S. Kang et al. / European Journal of Medicinal Chemistry 151 (2018) 186e198
195
(
3
6
m, 1H), 2.46 (s, 3H), 3.40 (t, J ¼ 6.2 Hz, 1H), 3.53 (t, J ¼ 6.2 Hz, 1H),
Found 407.1818.
.90 (t, J ¼ 6.3 Hz, 2H), 6.79 (d, J ¼ 1.7 Hz, 1H), 6.82e6.88 (m, 2H),
13
.94 (t, J ¼ 6.9 Hz, 1H), 7.06 (d, J ¼ 8.0 Hz, 1H), 7.13e7.16 (m, 2H).
16.42, 24.13, 29.83, 44.82, 46.44, 114.51,
15.88, 120.84, 122.83, 125.49, 127.41, 127.61, 127.73, 137.82, 144.84,
C
4.1.3.4. 2-Chloro-10-(3-(4-methylpiperidin-1-yl)propyl)-10H-pheno-
NMR (100.6 MHz, CDCl
1
1
3
)
d
thiazine (3ba). Yield: 39.1%, brown solid, HPLC purity: 5.95 min,
1
99.83%. H NMR (400 MHz, CDCl
3
)
d
0.91 (d, J ¼ 8.0 Hz, 3H),
45.68, 171.06.
1.28e1.35 (m, 3H), 1.60 (d, J ¼ 12.0 Hz, 2H), 1.86e1.92 (m, 2H),
.93e1.98 (m, 2H), 2.44 (t, J ¼ 6.8 Hz, 2H), 2.85 (d, J ¼ 12.0 Hz, 2H)
4.00 (t, J ¼ 6.9 Hz, 2H), 6.84e6.93 (m, 4H), 6.99e7.00 (m, 1H)
1
4
.1.2.6. 10-(3-Chloropropyl)-2-(methylthio)-10H-phenothiazine (5f).
1
13
Yield: 53.0%, colorless oil. H NMR (400 MHz, CDCl
3
)
d
2.23e2.27
3
7.09e7.16 (m, 2H). C NMR (100.6 MHz, CDCl ) d 20.89, 21.18, 29.19,
(
(
6
m, 1H), 2.29e2.32 (m, 1H), 2.46 (s, 3H), 3.50 (t, J ¼ 6.0 Hz, 1H), 3.56
30.75, 44.70, 53.22, 55.21, 116.28, 116.50, 122.99, 123.63, 124.43,
þ
t, J ¼ 6.1 Hz, 1H), 4.05 (t, J ¼ 6.3 Hz, 2H), 6.81e6.84 (m, 2H),
125.65, 127.80, 127.90, 128.23, 133.57, 143.72, 146.17. HRMS (ES ):
13
þ
.87e6.95 (m, 2H), 7.05 (d, J ¼ 8.2 Hz, 1H), 7.13e7.17 (m, 2H).
16.47, 29.63, 42.48, 44.04, 114.59, 115.84,
21.07, 122.60, 122.94, 125.77, 127.42, 127.68, 127.77, 137.82, 144.80,
C
m/z calculated for C21
H25ClN
2
S: 373.1505 [MþH] . Found 373.1573.
3
NMR (100.6 MHz, CDCl ) d
1
4.1.3.5. 10-(3-(4-Methylpiperidin-1-yl)propyl)-2-(methylthio)-10H-
1
45.56.
phenothiazine (3ca). Yield: 44.9%, yellow solid, HPLC purity:
1
5
.97 min, 100%. H NMR (400 MHz, CDCl
3
)
d
0.90 (d, J ¼ 6.4 Hz, 3H),
4.1.2.7. 10-(4-Chlorobutyl)-2-fluoro-10H-phenothiazine
(5g).
1.86e2.06
1.17e1.26 (m, 2H), 1.27e1.33 (m, 1H), 1.59 (d, J ¼ 12.6 Hz, 2H),
1.83e1.89 (m, 2H), 1.90e1.98 (m, 2H), 2.43 (t, J ¼ 7.3 Hz, 2H), 2.44 (s,
3H), 2.83 (d, J ¼ 11.6 Hz, 2H), 3.89 (t, J ¼ 6.9 Hz, 2H), 6.78e6.81 (m,
1
Yield: 95.0%, colorless oil. H NMR (400 MHz, CDCl
3
)
d
(
m, 4H), 3.54 (t, J ¼ 6.2 Hz, 2H), 3.88 (t, J ¼ 5.8 Hz, 2H), 6.58e6.67
1
3
(
m, 2H), 6.88 (d, J ¼ 8.1 Hz, 1H), 6.95 (t, J ¼ 7.2 Hz, 2H), 7.04e7.08 (m,
2H), 6.87e6.90 (m, 2H), 7.00e7.03 (m, 1H), 7.09e7.14 (m, 2H).
C
13
1
4
H), 7.14e7.19 (m, 1H). C NMR (100.6 MHz, CDCl
3
)
d
24.06, 29.78,
3
NMR (100.6 MHz, CDCl ) d 16.54, 21.95, 24.65, 30.82, 34.37, 45.62,
4.72, 46.55, 103.62 (JC-F ¼ 26.2 Hz), 109.23 (JC-F ¼ 22.1 Hz), 115.83,
54.21, 56.24, 114.62, 115.76, 120.78, 122.04, 122.53, 125.05, 127.24,
þ
1
20.08, 120.11, 123.16, 125.38, 127.61 (JC-F ¼ 18.1 Hz), 128.08 (JC-
127.41, 127.51, 137.51, 144.93, 145.75. HRMS (ES ): m/z calculated for
þ
F
¼ 10.1 Hz), 144.49, 147.03 (JC-F ¼ 10.1 Hz), 162.97 (JC-F ¼ 243.5 Hz).
C
22
H
28
N
2
S
2
: 385.1772 [MþH] . Found 385.1775.
4
.1.3. General methods of TFP analogs 3aaꢀga
4.1.3.6. 10-(4-(4-Methylpiperidin-1-yl)butyl)-2-(trifluoromethyl)-
To a solution of the appropriate intermediate (5aꢀg, 0.6 mmol)
10H-phenothiazine (3da). Yield: 93.4%, yellow solid, HPLC purity:
1
in 2-butanone were added sodium iodide (83.8 mg, 0.6 mmol),
potassium carbonate (77.3 g, 0.6 mmol) and the appropriate cyclic
amine derivative (0.6 mmol) and stirred at 80 C for 24 h. After the
reaction was complete, the reaction mixture was extracted with EA
and water. The residue was dried over anhydrous MgSO
6.18 min, 99.48%. H NMR (400 MHz, CDCl
3
)
d
0.89e0.93 (m, 3H),
1.14e1.25 (m, 3H), 1.29e1.33 (m, 2H), 1.63e1.66 (m, 2H), 1.79e1.87
(m, 4H), 2.33 (t, J ¼ 7.4 Hz, 2H), 2.84 (d, J ¼ 11.4 Hz, 2H), 3.91 (t,
J ¼ 7.1 Hz, 2H), 6.91 (d, J ¼ 8.2 Hz, 1H), 6.92e6.96 (m, 1H), 7.01 (s,
ꢁ
13
4
, filtered
1H), 7.10e7.12 (m, 1H), 7.15e7.20 (m, 4H). C NMR (100.6 MHz,
and concentrated under reduced pressure. The residue was purified
by column chromatography (DCM:MeOH ¼ 15:1) to get the target
final compounds.
3
CDCl ) d 20.90, 20.93, 23.89, 29.43, 30.75, 46.38, 52.95, 56.91,
112.20, 112.24, 116.38, 119.51, 119.55, 123.62, 124.63, 127.80, 127.81,
þ
128.00, 129.72, 130.04, 130.56. HRMS (ES ): m/z calculated for
þ
C
23
H F
27 3
N
2
S: 421.1925 [MþH] . Found 421.2000.
4
.1.3.1. 10-(3-(Piperazin-1-yl)propyl)-2-(trifluoromethyl)-10H-
phenothiazine (3aa). Yield: 59.8%, colorless oil, HPLC purity:
.06 min, 97.38%. 1H NMR (400 MHz, CDCl
1.21e1.37 (m, 1H),
4.1.3.7. 4-(1-(4-(2-(Trifluoromethyl)-10H-phenothiazin-10-yl)butyl)
6
3
)
d
piperidin-4-yl)morpholine (3db). Yield: 76.0%, white solid, HPLC
1
1
.86e1.96 (m, 2H), 2.52 (t, J ¼ 6.7 Hz, 2H), 2.55e2.61 (m, 4H), 2.98
purity: 5.44 min, 99.05%. H NMR (400 MHz, CDCl
3
)
d
1.54e1.56 (m.
(
1
s, 4H), 4.00 (t, J ¼ 6.5 Hz, 2H), 6.90 (d, J ¼ 8.2 Hz, 1H), 6.93e6.97 (m,
2H),1.64e1.66 (m, 4H),1.77e1.91 (m, 6H), 2.16e2.19 (m,1H), 2.52 (t,
J ¼ 4.4 Hz, 4H), 2.95 (d, J ¼ 10.2 Hz, 2H), 3.71 (t, J ¼ 4.6 Hz, 4H), 3.91
(t, J ¼ 6.9 Hz, 2H), 6.89 (d, J ¼ 8.1 Hz, 1H), 6.93e6.97 (m, 1H),
þ
H), 7.02 (s, 1H), 7.10e7.12 (m, 1H), 7.13e7.19 (m, 3H). HRMS (ES ):
þ
m/z calculated for C20
H F
22 3
N
3
S: 394.1565 [MþH] . Found 394.1660.
13
7
3
.11e7.21 (m, 4H). C NMR (100.6 MHz, CDCl ) d 24.09, 24.59, 27.90,
4
.1.3.2. 10-(3-(4-(Pyrrolidin-1-yl)piperidin-1-yl)propyl)-2-(tri-
47.26, 49.71, 53.01, 57.75, 62.17, 67.35, 111.83, 111.87, 115.90, 119.01,
122.83, 123.08, 124.09, 127.47, 127.56, 127.62, 129.55, 129.74, 129.98.
fluoromethyl)-10H-phenothiazine (3ab). Yield: 82.1%, white solid,
1
þ
þ
HPLC purity: 5.17 min, 98.44%.
1.51e1.61 (m, 2H), 1.82e1.84 (m, 5H), 1.88e1.97 (m, 5H), 2.11e2.18
m, 1H), 2.43 (t, J ¼ 6.9 Hz, 2H), 2.67 (s, 4H), 2.87 (d, J ¼ 11.8 Hz, 2H),
.94 (t, J ¼ 6.8 Hz, 2H), 6.93 (t, J ¼ 8.1 Hz, 2H), 7.03 (s, 1H), 7.09e7.19
m, 4H). 13C NMR (100.6 MHz, DMSO‑d
22.70, 25.24, 44.07,
H
NMR (400 MHz, CDCl
3
)
HRMS (ES ): m/z calculated for C26
Found 492.2299.
H
32
F
3
N
3
OS: 492.2218 [MþH] .
d
(
3
(
4.1.3.8. 10-(4-(4-(Pyrrolidin-1-yl)piperidin-1-yl)butyl)-2-(tri-
6
)
d
fluoromethyl)-10H-phenothiazine (3dc). Yield: 68.0%, white solid,
1
5
0.38, 53.48, 112.10, 116.60, 119.30, 123.00, 123.50, 127.40, 127.90,
HPLC purity: 5.30 min, 98.29%.
3
H NMR (400 MHz, CDCl )
þ
1
28.10, 129.60, 144.50 (JC-F ¼ 192.0 Hz). HRMS (ES ): m/z calculated
d
1.47e1.58 (m, 2H),1.59e1.65 (m, 2H), 1.77e1.86 (m, 8H),1.89e1.91
(m, 2H), 1.94e1.98 (m, 1H), 2.31 (t, J ¼ 7.2 Hz, 2H), 2.56 (s, 4H), 2.86
d, J ¼ 11.4 Hz, 2H), 3.89 (t, J ¼ 6.9 Hz, 2H), 6.88e6.95 (m, 2H), 7.01
þ
for C25
H F
30 3
N
3
S: 462.2191 [MþH] . Found 462.2244.
(
13
4
.1.3.3. 10-(3-(4-Methylpiperidin-1-yl)propyl)-2-(trifluoromethyl)-
6
(s, 1H), 7.10e7.19 (m, 4H). C NMR (100.6 MHz, DMSO‑d ) d 21.24,
1
0H-phenothiazine (3ac). Yield: 68.7%, white solid, HPLC purity:
23.20, 24.14, 25.55, 46.56, 50.24, 50.97, 55.71, 58.42, 112.53, 117.08,
1
6
.08 min, 100%. H NMR (400 MHz, CDCl
m, 2H), 1.26e1.35 (m, 1H), 1.60 (d, J ¼ 12.0 Hz, 2H), 1.85e1.98 (m,
H), 2.46 (t, J ¼ 6.7 Hz, 2H), 2.83 (d, J ¼ 12.0 Hz, 2H), 4.00 (t,
J ¼ 8.0 Hz, 2H), 6.91e6.95 (m, 2H), 7.03 (s, 1H), 7.09e7.11 (m, 1H),
3
)
d
0.90 (s, 3H), 1.14e1.21
119.62, 123.30, 123.53, 123.85, 126.01, 127.92, 128.38, 128.53, 130.10,
þ
(
4
144.28, 146.01. HRMS (ES ): m/z calculated for C26
H
32
F
3
N
3
S:
þ
476.2347 [MþH] . Found 476.2388.
13
0
0
7.14 (s, 1H), 7.16e7.19 (m, 2H). C NMR (100.6 MHz, CDCl
3
)
d
20.86,
4.1.3.9. 10-(4-([1,4 -Bipiperidin]-1 -yl)butyl)-2-(trifluoromethyl)-
2
1.09, 29.29, 30.73, 44.78, 53.23, 55.25,112.31,116.60,119.78,119.81,
10H-phenothiazine (3dd). Yield: 21.0%, white solid, HPLC purity:
1
122.59, 123.91, 125.03, 127.90, 128.14, 130.14, 130.97, 143.45, 145.53.
5.31 min, 98.26%. H NMR (400 MHz, DMSO‑d
6
)
d
1.39e1.42 (m, 2H),
þ
þ
HRMS (ES ): m/z calculated for C22
H
25
F
3
N
2
S: 407.1769 [MþH] .
1.69e1.75 (m, 4H), 1.77e1.82 (m, 6H), 2.03e2.09 (m, 3H), 2.26e2.33