D. Luo, Y. Zhang, S. Yang et al.
European Journal of Medicinal Chemistry 225 (2021) 113775
4-Chloro-N-phenyl-6-(pyrrolidin-1-yl)-1,3,5-triazin-2-amine
DMSO‑d6)
d
9.79 (s, 2H), 8.23 (d, J ¼ 5.6 Hz, 1H), 7.64 (d, J ¼ 1.8 Hz,
(27). White solid (60 %). 1H NMR (500 MHz, DMSO‑d6)
d
9.98 (s, 1H),
1H), 7.55 (s, 2H), 7.37 (dd, J ¼ 5.6, 1.9 Hz, 1H). 13C NMR (100 MHz,
7.72 (s, 2H), 7.28 (t, J ¼ 7.8 Hz, 2H), 7.03e6.96 (m, 1H), 3.48 (dt,
DMSO‑d6) d 151.71, 151.45, 150.94, 150.53, 150.08, 148.68, 112.77,
J ¼ 30.2, 6.2 Hz, 4H), 1.95e1.82 (m, 4H). 13C NMR (125 MHz,
112.39, 111.72. HRESIMS m/z 316.9763 [MþH]þ (calcd for
DMSO‑d6)
25.10, 24.96.
2,6-Dichloroisonicotinoyl azide (28). White solid (67 %). 1H NMR
(500 MHz, DMSO‑d6)
7.88 (s, 2H). 13C NMR (125 MHz, DMSO‑d6)
169.37, 150.92, 143.78, 122.71.
N-(2,6-dichloropyridin-4-yl)-2-(4-(phenylamino)-6-(pyrrolidin-
1-yl)-1,3,5-triazin-2-yl)hydrazine-1-carboxamide (29). White solid
(55 %): mp 243.6e243.9 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
9.72 (d,
d
162.89, 139.50, 128.99, 123.14, 120.24, 46.93, 46.71,
C
11H8Cl3N4O 316.9764).
1-(3,5-Dichloro-4-methoxyphenyl)-3-(2,6-dichloropyridin-4-yl)
urea (39): mp 237e237.5 ꢀC; White solid (49 %). 1H NMR (400 MHz,
d
DMSO‑d6)
d
9.74 (s, 1H), 9.37 (s, 1H), 7.57 (d, J ¼ 15.0 Hz, 4H), 3.79 (s,
d
3H). 13C NMR (100 MHz, DMSO‑d6)
d
152.04, 151.43, 150.04, 147.24,
136.46, 128.62, 119.66, 111.56, 61.12. HRESIMS m/z 379.9524
[MþH]þ (calcd for C13H10Cl4N3O2 379.9527).
d
1,3-Bis(2,6-dichloropyridin-4-yl)urea (40). White solid (55 %): mp
J ¼ 95.6 Hz, 1H), 9.16 (s, 1H), 8.72 (s, 2H), 7.99e7.47 (m, 4H), 7.06 (d,
245.3e246.1 ꢀC; 1H NMR (400 MHz, DMSO‑d6)
d 9.97 (s, 2H), 7.55 (s,
J ¼ 131.0 Hz, 3H), 3.49 (s, 4H), 1.90 (s, 4H). 13C NMR (150 MHz,
4H). 13C NMR (100 MHz, DMSO‑d6)
d 151.63, 150.84, 150.12, 111.93.
DMSO‑d6)
d
164.45, 163.76, 152.21, 140.95, 130.17, 128.78, 128.63,
HRESIMS m/z 350.9372 [MþH]þ (calcd for C11H7Cl4N4O 350.9374).
121.87, 120.05, 111.88, 46.52, 46.34, 31.82, 29.56, 29.24, 29.11, 25.32,
22.63, 14.50. HRESIMS m/z 460.1149 [MþH]þ (calcd for
4.1.5. Procedure for preparation of compounds 44a-44d
C
19H20Cl2N9O 460.1168).
A mixture of 2,6-dichloroisonicotinic acid (1000 mg, 5.24 mmol)
in methanol (15 mL) was stirred at room temperature and 1 M
NaOH (7 mL) was added dropwise, then the mixture was heated at
70 ꢀC for 8 h. The pH value of the reaction mixture was adjusted to
5. The mixture was washed with water, and extracted with DCM,
and the extract was washed with saturated NaCl solution, dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. The
crude product was purified by column chromatography to afford
compound 41a (636 mg, 65 %) as a white solid. The acid azide 42a
was prepared from compound 41a through the similar procedure of
compound 7. Then compound 44a was prepared through a similar
procedure to compound 10, and compounds 44a-44d were also
prepared from compound 6.
2-Chloro-N,6-dimethylpyrimidin-4-amine (31). White solid
(33 %). 1H NMR (600 MHz, CDCl3)
d 6.35 (s, 1H), 6.07 (s, 1H), 2.92 (d,
J ¼ 4.6 Hz, 3H), 2.31 (s, 3H). 13C NMR (150 MHz, CDCl3)
d 165.06,
160.08, 159.99, 98.34, 29.76, 28.52, 23.92.
2-Hydrazinyl-N,6-dimethylpyrimidin-4-amine (32). White solid
(95 %). 1H NMR (600 MHz, DMSO‑d6)
d 7.26 (s, 1H), 6.68 (s, 1H), 5.56
(s, 1H), 3.96 (s, 2H), 2.69 (d, J ¼ 4.2 Hz, 3H), 2.02 (s, 3H). 13C NMR
(150 MHz, CDCl3)
d 169.63, 169.08, 32.24, 28.77.
N-(2,6-dichloropyridin-4-yl)-2-(4-methyl-6-(methylamino)pyr-
imidin-2-yl)hydrazine-1-carboxamide (33). White solid (51 %): mp
214.0e214.2 ꢀC; 1H NMR (500 MHz, DMSO‑d6)
d
9.53 (s, 1H), 8.58 (s,
1H), 8.19 (s, 1H), 7.68 (d, J ¼ 168.2 Hz, 2H), 6.92 (s, 1H), 5.76 (s, 1H),
2.68 (s, 3H), 2.05 (s, 3H). 13C NMR (125 MHz, DMSO‑d6)
164.39,
d
2-Chloro-6-methoxyisonicotinic acid (41a). White solid (65 %). 1H
163.37, 152.18, 149.75, 111.69, 23.90. HRESIMS m/z 342.0465
[MþH]þ (calcd for C12H14Cl2N7O 342.0637).
NMR (400 MHz, DMSO‑d6)
d
13.97 (s, 1H), 7.40 (d, J ¼ 1.0 Hz, 1H),
7.19 (d, J ¼ 1.0 Hz, 1H), 3.91 (s, 3H). 13C NMR (100 MHz, DMSO‑d6)
d
165.09, 164.51, 148.56, 144.77, 115.99, 109.78, 54.96.
4.1.4. Procedure for preparation of compounds 34e40
Compounds 34e40 were prepared from acid azide 7 and
different amines through the similar procedure described for the
synthesis of compound 10.
2-Chloro-6-ethoxyisonicotinic acid (41b). White solid (82 %). 1H
NMR (400 MHz, DMSO‑d6)
d
13.94 (s, 1H), 7.38 (d, J ¼ 1.0 Hz, 1H),
7.14 (d, J ¼ 1.0 Hz, 1H), 4.33 (q, J ¼ 7.0 Hz, 2H), 1.33 (t, J ¼ 7.0 Hz, 3H).
13C NMR (100 MHz, DMSO‑d6)
d 165.11, 164.10, 148.53, 144.74,
1-(2,6-Dichloropyridin-4-yl)-3-(2,6-dimethylpyridin-4-yl)urea
115.81, 109.83, 63.37, 14.65.
(34). White solid (59 %): mp 209.9e210.6 ꢀC; 1H NMR (400 MHz,
2-Chloro-6-isopropoxyisonicotinic acid (41c). White solid (85 %).
DMSO‑d6)
d
9.74 (s, 1H), 9.48e9.36 (m, 1H), 7.55 (s, 2H), 7.14 (s, 2H),
158.12, 151.87, 151.23,
1H NMR (400 MHz, DMSO‑d6)
d
13.89 (s, 1H), 7.34 (d, J ¼ 1.0 Hz, 1H),
2.37 (s, 6H). 13C NMR (100 MHz, DMSO‑d6)
d
7.08 (d, J ¼ 1.0 Hz,1H), 5.18 (h, J ¼ 6.2 Hz,1H),1.30 (d, J ¼ 6.2 Hz, 6H).
150.08, 146.86, 111.52, 109.58, 24.47. HRESIMS m/z 311.0468
13C NMR (100 MHz, DMSO‑d6)
d 165.10, 163.62, 148.49, 144.75,
[MþH]þ (calcd for C13H13Cl2N4O 311.0466).
115.53, 110.28, 70.15, 21.99.
1-(3,5-Dichlorophenyl)-3-(2,6-dichloropyridin-4-yl)urea
(35).
2-Chloro-6-(cyclopentyloxy)isonicotinic acid (41d). White solid
White solid (49 %): mp 243.8e244.9 ꢀC; 1H NMR (400 MHz,
(60 %). 1H NMR (400 MHz, DMSO‑d6)
d
13.86 (s, 1H), 7.33 (d,
DMSO‑d6)
d
9.58 (d, J ¼ 72.3 Hz, 2H), 7.55e7.50 (m, 4H), 7.18 (t,
J ¼ 1.0 Hz, 1H), 7.08 (d, J ¼ 1.0 Hz, 1H), 5.29 (td, J ¼ 5.9, 3.0 Hz, 1H),
J ¼ 1.9 Hz, 1H). 13C NMR (100 MHz, DMSO‑d6)
d 151.91, 151.26,
2.04e1.83 (m, 2H),1.78e1.51 (m, 6H). 13C NMR (100 MHz, DMSO‑d6)
150.04, 141.61, 134.59, 122.42, 117.47, 111.56. HRESIMS m/z 349.9423
d
165.09, 163.80, 148.50, 144.61, 115.54, 110.18, 79.56, 32.57, 23.82.
[MþH]þ (calcd for C12H8Cl4N3O 349.9421).
2-Chloro-6-methoxyisonicotinoyl azide (42a). White solid (58 %).
N-(2,6-Dichloropyridin-4-yl)-4-methylpiperazine-1-carboxamide
(36). White solid (44 %): mp 105.3e106.4 ꢀC; 1H NMR (400 MHz,
1H NMR (400 MHz, DMSO‑d6)
d
7.41 (d, J ¼ 1.1 Hz, 1H), 7.20 (d,
J ¼ 1.1 Hz, 1H), 3.92 (s, 3H). 13C NMR (100 MHz, DMSO‑d6)
d 170.24,
DMSO‑d6)
d
9.38 (d, J ¼ 4.5 Hz, 1H), 7.61 (t, J ¼ 4.0 Hz, 2H), 3.47 (q,
164.59, 149.02, 143.43, 115.11, 109.39, 55.17.
J ¼ 4.8 Hz, 4H), 2.33 (q, J ¼ 4.7 Hz, 4H), 2.21 (d, J ¼ 4.5 Hz, 3H). 13
C
2-Chloro-6-ethoxyisonicotinoyl azide (42b). White solid (50 %). 1H
NMR (100 MHz, DMSO‑d6)
d
153.73, 152.72, 149.70, 111.72, 54.73,
NMR (400 MHz, CDCl3)
d
7.39 (d, J ¼ 1.1 Hz, 1H), 7.18 (d, J ¼ 1.1 Hz,
46.08, 44.16. HRESIMS m/z 371.0673 [MþH]þ (calcd for
1H), 4.39 (q, J ¼ 7.1 Hz, 2H), 1.40 (t, J ¼ 7.1 Hz, 3H). 13C NMR
C
15H17Cl3N4O2 371.0678).
(100 MHz, CDCl3)
63.36, 14.32.
d 170.37, 164.24, 149.64, 142.38, 114.80, 109.39,
1-(2,6-Dichloropyridin-4-yl)-3-(1,3-dimethyl-1H-pyrazol-5-yl)
urea (37). White solid (67 %): mp 168.3e169.6 ꢀC; 1H NMR
2-Chloro-6-isopropoxyisonicotinoyl azide (42c). White solid
(400 MHz, DMSO‑d6)
d
9.73 (s, 1H), 8.96 (s, 1H), 7.55 (s, 2H), 5.98 (s,
151.76,
(81 %). 1H NMR (400 MHz, CDCl3)
d
7.36 (d, J ¼ 1.2 Hz, 1H), 7.13 (d,
1H), 3.59 (s, 3H), 2.10 (s, 3H). 13C NMR (100 MHz, DMSO‑d6)
d
J ¼ 1.2 Hz, 1H), 5.31 (p, J ¼ 6.2 Hz, 1H), 1.36 (d, J ¼ 6.1 Hz, 6H). 13
C
151.48, 150.04, 145.92, 136.63, 111.40, 98.62, 35.32, 14.10. HRESIMS
NMR (100 MHz, CDCl3)
109.84, 70.15, 21.74.
d 170.38, 163.80, 149.56, 142.33, 114.43,
m/z 300.0423 [MþH]þ (calcd for C11H12Cl2N5O 300.0419).
1-(2-Chloropyridin-4-yl)-3-(2,6-dichloropyridin-4-yl)urea (38).
White solid (56 %): mp 200.6e201.5 ꢀC; 1H NMR (400 MHz,
2-Chloro-6-(cyclopentyloxy)isonicotinoyl azide (42d). White solid
(79 %). 1H NMR (400 MHz, CDCl3)
d
7.35 (d, J ¼ 1.2 Hz, 1H), 7.13 (d,
11