X. Jiang, B. Huang, F.A. Olotu et al.
European Journal of Medicinal Chemistry xxx (xxxx) xxx
(s, 4H, piperazine-H), 2.64e2.53 (m, 1H, CH), 2.40 (s, 4H,
piperazine-H), 2.12 (s, 6H, Ph-CH3 ꢃ 2), 1.10e0.85 (m, 4H, CH2 ꢃ 2).
54.09, 47.97, 46.99, 36.75, 28.20, 16.57 (Ph-CH3 ꢃ 2). ESI-MS: m/z
533.01 (M þ H) þ, C28H32N6O3S (532.23).
13C NMR (101 MHz, DMSO)
d 168.31, 161.02, 160.07, 154.06, 139.38,
133.24, 133.04 (Ph-C ꢃ 2), 131.11 (Ph-C ꢃ 2), 129.06 (Ph-C ꢃ 2),
4.1.6.10. (E)-3-(4-((2-((4-((4-(isopropylsulfonyl)-1,4-diazepan-1-yl)
methyl)phenyl)amino)pyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acry-
lonitrile (10e). White solid, yield: 59.4%, mp: 196e198 ꢁC. 1H NMR
119.13 (Ph-C ꢃ 2), 118.79, 108.83, 97.67, 61.55, 52.29 (piperazine-
C ꢃ 2), 46.32 (piperazine-C ꢃ 2), 25.00, 16.28 (Ph-CH3 ꢃ 2), 4.29
þ
(CH2 ꢃ 2). ESI-MS: m/z 519.10 (M þ H) þ, 541.32 (M þ Na)
,
(400 MHz, DMSO‑d6)
d
9.55 (s, 1H, NH), 8.37 (d, J ¼ 5.4 Hz, 1H,
C
27H30N6O3S (518.21).
pyrimidine-H), 7.66 (d, J ¼ 16.6 Hz, 1H, CH ¼ ), 7.53 (s, 2H, Ph-H),
7.28 (d, J ¼ 6.5 Hz, 2H, Ph-H), 6.94 (d, J ¼ 7.7 Hz, 2H, Ph-H), 6.49
(d, J ¼ 5.4 Hz, 1H, pyrimidine-H), 6.47 (d, J ¼ 16.7 Hz, 1H, CH ¼ ),
3.49 (s, 2H, CH2), 3.38 (dd, J ¼ 15.4, 9.3 Hz, 4H, diazepane-H), 3.29 (s,
1H, CH), 2.57 (s, 4H, diazepane-H), 2.09 (s, 6H, Ph-CH3 ꢃ 2), 1.75 (s,
2H, diazepane-H), 1.21 (d, J ¼ 6.6 Hz, 6H, CH3 ꢃ 2). 13C NMR
4.1.6.6. 4-((2-((4-((4-(isopropylsulfonyl)piperazin-1-yl)methyl)
phenyl)amino)pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (9i).
Yellow solid, yield: 50.4%, mp: 178e180 ꢁC. 1H NMR (400 MHz,
DMSO‑d6)
d
9.60 (s, 1H, NH), 8.40 (d, J ¼ 5.6 Hz, 1H, pyrimidine-H),
7.75 (s, 2H, Ph-H), 7.25 (d, J ¼ 6.6 Hz, 2H, Ph-H), 6.97 (d, J ¼ 8.2 Hz,
2H, Ph-H), 6.56 (d, J ¼ 5.6 Hz, 1H, pyrimidine-H), 3.39 (s, 2H, CH2),
3.28 (d, J ¼ 6.9 Hz, 1H, CH), 3.27e3.19 (m, 4H, piperazine-H), 2.36 (s,
4H, piperazine-H), 2.11 (s, 6H, Ph-CH3 ꢃ 2), 1.21 (d, J ¼ 6.8 Hz, 6H,
(101 MHz, DMSO) d 168.70, 160.76, 160.18, 152.39, 150.56, 139.36,
132.23, 131.82 (Ph-C ꢃ 2), 131.77 (Ph-C ꢃ 2), 128.67 (Ph-C ꢃ 2),
119.40 (Ph-C ꢃ 2), 118.72, 97.59, 96.70, 61.08, 56.87, 53.87, 52.01,
48.82, 47.40, 29.04,16.84 (CH3 ꢃ 2),16.56 (Ph-CH3 ꢃ 2). ESI-MS: m/z
561.05 (M þ H) þ, C30H36N6O3S (560.26).
CH3 ꢃ 2). 13C NMR (151 MHz, DMSO)
d 168.31,161.02,160.07,154.06,
139.39, 136.01, 133.24 (Ph-C ꢃ 2), 131.00 (Ph-C ꢃ 2), 129.13 (Ph-
C ꢃ 2), 119.12 (Ph-C ꢃ 2), 118.77, 108.84, 97.63, 61.68, 52.96
(piperazine-C ꢃ 2), 52.15, 46.10 (piperazine-C ꢃ 2), 16.94 (CH3 ꢃ 2),
16.28 (Ph-CH3 ꢃ 2). ESI-MS: m/z 521.08 (M þ H) þ, 543.30 (M þ Na)
þ, C27H32N6O3S (520.23).
4.1.6.11. (E)-4-(4-((4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)pyr-
imidin-2-yl)amino)benzyl)-N,N-dimethyl-1,4-diazepane-1-
sulfonamide (10f). White solid, yield: 59.4%, mp: 192e194 ꢁC. 1H
NMR (400 MHz, DMSO‑d6)
d
9.55 (s, 1H, NH), 8.37 (d, J ¼ 5.4 Hz, 1H,
pyrimidine-H), 7.65 (d, J ¼ 16.5 Hz, 1H, CH ¼ ), 7.53 (s, 2H, Ph-H),
7.28 (d, J ¼ 6.6 Hz, 2H, Ph-H), 6.94 (d, J ¼ 7.7 Hz, 2H, Ph-H), 6.50
(d, J ¼ 5.5 Hz, 1H, pyrimidine-H), 6.46 (d, J ¼ 16.8 Hz, 1H, CH ¼ ),
3.48 (s, 2H, CH2), 3.40e3.32 (m, 4H, diazepane-H), 2.69 (s, 6H,
CH3 ꢃ 2), 2.61e2.52 (m, 4H, diazepane-H), 2.09 (s, 6H, Ph-CH3 ꢃ 2),
4.1.6.7. 4-(4-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)
amino)benzyl)-N,N-dimethylpiperazine-1-sulfonamide
White solid, yield: 58.6%, mp: 190e192 ꢁC. 1H NMR (400 MHz,
DMSO‑d6)
(9j).
d
9.60 (s, 1H, NH), 8.40 (d, J ¼ 5.6 Hz, 1H, pyrimidine-H),
7.75 (s, 2H, Ph-H), 7.25 (d, J ¼ 6.6 Hz, 2H, Ph-H), 6.96 (d, J ¼ 8.3 Hz,
2H, Ph-H), 6.56 (d, J ¼ 5.6 Hz, 1H, pyrimidine-H), 3.38 (s, 2H, CH2),
3.15 (s, 4H, piperazine-H), 2.76 (s, 6H, CH3 ꢃ 2), 2.36 (s, 4H,
piperazine-H), 2.11 (s, 6H, Ph-CH3 ꢃ 2). 13C NMR (151 MHz, DMSO)
1.75 (s, 2H, diazepane-H). 13C NMR (101 MHz, DMSO)
d 168.70,
160.76, 160.17, 152.38, 150.55, 139.36, 132.16, 131.82 (Ph-C ꢃ 2),
128.85 (Ph-C ꢃ 2), 128.66 (Ph-C ꢃ 2), 119.39 (Ph-C ꢃ 2), 118.72,
97.60, 96.70, 61.18, 56.13, 54.03, 48.85, 47.68, 38.15 (CH3 ꢃ 2), 28.50,
16.56 (Ph-CH3 ꢃ 2). ESI-MS: m/z 562.07 (M þ H) þ, C29H35N7O3S
(561.25).
d
168.31, 161.11, 160.07, 154.06, 139.38, 133.24, 133.03 (Ph-C ꢃ 2),
131.02 (Ph-C ꢃ 2), 129.13 (Ph-C ꢃ 2), 119.10 (Ph-C ꢃ 2), 118.77,
108.84, 97.73, 61.66, 52.43 (piperazine-C ꢃ 2), 46.55 (piperazine-
C ꢃ 2), 38.35 (CH3 ꢃ 2), 16.28 (Ph-CH3 ꢃ 2). ESI-MS: m/z 522.08
(M þ H) þ, 544.38 (M þ Na) þ, C26H31N7O3S (521.22).
4.1.6.12. (E)-3-(4-((2-((4-((4-(ethylsulfonyl)piperazin-1-yl)methyl)
phenyl)amino)pyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acrylonitrile
(10g). White solid, yield: 53.8%, mp: 172e174 ꢁC. 1H NMR
4.1.6.8. 4-((2-((4-((4-acryloylpiperazin-1-yl)methyl)phenyl)amino)
(400 MHz, DMSO‑d6)
d
9.58 (s, 1H, NH), 8.37 (d, J ¼ 5.4 Hz, 1H,
pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (9k). White solid,
pyrimidine-H), 7.67 (d, J ¼ 16.7 Hz, 1H, CH ¼ ), 7.53 (s, 2H, Ph-H),
7.36e7.24 (m, 2H, Ph-H), 6.93 (d, J ¼ 7.5 Hz, 2H, Ph-H), 6.51 (d,
J ¼ 5.4 Hz,1H, pyrimidine-H), 6.48 (d, J ¼ 16.7 Hz,1H, CH ¼ ), 3.36 (s,
2H, CH2), 3.16 (s, 4H, piperazine-H), 3.05 (q, J ¼ 7.2 Hz, 2H, CH2),
2.36 (s, 4H, piperazine-H), 2.09 (s, 6H, Ph-CH3 ꢃ 2), 1.21 (t,
yield: 54.7%, mp: 185e187 ꢁC. 1H NMR (600 MHz, DMSO‑d6)
d 9.61
(s, 1H, NH), 8.40 (d, J ¼ 5.5 Hz, 1H, pyrimidine-H), 7.75 (s, 2H, Ph-H),
7.26 (s, 2H, Ph-H), 6.98 (d, J ¼ 7.5 Hz, 2H, Ph-H), 6.77 (dd, J ¼ 16.7,
10.5 Hz, 1H, CH ¼ ), 6.56 (d, J ¼ 5.5 Hz, 1H, pyrimidine-H), 6.10 (dd,
J ¼ 16.7, 2.2 Hz, 1H, ¼ CH2eH), 5.67 (dd, J ¼ 10.5, 2.2 Hz, 1H, ¼
CH2eH), 3.54 (d, J ¼ 13.1 Hz, 4H, piperazine-H), 3.37 (s, 2H, CH2),
2.30 (s, 4H, piperazine-H), 2.12 (s, 6H, Ph-CH3 ꢃ 2). 13C NMR
J ¼ 7.2 Hz, 3H, CH3). 13C NMR (151 MHz, DMSO)
d 168.69, 160.76,
160.15, 152.42, 150.59, 139.53, 131.81, 130.84 (Ph-C ꢃ 2), 129.21 (Ph-
C ꢃ 2), 128.68 (Ph-C ꢃ 2), 119.44 (Ph-C ꢃ 2), 118.74, 97.64, 96.71,
61.69, 52.50 (piperazine-C ꢃ 2), 45.75, 42.70 (piperazine-C ꢃ 2),
16.57 (Ph-CH3 ꢃ 2), 7.92. ESI-MS: m/z 532.77 (M þ H) þ, 555.16
(M þ Na) þ, C28H32N6O3S (532.23).
(151 MHz, DMSO)
d 168.31, 164.59, 161.01, 160.08, 154.05, 139.36,
133.23, 133.03 (Ph-C ꢃ 2), 131.05 (Ph-C ꢃ 2), 129.18 (Ph-C ꢃ 2),
128.65, 127.74, 119.11 (Ph-C ꢃ 2), 118.79, 108.84, 97.64, 61.77, 53.33
(piperazine-C ꢃ 2), 52.64 (piperazine-C ꢃ 2), 16.28 (Ph-CH3 ꢃ 2).
ESI-MS: m/z 467.37 (M ꢂ H) -, C27H28N6O2 (468.23).
4.1.6.13. (E)-3-(4-((2-((4-((4-(cyclopropylsulfonyl)piperazin-1-yl)
methyl)phenyl)amino)pyrimidin-4-yl)oxy)-3,5-dimethylphenyl)acry-
lonitrile (10h). White solid, yield: 57.9%, mp: 172e174 ꢁC. 1H NMR
4.1.6.9. (E)-3-(3,5-dimethyl-4-((2-((4-((4-(methylsulfonyl)-1,4-
diazepan-1-yl)methyl)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)
acrylonitrile (10d). White solid, yield: 61.2%, mp: 145e147 ꢁC. 1H
(400 MHz, DMSO‑d6)
d
9.58 (s, 1H, NH), 8.37 (d, J ¼ 5.5 Hz, 1H,
pyrimidine-H), 7.67 (d, J ¼ 16.6 Hz, 1H, CH ¼ ), 7.53 (s, 2H, Ph-H),
7.30 (d, J ¼ 5.2 Hz, 2H, Ph-H), 6.94 (d, J ¼ 7.6 Hz, 2H, Ph-H), 6.51
(d, J ¼ 5.4 Hz, 1H, pyrimidine-H), 6.48 (d, J ¼ 16.7 Hz, 1H, CH ¼ ),
3.37 (s, 2H, CH2), 3.18 (s, 4H, piperazine-H), 2.59 (tt, J ¼ 8.4, 5.2 Hz,
1H, CH), 2.38 (s, 4H, piperazine-H), 2.09 (s, 6H, Ph-CH3 ꢃ 2), 0.99 (d,
J ¼ 7.3 Hz, 2H, CH2), 0.95e0.89 (m, 2H, CH2). 13C NMR (101 MHz,
NMR (600 MHz, DMSO‑d6)
d
9.57 (s, 1H, NH), 8.37 (d, J ¼ 5.0 Hz, 1H,
pyrimidine-H), 7.66 (d, J ¼ 16.7 Hz, 1H, CH ¼ ), 7.53 (s, 2H, Ph-H),
7.29 (s, 2H, Ph-H), 6.95 (s, 2H, Ph-H), 6.51 (d, J ¼ 4.7 Hz, 1H,
pyrimidine-H), 6.47 (d, J ¼ 16.7 Hz,1H, CH ¼ ), 3.49 (s, 2H, CH2), 3.31
(s, 4H, diazepane-H), 2.88 (s, 3H, CH3), 2.57 (d, J ¼ 15.5 Hz, 4H,
diazepane-H), 2.09 (s, 6H, Ph-CH3 ꢃ 2), 1.76 (s, 2H, diazepane-H).
DMSO)
d 168.70, 160.75, 160.17, 152.35, 150.58, 139.54, 131.81,
13C NMR (151 MHz, DMSO)
d
168.69, 160.77, 160.16, 152.39,
130.88 (Ph-C ꢃ 2), 129.21 (Ph-C ꢃ 2), 128.69 (Ph-C ꢃ 2), 119.42 (Ph-
C ꢃ 2), 118.77, 97.65, 96.71, 61.69, 52.29 (piperazine-C ꢃ 2), 46.32
(piperazine-C ꢃ 2), 25.11, 16.56 (Ph-CH3 ꢃ 2), 4.31 (CH2 ꢃ 2). ESI-
150.58, 139.37, 131.82, 131.76 (Ph-C ꢃ 2), 128.88 (Ph-C ꢃ 2), 128.67
(Ph-C ꢃ 2), 119.43 (Ph-C ꢃ 2), 118.72, 97.59, 96.69, 61.21, 55.81,
14