Z. Fu et al.
Bioorganic & Medicinal Chemistry 42 (2021) 116239
4.1.9.2. 2-((4-(3-(4-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-
3,5-dimethylphenyl)prop-2-yn-1-ylidene)piperidin-1-yl)methyl)benzonitrile
(FS4). Brown powder, 40 mg, yield: 55%, purity: 97%, mp: 169–171 ◦C;
1H NMR (400 MHz, DMSO‑d6): δ 10.14 (s, 1H, NH), 8.47 (d, J = 5.6 Hz,
1H, C6-pyrimidine-H), 7.82 (d, J = 7.6 Hz, 1H, Ph-H), 7.69 (t, J = 8.3
Hz, 1H, Ph-H), 7.60 (dd, J = 12.8, 8.3 Hz, 3H, Ph-H), 7.47 (d, J = 7.4 Hz,
3H, Ph-H), 7.32 (s, 2H, Ph-H), 6.64 (d, J = 5.6 Hz, 1H, C5-pyrimidine-
H), 5.62 (s, 1H, CH), 3.70 (s, 2H, CH2), 2.56 (s, 2H, CH2), 2.34 (t, J =
4.7 Hz, 2H), 2.05 (s, 6H, 2 × CH3). 13C NMR (100 MHz, DMSO‑d6) δ
168.8, 160.9, 159.6, 153.0, 150.0, 145.0, 142.7, 133.5, 133.0, 131.9,
131.6, 130.5, 128.4, 120.9, 119.8, 118.7, 118.2, 112.5, 103.1, 103.0,
99.3, 91.7, 87.0, 59.8, 54.5, 53.9, 34.8, 31.3, 16.3. EI-HRMS: m/z
[M+H]+ calcd for C35H30N6O: 551.2554, found: 551.2552.
4.1.10.2. 4-((4-(4-(3-(1-(ethylsulfonyl)piperidin-4-ylidene)prop-1-yn-1-
yl)-2,6-dimethylphenoxy) pyrimidin-2-yl)amino)benzonitrile (FS8). Light
yellow powder, 39 mg, yield: 55%, purity: 99%, mp: 211–214 ◦C; 1H
NMR (400 MHz, DMSO‑d6): δ 10.16 (s, 1H, NH), 8.47 (d, J = 5.6 Hz, 1H,
C6-pyrimidine-H), 7.57 (d, J = 8.6 Hz, 2H, Ph-H), 7.47 (d, J = 8.7 Hz,
2H, Ph-H), 7.35 (s, 2H, Ph-H), 6.65 (d, J = 5.6 Hz, 1H, C5-pyrimidine-
H), 5.76 (s, 1H, CH), 3.37–3.30 (m, 2H, CH2), 3.30–3.19 (m, 2H,
CH2), 3.07 (q, J = 7.3 Hz, 2H, CH2), 2.63 (t, J = 5.6 Hz, 2H, CH2),
2.47–2.35 (m, 2H, CH2), 2.06 (s, 6H, 2 × CH3), 1.22 (t, J = 7.4 Hz, 3H,
CH3). 13C NMR (100 MHz, DMSO‑d6): δ 168.8, 160.9, 159.6, 150.7,
150.2, 145.0, 133.0, 131.9, 131.7, 120.7, 119.9, 118.7, 104.8, 102.9,
99.3, 92.3, 86.6, 46.9, 46.3, 43.7, 34.7, 31.3, 16.3, 8.0. EI-HRMS: m/z
[M+H]+ calcd for C29H29N5O3S: 528.2064, found: 528.2060.
4.1.9.3. Methyl 4-((4-(3-(4-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)
4.1.10.3. 4-((4-(4-(3-(1-(cyclopropylsulfonyl)piperidin-4-ylidene)prop-1-
yn-1-yl)-2,6-dimethylphenoxy)pyrimidin-2-yl)amino)benzonitrile (FS9).
White powder, 46 mg, yield: 53%, purity: 97%, mp: 190–193 ◦C; 1H
NMR (400 MHz, DMSO‑d6): δ 10.17 (s, 1H, NH), 8.47 (d, J = 5.6 Hz, 1H,
C6-pyrimidine-H), 7.56 (d, J = 8.5 Hz, 2H, Ph-H), 7.47 (d, J = 8.7 Hz,
2H, Ph-H), 7.35 (s, 2H, Ph-H), 6.66 (d, J = 5.6 Hz, 1H, C5-pyrimidine-
H), 5.76 (s, 1H, CH), 3.30 (t, J = 5.7 Hz, 2H, CH2), 2.66 (t, J = 5.4
Hz, 2H, CH2), 2.63–2.58 (m, 1H, CH), 2.43 (t, J = 5.3 Hz, 2H, CH2), 2.06
oxy)-3,5-dimethylphenyl)
prop-2-yn-1-ylidene)piperidin-1-yl)methyl)
benzoate (FS5). White powder, 45 mg, yield: 52%, purity: 99%, mp:
197–199 ◦C; 1H NMR (400 MHz, DMSO‑d6): δ 10.14 (s, 1H, NH), 8.46 (d,
J = 5.6 Hz, 1H, C6-pyrimidine-H), 7.93 (d, J = 8.2 Hz, 2H, Ph-H), 7.57
(d, J = 8.6 Hz, 2H, Ph-H), 7.48 (t, J = 7.6 Hz, 4H, Ph-H), 7.32 (s, 2H, Ph-
H), 6.64 (d, J = 5.6 Hz, 1H, C5-pyrimidine-H), 5.61 (s, 1H, CH), 3.85 (s,
3H, CH3), 3.60 (s, 2H, CH2), 2.57 (d, J = 5.1 Hz, 2H, CH2), 2.48–2.42 (m,
2H, CH2), 2.34 (d, J = 5.0 Hz, 2H, CH2), 2.05 (s, 6H, 2 × CH3). 13C NMR
(100 MHz, DMSO‑d6): δ 168.8, 166.6, 160.9, 159.6, 153.3, 150.0, 145.0,
144.8, 133.0, 131.9, 131.6, 129.6, 129.3, 128.8, 120.9, 119.8, 118.7,
103.0, 99.3, 91.6, 87.1, 61.5, 54.5, 54.0, 52.5, 34.8, 31.4, 16.3. EI-
HRMS: m/z [M+H]+ calcd for C36H33N5O3: 584.2654, found: 584.2658.
(s, 6H, 2 × CH3), 1.03–0.97 (m, 2H, CH2), 0.97–0.90 (m, 2H, CH2). 13
C
NMR (100 MHz, DMSO‑d6): δ 168.8, 161.0, 159.6, 150.6, 150.2, 145.0,
133.0, 132.0, 131.7, 120.7, 119.9, 118.7, 104.7, 102.9, 99.3, 92.3, 86.5,
47.5, 46.9, 34.4, 31.0, 26.1, 16.3, 4.5. EI-HRMS: m/z [M+H]+ calcd for
C30H29N5O3S: 540.2064, found: 540.2063.
4.1.9.4. 4-((4-(2,6-dimethyl-4-(3-(1-(pyridin-2-ylmethyl)piperidin-4-yli-
dene)prop-1-yn-1-yl)phenoxy)pyrimidin-2-yl)amino)benzonitrile (FS6).
Yellow powder, 45 mg, yield: 56%, purity: 98%, mp: 138–140 ◦C; 1H
NMR (400 MHz, DMSO‑d6): δ 10.15 (s, 1H, NH), 8.50 (d, J = 4.3 Hz, 1H,
pyridine-H), 8.47 (d, J = 5.6 Hz, 1H, C6-pyrimidine-H), 7.78 (td, J = 7.7,
1.7 Hz, 1H, pyridine-H), 7.59 (d, J = 8.6 Hz, 2H, Ph-H), 7.49 (s, 2H, Ph-
H), 7.47 (d, J = 2.3 Hz, 1H, pyridine-H), 7.32 (s, 2H, Ph-H), 7.27 (dd, J
= 6.7, 5.2 Hz, 1H, pyridine-H), 6.64 (d, J = 5.6 Hz, 1H, C5-pyrimidine-
H), 5.61 (s, 1H, CH), 3.65 (s, 2H, CH2), 2.64 – 2.54 (m, 2H, CH2), 2.49 (d,
J = 6.1 Hz, 2H, CH2), 2.34 (t, J = 5.1 Hz, 2H, CH2), 2.05 (s, 6H, 2 × CH3).
13C NMR (100 MHz, DMSO‑d6): δ 168.8, 160.9, 159.6, 159.0, 153.3,
150.0, 149.2, 145.0, 137.0, 133.0, 131.9, 131.6, 123.1, 122.6, 120.9,
119.8, 118.7, 103.0, 99.3, 91.6, 87.1, 63.7, 54.6, 54.2, 34.9, 31.4, 16.3.
EI-HRMS: m/z [M+H]+ calcd for C33H30N6O: 527.2554, found:
527.2552.
4.1.10.4. 4-(3-(4-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-3,5-
dimethylphenyl)prop-2-yn-1-ylidene)-N,N-dimethylpiperidine-1-sulfon-
amide (FS10). Light brown powder, 39 mg, yield: 52%, purity: 97%, mp:
206–208 ◦C; 1H NMR (400 MHz, DMSO‑d6): δ 10.17 (s, 1H, NH), 8.47 (d,
J = 5.6 Hz, 1H, C6-pyrimidine-H), 7.57 (d, J = 8.5 Hz, 2H, Ph-H), 7.47
(d, J = 8.7 Hz, 2H, Ph-H), 7.35 (s, 2H, Ph-H), 6.65 (d, J = 5.6 Hz, 1H, C5-
pyrimidine-H), 5.74 (s, 1H, CH), 3.32 (d, J = 5.9 Hz, 2H, CH2),
3.31–3.19 (m, 2H, CH2), 2.77 (s, 6H, 2 × CH3), 2.62 (t, J = 5.6 Hz, 2H,
CH2), 2.39 (t, J = 5.3 Hz, 2H, CH2), 2.06 (s, 6H, 2 × CH3). 13C NMR (100
MHz, DMSO‑d6): δ 168.8, 160.9, 159.6, 150.8, 150.2, 145.0, 133.0,
131.9, 131.7, 120.7, 119.9, 118.7, 104.6, 102.9, 99.3, 92.3, 86.6, 47.7,
47.2, 38.3, 34.6, 31.2, 16.3. EI-HRMS: m/z [M+H]+ calcd for
C29H30N6O3S: 543.2173, found: 543.2168.
4.1.10.5. 4-((4-(4-(3-(1-(isopropylsulfonyl)piperidin-4-ylidene)prop-1-
yn-1-yl)-2,6-dimethylphenoxy) pyrimidin-2-yl)amino)benzonitrile (FS11).
White powder, 49 mg, yield: 55%, purity: 96%, mp: 199–202 ◦C; 1H
NMR (400 MHz, DMSO‑d6): δ 10.16 (s, 1H, NH), 8.47 (d, J = 5.6 Hz, 1H,
C6-pyrimidine-H), 7.57 (d, J = 8.6 Hz, 2H, Ph-H), 7.47 (d, J = 8.7 Hz,
2H, Ph-H), 7.35 (s, 2H, Ph-H), 6.65 (d, J = 5.6 Hz, 1H, C5-pyrimidine-
H), 5.74 (s, 1H, CH), 3.41–3.37 (m, 2H, CH2), 3.31 (d, J = 6.8 Hz, 2H,
CH2), 2.68–2.57 (m, 2H, CH2), 2.47–2.27 (m, 2H, CH2), 2.06 (s, 6H, 2 ×
CH3), 1.23 (d, J = 6.8 Hz, 6H, 2 × CH3). 13C NMR (150 MHz, DMSO‑d6):
δ 168.8, 160.9, 159.6, 150.9, 150.2, 145.0, 133.0, 131.9, 131.7, 120.7,
119.9, 118.7, 104.7, 102.9, 99.3, 92.4, 86.6, 52.6, 47.3, 46.7, 35.3, 31.9,
16.9, 16.3. EI-HRMS: m/z [M+H]+ calcd for C30H31N5O3S: 542.2220,
found: 542.2218.
4.1.10. General procedure for synthesis of target compounds (FS7-15)
In a Schlenk-type flask, FS2 (1.0 equiv.), acyl compounds or sulfonyl
compounds (1.0 equiv.) and K2CO3 (1.2 equiv.) were dissolved in DMF
stirring for 10 h at room temperature. The products were obtained by
vacuum distillation from the reaction liquid. Purification on silica gel
gave the target compounds FS7-15, which were recrystallized using an
acetate/petroleum ether system.
4.1.10.1. 4-((4-(2,6-dimethyl-4-(3-(1-(methylsulfonyl)piperidin-4-yli-
dene)prop-1-yn-1-yl)phenoxy) pyrimidin-2-yl)amino)benzonitrile (FS7).
White powder, 38 mg, yield: 46%, purity: 99%, mp: 209–211 ◦C; 1H
NMR (400 MHz, DMSO‑d6): δ 10.18 (s, 1H, NH), 8.47 (d, J = 5.6 Hz, 1H,
C6-pyrimidine-H), 7.57 (d, J = 8.5 Hz, 2H, Ph-H), 7.47 (d, J = 8.7 Hz,
2H, Ph-H), 7.35 (s, 2H, Ph-H), 6.65 (d, J = 5.6 Hz, 1H, C5-pyrimidine-
H), 5.76 (s, 1H, CH), 3.30–3.24 (m, 2H, CH2), 3.22 (t, J = 5.6 Hz, 2H,
CH2), 2.90 (s, 3H, CH3), 2.66 (t, J = 5.5 Hz, 2H, CH2), 2.44 (t, J = 5.3 Hz,
2H, CH2), 2.06 (s, 6H, 2 × CH3). 13C NMR (100 MHz, DMSO‑d6): δ 168.8,
160.9, 159.6, 150.5, 150.2, 145.0, 133.0, 131.9, 131.7, 120.7, 119.9,
118.7, 104.7, 102.9, 99.3, 92.3, 86.5, 47.1, 46.5, 35.2, 34.2, 30.8, 16.3.
EI-HRMS: m/z [M+Na]+ calcd for C28H27N5O3S: 536.1727, found:
536.1718.
4.1.10.6. Ethyl
2-(4-(3-(4-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)
oxy)-3,5-dimethylphenyl)prop-2-yn-1-ylidene)piperidin-1-yl)acetate
(FS12). Light yellow powder, 40 mg, yield: 55%, purity: 95%, mp:
101–104 ◦C; 1H NMR (400 MHz, DMSO‑d6): δ 8.33 (d, J = 5.6 Hz, 1H,
C6-pyrimidine-H), 7.71 (d, J = 8.5 Hz, 2H, Ph-H), 7.44 (d, J = 8.5 Hz,
2H, Ph-H), 7.21 (s, 2H, Ph-H), 6.60 (d, J = 5.6 Hz, 1H, C5-pyrimidine-
H), 5.58 (s, 1H, CH), 4.42 (s, 2H, CH2), 4.09 (q, J = 7.1 Hz, 1H, CH),
3.98 (q, J = 7.1 Hz, 1H, CH), 2.60–2.55 (m, 2H, CH2), 2.55–2.50 (m, 4H,
2 × CH2), 2.30 (t, J = 5.2 Hz, 2H, CH2), 2.19–1.45 (m, 6H, 2 × CH3),
9