Carbazole derivatives acting on 5-HT7 receptor

Carbazole (2 g, 11.96 mmol) was dissolved in toluene (100 ml) in the reactor, which was covered with a foil to prevent light from entering. To the solution was added 6-bromohexanoyl chloride (5.1 g, 23.92 mmol). The mixture was heated to reflux at 115° C. for 18 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure and diluted with CH 2 C 12 . The diluted solution was washed with 1 N HCl and H 2 O, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure. The resulting concentrate was purified by silica gel column chromatography (hexane:EtOAc=20:1), giving 3.4 g (9.88 mmol, 83% yield) of the title compound.

1 H NMR (400 MHz, CDCl 3 ) δ 7.77 (dd, J=7.7 Hz, J=1.2 Hz, 1H), 7.64 (td, J=7.7 Hz, J=1.2 Hz, 1H), 7.58-7.42 (m, 7H)

The title compound was prepared in the same manner as in Example 1.1, except that 5-bromopentanoyl chloride was used instead of 6-bromohexanoyl chloride.

The title compound was prepared in the same manner as in Example 1.1, except that 4-bromobutanoyl chloride was used instead of 6-bromohexanoyl chloride.

Carbazole (2 g, 11.96 mmol), 1,6-dibromohexane (2.8 ml, 17.94 mmol), and t-BuOK (1.3 g, 11.96 mmol) were dissolved in THF (15 ml) in a reactor. The solution was stirred under heating at 40° C. for 10 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure and diluted with CH 2 C 12 . The diluted solution was washed with H 2 O, dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:MC=8:1), giving 2.1 g (6.36 mmol, 53% yield) of the title compound.

1 H NMR (400 MHz, CDCl 3 ) δ 8.03-8.01 (m, 2H), 7.39-7.35 (m, 2H), 7.25 (d, J=8.2 Hz, 2H), 7.15 (td, J=7.4 Hz, J=0.8 Hz, 2H), 4.07 (t, J=7.1 Hz, 2H), 3.17 (t, J=6.7 Hz, 2H), 1.72-1.57 (m, 4H), 1.30-1.14 (m, 4H)

The title compound was prepared in the same manner as in Example 1.4, except that 1,5-dibromopentane was used instead of 1,6-dibromohexane.

The title compound was prepared in the same manner as in Example 1.4, except that 1,4-dibromobutane was used instead of 1,6-dibromohexane.

The title compound was prepared in the same manner as in Example 1.4, except that 1,3-dibromopropane was used instead of 1,6-dibromohexane.

The compound of Example 1.1 (100 mg, 0.29 mmol) and N-methylbutylamine (0.02 ml, 0.35 mmol) were dissolved in acetonitrile (10 ml) in a reactor. The solution was heated to reflux at 85° C. for 21 h. After completion of the reaction, the reaction mixture was diluted with CH 2 C 12 , and 0.5 N HCl and H 2 O were then added thereto. The aqueous layer was extracted with CH 2 C 12 . The obtained organic layer was dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (MC:MeOH=20:1). The crude product was added dropwise to a solution of 0.5 N hydrochloric acid (0.30 ml, 0.34 mmol) in dimethyl ether to obtain a solid precipitate. Filtration of the precipitate gave 64.4 mg (0.17 mmol, 57% yield) of the title compound.

1 H NMR (400 MHz, CDCl 3 ) δ 11.57 (brs, 0.8H), 8.21 (d, J=8.4 Hz, 2H), 7.99 (dd, J=5.7 Hz, J=0.9 Hz, 2H), 7.48 (td, J=7.8 Hz, J=1.2 Hz, 2H), 7.38 (t, J=7.2 Hz, 2H), 3.19 (t, J=6.7 Hz, 2H), 3.11-2.90 (m, 4H), 2.76 (d, J=4.6 Hz, 3H), 2.04-1.77 (m, 6H), 1.63-1.58 (m, 2H), 1.45-1.36 (m, 2H), 0.97 (t, J=7.3 Hz, 3H)

70.0 mg (0.17 mmol, 57% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and N-benzylmethylamine (0.04 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 12.08 (brs, 0.8H), 8.22 (d, J=8.4 Hz, 2H), 8.00 (dd, J=5.7 Hz, J=0.9 Hz, 2H), 7.61-7.59 (m, 2H), 7.51-7.38 (m, 7H), 4.18 (brd, J=12.6 Hz, 2H), 3.18 (t, J=6.7 Hz, 2H), 3.12 (brs, 1H), 2.89 (brs, 1H), 2.69 (s, 3H), 2.12 (brs, 1H), 1.97 (quint, J=7.1 Hz, 3H), 1.58 (brs, 2H)

98.0 mg (0.26 mmol, 91% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and pyrrolidine (0.03 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (300 MHz, CDCl 3 ) δ 11.85 (brs, 0.8H), 8.22 (d, J=8.2 Hz, 2H), 8.00 (d, J=7.2 Hz, 2H), 7.49 (t, J=7.4 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 3.82 (brs, 2H), 3.19 (t, J=6.3 Hz, 2H), 3.09 (brs, 2H), 2.79 (brs, 2H), 2.26 (brs, 2H), 2.06-1.99 (m, 6H), 1.64 (s, 2H)

The compound of Example 1.1 (100 mg, 0.29 mmol) and 4-methylpiperidine (0.04 ml, 0.35 mmol) were dissolved in acetonitrile (10 ml) in a reactor. The solution was heated to reflux at 85° C. for 21 h. After completion of the reaction, the reaction mixture was diluted with CH 2 C 12 , and 0.5 N HCl and H 2 O were then added thereto. The aqueous layer was extracted with CH 2 C 12 . The obtained organic layer was dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane:EtOAc=4:1), giving 51 mg (0.14 mmol, 48% yield) of the final title compound.

1 H NMR (300 MHz, CDCl 3 ) δ 8.22 (d, J=8.3 Hz, 2H), 8.02-7.99 (m, 2H), 7.51-7.45 (m, 2H), 7.38 (td, J=7.5 Hz, J=0.9 Hz, 2H), 3.16 (t, J=7.4 Hz, 2H), 2.91 (brd, J=11.7 Hz, 2H), 2.36 (t, J=7.6 Hz, 2H), 2.04-1.83 (m, 4H), 1.67-1.47 (m, 6H), 1.38-1.19 (m, 3H), 0.92 (d, J=6.0 Hz, 3H)

63.6 mg (0.16 mmol, 55% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and 3-methylpiperidine (0.04 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 11.22 (brs, 0.8H), 8.23 (d, J=8.4 Hz, 2H), 8.01 (dd, J=5.7 Hz, J=0.9 Hz, 2H), 7.52-7.47 (m, 2H), 7.39 (t, J=7.3 Hz, 2H), 3.57 (brd, J=10.2 Hz, 1H), 3.49-3.43 (m, 1H), 3.20 (t, J=6.7 Hz, 2H), 2.98-2.97 (m, 2H), 2.54-2.37 (m, 3H), 2.21 (q, J=10.9 Hz, 1H), 2.08-1.85 (m, 7H), 1.59 (s, 1H), 1.14-1.04 (m, 1H), 0.96 (d, J=6.6 Hz, 3H)

82.5 mg (0.20 mmol, 69% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and 3,5-dimethylpiperidine (0.05 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 11.64 (brs, 0.8H) 8.22 (d, J=8.3 Hz, 2H), 8.00 (d, J=7.6 Hz, 2H), 7.49 (t, J=7.4 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 3.40 (brd, J=9.2 Hz, 2H), 3.19 (t, J=6.2 Hz, 2H), 2.96 (brs, 2H), 2.52 (brs, 2H), 2.16-1.90 (m, 7H), 1.58 (brs, 3H), 0.95 (d, J=6.3 Hz, 6H);

95.7 mg (0.24 mmol, 83% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and hexamethyleneimine (0.04 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (300 MHz, CDCl 3 ) δ 11.53 (brs, 0.8H), 8.22 (d, J=8.3 Hz, 2H), 8.00 (d, J=7.6 Hz, 2H), 7.49 (t, J=7.8 Hz, 2H), 7.39 (t, J=7.4 Hz, 2H), 3.56-3.54 (m, 2H), 3.19 (t, J=6.7 Hz, 2H), 3.03-2.88 (m, 4H), 2.22-2.15 (m, 2H), 2.04-1.94 (m, 4H), 1.87-1.81 (m, 4H), 1.61 (s, 4H)

31.6 mg (0.08 mmol, 28% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and morpholine (0.03 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 12.75 (brs, 0.8H), 8.22 (brd, J=6.7 Hz, 2H), 8.00 (d, J=7.6 Hz, 2H), 7.49 (brs, 2H), 7.39 (t, J=7.2 Hz, 2H), 4.36 (brs, 2H), 3.99 (brs, 2H), 3.49-3.45 (m, 2H), 3.20 (brs, 2H), 3.04 (brs, 2H), 2.88 (brs, 2H), 2.05 (brd, J=30.7 Hz, 4H), 1.60 (s, 2H)

45.6 mg (0.10 mmol, 34% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and 4-phenylpiperidine (56 mg, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 11.95 (brs, 0.8H), 8.23 (d, J=8.4 Hz, 2H), 8.01 (dd, J=5.7 Hz, J=0.8 Hz, 2H), 7.52-7.48 (m, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.34-7.23 (m, 5H), 3.70 (brd, J=10.2 Hz, 2H), 3.21 (t, J=6.7 Hz, 2H), 3.04 (brs, 2H), 2.80-2.65 (m, 4H), 2.11 (brs, 3H), 2.02 (brd, J=11.0 Hz, 3H), 1.63-1.58 (m, 3H)

88.4 mg (0.19 mmol, 64% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and 4-benzylpiperidine (0.06 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 11.51 (brs, 0.8H), 8.22 (brs, 2H), 7.99 (brd, J=6.6 Hz, 2H), 7.49 (brs, 2H), 7.38 (brs, 2H), 7.29 (brs, 2H), 7.22 (brs, 1H), 7.14 (brs, 2H), 3.66 (brs, 2H), 3.19 (brs, 2H), 3.03 (brs, 2H), 2.64 (s, 4H), 2.10 (brd, J=59.6 Hz, 6H), 1.85 (brs, 3H), 1.71 (s, 2H)

55.4 mg (0.13 mmol, 45% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and acetylpiperazine (45 mg, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, MeOD) δ 8.24 (brs, 2H), 8.05 (brs, 2H), 7.47 (brs, 2H), 7.38 (brd, J=3.3 Hz, 2H), 4.64 (brd, J=12.9 Hz, 1H), 4.12 (brs, 1H), 3.59 (brs, 4H), 3.24-2.99 (m, 4H), 2.15 (s, 3H), 1.92 (brd, J=32.3 Hz, 5H), 1.59 (brs, 3H)

83.8 mg (0.21 mmol, 72% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and methylpiperazine (0.03 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, MeOD) δ 8.26 (d, J=8.4 Hz, 2H), 8.07 (d, J=7.6 Hz, 2H), 7.51-7.47 (m, 2H), 7.39 (t, J=7.4 Hz, 2H), 3.48-3.24 (m, 10H), 2.99 (brs, 2H), 2.78 (s, 3H), 1.96 (quint, J=7.3 Hz, 2H), 1.79 (brs, 2H), 1.58 (quint, J=7.5 Hz, 2H)

135.0 mg (0.28 mmol, 98% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and benzylpiperazine (0.06 ml, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, DMSO) δ 11.48 (brs, 0.8H), 8.27 (d, J=8.4 Hz, 2H), 8.19 (dd, J=5.7 Hz, J=0.7 Hz, 2H), 7.60 (brs, 2H), 7.54-7.49 (m, 2H), 7.45-7.40 (m, 5H), 4.32 (brs, 2H), 3.66 (brs, 2H), 3.42 (s, 4H), 3.27 (t, J=7.0 Hz, 4H), 3.11 (brs, 2H), 1.83-1.77 (m, 4H), 1.49-1.47 (m, 2H)

Example 2.14: 6-(4-Benzo[d]isoxazol-3-yl)piperazin-1-yl)-1-(9H-carbazol-9-yl)hexan-1-one hydrochloride

6.3 mg (0.01 mmol, 4% yield) of the title compound was prepared using the compound of Example 1.1 (100 mg, 0.29 mmol) and 3-(1-piperazinyl)-1,2-benzisoxazole (71 mg, 0.35 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 13.21 (brs, 0.8H), 8.20 (brd, J=6.4 Hz, 2H), 7.99 (d, J=7.5 Hz, 2H), 7.61 (brs, 2H), 7.55-7.48 (m, 4H), 7.38 (t, J=7.1 Hz, 2H), 4.15 (brs, 4H), 3.56 (brs, 2H), 3.19 (brs, 2H), 3.05 (brs, 5H), 2.08-1.99 (m, 5H)

195 mg (0.44 mmol, 76% yield) of the title compound was prepared using 1-(2-hydroxyphenyl)piperazine (124 mg, 0.70 mmol), the compound of Example 1.1 (200 mg, 0.58 mmol), and K 2 CO 3 (80 mg, 0.58 mmol) in accordance with the procedure of Example 2.4.

1 H NMR (300 MHz, CDCl 3 ) δ 8.24 (d, J=9.0 Hz, 2H), 8.02 (dd, J=7.6, 0.7 Hz, 2H), 7.49 (td, J=7.8, 1.4 Hz, 2H), 7.40 (td, J=7.4, 0.8 Hz, 2H), 7.17 (dd, J=7.8, 1.2 Hz, 1H), 7.10-7.05 (m, 1H), 6.95 (dd, J=8.1, 1.5 Hz, 1H), 6.88-6.83 (m, 1H), 3.19 (t, J=7.4 Hz, 2H), 2.91 (brt, J=4.5 Hz, 4H), 2.63 (brs, 4H), 2.47 (t, J=7.2 Hz, 2H), 2.05-1.94 (m, 2H), 1.66-1.53 (m, 4H)

21 mg (0.046 mmol, 77% yield) of the title compound was prepared using 1-(2-methoxyphenyl)piperazine (13.4 mg, 0.07 mmol), the compound of Example 1.1 (20 mg, 0.06 mmol), and K 2 CO 3 (8 mg, 0.06 mmol) in accordance with the procedure of Example 2.4.

1 H NMR (300 MHz, CDCl 3 ) δ 8.22 (d, J=8.4 Hz, 2H), 7.99 (dt, J=7.6, 0.7 Hz, 2H), 7.50-7.45 (m, 2H), 7.38 (td, J=7.4, 1.0 Hz, 2H), 7.02-6.92 (m, 4H), 3.86 (s, 3H), 3.17-3.12 (m, 6H), 2.66 (brs, 4H), 2.46 (t, J=7.5 Hz, 2H), 2.02-1.92 (m, 2H), 1.68-1.51 (m, 4H)

82.0 mg (0.22 mmol, 73% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and N-methylbutylamine (0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 11.41 (brs, 0.8H), 8.19 (d, J=8.3 Hz, 2H), 7.99 (d, J=7.5 Hz, 2H), 7.47 (t, J=7.5 Hz, 2H), 7.38 (t, J=7.5 Hz, 2H), 3.25 (t, J=6.0 Hz, 2H), 3.17-3.06 (m, 5H), 2.77 (s, 3H), 2.12 (brs, 2H), 2.02-2.00 (m, 2H), 1.90 (brs, 1H), 1.80 (brs, 1H), 1.40 (brd, J=6.7 Hz, 2H), 0.97 (t, J=7.3 Hz, 3H)

90.7 mg (0.22 mmol, 74% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and N-benzylmethylamine (0.05 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 12.72 (brs, 0.8H), 8.20 (d, J=8.2 Hz, 2H), 8.01 (dd, J=5.7 Hz, J=0.8 Hz, 2H), 7.62 (brd, J=3.4 Hz, 2H), 7.51-7.38 (m, 7H), 4.20 (q, J=14.0 Hz, 2H), 3.23-3.17 (m, 3H), 2.93 (brs, 1H), 2.72 (s, 3H), 2.18 (brd, J=33.3 Hz, 2H), 1.98 (brs, 2H)

38.7 mg (0.11 mmol, 36% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and pyrrolidine (0.03 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 11.66 (brs, 0.8H), 8.20 (d, J=8.3 Hz, 2H), 8.00 (d, J=7.2 Hz, 2H), 7.51-7.46 (m, 2H), 7.39 (t, J=7.3 Hz, 2H), 3.86-3.84 (m, 2H), 3.25 (t, J=6.7 Hz, 2H), 3.19-3.13 (m, 2H), 2.86-2.78 (m, 2H), 2.28-1.97 (m, 8H)

44.2 mg (0.11 mmol, 38% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and 4-methylpiperidine (0.04 ml, 0.30 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 11.89 (brs, 0.8H), 8.20 (d, J=8.4 Hz, 2H), 7.99 (dd, J=5.7 Hz, J=0.9 Hz, 2H), 7.48 (td, J=7.8 Hz, J=1.2 Hz, 2H), 7.41-7.37 (m, 2H), 3.59 (brd, J=11.4 Hz, 2H), 3.25 (t, J=6.7 Hz, 2H), 3.02 (quint, J=5.3 Hz, 2H), 2.63 (q, J=10.8 Hz, 2H), 2.18-2.13 (m, 2H), 2.09-1.94 (m, 5H), 1.81 (brd, J=14.0 Hz, 2H), 1.07-1.03 (m, 3H)

59.5 mg (0.15 mmol, 51% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and 3-methylpiperidine (0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 11.26 (brs, 0.8H) 8.20 (d, J=8.4 Hz, 2H), 7.98 (d, J=7.1 Hz, 2H), 7.50-7.45 (m, 2H), 7.38 (t, J=7.3 Hz, 2H), 3.58 (brd, J=10.4 Hz, 1H), 3.48-3.44 (m, 1H), 3.24 (t, J=6.7 Hz, 2H), 3.05 (brt, J=7.6 Hz, 2H), 2.58-2.14 (m, 6H), 2.00-1.85 (m, 5H), 0.95 (m, J=6.2 Hz, 3H)

60.6 mg (0.15 mmol, 50% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and 3,5-dimethylpiperidine (0.05 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 12.16 (brs, 0.8H), 8.19 (d, J=8.3 Hz, 2H), 7.99 (d, J=7.3 Hz, 2H), 7.49-7.45 (m, 2H), 7.38 (t, J=7.3 Hz, 2H), 3.41 (brd, J=11.0 Hz, 2H), 3.24 (t, J=6.7 Hz, 2H), 3.01 (brt, J=7.9 Hz, 2H), 2.47 (brs, 2H), 2.16-2.09 (m, 4H), 1.97 (quint, J=7.2 Hz, 2H), 1.89 (brd, J=13.2 Hz, 2H), 0.94 (d, J=6.6 Hz, 6H)

37.0 mg (0.10 mmol, 32% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and hexamethyleneimine (0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 11.39 (brs, 0.8H), 8.19 (d, J=8.3 Hz, 2H), 7.98 (dd, J=5.7 Hz, J=0.9 Hz, 2H), 7.47 (t, J=7.3 Hz, 2H), 7.38 (t, J=7.4 Hz, 2H), 3.58 (brs, 2H), 3.24 (t, J=6.0 Hz, 2H), 3.09 (brs, 2H), 2.95 (brs, 2H), 2.18 (s, 4H), 1.98-1.97 (m, 2H), 1.86-1.83 (m, 4H), 1.63 (s, 2H)

80.7 mg (0.22 mmol, 71% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and morpholine (0.03 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 12.94 (brs, 0.8H), 8.18 (d, J=8.2 Hz, 2H), 7.98 (d, J=7.3 Hz, 2H), 7.47 (t, J=7.5 Hz, 2H), 7.38 (t, J=7.4 Hz, 2H), 4.32 (t, J=12.0 Hz, 2H). 3.97 (d, J=11.6 Hz, 2H), 3.48-3.43 (m, 2H), 3.25 (s, 2H), 3.07 (s, 2H), 2.88 (s, 2H), 2.17 (s, 2H), 2.00 (s, 2H)

109.2 mg (0.24 mmol, 81% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and 4-phenylpiperidine (73 mg, 0.45 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 11.67 (brs, 0.8H), 8.21 (d, J=8.4 Hz, 2H), 7.99 (dd, J=5.8 Hz, J=0.8 Hz, 2H), 7.50-7.46 (m, 2H), 7.38 (td, J=7.5 Hz, J=0.7 Hz, 2H), 7.34-7.19 (m, 5H), 3.73 (brd, =10.4 Hz, 2H), 3.27 (t, J=6.7 Hz, 2H), 3.12-3.07 (m, 2H), 2.86-2.64 (m, 5H), 2.27-2.19 (m, 2H), 2.04-1.97 (m, 4H)

113.5 mg (0.25 mmol, 81% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and 4-benzylpiperidine (0.06 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 12.15 (brs, 0.8H), 8.18 (d, J=8.1 Hz, 2H), 7.98 (d, J=7.6 Hz, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.4 Hz, 2H), 7.29-7.17 (m, 3H), 7.11 (d, J=7.2 Hz, 2H), 3.57 (brd, J=9.8 Hz, 2H), 3.23 (s, 2H), 2.99 (s, 2H), 2.66-2.55 (m, 4H), 2.15-2.05 (m, 4H), 1.96 (s, 2H), 1.80 (d, J=13.5 Hz, 2H), 1.70 (brs, 1H)

117.4 mg (0.28 mmol, 94% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and acetylpiperazine (47 mg, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, DMSO) δ 9.52 (brs, 0.8H), 8.29 (d, J=8.4 Hz, 2H), 8.21 (dd, J=5.8 Hz, J=0.8 Hz, 2H), 7.55-7.51 (m, 2H), 7.45-7.41 (m, 2H), 4.42 (brd, J=9.2 Hz, 1H), 4.01 (brd, J=14.4 Hz, 1H), 3.50 (brd, J=8.0 Hz, 2H), 3.41-3.32 (m, 2H), 3.20 (s, 2H), 3.04 (brd, J=10.0 Hz, 2H), 2.91 (brd, J=8.4 Hz, 2H), 2.03 (s, 3H), 1.83 (s, 4H)

91.0 mg (0.24 mmol, 78% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and methylpiperazine (0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, DMSO) δ 11.61 (brs, 0.8H), 8.29 (d, J=8.4 Hz, 2H), 8.20 (dd, J=5.8 Hz, J=0.8 Hz, 2H), 7.55-7.50 (m, 2H), 7.44-7.40 (m, 2H), 3.32 (s, 9H), 3.16 (s, 3H), 2.72 (brs, 3H), 1.83 (s, 4H)

28.3 mg (0.06 mmol, 20% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and benzylpiperazine (0.06 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, MeOD) δ 8.30 (d, J=8.4 Hz, 2H), 8.09 (d, J=7.6 Hz, 2H), 7.56 (brd, J=3.1 Hz, 2H), 7.52-7.48 (m, 5H), 7.43-7.39 (m, 2H), 4.34 (s, 2H), 3.82-3.21 (m, 12H), 2.00 (t, J=3.1 Hz, 4H)

65.8 mg (0.14 mmol, 23% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and 1-(2-hydroxyphenyl)piperazine (162 mg, 0.91 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 10.22 (brs, 0.8H), 8.31 (d, J=8.4 Hz, 2H), 8.20 (dd, J=5.7 Hz, J=0.8 Hz, 2H), 7.53 (td, J=7.8 Hz, J=1.2 Hz, 2H), 7.43 (t, J=7.2 Hz, 2H), 6.90-6.81 (m, 3H), 6.75 (td, J=7.4 Hz, J=1.6 Hz, 1H), 3.47 (brd, J=12.8 Hz, 3H), 3.39-3.33 (m, 4H), 3.22-3.15 (m, 4H), 3.00 (t, J=11.5 Hz, 2H), 1.89-1.85 (m, 4H)

43.1 mg (0.09 mmol, 30% yield) of the title compound was prepared using the compound of Example 1.2 (100 mg, 0.30 mmol) and 1-(2-methoxyphenyl)piperazine (0.06 ml, 0.36 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (300 MHz, DMSO) δ 10.62 (brs, 0.8H), 8.32 (d, J=8.3 Hz, 2H), 8.22 (d, J=7.5 Hz, 2H), 7.56-7.51 (m, 2H), 7.43 (t, J=7.4 Hz, 2H), 7.05-6.87 (m, 4H), 3.79 (s, 3H), 3.53 (q, J=10.4 Hz, 4H), 3.35 (t, J=6.3 Hz, 2H), 3.23-3.02 (m, 6H), 1.91-1.85 (m, 4H)

27.7 mg (0.06 mmol, 17% yield) of the title compound was prepared using the compound of Example 1.3 (100 mg, 0.37 mmol) and benzylpiperazine (0.08 ml, 0.44 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 11.47 (brs, 0.8H), 8.33 (d, J=8.4 Hz, 2H), 8.20 (d, J=7.0 Hz, 2H), 7.59 (s, 3H), 7.54-7.49 (m, 2H), 7.44-7.41 (m, 4H), 4.30 (brs, 4H), 3.73-3.08 (m, 6H), 2.42 (t, J=7.3 Hz, 2H), 2.21-2.20 (m, 2H), 1.95-1.89 (m, 2H)

148.1 mg (0.36 mmol, 49% yield) of the title compound was prepared using the compound of Example 1.3 (200 mg, 0.74 mmol) and 1-(2-hydroxyphenyl)piperazine (197 mg, 1.10 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (d, J=8.4 Hz, 2H), 8.03-8.01 (m, 2H), 7.52-7.47 (m, 2H), 7.40 (td, J=7.5 Hz, J=0.8 Hz, 2H), 7.08-7.03 (m, 2H), 6.93 (dd, J=6.0 Hz, J=1.2 Hz, 1H), 6.85-6.81 (m, 1H), 3.25 (t, J=7.0 Hz, 2H), 2.81 (t, J=4.7 Hz, 4H), 2.61 (t, J=7.0 Hz, 6H), 2.17 (quint, J=7.0 Hz, 2H)

78 mg (0.18 mmol, 50% yield) of the title compound was prepared using the compound of Example 1.3 (100 mg, 0.37 mmol) and 1-(2-hydroxyphenyl)piperazine (197 mg, 1.10 mmol) in accordance with the procedure of Example 2.1.

1 H NMR (400 MHz, CDCl 3 ) δ 8.25 (d, J=8.4 Hz, 2H), 7.98 (d, J=7.6 Hz, 2H), 7.48-7.44 (m, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.00-6.94 (m, 1H), 6.92-6.87 (m, 2H), 6.84 (d, J=7.9 Hz, 1H), 3.21 (t, J=7.1 Hz, 2H), 3.06 (s, 4H), 2.69 (s, 4H), 2.60 (t, J=7.0 Hz, 2H), 2.16 (quint, J=7.1 Hz, 2H)

The compound of Example 1.4 (100 mg, 0.30 mmol) and N-methylbutylamine (0.04 ml, 0.36 mmol) were dissolved in acetonitrile (10 ml) in a reactor. The solution was heated to reflux at 40° C. until the next day. After completion of the reaction, the reaction mixture was diluted with CH 2 C 12 , and H 2 O were then added thereto. The aqueous layer was extracted with CH 2 C 12 . The obtained organic layer was dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (MC:MeOH=20:1), giving 68 mg (0.20 mmol, 67% yield) of the final title compound.

1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J=7.7 Hz, 2H), 7.45-7.40 (m, 2H), 7.36 (d, J=8.2 Hz, 2H), 7.22-7.18 (m, 2H), 4.25 (t, J=6.9 Hz, 2H), 2.82-2.71 (m, 4H), 2.54 (s, 3H), 1.83 (quint, J=7.2 Hz, 2H), 1.71-1.61 (m, 4H), 1.35-1.20 (m, 6H), 0.90 (t, J=7.4 Hz, 3H)

111.0 mg (0.30 mmol, 99% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and N-benzylmethylamine (0.05 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J=7.6 Hz, 2H), 7.44-7.39 (m, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.29-7.24 (m, 4H), 7.23-7.17 (m, 3H), 4.21 (t, J=7.2 Hz, 2H), 3.40 (s, 2H), 2.26 (t, J=7.3 Hz, 2H), 2.11 (s, 3H), 1.80 (quint, J=7.2 Hz, 2H), 1.42 (quint, J=7.1 Hz, 2H), 1.36-1.24 (m, 4H)

61.4 mg (0.19 mmol, 63% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and pyrrolidine (0.03 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J=7.7 Hz, 2H), 7.47-7.43 (m, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.23-7.19 (m, 2H), 4.28 (t, J=6.8 Hz, 2H), 3.07 (brs, 3H), 2.78-2.74 (m, 2H), 2.04-2.02 (m, 4H), 1.84 (quint, J=7.2 Hz, 2H), 1.75-1.67 (m, 2H), 1.36-1.22 (m, 5H)

103 mg (0.30 mmol, 98% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and 4-methylpiperidine (0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J=7.7 Hz, 2H), 7.45-7.41 (m, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.22-7.18 (m, 2H), 4.26 (t, J=7.2 Hz, 2H), 2.83 (brd, J=11.6 Hz, 2H), 2.22 (t, J=7.7 Hz, 2H), 1.88-1.80 (m, 4H), 1.58 (brd, J=12.6 Hz, 2H), 1.48-1.17 (m, 9H), 0.89 (d, J=6.1 Hz, 3H)

98.0 mg (0.28 mmol, 93% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and 3-methylpiperidine (0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J=7.7 Hz, 2H), 7.46-7.42 (m, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.23-7.18 (m, 2H), 4.25 (t, J=7.1 Hz, 2H), 2.89-2.82 (m, 2H), 2.28 (t, J=7.9 Hz, 2H), 1.86-1.58 (m, 8H), 1.55-1.45 (m, 2H), 1.40-1.24 (m, 5H), 0.83 (d, J=6.5 Hz, 3H)

91.3 mg (0.25 mmol, 83% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and 3,5-dimethylpiperidine (0.05 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (d, J=7.7 Hz, 2H), 7.45-7.41 (m, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.20 (td, J=7.4 Hz, J=0.9 Hz, 2H), 4.23 (t, J=7.1 Hz, 2H), 2.80 (brdt, J=10.5 Hz, J=1.7 Hz, 2H), 2.25-2.21 (m, 2H), 1.88-1.65 (m, 5H), 1.50-1.22 (m, 9H), 0.92 (d, J=6.8 Hz, 1H), 0.81 (d, J=6.5 Hz, 5H)

57.5 mg (0.16 mmol, 54% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and hexamethyleneimine (0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J=7.7 Hz, 2H), 7.45-7.41 (m, 2H), 7.36 (d, J=8.2 Hz, 2H), 7.22-7.18 (m, 2H), 4.25 (t, J=6.9 Hz, 2H), 3.03 (brs, 3H), 2.75-2.71 (m, 2H), 1.86-1.63 (m, 12H), 1.35-1.18 (m, 5H)

97.0 mg (0.29 mmol, 95% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and morpholine (0.03 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J=7.8 Hz, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.19 (t, J=7.4 Hz, 2H), 4.23 (t, J=7.1 Hz, 2H), 3.66 (t, J=4.5 Hz, 4H), 2.33 (s, 4H), 2.21 (t, J=7.5 Hz, 2H), 1.82 (quint, J=7.2 Hz, 2H), 1.43-1.27 (m, 6H)

92.9 mg (0.21 mmol, 69% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and 4-phenylpiperidine (59 mg, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.06-8.04 (m, 2H), 7.44-7.39 (m, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.27-7.16 (m, 7H), 4.22 (t, J=7.0 Hz, 2H), 3.15 (brd, J=11.6 Hz, 2H), 2.54-2.44 (m, 3H), 2.25 (brt, J=11.3 Hz, 2H), 2.16-2.05 (m, 2H), 1.84-1.79 (m, 4H), 1.61-1.53 (m, 2H), 1.35-1.18 (m, 4H)

83.0 mg (0.18 mmol, 59% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and 4-benzylpiperidine (0.06 mg, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J=7.7 Hz, 2H), 7.41 (td, J=7.6 Hz, J=1.1 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 7.25-7.13 (m, 5H), 7.10-7.08 (m, 2H), 4.20 (t, J=7.1 Hz, 2H), 2.84 (brd, J=11.7 Hz, 2H), 2.48 (d, J=7.0 Hz, 2H), 2.20 (t, J=7.9 Hz, 2H), 1.83-1.76 (m, 4H), 1.57 (brd, J=12.8 Hz, 2H), 1.50-1.19 (m, 9H)

103.6 mg (0.27 mmol, 91% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and acetylpiperazine (47 mg, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (d, J=7.6 Hz, 2H), 7.44-7.40 (m, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.22-7.18 (m, 2H), 4.24 (t, J=7.1 Hz, 2H), 3.55 (t, J=5.1 Hz, 2H), 3.34 (t, J=5.1 Hz, 2H), 2.27 (t, J=4.6 Hz, 4H), 2.20 (t, J=7.4 Hz, 2H), 2.02 (s, 3H), 1.83 (quint, J=7.3 Hz, 2H), 1.41-1.21 (m, 6H)

62.0 mg (0.18 mmol, 59% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and methylpiperazine (0.04 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J=7.7 Hz, 2H), 7.44 (t, J=7.6 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.23-7.19 (m, 2H), 4.26 (t, J=7.1 Hz, 2H), 2.43 (brs, 10H), 2.28-2.24 (m, 3H), 1.85 (quint, J=7.3 Hz, 2H), 1.47-1.25 (m, 6H)

111.2 mg (0.24 mmol, 79% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and benzylpiperazine (0.06 ml, 0.36 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.07-8.05 (m, 2H), 7.44-7.40 (m, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.30-7.19 (m, 7H), 4.23 (t, J=7.2 Hz, 2H), 3.47 (s, 2H), 2.42 (brs, 8H), 2.23 (t, J=7.6 Hz, 2H), 1.82 (quint, J=7.3 Hz, 2H), 1.44-1.23 (m, 6H)

111.2 mg (0.26 mmol, 86% yield) of the title compound was prepared using the compound of Example 1.4 (100 mg, 0.30 mmol) and 1-(2-hydroxyphenyl)piperazine (81 mg, 0.45 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J=7.7 Hz, 2H), 7.43-7.39 (m, 2H), 7.34 (d, J=8.2 Hz, 2H), 7.20-7.16 (m, 2H), 7.10 (dd, J=5.9 Hz, J=1.5 Hz, 1H), 7.02 (td, J=7.7 Hz, J=1.3 Hz, 1H), 6.92 (dd, J=6.0 Hz, J=1.4 Hz, 1H), 6.81 (td, J=7.6 Hz, J=1.5 Hz, 1H), 4.21 (t, J=7.1 Hz, 2H), 2.83 (t, J=4.7 Hz, 4H), 2.48 (brs, 3H), 2.26 (t, J=7.6 Hz, 2H), 1.82 (quint, J=7.3 Hz, 2H), 1.44-1.25 (m, 7H)

650 mg (1.47 mmol, 49% yield) of the title compound was prepared using 1-(2-methoxyphenyl)piperazine (699 mg, 3.64 mmol), the compound of Example 1.4 (1 g, 3.03 mmol), and K 2 CO 3 (418 mg, 3.03 mmol) in accordance with the procedure of Example 235

1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (d, J=7.2 Hz, 2H), 7.58 (t, J=7.6 Hz, 2H), 7.50 (d, J=8.1 Hz, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.13-7.04 (m, 3H), 6.95 (d, J=7.7 Hz, 1H), 4.35 (t, J=7.0 Hz, 2H), 3.94 (s, 3H), 3.21 (brs, 4H), 2.73 (brs, 4H), 2.46 (t, J=7.5 Hz, 2H), 1.99-1.94 (m, 2H), 1.60-1.47 (m, 4H)

226.4 mg (0.52 mmol, 83% yield) of the title compound was prepared using the compound of Example 1.5 (200 mg, 0.63 mmol) and 4-phenylpiperidine (153 mg, 0.95 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (d, J=7.7 Hz, 2H), 7.42-7.38 (m, 2H), 7.32 (d, J=8.2 Hz, 2H), 7.24-7.12 (m, 7H), 4.18 (t, J=6.8 Hz, 2H), 3.10 (brd, J=11.7 Hz, 2H), 2.52-2.41 (m, 3H), 2.29 (t, J=11.4 Hz, 2H), 2.16-2.05 (m, 2H), 1.82-1.73 (m, 4H), 1.63-1.55 (m, 2H), 1.22 (quint, J=7.7 Hz, 2H)

248.0 mg (0.60 mmol, 95% yield) of the title compound was prepared using the compound of Example 1.5 (200 mg, 0.63 mmol) and benzylpiperazine (0.13 ml, 0.76 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (d, J=7.7 Hz, 2H), 7.41-7.37 (m, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.26-7.15 (m, 7H), 4.17 (t, J=7.1 Hz, 2H), 3.44 (s, 2H), 2.39 (brs, 8H), 2.19 (t, J=7.7 Hz, 2H), 1.79 (quint, J=7.4 Hz, 2H), 1.43 (quint, J=7.6 Hz, 2H), 1.28 (quint, J=7.6 Hz, 2H)

172.3 mg (0.42 mmol, 66% yield) of the title compound was prepared using the compound of Example 1.5 (200 mg, 0.63 mmol) and 1-(2-hydroxyphenyl)piperazine (169 mg, 0.95 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (d, J=7.7 Hz, 2H), 7.42-7.38 (m, 2H), 7.31 (d, J=8.2 Hz, 2H), 7.19-7.15 (m, 2H), 7.09-7.06 (m, 1H), 7.03-6.99 (m, 1H), 6.92 (dd, J=6.0 Hz, J=1.5 Hz, 1H), 6.80 (td, J=7.6 Hz, J=1.5 Hz, 1H), 4.16 (t, J=7.1 Hz, 2H), 2.79 (t, J=4.7 Hz, 4H), 2.41 (brs, 4H), 2.20 (t, J=7.6 Hz, 2H), 1.79 (quint, J=7.4 Hz, 2H), 1.41 (quint, J=7.5 Hz, 2H), 1.32-1.24 (m, 2H)

247.7 mg (0.58 mmol, 92% yield) of the title compound was prepared using the compound of Example 1.5 (200 mg, 0.63 mmol) and 1-(2-methoxyphenyl)piperazine (0.13 ml, 0.76 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J=7.7 Hz, 2H), 7.43-7.39 (m, 2H), 7.32 (d, J=8.2 Hz, 2H), 7.20-7.16 (m, 2H), 6.95-6.84 (m, 3H), 6.77 (d, J=7.6 Hz, 1H), 4.18 (t, J=7.1 Hz, 2H), 3.76 (s, 3H), 3.04 (brs, 4H), 2.55 (brs, 4H), 2.27 (t, J=7.7 Hz, 2H), 1.81 (quint, J=7.4 Hz, 2H), 1.48 (quint, J=7.6 Hz, 2H), 1.31 (quint, J=7.6 Hz, 2H)

213.5 mg (0.56 mmol, 84% yield) of the title compound was prepared using the compound of Example 1.6 (200 mg, 0.66 mmol) and 4-phenylpiperidine (160 mg, 0.99 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (d, J=7.7 Hz, 2H), 7.40-7.36 (m, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.23-7.09 (m, 7H), 4.14 (t, J=7.2 Hz, 2H), 2.85 (brd, J=11.2 Hz, 2H), 2.36-2.29 (m, 1H), 2.21 (t, J=7.5 Hz, 2H), 1.87-1.67 (m, 8H), 1.49 (quint, J=7.6 Hz, 2H)

104.5 mg (0.26 mmol, 40% yield) of the title compound was prepared using the compound of Example 1.6 (200 mg, 0.66 mmol) and 1-(2-hydroxyphenyl)piperazine (177 mg, 0.99 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J=7.7 Hz, 2H), 7.45-7.41 (m, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.22-7.18 (m, 2H), 7.09 (dd, J=5.9 Hz, J=1.5 Hz, 1H), 7.05-7.01 (m, 1H), 6.92 (dd, J=6.0 Hz, J=1.4 Hz, 1H), 6.81 (td, J=7.6 Hz, J=1.5 Hz, 1H) 4.25 (t, J=7.1 Hz, 2H), 2.80 (t, J=4.7 Hz, 4H), 2.45 (brs, 4H), 2.31 (t, J=7.4 Hz, 2H), 1.86 (quint, J=7.4 Hz, 2H), 1.52 (quint, J=7.5 Hz, 2H)

256.4 mg (0.62 mmol, 94% yield) of the title compound was prepared using the compound of Example 1.6 (200 mg, 0.66 mmol) and 1-(2-methoxyphenyl)piperazine (0.14 ml, 0.79 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (d, J=7.7 Hz, 2H), 7.42-7.38 (m, 2H), 7.33 (d, J=8.1 Hz, 2H), 7.19-7.15 (m, 2H), 6.95-6.88 (m, 1H), 6.85 (d, J=4.0 Hz, 2H), 6.75 (d, J=7.8 Hz, 1H), 4.18 (t, J=7.2 Hz, 2H), 3.74 (s, 3H), 3.00 (brs, 4H), 2.50 (brs, 4H), 2.31 (t, J=7.4 Hz, 2H), 1.81 (quint, J=7.4 Hz, 2H), 1.50 (quint, J=7.5 Hz, 2H)

132.9 mg (0.36 mmol, 52% yield) of the title compound was prepared using the compound of Example 1.7 (200 mg, 0.69 mmol) and 4-benzylpiperidine (168 mg, 1.04 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (dt, J=7.7 Hz, J=0.8 Hz, 2H), 7.46-7.40 (m, 4H), 7.29-7.26 (m, 2H), 7.23-7.15 (m, 5H), 4.32 (t, J=6.7 Hz, 2H), 2.90 (brd, J=11.5 Hz, 2H), 2.46-2.38 (m, 1H), 2.27 (t, J=6.8 Hz, 2H), 1.99 (quint, J=6.8 Hz, 2H), 1.93-1.85 (m, 2H), 1.83-1.71 (m, 4H)

204.6 mg (0.53 mmol, 77% yield) of the title compound was prepared using the compound of Example 1.7 (200 mg, 0.69 mmol) and benzylpiperazine (0.14 ml, 0.83 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.04-8.02 (m, 2H), 7.41-7.36 (m, 4H), 7.30-7.24 (m, 4H), 7.23-7.14 (m, 3H), 4.26 (t, J=6.7 Hz, 2H), 3.46 (s, 2H), 2.39 (brd, J=41.2 Hz, 8H), 2.21 (t, J=6.8 Hz, 2H), 1.92 (quint, J=6.7 Hz, 2H)

131.6 mg (0.34 mmol, 60% yield) of the title compound was prepared using the compound of Example 1.7 (176 mg, 0.61 mmol) and 1-(2-hydroxyphenyl)piperazine (153 mg, 0.86 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (d, J=7.7 Hz, 2H), 7.46-7.41 (m, 4H), 7.24-7.15 (m, 3H), 7.08-7.03 (m, 1H), 6.94 (dd, J=6.0 Hz, J=1.4 Hz, 1H), 6.85 (td, J=7.6 Hz, J=1.5 Hz, 1H), 4.36 (t, J=6.6 Hz, 2H), 2.85 (t, J=4.7 Hz, 4H), 2.47 (brs, 4H), 2.30 (t, J=6.7 Hz, 2H), 2.01 (quint, J=6.6 Hz, 2H)

145.8 mg (0.36 mmol, 60% yield) of the title compound was prepared using the compound of Example 1.7 (176 mg, 0.61 mmol) and 1-(2-methoxyphenyl)piperazine (0.13 ml, 0.73 mmol) in accordance with the procedure of Example 2.35.

1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (d, J=7.8 Hz, 2H), 7.43-7.37 (m, 4H), 7.19-7.15 (m, 2H), 6.96-6.86 (m, 3H), 6.78-6.76 (m, 1H), 4.29 (t, J=6.6 Hz, 2H), 3.75 (s, 3H), 3.06 (brs, 4H), 2.50 (brs, 4H), 2.26 (t, J=6.7 Hz, 2H), 1.94 (quint, J=6.6 Hz, 2H)

Formulation Examples

The inventive carbazole derivatives can be formulated into various dosage forms according to the intended purpose. Exemplary formulations containing the carbazole derivatives or pharmaceutically acceptable salts thereof as an active ingredient are provided hereinbelow. However, these formulation examples are merely illustrative and the scope of the present invention is not limited thereto.

Formulation Example 1: Tablets (Direct Compression)

5.0 mg of the compound prepared in Example 2.15 was sieved and mixed with 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate. The mixture was compressed into tablets.

Formulation Example 2: Tablets (Wet Granulation)

5.0 mg of the compound prepared in Example 2.15 was sieved and mixed with 16.0 mg of lactose and 4.0 mg of starch. To the mixture was added an appropriate amount of a solution of 0.3 mg of polysorbate 80 in pure water. The resulting mixture was granulated. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The mixture was compressed into tablets.

Formulation Example 3: Powders and Capsules

5.0 mg of the compound prepared in Example 2.15 was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone, and 0.2 mg of magnesium stearate. The mixture was filled in hard No. 5 gelatin capsules using a proper device.

Formulation Example 4: Injectable Preparations

100 mg of the compound prepared in Example 2.15, 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O, and 2,974 mg of distilled water were mixed to produce injectable preparations.

Experimental Example 1: Measurement of Binding Affinity for the 5-HT 7 Serotonin Receptor

In this example, the human gene recombinant 5-HT 7 receptor expressed in CHO cells was used. 1 nM [ 3 H]LSD, 5-HT 7 receptor membrane (15 μg/well), a test drug, 10 mM MgCl 2 , 50 mM Tris-HCl buffer (pH 7.4) containing 0.1 mM EDTA, etc. were added to a vessel until the final volume reached 0.25 ml. The test drug was used at various concentrations. The mixture was cultured at 25° C. for 90 min. The culture was rapidly filtered through a Whatman GF/C glass fiber filter, which had been previously wetted with 0.3% polyethyleneimine using a Brandel harvester, to quench the reaction. The reaction mixture was washed with cold 50 mM Tris-HCl buffer. The filter was covered with MeltiLex, sealed in a sample bag, and dried in an oven. Counting was performed using MicroBeta (Wallac) and nonspecific binding was measured in the presence of 0.5 mianserin. The K value of the test drug was obtained from nonlinear regression analysis (GraphPad Prism Program, San Diego, USA) of isotherms obtained by repeatedly performing the experiment on the drug at 10-11 stage concentrations in two test tubes (each twice).

The % inhibition values of the inventive compounds having different Y structures at a concentration of 10 μM against the 5-HT 7 serotonin receptor were measured. Further, the binding affinity (K i ) values of the inventive compounds having different Y structures at a concentration of 10 μM for the 5-HT 7 serotonin receptor were measured. The results are shown in Tables 1 to 3.

Referring to the results in Table 1, the compounds wherein Y is NR 1 R 2 (R 1 and R 2 are alkyl groups that are not bonded to each other and cannot form a ring) showed good inhibitory effects on both 5-HT 7 and 5-HT 2C , and particularly, they showed very good inhibitory effects on 5-HT 1E compared to the other carbazole compounds.

Meanwhile, the compounds wherein Y is NR 1 R 2 and (R 1 and R 2 are not bonded to each other and cannot form a ring and either R 1 or R 2 is a benzyl group) and the compounds wherein Y is NR 1 R 2 (R 1 and R 2 are bonded to each other to form a ring) showed no inhibitory effects on 5-HT 1E but showed good inhibitory effects on 5-HT 7 and 5-HT 2C . Particularly, the compounds in which the alkyl chain between X and Y consists of 5 carbon atoms had significantly high % inhibition values against 5-HT 2C .

Referring to the results in Table 2, the compounds wherein Y is a substituted piperidinyl group were found to have very high % inhibition values of 89.9 to 103.0 against 5-HT 7 , together with good inhibitory effects on 5-HT 2C and 5-HT 6 . Meanwhile, the compounds had very low % inhibition values of −12.4 to 13.5 against 5-HT 1E . The % inhibition values of the compounds against 5-HT 6 were greatly affected by the number (n) of carbon atoms of the alkyl chain between X and Y. Specifically, the compounds in which the alkyl chain consists of 5 carbon atoms had the highest % inhibition values. The % inhibition value decreased significantly with decreasing length of the alkyl chain. The compounds wherein X is CO showed higher % inhibition values against 5-HT 7 , whereas the compounds wherein X is CH 2 showed higher % inhibition values against 5-HT 6 .

Referring to the results in Table 3, the compounds wherein Y a piperazinyl groups whose nitrogen atom is substituted with alkyl (R 5 ) showed good inhibitory effects on 5-HT 2C and 5-HT 6 together with 5-HT 7 . On the other hand, the compounds wherein R 5 is an aryl group, a heteroaryl group or benzyl showed good inhibitory effects on 5-HT 1A as well as 5-HT 2C and 5-HT 6 , together with 5-HT 7 . Particularly, the compounds wherein R 5 is an aryl group showed excellent inhibitory effects on 5-HT 1A . On the other hand, the compounds in which the alkyl chain consists of 5 carbon atoms had the highest % inhibition values against 5-HT 6 , as in the results in Table 2. The % inhibition value decreased significantly with decreasing length of the alkyl chain. The compounds wherein X is CO showed higher % inhibition values against 5-HT 7 , whereas the compounds wherein X is CH 2 showed higher % inhibition values against 5-HT 6 .

Referring to the results in Tables 1-3, when Y has a structure within the range defined above and X is CH 2 irrespective of the structure of Y, the compounds wherein n is 5 showed lower % inhibition values against the 5-HT 7 receptor compared to the compounds wherein n is from 2 to 4. The compounds wherein n is 5 have a carbazole-(CH 2 ) 5 —Y structure in which X (CH 2 ) is connected to the alkyl chain ((CH 2 ) 5 ). This structure is estimated to lower the % inhibition values of the compounds wherein n is 5 against the 5-HT 7 receptor.

In order to investigate the inhibitory effect of the length of the alkyl chain between the carbazole moiety and the tertiary amine (Y) on the 5-HT 7 receptor when n is greater than 5, the compounds wherein n is 6 and the compounds wherein n is 7 were prepared (Comparative Examples 1-6).

The compound of Comparative Example 1 wherein Y is 4-phenylpiperidyl, X is CO, and n is 6 and the compound of Comparative Example 2 wherein Y is 4-phenylpiperidyl, X is CO, and n is 7 were measured to have % inhibition values of 47.5 and 32.8 against the 5-HT 7 receptor, respectively, which were lower than those of the compounds of Examples 2.9 and 2.25 shown in Table 2. The compound of Comparative Example 3 wherein Y is 4-phenylpiperidyl, X is CH 2 , and n is 6 was measured to have a % inhibition value of 42.7 against the 5-HT 7 receptor, which was lower than that of the compound of Example 2.43 shown in Table 2.

The compound of Comparative Example 4 wherein Y is 2-methoxyphenylpiperazinyl, X is CO, n is 6, the compound of Comparative Example 5 wherein Y is 2-methoxyphenylpiperazinyl, X is CH 2 , and n is 6, and the compound of Comparative Example 6 wherein Y is 2-methoxyphenylpiperazinyl, X is CH 2 , and n is 7 were measured to have % inhibition values of 44.5, 42.7, and 19.7 against the 5-HT 7 receptor, respectively, which were lower in efficacy than those of the inventive compounds wherein Y is 2-methoxyphenylpiperazinyl shown in Table 3.

From these results, it can be seen that the compounds wherein n is from 2 to 5 can effectively act on the 5-HT 7 receptor. Particularly, the compounds wherein n is 7 or greater had considerably low % inhibition values, making it substantially difficult to apply the compounds as antagonists against the 5-HT 7 receptor, and therefore, they are not expected to be useful for the treatment or prevention of central nervous system diseases, such as depression, migraine, anxiety, pain, inflammatory pain, neuropathic pain, body temperature dysregulation, circadian rhythm dysregulation, sleep disturbance, and smooth muscle-related diseases.

Experimental Example 2: Antagonism Against Migraine

It is known that inflammatory proteins leaked from meningeal vessels by 5-HT are implicated in causing migraine. The amount of the proteins leaked in the presence of the compound of Example 2.10 was measured and the preventive effect of the compound on migraine was assessed by a partial modification of the method described in the literature [Rachel A. Spokes, Vicki C. Middlefell, European Journal of Pharmacology (1995) 281, 75-79]. SB-269970, which is known as a 5-HT 7 receptor antagonizing compound (J. Med. Chem. (2000) 43, 342-345), was used as a comparative compound. A negative control free of 5-HT 7 was prepared. The fluorescence intensity of the negative control was defined as a reference value. As a positive control, physiological saline was added instead of the compound of Example 2-10.

Rats (350-450 g) were administered urethane (1.5 g/kg) intraperitoneally. 50 mg/kg of a fluorescent protein (FITC-BSA) was administered intravenously through a cannula introduced into the saphenous vein, and 1 μM 5-HT 7 was administered intravenously. SB-269970 and the compound of Example 2.10 were administered intraperitoneally. The cerebral lobes were separated and the meninges were drawn from each rat. The meninges were allowed to stand at 37° C. for 16 h in the presence of physiological saline at pH 11, followed by centrifugation. The supernatant was plated on plates. The fluorescence intensity was measured using a fluorescence leader (excitation wavelength 485 nm, absorption wavelength 530 nm) and the meninges were weighed. The fluorescence intensity per mg of the meningeal proteins was calculated.

The 5-HT 7 receptor antagonizing compound SB-269970 reduced the amount of the proteins leaked by 10 mg/kg. Even when SB-269970 was administered at an increased dose of 30 mg/kg, the amount of the proteins leaked was not lowered down to the reference value. In contrast, when the compound of Example 2.10 was administered at a dose of 3 mg/kg, the amount of the proteins leaked was effectively suppressed to a level close to the reference value. The results are shown in FIG. 1 .

When each of the compounds of Examples 2.4, 2.9, 2.14, 2.15, 2.31, and 2.55 was administered in an amount of 5 mg/kg to 20 mg/kg, the protein leakage was suppressed to a level close to the reference value.

These results lead to the conclusion that the inventive compounds can effectively inhibit migraine.