241

Step 1: Synthesis of methyl 7-(4-(1-phenylethyl)piperazine-1-carboxamido)heptanoate (Formula 9-2)

(110) ##STR00089##

(111) The compound of formula 2-5 (0.150 g, 0.553 mmol) and acetophenone (0.100 g, 0.829 mmol) were dissolved in methylene chloride (3 mL), and the solution was stirred at room temperature for 10 minutes. Then, NaBH(OAc).sub.3 (0.234 g, 1.106 mmol) was added to the solution, followed by stirring at the same temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 4 g cartridge; methanol/methylene chloride=from 0% to 5%) and concentrated to afford the desired compound of formula 9-2 (0.038 g, 18.3%) as a colorless oil.

Step 2: Synthesis of N-(7-(hydroxyamino)-7-oxoheptyl)-4-(1-phenylethyl)piperazine-1-carboxamide (Compound 1241)

(112) ##STR00090##

(113) The compound of formula 9-2 (0.038 g, 0.101 mmol) prepared in step 1, hydroxylamine (50.00% aqueous solution, 0.124 mL, 2.024 mmol) and potassium hydroxide (0.057 g, 1.012 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium bicarbonate was added to the concentrate, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The desired compound 1241 (0.013 g, 34.1%) was obtained as a light orange solid without additional purification.

(114) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.32-7.30 (m, 4H), 7.26-7.23 (m, 1H), 3.71-3.34 (m, 5H), 3.11 (t, 2H, J=7.1 Hz), 2.50-2.45 (m, 2H), 2.37-2.32 (m, 2H), 2.05 (t, 2H, J=7.4 Hz), 1.61-1.56 (m, 2H), 1.49-1.44 (m, 2H), 1.37 (d, 3H, J=7.6 Hz), 1.33-1.29 (m, 4H); MS (ESI) m/z 477.2 (M.sup.++H).

EXAMPLE 15

Synthesis of Compound 1243

Step 1: Synthesis of ethyl 1-(1-phenylethyl)piperidine-4-carboxylate (Formula 10-2)

(115) ##STR00091##

(116) Acetophenone (1.050 g, 8.739 mmol) and ethyl piperidine-4-carboxylate (1.751 mL, 11.361 mmol) were dissolved in methylene chloride (10 mL) at room temperature, and STAB (2.408 g, 11.361 mmol) was added to the solution, followed by stirring at the same temperature for 12 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 50%) and concentrated to afford the desired compound of formula 10-2 (0.700 g, 30.6%) as a colorless oil.

Step 2: Synthesis of 1-(1-phenylethyl)piperidine-4-carboxylic acid (Formula 10-3)

(117) ##STR00092##

(118) The compound of formula 10-2 (0.700 g, 2.678 mmol) prepared in step 1 and LiOH (0.096 g, 4.017 mmol) were dissolved in methanol (3 mL)/water (1 mL) at 40° C., and the solution was stirred at the same temperature for 5 hours, and then cooled to room temperature. Then, 1 M HCl was added to the reaction mixture at 0° C., followed by stirring for 10 minutes. After completion of the reaction, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The product (0.500 g, 69.2%, white foam solid) was used without additional purification.

Step 3: Synthesis of methyl 7-(1-(1-phenylethyl)piperidine-4-carboxamido)heptanoate (Formula 10-4)

(119) ##STR00093##

(120) The compound of formula 10-3 (0.300 g, 1.286 mmol) prepared in step 2, methyl 7-aminoheptanoate hydrochloride (0.503 g, 2.572 mmol), EDC (0.493 g, 2.572 mmol), HOBt (0.347 g, 2.572 mmol) and diisopropylamine (1.123 mL, 6.429 mmol) were dissolved in methylene chloride (4 mL)/N,N-dimethylformamide (1 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 4 g cartridge; methanol/methylene chloride=from 0% to 10%) and concentrated to afford the desired compound of formula 10-4 (0.122 g, 25.3%) as a brown oil.

Step 4: Synthesis of N-(7-(hydroxyamino)-7-oxoheptyl)-1-(1-phenylethyl)piperidine-4-carboxamide (Compound 1243)

(121) ##STR00094##

(122) The compound of formula 10-4 (0.122 g, 0.326 mmol) prepared in step 3, hydroxylamine (50.00% aqueous solution, 0.398 mL, 6.515 mmol) and potassium hydroxide (0.183 g, 3.257 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium bicarbonate was added to the concentrate, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The desired compound 1243 (0.074 g, 60.5%) was obtained as an orange solid without additional purification.

(123) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.19 (brs, 1H), 8.71 (brs, 1H), 7.64 (t, 1H, J=5.6 Hz), 7.32-7.27 (m, 4H), 7.23-7.20 (m, 1H), 3.40-3.37 (m, 1H), 3.00-2.95 (m, 3H); MS (ESI) m/z 376.3 (M.sup.++H).

EXAMPLE 16

Synthesis of Compound 1256

Step 1: Synthesis of methyl 7-(1-benzhydryl-N-methylpiperidine-4-carboxamido)heptanoate (Formula 5-5)

(124) ##STR00095##

(125) Methyl 7-(1-benzhydrylpiperidine-4-carboxamido)heptanoate (0.200 g, 0.458 mmol) and sodium hydride (60.00%, 0.092 g, 2.290 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the solution was stirred at room temperature for 10 minutes. Then, iodomethane (0.143 mL, 2.290 mmol) was added to the stirred solution, followed by stirring at the same temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=from 10% to 70%) and concentrated to afford the desired compound of formula 5-5 (0.089 g, 43.1%) as a light yellow oil.

Step 2: Synthesis of 1-benzhydryl-N-(7-(hydroxyamino)-7-oxoheptyl)-N-methylpiperidine-4-carboxamide (Compound 1256)

(126) ##STR00096##

(127) The compound of formula 5-5 (0.089 g, 0.198 mmol) prepared in step 1, hydroxylamine (50.00% aqueous solution, 0.242 mL, 3.950 mmol) and potassium hydroxide (0.111 g, 1.975 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium bicarbonate was added to the concentrate, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The desired compound 1256 (0.089 g, 99.8%) was obtained as a white solid without additional purification.

(128) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.50 (brs, 2H), 7.40 (d, 4H, J=7.2 Hz), 7.29 (t, 4H, J=7.6 Hz), 7.18 (t, 2H, J=7.3 Hz), 4.30 (s, 1H), 3.23 (q, 2H, J=7.5 Hz), 2.94 (s, 2H), 2.81 (d, 2H, J=11.4 Hz), 2.76 (s, 1H), 1.91-1.83 (m, 4H), 1.69-1.53 (m, 4H), 1.46-1.37 (m, 4H), 1.24-1.19 (m, 4H); MS (ESI) m/z 452.6 (M.sup.++H).

EXAMPLE 17

Synthesis of Compound 1257

Step 1: Synthesis of methyl 6-(4-benzhydrylpiperazine-1-carboxamido)hexanoate (Formula 1-3)

(129) ##STR00097##

(130) Triphosgene (0.294 g, 0.991 mmol) and diisopropylamine (2.076 mL, 11.888 mmol) were dissolved in methylene chloride (10 mL) at 0° C., and methyl 6-aminohexanoate hydrochloride (0.360 g, 1.981 mmol) was added to the solution, followed by stirring at the same temperature. 1-Benzhydrylpiperazine (0.500 g, 1.981 mmol) was added to the reaction mixture, followed by stirring at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 40%) and concentrated to afford the desired compound of formula 1-3 (0.320 g, 38.1%) as a yellow oil.

Step 2: Synthesis of 4-benzhydryl-N-(6-(hydroxyamino)-6-oxohexyl)piperazine-1-carboxamide (Compound 1257)

(131) ##STR00098##

(132) The compound of formula 1-3 (0.200 g, 0.472 mmol) prepared in step 1, hydroxylamine (50.00% aqueous solution, 0.578 mL, 9.444 mmol) and potassium hydroxide (0.265 g, 4.722 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium bicarbonate was added to the concentrate, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The desired compound 1257 (0.049 g, 24.4%) was obtained as a light yellow solid without additional purification.

(133) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.43 (d, 4H, J=7.2 Hz), 7.30 (t, 4H, J=7.6 Hz), 7.19 (t, 2H, J=7.3 Hz), 6.42 (t, 1H, J=5.4 Hz), 4.29 (s, 1H), 3.27 (t, 4H, J=4.5 Hz), 2.96 (q, 2H, J=6.4 Hz), 2.23 (t, 4H, J=4.6 Hz), 1.90 (t, 2H, J=7.4 Hz), 1.47-1.44 (m, 2H), 1.38-1.34 (m, 2H), 1.20-1.16 (m, 2H); MS (ESI) m/z 425.5 (M.sup.++H).

EXAMPLE 18

Synthesis of Compound 1316

Step 1: Synthesis of methyl 6-(1-benzhydrylpiperidine-4-carboxamido)hexanoate (Formula 5-4)

(134) ##STR00099##

(135) The compound of formula 5-3 (0.300 g, 1.016 mmol), methyl 6-aminohexanoate hydrochloride (0.369 g, 2.031 mmol), EDC (0.389 g, 2.031 mmol), HOBt (0.274 g, 2.031 mmol) and diisopropylamine (0.887 mL, 5.078 mmol) were dissolved in methylene chloride (3 mL)/N,N-dimethylformamide (0.5 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 30%) and concentrated to afford the desired compound of formula 5-4 (0.161 g, 37.5%) as a light yellow oil.

Step 2: Synthesis of 1-benzhydryl-N-(6-(hydroxyamino)-6-oxohexyl)piperidine-4-carboxamide (Compound 1316)

(136) ##STR00100##

(137) The compound of formula 5-4 (0.161 g, 0.381 mmol) prepared in step 1, hydroxylamine (50.00% aqueous solution, 0.466 mL, 7.620 mmol) and potassium hydroxide (0.214 g, 3.810 mmol) were dissolved in methanol (3 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium bicarbonate was added to the concentrate, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The desired compound 1316 (0.056 g, 34.7%) was obtained as a white solid without additional purification.

(138) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.33 (brs, 1H), 8.66 (brs, 1H), 7.70 (t, 1H, J=5.6 Hz), 7.41 (d, 4H, J=7.4 Hz), 7.17 (t, 2H, J=7.4 Hz), 4.26 (s, 2H), 2.99˜2.28 (m, 2H), 2.80 (d, 2H, J=11.5 Hz), 2.09˜2.02 (m, 1H), 1.91 (t, 2H, J=7.5 Hz), 1.80˜1.75 (m, 2H), 1.68˜1.59 (m, 4H).

EXAMPLE 19

Synthesis of Compound 1317

Step 1: Synthesis of methyl 8-(1-benzhydrylpiperidine-4-carboxamido)octanoate (Formula 5-4)

(139) ##STR00101##

(140) The compound of formula 5-3 (0.300 g, 1.016 mmol), methyl 8-aminooctanoate hydrochloride (0.426 g, 2.031 mmol), EDC (0.389 g, 2.031 mmol), HOBt (0.274 g, 2.031 mmol) and diisopropylamine (0.887 mL, 5.078 mmol) were dissolved in methylene chloride (3 mL)/N,N-dimethylformamide (0.5 mL) at room temperature, and the solution was stirred at the same temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 30%) and concentrated to afford to the desired compound of formula 5-4 (0.220 g, 49.6%) as a colorless oil.

Step 2: Synthesis of 1-benzhydryl-N-(8-(hydroxyamino)-8-oxoethyl)piperidine-4-carboxamide (Compound 1317)

(141) ##STR00102##

(142) The compound of formula 5-4 (0.220 g, 0.488 mmol) prepared in step 1, hydroxylamine (50.00% aqueous solution, 0.597 mL, 9.764 mmol) and potassium hydroxide (0.274 g, 4.882 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium bicarbonate (20 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water and dried to afford the desired compound 1317 (0.189 g, 85.7%) as a white solid.

(143) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.46 (brs, 2H), 7.73 (t, 1H, J=5.3 Hz), 7.41 (d, 4H, J=8.0 Hz), 7.28 (t, 4H, J=7.5 Hz), 7.17 (t, 2H, J=7.3 Hz), 4.26 (s, 1H), 2.99 (q, 2H, J=6.4 Hz), 2.80 (d, 2H, J=11.1 Hz), 2.10-2.04 (m, 1H), 1.87 (t, 2H, J=7.3 Hz), 1.78 (t, 2H, J=10.0 Hz), 1.67-1.56 (m, 4H), 1.46-1.42 (m, 2H), 1.36-1.33 (m, 2H), 1.21 (brs, 6H).

EXAMPLE 20

Synthesis of Compound 1647

Step 1: Synthesis of 2,2′-(chloromethylene)bis(fluorobenzene) (Formula 2-4)

(144) ##STR00103##

(145) Bis(2-fluorophenyl)methanol (0.500 g, 2.270 mmol) and triethylamine (0.348 mL, 2.498 mmol) were dissolved in methylene chloride (5 mL) at room temperature, and methanesulfonyl chloride (0.193 mL, 2.498 mmol) was added to the solution, followed by stirring at the same temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 5%) and concentrated to afford the desired compound of formula 2-4 (0.290 g, 53.5%) as a colorless oil.

Step 2: Synthesis of methyl 7-(4-(bis(2-fluorophenyl)methyl)piperazine-1-carboxamido)heptanoate (Formula 2-6)

(146) ##STR00104##

(147) The compound of formula 2-4 (0.448 g, 1.877 mmol) prepared in step 1, methyl 7-(piperazin-1-yl)heptanoate hydrochloride (0.746 g, 2.816 mmol) and potassium carbonate (1.297 g, 9.386 mmol) were dissolved in N,N-dimethylformamide (8 mL) at 80° C., and the solution was stirred at the same temperature for 16 hours, and then cooled to room temperature to terminate the reaction. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 60%) and concentrated to afford the desired compound of formula 2-6 (0.170 g, 19.1%) as a bright yellow solid.

Step 3: Synthesis of 4-(bis(2-fluorophenyl)methyl)-N-(7-(hydroxyamino)-7-oxoheptyl)piperazine-1-carboxamide (Compound 1647)

(148) ##STR00105##

(149) The compound of formula 2-6 (0.200 g, 0.422 mmol) prepared in step 2 and hydroxylamine (50.00% aqueous solution, 0.258 mL, 4.223 mmol) were dissolved in methanol (5 mL) at 0° C., and the solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and methanol (10 mL) and a saturated aqueous solution of sodium bicarbonate (90 mL) were added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water and dried to afford the desired compound 1647 (0.200 g, 99.8%) as a white solid.

(150) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.59-7.55 (m, 2H), 7.31-7.26 (m, 2H), 7.23-7.19 (m, 2H), 7.16-7.11 (m, 2H), 6.42 (t, 1H, J=5.5 Hz), 4.96 (s, 1H), 3.29-3.28 (m, 4H), 2.99-2.94 (m, 2H), 2.28-2.26 (m, 4H), 1.93-1.89 (m, 2H), 1.47-1.43 (m, 2H), 1.37-1.33 (m, 2H), 1.19-1.20 (m, 4H); MS (ESI) m/z 475.4 (M.sup.++H).

EXAMPLE 21

Synthesis of Compound 1648

Step 1: Synthesis of 3,3′-(chloromethylene)bis(fluorobenzene) (Formula 2-4)

(151) ##STR00106##

(152) Bis(3-fluorophenyl)methanol (1.000 g, 4.541 mmol) and triethylamine (0.696 mL, 4.995 mmol) were dissolved in methylene chloride (10 mL), and methanesulfonyl chloride (0.387 mL, 4.995 mmol) was added to the solution, followed by stirring at the same temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 5%) and concentrated to afford the desired compound of formula 2-4 (0.670 g, 61.8%) as a colorless oil.

Step 2: Synthesis of 7-(4-(bis(3-fluorophenyl)methyl)piperazine-1-carboxamido)heptanoate (Formula 2-6)

(153) ##STR00107##

(154) The compound of formula 2-4 (0.670 g, 2.807 mmol) prepared in step 1, methyl 7-(piperazin-1-yl)heptanoate hydrochloride (1.115 g, 4.211 mmol) and potassium carbonate (1.940 g, 14.037 mmol) were dissolved in N,N-dimethylformamide (10 mL) at 80° C., and the solution was stirred at the same temperature for 16 hours, and then cooled to room temperature to terminate the reaction. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 24 g cartridge; ethyl acetate/hexane=from 0% to 50%) and concentrated to afford the desired compound of formula 2-6 (0.294 g, 22.1%) as a white solid.

Step 3: Synthesis of 4-(bis(3-fluorophenyl)methyl)-N-(7-(hydroxyamino)-7-oxoheptyppiperazine-1-carboxamide (Compound 1648)

(155) ##STR00108##

(156) The compound of formula 2-6 (0.100 g, 0.211 mmol) prepared in step 2 and hydroxylamine (50.00% aqueous solution, 0.129 mL, 2.112 mmol) were dissolved in methanol (3 mL) at 0° C., and the solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and methanol (10 mL) and a saturated aqueous solution of sodium bicarbonate (90 mL) were added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water and dried to afford the desired compound 1648 (0.097 g, 97.1%) as a white solid.

(157) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.34 (s, 1H), 8.72 (s, 1H), 7.38-7.33 (m, 2H), 7.28-7.25 (m, 4H), 7.06-7.01 (m, 2H), 6.40 (t, 1H, J=5.5 Hz), 4.41 (s, 1H), 3.29-3.27 (m, 4H), 2.99-2.94 (m, 2H), 2.24-2.22 (m, 4H), 1.93-1.90 (m, 2H), 1.47-1.44 (m, 2H), 1.37-1.33 (m, 2H), 1.21-1.20 (m, 4H); MS (ESI) m/z 475.4 (M.sup.++H).

EXAMPLE 22

Synthesis of Compound 1649

Step 1: Synthesis of methyl 7-(4-(hydroxydiphenylmethyl)piperidine-1-carboxamido)heptanoate (Formula 7-4)

(158) ##STR00109##

(159) Methyl 7-aminoheptanoate hydrochloride (0.366 g, 1.870 mmol) and triphosgene (0.277 g, 0.935 mmol) were dissolved in methylene chloride (10 mL) at 0° C., and N,N-diisopropylethylamine (0.977 mL, 5.610 mmol) was added to the solution, followed by stirring for 1 hour. Diphenyl(piperidin-4-yl)methanol (0.500 g, 1.870 mmol) was added to the reaction mixture, followed by stirring at the same temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 50%) and concentrated to afford the desired compound of formula 7-4 (0.609 g, 71.9%) as a colorless oil.

Step 2: Synthesis of methyl 7-(4-(fluorodiphenylmethyl)piperidine-1-carboxamido)heptanoate (Formula 7-5)

(160) ##STR00110##

(161) The compound of formula 7-4 (0.300 g, 0.663 mmol) prepared in step 1 was dissolved in methylene chloride (5 mL) at 0° C., and diethylaminosulfur trifluoride (DAST, 0.114 mL, 0.862 mmol) was added to the solution, followed by stirring at room temperature for 16 hours. Water was added to the reaction mixture, followed by extraction with methylene chloride. The extract was filtered through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Sift, 12 g cartridge; ethyl acetate/hexane=from 0% to 50%) and concentrated to afford the desired compound of formula 7-5 (0.143 g, 47.5%) as a white solid.

Step 3: Synthesis of 4-(fluorodiphenylmethyl)-N-(7-(hydroxyamino)-7-oxoheptyl)piperidine-1-carboxamide (Compound 1649)

(162) ##STR00111##

(163) The compound of formula 7-5 (0.140 g, 0.308 mmol) prepared in step 2 and hydroxylamine (50.00% aqueous solution, 0.188 mL, 3.080 mmol) was dissolved in methanol (3 mL) at 0° C., and the solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and methanol (10 mL) and a saturated aqueous solution of sodium bicarbonate (90 mL) were added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with water and dried to afford the desired compound 1649 (0.122 g, 87.0%) as a white solid.

(164) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.49-7.47 (m, 4H), 7.37-7.33 (m, 4H), 7.26-7.22 (m, 2H), 6.36 (t, 1H, J=5.5 Hz), 3.95-3.92 (m, 2H), 2.98-2.79 (m, 3H), 2.65-2.59 (m, 2H), 1.93-1.89 (m, 2H), 1.47-1.44 (m, 2H), 1.36-1.33 (m, 2H), 1.29-1.20 (m, 8H); MS (ESI) m/z 456.6 (M.sup.++H).

EXAMPLE 23

Synthesis of Compound 1719

Step 1: Synthesis of tert-butyl 4-(phenylamino)piperidine-1-carboxylate (Formula 6-2)

(165) ##STR00112##

(166) Tert-butyl 4-oxopiperidine-1-carboxylate (5.000 g, 25.094 mmol), aniline (2.749 mL, 30.113 mmol) and acetic acid (2.155 mL, 37.641 mmol) were dissolved in methylene chloride (50 mL) at room temperature, and sodium triacetoxyborohydride (5.850 g, 27.604 mmol) was added to the solution, followed by stirring at the same temperature for 16 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. Ethyl acetate (100 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with hexane and dried to afford the desired compound of formula 6-2 (4.640 g, 66.9%) as a white solid.

Step 2: Synthesis of tert-butyl 4-((3-fluorophenyl)(phenyl)amino)piperidine-1-carboxylate (Formula 6-3)

(167) ##STR00113##

(168) The compound of formula 6-2 (0.500 g, 1.809 mmol) prepared in step 1, 1-fluoro-3-iodobenzene (0.422 g, 1.900 mmol), palladium acetate (II, 0.016 g, 0.072 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.051 g, 0.081 mmol) and potassium tert-butoxide (0.254 g, 2.261 mmol) were dissolved in toluene (5 mL) at 110° C., and the solution was stirred at the same temperature for 16 hours, and then cooled to room temperature to terminate the reaction. The reaction mixture was filtered through a celite pad to remove solids, and a saturated aqueous solution of sodium chloride was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 10%) and concentrated to afford the desired compound of formula 6-3 (0.292 g, 43.6%) as a yellow solid.

Step 3: Synthesis of N-(3-fluorophenyl)-N-phenylpiperidine-4-amine hydrochloride (Formula 6-4)

(169) ##STR00114##

(170) The compound of formula 6-3 (0.285 g, 0.769 mmol) prepared in step 2 was dissolved in methylene chloride (10 mL) at the same temperature, and hydrogen chloride (4.00 M solution in dioxane, 0.962 mL, 3.846 mmol) was added to the solution, followed by stirring at the same temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The product (0.212 g, 89.8%, yellow solid) was used without additional purification.

Step 4: Synthesis of methyl 7-(4-((3-fluorophenyl)(phenyl)amino)piperidine-1-carboxamido)heptanoate (Formula 6-6)

(171) ##STR00115##

(172) Methyl 7-aminoheptanoate hydrochloride (0.135 g, 0.691 mmol) and triphosgene (0.103 g, 0.345 mmol) were dissolved in methylene chloride (10 mL) at 0° C., and N,N-diisopropylethylamine (0.361 mL, 2.073 mmol) was added to the solution, followed by stirring at the same temperature. To the reaction mixture, the compound of formula 6-4 (0.212 g, 0.691 mmol) prepared in step 3 was added, followed by stirring at room temperature for 3 hours. Then, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=from 0% to 50%) and concentrated to afford the desired compound of formula 6-6 (0.219 g, 69.6%) as a colorless oil.

Step 5: Synthesis of 4-((3-fluorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)piperidine-1-carboxamide (compound 1719)

(173) ##STR00116##

(174) The compound of formula 6-6 (0.219 g, 0.481 mmol) prepared in step 4, hydroxylamine (50.00% aqueous solution, 0.294 mL, 4.807 mmol) and potassium hydroxide (0.270 g, 4.807 mmol) were dissolved in methanol (5 mL) at 0° C., and the solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and methanol (1 mL) and a saturated aqueous solution of sodium bicarbonate (30 mL) were added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with hexane and dried to afford the desired compound 1719 (0.196 g, 89.3%) as a white solid.

(175) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.44-7.42 (m, 2H), 7.32-7.28 (m, 1H), 7.16-7.10 (m, 1H), 7.05-7.03 (m, 2H), 6.51-6.46 (m, 1H), 6.37-6.32 (m, 3H), 4.10-4.08 (m, 1H), 3.97-3.94 (m, 2H), 2.92-2.87 (m, 2H), 2.83-2.77 (m, 2H), 1.92-1.88 (m, 2H), 1.85-1.52 (m, 2H), 1.45-1.41 (m, 2H), 1.30-1.27 (m, 2H), 1.16-1.08 (m, 4H), 1.06-1.00 (m, 2H); MS (ESI) m/z 457.5 (M.sup.++H).

EXAMPLE 24

Synthesis of Compound 1726

Step 1: Synthesis of tert-butyl 4-(phenyl(4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate (Formula 6-3)

(176) ##STR00117##

(177) Tert-butyl 4-(phenylamino)piperidine-1-carboxylate (1.000 g, 3.618 mmol), 1-iodo-4-(trifluoromethyl)benzene (1.033 g, 3.799 mmol), palladium acetate (II, 0.032 g, 0.145 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.101 g, 0.163 mmol) and potassium tert-butoxide (0.507 g, 4.523 mmol) were dissolved in toluene (5 mL) at 110° C., and the solution was stirred at the same temperature for 16 hours, and then cooled to room temperature to terminate the reaction. The reaction mixture was filtered through a celite pad to remove solids, and water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 10%) and concentrated to afford the desired compound of formula 6-3 (0.040 g, 2.9%) as a brown oil.

Step 2: Synthesis of N-phenyl-N-(4-(trifluoromethyl)phenyl)piperidine-4-amine hydrochloride (Formula 6-4)

(178) ##STR00118##

(179) The compound of formula 6-3 (0.890 g, 2.494 mmol) prepared in step 1 was dissolved in methylene chloride (20 mL) at room temperature, and hydrochloric acid (4.00 M solution, 3.118 mL, 12.471 mmol) was added to the solution, followed by stirring at the same temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The product (0.890 g, 100.0%, yellow solid) was used without additional purification.

Step 3: Synthesis of methyl 7-(4-(phenyl(4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxamido)heptanoate (Formula 6-6)

(180) ##STR00119##

(181) Methyl 7-aminoheptanoate hydrochloride (0.219 g, 1.121 mmol) and triphosgene (0.166 g, 0.561 mmol) were dissolved in methylene chloride (10 mL) at 0° C., and N,N-diisopropylethylamine (0.586 mL, 3.363 mmol) was added to the solution, followed by stirring at the same temperature. To the reaction mixture, the compound of formula 6-4 (0.400 g, 1.121 mmol) was added, followed by stirring at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 50%) and concentrated to afford the desired compound of formula 6-6 (0.277 g, 48.9%) as a colorless oil.

Step 4: Synthesis of N-(7-(hydroxyamino)-7-oxoheptyl)-4-(phenyl(4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxamie (Compound 1726)

(182) ##STR00120##

(183) The compound of formula 6-6 (0.170 g, 0.336 mmol) prepared in step 3 and hydroxylamine (50.00% aqueous solution, 0.205 mL, 3.356 mmol) were dissolved in methanol (5 mL) at room temperature, and potassium hydroxide (0.188 g, 3.356 mmol) was added to the solution, followed by stirring at the same temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the precipitated solid was filtered, washed with hexane and dried to afford the desired compound 1726 (0.139 g, 81.8%) as a white solid.

(184) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.21-7.16 (m, 4H), 6.97-6.93 (m, 2H), 6.84-6.80 (m, 1H), 6.67-6.65 (m, 2H), 6.36-6.34 (m, 1H), 4.07-4.02 (m, 1H), 3.98-3.95 (m, 2H), 2.93-2.88 (m, 2H), 2.81-2.75 (m, 2H), 1.93-1.89 (m, 2H), 1.85-1.82 (m, 2H), 1.45-1.43 (m, 2H), 1.31-1.27 (m, 2H), 1.18-1.15 (m, 4H), 1.05-1.01 (m, 2H); MS (ESI) m/z 457.5 (M.sup.++H).

EXAMPLE 25

Synthesis of Compound 1734

Step 1: Synthesis of tert-butyl 4-((4-fluorophenyl)(phenyl)amino)piperidine-1-carboxylate (Formula 6-3)

(185) ##STR00121##

(186) Tert-butyl 4-(phenylamino)piperidine-1-carboxylate (0.820 g, 2.967 mmol), 1-fluoro-4-iodobenzene (0.358 mL, 3.115 mmol), palladium acetate (II, 0.027 g, 0.119 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthayl (0.083 g, 0.134 mmol) and potassium tert-butoxide (0.416 g, 3.709 mmol) were dissolved in toluene (5 mL) at 110° C., and the solution was stirred at the same temperature for 16 hours, and then cooled to room temperature to terminate the reaction. The reaction mixture was filtered through a celite pad to remove solids, and water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 12 g cartridge; ethyl acetate/hexane=from 0% to 10%) and concentrated to afford the desired compound of formula 6-3 (0.352 g, 32.0%) as a bright yellow solid.

Step 2: Synthesis of N-(4-fluorophenyl)-N-phenylpiperidine-4-amine hydrochloride (Formula 6-4)

(187) ##STR00122##

(188) The compound of formula 6-3 (0.340 g, 0.918 mmol) prepared in step 1 and hydrochloric acid (4.00 M solution, 1.147 mL, 4.589 mmol) were dissolved in methylene chloride (5 mL) at room temperature, and the solution was stirred at the same temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The product (0.281 g, 99.8%, yellow solid) was used without additional purification.

Step 3: Synthesis of methyl 7-(4-((4-fluorophenyl)(phenyl)amino)piperidine-1-carboxamido)heptanoate (Formula 6-6)

(189) ##STR00123##

(190) Methyl 7-aminoheptanoate hydrochloride (0.179 g, 0.913 mmol) and triphosgene (0.135 g, 0.456 mmol) were dissolved in methylene chloride (10 mL) at 0° C., and N,N-diisopropylethylamine (0.477 mL, 2.738 mmol) was added to the solution, followed by stirring at the same temperature. To the reaction mixture, the compound of formula 6-4 (0.280 g, 0.913 mmol) prepared in step 2 was added, followed by stirring at room temperature for 3 hours. Then, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 4 g cartridge; ethyl acetate/hexane=from 0% to 50%) and concentrated to afford the desired compound of formula 6-6 (0.185 g, 44.5%) as a colorless oil.

Step 4: Synthesis of 4-((4-fluorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)piperidine-1-carboxamide (Compound 1734)

(191) ##STR00124##

(192) The compound of formula 6-6 (0.260 g, 0.569 mmol) prepared in step 3 and hydroxylamine (50.00% aqueous solution, 0.348 mL, 5.695 mmol) were dissolved in methanol (5 mL) at 0° C., and the solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the precipitated solid was filtered, washed with hexane and dried to afford the desired compound 1734 (0.185 g, 71.2%) as a white solid.

(193) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.21-7.16 (m, 4H), 6.97-6.93 (m, 2H), 6.84-6.80 (m, 1H), 6.67-6.65 (m, 2H), 6.36-6.34 (m, 1H), 4.07-4.02 (m, 1H), 3.98-3.95 (m, 2H), 2.93-2.88 (m, 2H), 2.81-2.75 (m, 2H), 1.93-1.89 (m, 2H), 1.85-1.82 (m, 2H), 1.45-1.43 (m, 2H), 1.31-1.27 (m, 2H), 1.18-1.15 (m, 4H), 1.05-1.01 (m, 2H); MS (ESI) m/z 457.5 (M.sup.++H).

EXAMPLE 26

Synthesis of Compound 1763

Step 1: Synthesis of tert-butyl 7-benzhydryl-2,7-diazaspiro[3.5]nonane-2-carboxylate (Formula 4-5)

(194) ##STR00125##

(195) (Chloromethylene)dibenzene (0.439 mL, 2.467 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (0.614 g, 2.714 mmol) and potassium carbonate (1.705 g, 12.335 mmol) were dissolved in N,N-dimethylformamide (10 mL) at 80° C., and the solution was stirred at the same temperature for 16 hours, and then cooled to room temperature to terminate the reaction. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. Then, ethyl acetate (100 mL) was added to the concentrate, followed by stirring, and the precipitated solid was filtered, washed with ethyl acetate and dried to afford the desired compound of formula 4-5 (0.411 g, 42.4%) as a white solid.

Step 2: Synthesis of 7-benzhydryl-2,7-diazaspiro[3.5]nonane hydrochloride (Formula 4-6)

(196) ##STR00126##

(197) The compound of formula 4-5 (0.411 g, 1.047 mmol) prepared in step 1 was dissolved in methylene chloride (8 mL) at room temperature, and hydrochloric acid (4.00 M solution in dioxane, 1.309 mL, 5.235 mmol) was added to the solution, followed by stirring at the same temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the product (0.344 g, 99.9%, white solid) was used without additional purification.

Step 3: Synthesis of methyl 6-(7-benzhydryl-2,7-diazaspiro[3.5]nonane-2-carboxamido)hexanoate (Formula 4-7)

(198) ##STR00127##

(199) Methyl 6-aminohexanoate hydrochloride (0.100 g, 0.549 mmol) and triphosgene (0.078 g, 0.261 mmol) were dissolved in methylene chloride (5 mL) at 0° C., and N,N-diisopropylethylamine (0.273 mL, 1.569 mmol) was added to the solution, followed by stirring at the same temperature. To the reaction mixture, the compound of formula 4-6 (0.172 g, 0.523 mmol) prepared in step 2 was added, followed by stirring at room temperature for 3 hours. Then, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 4 g cartridge; methanol/methylene chloride=from 0% to 3%) and concentrated to afford the desired compound of formula 4-7 (0.148 g, 61.0%) as a bright red solid.

Step 4: Synthesis of 7-benzhydryl-N-(6-(hydroxyamino)-6-oxohexyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide (Compound 1763)

(200) ##STR00128##

(201) The compound of formula 4-7 (0.148 g, 0.319 mmol) prepared in step 3 and hydroxylamine (50.00% aqueous solution, 0.195 mL, 3.192 mmol) was dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and methanol (1 mL) and a saturated aqueous solution of sodium bicarbonate (30 mL) were added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with hexane and dried, and the resulting material was recrystallized from ethyl acetate (10 mL) at 25° C. and filtered. The obtained solid was washed with hexane and dried to afford the desired compound 1763 (0.044 g, 29.7%) as a white solid.

(202) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.40-7.38 (m, 4H), 7.29-7.25 (m, 4H), 7.18-7.14 (m, 2H), 6.18-6.17 (m, 1H), 4.26 (s, 1H), 3.42-3.33 (m, 4H), 2.91-2.90 (m, 2H), 2.20-2.19 (m, 4H), 1.85-1.82 (m, 2H), 1.65-1.64 (m, 4H), 1.43-1.40 (m, 2H), 1.33-1.30 (m, 2H), 1.19-1.15 (m, 2H); MS (ESI) m/z 465.3 (M.sup.++H).

EXAMPLE 27

Synthesis of Compound 1764

Step 1: Synthesis of methyl 7-(7-benzhydryl-2,7-diazaspiro[3.5]nonane-2-carboxamido)heptanoate (Formula 4-7)

(203) ##STR00129##

(204) Methyl 7-aminoheptanoate hydrochloride (0.107 g, 0.549 mmol) and triphosgene (0.078 g, 0.261 mmol) were dissolved in methylene chloride (5 mL) at 0° C., and N,N-diisopropylethylamine (0.273 mL, 1.569 mmol) was added to the solution, followed by stirring at the same temperature. To the reaction mixture, the compound of formula 4-6 (0.172 g, 0.523 mmol) prepared in step 2 of Example 26 was added, followed by stirring at room temperature for 3 hours. Then, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO.sub.2, 4 g cartridge; methanol/methylene chloride=from 0% to 3%) and concentrated to afford the desired compound of formula 4-7 (0.136 g, 54.4%) as a bright red solid.

Step 2: Synthesis of 7-benzhydryl-N-(7-(hydroxyamino)-7-oxoheptyl)-2,7-diazaspiro[3.5]nonane-2-carboxamide (Compound 1764)

(205) ##STR00130##

(206) The compound of formula 4-7 (0.136 g, 0.285 mmol) prepared in step 1 and hydroxylamine (50.00%, 0.188 g, 2.847 mmol) were dissolved in methanol (5 mL) at room temperature, and the solution was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and methanol (1 mL) and a saturated aqueous solution of sodium bicarbonate (30 mL) were added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with hexane and dried, and the resulting material was recrystallized from ethyl acetate (10 mL) at 25° C. and filtered. The obtained solid was washed with hexane and dried to afford the desired compound 1764 (0.021 g, 15.4%) as a white solid.

(207) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.40-7.38 (m, 4H), 7.29-7.25 (m, 4H), 7.18-7.14 (m, 2H), 6.16 (t, 1H, J=5.5 Hz), 4.26 (s, 1H), 3.42-3.41 (m, 4H), 2.92-2.88 (m, 2H), 2.19-2.18 (m, 4H), 1.88-1.84 (m, 2H), 1.65-1.64 (m, 4H), 1.43-1.42 (m, 2H), 1.32-1.31 (m, 2H), 1.19-1.18 (m, 4H); MS (ESI) m/z 479.6 (M.sup.++H).

Measurement of Activities of Compounds According to the Present Invention and Analytical Protocol

EXPERIMENTAL EXAMPLE 1

Confirmation (In Vitro) on Inhibition of HDAC Enzyme Activities

(208) Because selective HDAC6 inhibitors are important for the selectivity of inhibition of HDAC1 that causes side effects, HDAC1/6 enzyme selectivities and cell selectivities (HDAC1: histone acetylation; HDAC6: tubulin acetylation) were analyzed.

(209) 1. Experimental Method

(210) Using a HDAC1 fluorimetric drug discovery assay kit (Enzolifesciences: BML-AK511) and a HDAC6 human recombinant (Calbiochem: 382180), the HDAC enzyme inhibitory abilities of test compounds were measured. It was treated with 100, 1000 and 10000 nM concentrations for HDAC1 assay, and 0.1, 1, 10, 100 and 1000 nM concentrations for HDAC6 assay. It was allowed to react at 37° C. for 60 minutes, and then was treated with a developer and allowed to react at 37° C. for 30 minutes, after which the fluorescence intensity (Ex 390 nm; Em 460 nm) was measured using FlexStatin3 (Molecular Device).

(211) 2. Experimental Results

(212) The results of the experiment are shown in Table 4 below.

(213) TABLE-US-00004 TABLE 4 Abilities to inhibit the activities of HDAC enzymes (HDAC 1 and 6) Compound HDAC6 (μM) HDAC1 (μM) ACY-1215 0.010 0.48 1102 0.004 3.84 1124 0.024 4.09 1188 0.014 1.68 1189 0.025 0.84 1190 0.065 1.34 1209 0.006 1.16 1210 0.07 1.19 1213 0.044 0.704 1221 0.079 1.88 1222 0.085 0.71 1223 0.073 1.16 1224 0.087 3.96 1240 0.07 0.41 1241 0.025 0.72 1243 0.017 0.54 1256 0.038 0.08 1257 0.063 0.159 1316 0.456 0.236 1317 0.336 0.023 1647 0.019 0.466 1648 0.029 0.729 1649 0.033 0.463 1719 0.116 1.729 1726 0.228 3.699 1734 0.094 0.886 1763 0.201 0.023 1764 0.04 0.236

(214) As shown in Table 4 above, the control compound ACY-1215 showed 48-fold selectivity (0.01 μM for HDAC6, and 0.48 μM for HDAC1), compound 1102 showed 960-fold selectivity (0.004 μM for HDAC6, and 3.84 μM for HDAC1), compound 1124 showed 170-fold selectivity (0.024 μM for HDAC6, and 4.09 μM for HDAC1), and compound 1209 showed 193-fold selectivity (0.006 μM for HDAC6, and 1.16 μM for HDAC1), suggesting that the novel derivatives of the present invention show excellent selectivity for HDAC1/6 enzymes.

EXPERIMENTAL EXAMPLE 2

Effect of Compound 1102 in Adjuvant-Induced Arthritis Models

(215) 1. Experimental Method

(216) 100 μM of complete Freund's adjuvant (Chondrex) was injected intradermally into the tail of each Lewis rat to induce animal models. From one day before induction, the rats were divided into groups based on body weight, and the test compound was administered orally to the rats at various doses once a day, followed by evaluation.

(217) Clinical score and body weight were measured twice a week from the day of first administration of the test compound. The clinical score was recorded as 0-4 points, and the total clinical score was evaluated after observing the foot of each rat (0: normal; and 16: the most severe edema).

(218) 2. Experimental Results

(219) The results of the experiment are shown in FIG. 1. The medicinal effect of the test compound in the arthritis models was evaluated based on the degree of joint edema, and a higher clinical score indicates a more severe degree of edema.

(220) As shown in FIG. 1, the group not treated with the compound (vehicle) showed a score of 9-11 (severe edema), whereas the group administered with 1 mg/kg of compound 1102 showed a score of 6-8, the group administered with 10 mg/kg of compound 1102 showed a score of 4-6, and the group administered with 50 mg/kg of compound 1102 showed a score of 1-3, indicating that compound 1102 of the present invention alleviates arthritis symptoms.

INDUSTRIAL APPLICABILITY

(221) The compounds represented by formula I according to the present invention, optical isomers thereof or pharmaceutically acceptable salts thereof can selectively inhibit HDAC, and thus can be effectively used for the prevention or treatment of histone deacetylase-mediated diseases.