10.1002/cmdc.201900522
ChemMedChem
FULL PAPER
m/z calcd for C30H32N6Cl [M+H]+: 511.2377, found: 511.2375. HPLC purity
= 94.00 %; TR = 10.45 min.
DCM, 5% MeOH. 1H NMR (300 MHz; DMSO-d6): δ 8.58 (d, J = 2.6 Hz,
1H), 8.30 (dd, J = 4.7, 1.3 Hz, 1H), 7.88-7.82 (m, 3H), 7.64-7.56 (m, 3H),
7.43 (dd, J = 8.3, 4.7 Hz, 1H), 7.24-7.18 (m, 2H), 6.64 (s, 1H), 6.45 (dd, J
= 6.0, 3.6 Hz, 1H), 5.19 (s, 1H), 3.13 (t, J = 7.0 Hz, 1H), 2.22 (t, J = 7.0 Hz,
5H), 1.66 (quintet, J = 7.0 Hz, 2H), 1.47-1.35 (m, 6H), 1.22 (bs, 3H). 13C
NMR (75 MHz; DMSO-d6): δ 152.6, 150.3, 144.44, 144.35, 144.1, 137.6,
136.3, 135.8, 134.96, 134.91, 132.1, 131.4, 131.2, 128.9, 128.4, 128.2,
124.4, 123.5, 114.6, 110.0, 98.9, 88.7, 57.3, 54.5, 48.2, 27.7, 26.0, 24.7.
HRMS (ESI) m/z calcd for C31H32N6Cl [M+H]+: 523.2377, found: 523.2379.
HPLC purity = 98.21%; TR = 10.17 min.
5-(4-Chlorophenyl)-N-(pyridin-3-yl)-3-((2-(pyrrolidin-1-yl)ethyl)imino)-
3,5-dihydrophenazin-2-amine trichlorhydrate (8)
Following the proposed general procedure, 238 mg of compound 8 (yield:
79%) were obtained from 200 mg (0.50 mmol) of 1a and 127 µL (1.00
mmol) of 2-(pyrrolidin-1-yl)ethanamine. CC = from 100 % DCM to 95%
DCM, 5% MeOH. 1H NMR (300 MHz; DMSO-d6): δ 8.58 (d, J = 2.6 Hz,
1H), 8.29 (dd, J = 4.7, 1.4 Hz, 1H), 7.87-7.81 (m, 3H), 7.64-7.56 (m, 3H),
7.42 (dd, J = 8.3, 4.7 Hz, 1H), 7.22-7.19 (m, 2H), 6.65 (s, 1H), 6.49-6.46
(m, 1H), 5.22 (s, 1H), 3.36-3.28 (m, 2H), 2.53-2.49 (2, 2H), 2.29-2.27 (m,
4H), 1.64-1.62 (m, 4H). 13C NMR (75 MHz; DMSO-d6): δ 153.3, 150.3,
144.39, 144.25, 144.21, 144.03, 137.4, 136.3, 135.8, 134.99, 134.88,
132.10, 131.97, 131.42, 131.30, 128.7, 128.5, 128.3, 124.3, 123.4, 114.6,
99.0, 88.9, 56.1, 55.4, 54.2, 23.6. HRMS (ESI) m/z calcd for C29H28N6Cl
[M+H]+: 495.2064, found: 495.2061. HPLC purity = 96.17 %; TR = 10.80
min.
5-(4-(Chlorophenyl)-3-((2-morpholinoethyl)imino)-N-(pyridin-3-yl)-
3,5-dihydrophenazin-2-amine trichlorhydrate (12)
Following the proposed general procedure, 249 mg of compound 12 (yield:
80%) were obtained from 200 mg (0.50 mmol) of 1a and 131 µL (1.00
mmol) of 2-morpholinoethanamine. CC = from 100 % DCM to 95% DCM,
5% MeOH. 1H NMR (300 MHz; DMSO-d6): δ 8.59-8.58 (m, 1H), 8.30 (dd,
J = 4.7, 1.4 Hz, 1H), 7.88-7.82 (m, 3H), 7.65-7.59 (m, 3H), 7.43 (ddd, J =
8.3, 4.7, 0.6 Hz, 1H), 7.26-7.18 (m, 2H), 6.66 (s, 1H), 6.50-6.46 (m, 1H),
5.20 (s, 1H), 3.53 (bt, 4H), 2.44-2.39 (m, 2H), 2.26 (bt, 4H). 13C NMR (75
MHz; DMSO-d6): 153.4, 150.3, 144.44, 144.31, 144.0, 137.4, 136.3, 135.8,
134.9, 132.1, 131.42, 131.34, 128.8, 128.5, 128.3, 124.3, 123.5, 114.7,
99.1, 88.7, 66.6, 58.5, 53.8, 47.4. HRMS (ESI) m/z calcd for C29H28N6OCl
[M+H]+: 511.2013, found: 511.2016. HPLC purity > 99%; TR = 10.24 min.
5-(4-Chlorophenyl)-N-(pyridin-3-yl)-3-((3-(pyrrolidin-1-
yl)propyl)imino)-3,5-dihydrophenazin-2-amine trichlorhydrate (9)
Following the proposed general procedure, 118 mg of compound 9 (yield:
38%) were obtained from 200 mg (0.50 mmol) of 1a and 111 µL (1.00
mmol) of 3-(pyrrolidin-1-yl)propan-1-amine. CC = from 100 % DCM to 95%
DCM, 5% MeOH. 1H NMR (300 MHz; DMSO-d6): δ 8.59-8.58 (m, 1H), 8.30
(dd, J = 4.7, 1.4 Hz, 1H), 7.87-7.82 (m, 3H), 7.64-7.58 (m, 3H), 7.43 (ddd,
J = 8.3, 4.7, 0.5 Hz, 1H), 7.22-7.19 (m, 2H), 6.64 (s, 1H), 6.45-6.42 (m,
1H), 5.20 (s, 1H), 3.18 (t, J = 7.1 Hz, 2H), 2.39-2.30 (m, 6H), 1.67-1.63 (m,
6H). 13C NMR (75 MHz; DMSO-d6): δ 152.7, 150.4, 144.45, 144.38, 144.1,
137.5, 136.3, 134.96, 134.91, 132.1, 131.5, 131.2, 128.9, 128.4, 128.2,
124.4, 123.5, 114.6, 98.9, 88.7, 54.5, 54.1, 48.3, 29.6, 23.6. HRMS (ESI)
m/z calcd for C30H30N6Cl [M+H]+: 509.2220, found: 509.2222. HPLC purity
= 95.00 %; TR = 10.96 min.
5-(4-(Chlorophenyl)-3-((3-morpholinopropyl)imino)-N-(pyridin-3-yl)-
3,5-dihydrophenazin-2-amine trichlorhydrate (13)
Following the proposed general procedure, 91 mg of compound 13 (yield:
48%) were obtained from 118 mg (0.29 mmol) of 1a and 86 µL (0.58 mmol)
of 3-morpholinopropan-1-amine. CC = from 100 % DCM to 95% DCM, 5%
MeOH. 1H NMR (300 MHz; DMSO-d6): δ 8.59 (d, J = 2.7 Hz, 1H), 8.30 (dd,
J = 4.7, 1.4 Hz, 1H), 7.89-7.82 (m, 3H), 7.64-7.56 (m, 3H), 7.45-7.41 (m,
1H), 7.22-7.19 (m, 2H), 6.64 (s, 1H), 6.47-6.44 (m, 1H), 5.18 (s, 1H), 3.53
(t, J = 4.6 Hz, 4H), 3.14 (t, J = 6.9 Hz, 2H), 2.30-2.25 (m, 6H), 1.68 (quintet,
J = 7.0 Hz, 2H). 13C NMR (75 MHz; DMSO-d6): δ 152.7, 150.3, 144.48,
144.36, 144.1, 137.5, 136.3, 134.94, 134.91, 132.1, 131.2, 128.9, 128.5,
128.2, 124.4, 123.5, 114.6, 99.0, 88.7, 66.6, 57.0, 53.8, 48.1, 27.3. HRMS
(ESI) m/z calcd for C30H30N6OCl [M+H]+: 525.2170, found: 525.2169.
HPLC purity = 98.64%; TR = 10.62 min.
5-(4-(Chlorophenyl)-3-((2-(piperidin-1-yl)ethyl)imino)-N-(pyridin-3-yl)-
3,5-dihydrophenazin-2-amine trichlorhydrate (10)
Following the proposed general procedure, 206 mg of compound 10 (yield:
70%) were obtained from 200 mg (0.50 mmol) of 1a and 143 µL (1.00
mmol) of 2-(piperidin-1-yl)ethanamine. CC = from 100 % DCM to 95%
DCM, 5% MeOH. 1H NMR (300 MHz; DMSO-d6): δ 8.58 (d, J = 2.5 Hz,
1H), 8.29 (dd, J = 4.7, 1.4 Hz, 1H), 7.87-7.81 (m, 3H), 7.64-7.57 (m, 3H),
7.42 (dd, J = 8.4, 4.5 Hz, 1H), 7.23-7.19 (m, 2H), 6.65 (s, 1H), 6.49-6.46
(m, 1H), 5.22 (s, 1H), 3.37-3.32 (m, 2H), 2.38-2.33 (m, 2H), 2.21-2.19 (m,
4H), 1.45-1.44 (m, 4H), 1.45-1.37 (m, J = 4.5 Hz, 2H). 13C NMR (75 MHz;
DMSO-d6): δ 153.4, 150.3, 144.42, 144.32, 144.12, 137.5, 136.3, 135.9,
134.99, 134.92, 132.1, 131.43, 131.34, 128.8, 128.5, 128.3, 124.3, 123.5,
114.7, 99.0, 88.8, 58.6, 54.5, 47.4, 26.1, 24.4. HRMS (ESI) m/z calcd for
C30H29N6Cl [M+H]+: 509.2220, found: 509.2219. HPLC purity = 98.62%; TR
= 10.64 min.
5-(4-(Chlorophenyl)-3-((2-(piperazin-1-yl)ethyl)imino)-N-(pyridin-3-
yl)-3,5-dihydrophenazin-2-amine tetrachlorhydrate (14)
Following the proposed general procedure, 168 mg of compound Boc-
protected 14 (yield: 55%) were obtained from 220 mg (0.50 mmol) of 1a
and 229 mg (1.00 mmol) of tert-butyl 4-(2-aminoethyl)piperazine-1-
carboxylate. The deprotected, tetrachlorhydrate derivative 14 was
obtained in quantitative yield after stirring with a 2M dioxane solution of
HCl (5 equiv.) at room temperature. CC = from 100 % DCM to 99% DCM,
1% MeOH for Boc-14. 1H NMR (300 MHz; DMSO-d6): δ 8.59 (d, J = 2.5
Hz, 1H), 8.30 (dd, J = 4.6, 1.0 Hz, 1H), 7.90-7.82 (m, 3H), 7.65-7.57 (m,
3H), 7.43 (dt, J = 6.2, 3.2 Hz, 1H), 7.25-7.19 (m, 2H), 6.66 (s, 1H), 6.50-
6.47 (m, 1H), 5.23 (s, 1H), 2.72-2.59 (m, 2H), 2.45-2.36 (m, 2H), 2.32-2.16
(m, 6H). 13C NMR (75 MHz; DMSO-d6): δ 144.45, 144.32, 144.13, 137.5,
136.3, 135.9, 135.0, 132.33, 132.25, 132.14, 132.05, 131.45, 131.34,
129.1, 128.8, 128.5, 128.3, 124.4, 123.5, 114.7, 88.8, 67.9, 58.8, 56.5,
54.7, 47.3, 46.1, 40.8. HRMS (ESI) m/z calcd for C29H29N7Cl [M+H]+:
510.2173, found: 510.2172. HPLC purity = 91.17%; TR = 10.12 min.
5-(4-(Chlorophenyl)-3-((3-(piperidin-1-yl)propyl)imino)-N-(pyridin-3-
yl)-3,5-dihydrophenazin-2-amine trichlorhydrate (11)
Following the proposed general procedure, 145 mg of compound 11 (yield:
46%) were obtained from 200 mg (0.50 mmol) of 1a and 159 µL (1.00
mmol) of 3-(piperidin-1-yl)propan-1-amine. CC = from 100 % DCM to 95%
8
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