Q. Liu et al.
Bioorganic & Medicinal Chemistry 36 (2021) 116094
2-(3-(2-((4-Fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-
2.85 (s, 3H), 2.42–2.44 (m, 2H), 2.30 (s, 1H), 2.18 (s, 6H). ESI-MS: 470.2
[M+H]+.
4-yl)-1H-indol-1-yl)ethan-1-ol (3b-4). Yield 68%, brown foam.
1HNMR (400 MHz, CD3OD): δ 8.25 (d, 1H), 8.26–8.28 (m, 1H), 7.89 (s,
1H), 7.60 (s, 1H), 7.44–7.46 (m, 1H), 7.22–7.26 (m, 2H), 7.05–7.14 (m,
2H), 4.24 (t, 2H), 3.74 (t, 2H), 3.69 (s, 3H). ESI-MS: 424.1 [M+H]+.
3-(2-((4-Fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-
yl)-N,N-dimethyl-1H-indole-1-sulfonamide (3b-5). Yield 44%,
brown foam. 1HNMR (400 MHz, CD3OD): δ 8.31–8.33 (m, 1H),
8.24–8.26 (m, 1H), 8.07–8.09 (m, 1H), 7.86 (s, 1H), 7.71–7.75 (m, 1H),
7.41–7.46 (m, 2H), 7.16 (s, 1H), 7.07 (s, 1H), 3.69 (s, 3H), 2.70 (s, 6H).
ESI-MS: 487.0 [M+H]+.
2-(3-(2-((5-Amino-4-((2-(dimethylamino)ethyl)(methyl)
amino)-2-methoxyphenyl)amino) pyrimidin-4-yl)-1H-indol-1-yl)
ethan-1-ol (5b-4). Yield 50%, brown oil. 1HNMR (400 MHz, CD3OD): δ
8.27–8.31 (m, 2H), 7.66 (s, 1H), 7.44–7.46 (m, 1H), 7.25–7.28 (m, 1H),
7.15–7.20 (m, 2H), 6.40 (s, 1H), 6.10 (s, 1H), 4.29 (t, 2H), 3.74 (t, 2H),
3.45 (s, 3H), 3.15–3.18 (m, 2H), 2.88 (s, 3H), 2.42–2.44 (m, 2H), 2.18 (s,
6H). ESI-MS: 476.2 [M+H]+.
3-(2-((5-Amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-
methoxyphenyl)amino)pyrimidin-4-yl)-N,N-dimethyl-1H-indole-1-
sulfonamide (5b-5). Yield 41%, brown oil. 1HNMR (400 MHz, CD3OD):
δ 8.30–8.35 (m, 2H), 8.07–8.09 (m, 1H), 7.73–7.75 (m, 1H), 7.41–7.46
(m, 2H), 7.15 (s, 1H), 6.44 (s, 1H), 6.12 (s, 1H), 3.48 (s, 3H), 3.15–3.18
(m, 2H), 2.88 (s, 3H), 2.79 (s, 6H), 2.43–2.47 (m, 2H), 2.21 (s, 6H). ESI-
MS: 539.2 [M+H]+.
1-(3-(2-((4-Fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-
4-yl)-1H-indol-1-yl)ethan-1-one (3b-6). Yield 70%, brown foam.
1HNMR (400 MHz, CD3OD): δ 8.34–8.37 (m, 2H), 7.98–8.00 (m, 1H),
7.89 (s, 1H), 7.49–7.53 (m, 3H), 7.43 (d, 1H), 7.07 (s, 1H), 3.69 (s, 3H),
2.44 (s, 3H). ESI-MS: 422.0 [M+H]+.
N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-(oxetan-3-yl)-1H-
indol-3-yl)pyrimidin-2-amine (3b-7). Yield 60%, brown foam.
1HNMR (400 MHz, CD3OD): δ 8.33 (d, 1H), 8.25 (d, 1H), 7.86 (s, 1H),
7.63 (s, 1H), 7.28–7.30 (m, 1H), 7.18–7.20 (m, 2H), 7.09–7.13 (m, 2H),
5.06–5.08 (m, 1H), 4.86–4.90 (m, 4H), 3.70 (s, 3H). ESI-MS: 436.1
[M+H]+.
1-(3-(2-((5-Amino-4-((2-(dimethylamino)ethyl)(methyl)
amino)-2-methoxyphenyl)amino) pyrimidin-4-yl)-1H-indol-1-yl)
ethan-1-one (5b-6). Yield 40%, brown oil. 1HNMR (400 MHz, CD3OD):
δ 8.30 (d, 1H), 7.97–8.01 (m, 2H), 7.43–7.53 (m, 4H), 6.35 (s, 1H), 6.02
(s, 1H), 3.48 (s, 3H), 3.15–3.18 (m, 2H), 2.88 (s, 3H), 2.58 (s, 3H),
2.43–2.47 (m, 2H), 2.20 (s, 6H). ESI-MS: 474.2 [M+H]+.
N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-
(oxetan-3-yl)-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-tri-
amine (5b-7). Yield 48%, yellow oil. 1HNMR (400 MHz, CD3OD): δ
8.26–8.31 (m, 2H), 7.63 (s, 1H), 7.20–7.26 (m, 3H), 7.09–7.11 (m, 1H),
6.44 (s, 1H), 6.06 (s, 1H), 4.96–4.98 (m, 1H), 4.84–4.88 (m, 4H), 3.49 (s,
3H), 3.15–3.18 (m, 2H), 2.88 (s, 3H), 2.43–2.47 (m, 2H), 2.20 (s, 6H).
ESI-MS: 488.3 [M+H]+.
4.4. General procedure for the synthesis of compounds 5a-1, 5a-2, 5b-
1~5b-7
Compound 3 (1 mmol) and N,N,N′-trimethylethane-1,2-diamine (1
mmol) were dissolved in 20 mL of DMA and the obtained solution was
heated to 140 ◦C and stirred for 5 h. thereafter, the solvent was removed
under reduced pressure; the residue was dissolved in MeOH, to which
catalytic amount of Pd/C was added. With the input of H2 gas the re-
action mixture was kept stirring for 3 h. Then the mixture was filtrated
and the product was obtained via column chromatography (CH2Cl2:
CH3OH = 10: 1).
4.5. General procedure for the synthesis of compounds 6a-1, 6a-2, 6b-
1~6b-7
Compound 5 (1 mmol) and DIPEA (1.1 mmol) were added into 20 mL
of THF and the obtained solution was cooled to 0 ◦C. Then acryloyl
chloride (1.1 mmol) was added dropwise. The reaction solution was
stirred for 5 h. Thereafter, the solvent was removed under reduced
pressure and the product was obtained via column chromatography
(CH2Cl2: CH3OH = 10: 1).
N4-(4-(1-Cyclopropyl-1H-indol-3-yl)-5-(trifluoromethyl)pyr-
imidin-2-yl)-N1-(2-(dimethylamino) ethyl)-5-methoxy-N1-methyl-
benzene-1,2,4-triamine (5a-1). Yield 50%, brown oil. 1HNMR (400
MHz, CD3OD): δ 8.50–8.55 (m, 2H), 7.06–7.17 (m, 4H), 6.41 (s, 1H),
6.08 (s, 1H), 3.48 (s, 3H), 3.16–3.18 (m, 2H), 2.94–2.96 (m, 1H), 2.86 (s,
3H), 2.42–2.44 (m, 2H), 2.18 (s, 6H), 1.14–1.29 (m, 4H). ESI-MS: 540.3
[M+H]+.
N-(5-((4-(1-Cyclopropyl-1H-indol-3-yl)-5-(trifluoromethyl)pyr-
imidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-
4-methoxyphenyl)acrylamide (6a-1). Yield 90%, yellow oil. 1HNMR
(400 MHz, CD3OD): δ 8.46 (d, 1H), 8.35–8.37 (m, 1H), 7.09–7.18 (m,
4H), 6.29–6.42 (m, 3H), 6.13 (s, 1H), 5.65–5.67 (m, 1H), 3.49 (s, 3H),
3.16–3.18 (m, 2H), 2.94–2.97 (m, 2H), 2.86 (s, 3H), 2.42–2.45 (m, 2H),
2.18 (s, 6H), 1.14–1.29 (m, 4H). 13CNMR (100 MHz, CD3OD): δ 165.4,
164.2, 163.3 (q), 156.9 (q), 139.2, 137.4, 136.8, 135.8, 133.7, 132.9,
130.0, 129.8, 123.3, 122.5, 120.7, 120.6, 120.1 (q), 119.2 (q), 116.5,
109.7, 101.0, 100.1, 55.6, 53.2, 50.5, 45.6 (2C), 40.2, 28.4, 7.7 (2C).
HR-MS(ESI) calcd for [M+H]+ = 594.2726, found 594.2732.
N1-(2-(Dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-
(oxetan-3-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)
benzene-1,2,4-triamine (5a-2). Yield 55%, yellow oil. 1HNMR (400
MHz, CD3OD): δ 8.73 (s, 1H), 8.47–8.49 (m, 1H), 7.41 (s, 1H), 7.27–7.35
(m, 2H), 7.09–7.11 (m, 1H), 6.40 (s, 1H), 6.11 (s, 1H), 4.96–4.98 (m,
1H), 4.84–4.88 (m, 4H), 3.48 (s, 3H), 3.15–3.18 (m, 2H), 2.88 (s, 3H),
2.42–2.44 (m, 2H), 2.18 (s, 6H). ESI-MS: 556.2 [M+H]+.
N4-(4-(1-Cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)-N1-(2-
(dimethylamino)ethyl)-5-methoxy-N1-methylbenzene-1,2,4-tri-
amine (5b-1). Yield 53%, orange oil. 1HNMR (400 MHz, CD3OD): δ
8.28–8.30 (m, 1H), 8.11–8.12 (m, 1H), 7.34 (s, 1H), 7.09–7.15 (m, 2H),
7.01–7.04 (m, 2H), 6.41 (s, 1H), 6.10 (s, 1H), 3.48 (s, 3H), 3.15–3.18 (m,
2H), 2.94–2.96 (m, 1H), 2.88 (s, 3H), 2.42–2.44 (m, 2H), 2.18 (s, 6H),
1.19–1.27 (m, 4H). ESI-MS: 472.2 [M+H]+.
N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-
((4-(1-(oxetan-3-yl)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-
2-yl)amino)phenyl)acrylamide (6a-2). Yield 88%, yellow foam.
1HNMR (400 MHz, CD3OD): δ 8.73 (s, 1H), 8.48–8.50 (m, 1H), 8.46 (s,
1H), 7.24–7.33 (m, 2H), 7.16 (s, 1H), 7.09–7.13 (m, 1H), 6.29–6.36 (m,
2H), 6.16 (s, 1H), 5.64–5.67 (m, 1H), 4.95–4.99 (m, 1H), 4.82–4.86 (m,
4H), 3.47 (s, 3H), 3.01–3.04 (m, 2H), 2.94–2.97 (m, 2H), 2.76 (s, 3H),
2.42–2.45 (m, 2H), 2.18 (s, 6H). 13CNMR (100 MHz, CD3OD): δ 164.2,
162.1, 160.8 (q), 155.5 (q), 139.2, 138.4, 136.7, 136.5, 133.7, 131.7,
130.0, 129.8, 123.5, 122.3, 120.5, 120.0 (q), 118.3 (q), 115.3, 110.9,
101.0, 100.2, 71.4 (2C), 55.6, 53.2, 53.0, 50.5, 40.5 (2C), 40.2. HR-MS
(ESI) calcd for [M+H]+ = 610.2675, found 610.2670.
N4-(4-(1-Allyl-1H-indol-3-yl)pyrimidin-2-yl)-N1-(2-(dimethyla-
mino)ethyl)-5-methoxy-N1-methylbenzene-1,2,4-triamine (5b-2).
Yield 51%, brown oil. 1HNMR (400 MHz, CD3OD): δ 8.33–8.39 (m, 2H),
7.71 (s, 1H), 7.22–7.35 (m, 4H), 6.41 (s, 1H), 6.02–6.08 (m, 2H),
5.23–5.31 (m, 2H), 4.86 (br, 2H), 3.45 (s, 3H), 3.15–3.17 (m, 2H), 2.88
(s, 3H), 2.42–2.44 (m, 2H), 2.18 (s, 6H). ESI-MS: 472.2 [M+H]+.
N1-(2-(Dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-
(prop-2-yn-1-yl)-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-tri-
amine (5b-3). Yield 78%, yellow oil. 1HNMR (400 MHz, CD3OD): δ
8.37–8.41 (m, 2H), 7.51 (s, 1H), 7.36–7.38 (m, 1H), 7.14–7.20 (m, 3H),
6.38 (s, 1H), 6.11 (s, 1H), 4.95 (s, 2H), 3.46 (s, 3H), 3.15–3.17 (m, 2H),
N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-
((2-(dimethylamino)ethyl)
(methyl)amino)-4-methoxyphenyl)
acrylamide (6b-1). Yield 85%, yellow oil. 1HNMR (400 MHz, CD3OD):
δ 8.28–8.31 (m, 1H), 8.11 (d, 1H), 7.11–7.30 (m, 4H), 7.02 (d, 1H),
7