X. Deng, et al.
BioorganicChemistryxxx(xxxx)xxxx
crude product. The crude product was purified by chromatography
(dichloromethane/methanol, 100:1 ~ 20:1) to afford amide 16a. The
Boc group of 16a was removed by using a similar procedure for the
preparation of compound 6 to afford compound 17a as white solid
(336 mg, yield 49%). HPLC purity: 95.6%; mp: 186.0–188.0 °C; 1H NMR
(500 MHz, DMSO‑d6) δ 8.40 (s, 3H), 8.32 – 8.27 (m, 1H), 7.51 – 7.42
(m, 1H), 7.24 – 7.11 (m, 2H), 5.29 (s, 1H), 5.02 (s, 2H), 4.71 – 4.59 (m,
1H), 4.55 – 4.38 (m, 1H), 3.40 – 3.37 (m, 1H), 3.35 – 3.32 (m, 1H), 3.18
– 3.08 (m, 1H), 3.05 – 2.97 (m, 1H), 2.95 – 2.87 (m, 1H), 2.77 (d,
J = 4.6 Hz, 3H), 2.03 – 1.87 (m, 2H), 1.79 (t, J = 2.3 Hz, 3H), 1.70 –
1.60 (m, 2H); 13C NMR (126 MHz, DMSO‑d6) δ 164.56, 162.09, 157.16
(d, J = 249.9 Hz), 156.18, 152.04, 130.45 (d, J = 4.4 Hz), 129.04 (d,
J = 3.0 Hz), 125.13 (d, J = 15.4 Hz), 124.84 (d, J = 15.2 Hz), 124.56
(d, J = 3.8 Hz), 88.70, 80.29, 74.98, 52.59, 51.82, 46.46, 38.14, 36.23,
52.58, 51.85, 46.44, 38.02, 36.18, 34.51, 27.40, 21.65, 15.24, 3.59; MS
(ESI) m/z: 442.39 [M+H]+
.
4.1.24. (R)-3-((4-(3-aminopiperidin-1-yl)-3-(but-2-yn-1-yl)-2,6-dioxo-
3,6-dihydropyrimidin-1(2H)-yl)methyl)-6-fluoro-N-methylbenzamide
(17e)
Following a similar procedure for the preparation of 17a. 17e was
prepared starting from compound 15c and methylamine hydrochloride.
The Boc group was removed by using the procedure described for
compound 10b. Compound 17e, white solid (350 mg, 42%); HPLC
purity: 99.2%; mp: 185.7–187.7 °C; 1H NMR (500 MHz, DMSO‑d6) δ
8.23 (s, 1H), 7.52 (dd, J = 6.9, 2.3 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.23
(dd, J = 10.4, 8.5 Hz, 1H), 5.19 (s, 1H), 4.93 (s, 2H), 4.51 – 4.43 (m,
2H), 3.25 – 3.20 (m, 1H), 3.19 – 3.10 (m, 2H), 2.86 – 2.78 (m, 1H), 2.76
(d, J = 4.5 Hz, 3H), 2.72 – 2.62 (m, 1H), 2.46 – 2.38 (m, 1H), 1.86 –
1.79 (m, 1H), 1.78 (t, J = 2.3 Hz, 3H), 1.76 – 1.68 (m, 1H), 1.61 – 1.52
(m, 1H); 13C NMR (126 MHz, DMSO‑d6) δ 164.35, 162.19, 159.52,
158.65 (d, J = 248.0 Hz), 152.03, 134.00, 132.32 (d, J = 8.6 Hz),
129.87, 124.31 (d, J = 15.4 Hz), 116.45 (d, J = 23.0 Hz), 88.85, 80.28,
74.95, 52.59, 51.80, 46.45, 43.20, 36.09, 27.43, 26.71, 21.74, 3.60; MS
27.48, 26.69, 21.80, 3.64. MS (ESI) m/z: 428.32 [M+H]+
.
4.1.21. (R)-3-((4-(3-aminopiperidin-1-yl)-3-(but-2-yn-1-yl)-2,6-dioxo-
3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-ethyl-2-fluorobenzamide
hydrochloride (17b)
Following a similar procedure for the preparation of 17a. 17b was
prepared starting from compound 15a and ethylamine. White solid
(136 mg, yield 47%). HPLC purity: 96.8%; mp: 169.5 °C −171.5 °C; 1H
NMR (500 MHz, DMSO‑d6) δ 8.44 (s, 3H), 8.37 (t, J = 5.8 Hz, 1H), 7.52
– 7.37 (m, 1H), 7.23 – 7.13 (m, 2H), 5.29 (s, 1H), 5.11 – 4.92 (m, 2H),
4.66 (d, J = 17.4 Hz, 1H), 4.51 – 4.39 (m, 1H), 3.39 – 3.32 (m, 2H),
3.31 – 3.22 (m, 2H), 3.17 – 3.05 (m, 1H), 3.04 – 2.95 (m, 1H), 2.94 –
2.84 (m, 1H), 2.04 – 1.87 (m, 2H), 1.79 (t, J = 2.3 Hz, 3H), 1.70 – 1.58
(m, 2H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, DMSO‑d6) δ
163.90, 162.08, 159.62, 157.11 (d, J = 249.7 Hz), 152.03, 130.29 (d,
J = 4.1 Hz), 128.95 (d, J = 3.2 Hz), 125.18 (d, J = 7.7 Hz), 125.05 (d,
J = 7.8 Hz), 124.51 (d, J = 3.9 Hz), 88.70, 80.27, 74.97, 52.58, 51.82,
46.46, 38.13, 36.23, 34.49, 27.48, 21.80, 15.08, 3.64; MS (ESI) m/z:
(ESI) m/z: 428.17 [M+H]+
.
4.1.25. (R)-3-((4-(3-aminopiperidin-1-yl)-3-(but-2-yn-1-yl)-2,6-dioxo-
3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-ethyl-6-fluorobenzamide
hydrochloride (17f)
Following a similar procedure for the preparation of 17a. 17f was
prepared starting from compound 15c and ethanamine. White solid
(154 mg, yield 49%). HPLC purity: 96.0%; mp: 180.3–182.3 °C; 1H NMR
(500 MHz, DMSO‑d6) δ 8.39 (s, 3H), 8.31 (d, J = 2.5 Hz, 1H), 7.51 (dd,
J = 6.9, 2.4 Hz, 1H), 7.46 – 7.39 (m, 1H), 7.22 (dd, J = 10.3, 8.5 Hz,
1H), 5.27 (s, 1H), 5.00 – 4.88 (m, 2H), 4.64 (d, J = 17.5 Hz, 1H), 4.51 –
4.38 (m, 1H), 3.41 – 3.30 (m, 2H), 3.28 – 3.22 (m, 2H), 3.12 – 2.96 (m,
2H), 2.93 – 2.78 (m, 1H), 2.00 – 1.85 (m, 2H), 1.78 (s, 3H), 1.71 – 1.58
(m, 2H), 1.10 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, DMSO‑d6) δ
163.69, 162.17, 159.50, 159.44 (d, J = 257.6 Hz), 152.01, 133.96 (d,
J = 3.2 Hz), 132.17 (d, J = 8.6 Hz), 129.84 (d, J = 3.4 Hz), 124.63 (d,
J = 15.5 Hz), 116.41 (d, J = 23.1 Hz), 88.85, 80.26, 74.94, 52.59,
51.80, 46.45, 43.19, 36.08, 34.53, 27.42, 21.72, 15.06, 3.60; MS (ESI)
442.48 [M+H]+
.
4.1.22. (R)-3-((4-(3-aminopiperidin-1-yl)-3-(but-2-yn-1-yl)-2,6-dioxo-
3,6-dihydropyrimidin-1(2H)-yl)methyl)-4-fluoro-N-methylbenzamide
hydrochloride (17c)
Following
a similar procedure for the preparation of 17a.
Compound 17c was prepared starting from compound 15b and me-
thylamine hydrochloride, white solid (350 mg, 42%); HPLC purity:
97.1%; mp: 185.7–187.7 °C; 1H NMR (500 MHz, DMSO‑d6) δ 8.67 –
8.48 (m, 4H), 7.85 – 7.76 (m, 1H), 7.59 (dd, J = 7.4, 2.2 Hz, 1H), 7.27
(t, J = 9.2 Hz, 1H), 5.28 (s, 1H), 5.07 – 4.93 (m, 2H), 4.73 – 4.63 (m,
1H), 4.50 – 4.41 (m, 1H), 3.42 – 3.32 (m, 2H), 3.20 – 3.00 (m, 2H), 2.99
– 2.86 (m, 1H), 2.73 (d, J = 3.6 Hz, 3H), 2.04 – 1.84 (m, 2H), 1.77 (t,
J = 2.3 Hz, 3H), 1.71 – 1.58 (m, 2H); 13C NMR (126 MHz, DMSO‑d6) δ
165.97, 162.15, 161.88 (d, J = 249.7 Hz), 152.04, 131.28 (d,
J = 3.1 Hz), 128.41, 128.33, 128.29, 124.61 (d, J = 14.7 Hz), 115.57
(d, J = 22.1 Hz), 88.69, 80.30, 74.92, 52.53, 51.84, 46.48, 38.03,
m/z: 442.34 [M+H]+
.
4.1.26. (R)-3-((4-(3-aminopiperidin-1-yl)-3-(but-2-yn-1-yl)-2,6-dioxo-
3,6-dihydropyrimidin-1(2H)-yl)methyl)-4-chloro-N-methylbenzamide
hydrochloride (17g)
Following a similar procedure for the preparation of 17a. 17g was
prepared starting from compound 15d and methanamine hydro-
chloride. White solid (139 mg, yield 51%). HPLC purity: 97.9%; mp:
210.8 – 212.9 °C 1H NMR (500 MHz, DMSO‑d6) δ 8.67 (d, J = 4.5 Hz,
1H), 8.63 – 8.49 (m, 3H), 7.77 (dd, J = 8.3, 2.1 Hz, 1H), 7.56 (d,
J = 8.2 Hz, 1H), 7.42 (d, J = 1.8 Hz, 1H), 5.32 (s, 1H), 5.12 – 4.94 (m,
2H), 4.70 (d, J = 17.3 Hz, 1H), 4.54 – 4.40 (m, 1H), 3.45 – 3.34 (m,
2H), 3.21 – 3.00 (m, 2H), 3.01 – 2.90 (m, 1H), 2.73 (d, J = 4.2 Hz, 3H),
2.03 – 1.88 (m, 2H), 1.77 (s, 3H), 1.73 – 1.61 (m, 2H); 13C NMR
36.23, 27.38, 26.66, 21.78, 3.60; MS (ESI) m/z: 428.53 [M+H]+
.
4.1.23. (R)-3-((4-(3-aminopiperidin-1-yl)-3-(but-2-yn-1-yl)-2,6-dioxo-
3,6-dihydropyrimidin-1(2H)-yl)methyl)-N-ethyl-4-fluorobenzamide
hydrochloride (17d)
(126 MHz, DMSO‑d6)
δ 165.90, 162.20, 159.76, 152.10, 134.79,
134.78, 133.86, 129.64, 127.43, 126.13, 88.67, 80.34, 74.89, 52.56,
Following a similar procedure for the preparation of 17a. 17d was
prepared starting from compound 15b and ethanamine. White solid
(139 mg, yield 45%). HPLC purity: 95.8%; mp: 183.2–185.2 °C; 1H NMR
(500 MHz, DMSO‑d6) δ 8.55 (t, J = 5.5 Hz, 1H), 8.38 (s, 3H), 7.84 –
7.76 (m, 1H), 7.60 (dd, J = 7.4, 2.2 Hz, 1H), 7.28 (dd, J = 9.9, 8.6 Hz,
1H), 5.31 (s, 1H), 5.08 – 4.93 (m, 2H), 4.66 (d, J = 17.3 Hz, 1H), 4.51 –
4.38 (m, 1H), 3.38 – 3.31 (m, 2H), 3.29 – 3.20 (m, 2H), 3.16 – 3.00 (m,
2H), 2.97 – 2.88 (m, 1H), 2.01 – 1.85 (m, 2H), 1.78 (t, J = 2.3 Hz, 3H),
1.71 – 1.59 (m, 2H), 1.09 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz,
DMSO‑d6) δ 165.28, 162.13, 161.92 (d, J = 249.8 Hz), 159.62, 152.00,
131.44 (d, J = 3.0 Hz), 128.64 (d, J = 4.7 Hz), 128.25 (d, J = 9.1 Hz),
124.62 (d, J = 14.7 Hz), 115.51 (d, J = 22.3 Hz), 88.75, 80.34, 74.89,
51.87, 46.48, 42.18, 36.35, 27.41, 26.69, 21.79, 3.63; MS (ESI) m/z:
444.31 [M+H]+
.
4.1.27. (R)-3-((4-(3-aminopiperidin-1-yl)-3-(but-2-yn-1-yl)-2,6-dioxo-
3,6-dihydropyrimidin-1(2H)-yl)methyl)-4-chloro-N-ethylbenzamide
hydrochloride (17h)
Following a similar procedure for the preparation of 17a. 17h was
prepared starting from compound 15d and ethanamine. White solid
(39 mg, yield 41%). HPLC purity: 96.8%; mp: 189.0 – 191.5 °C; 1H NMR
(500 MHz, DMSO‑d6) δ 8.61 (t, J = 5.5 Hz, 1H), 8.30 (s, 3H), 7.76 (dd,
J = 8.3, 2.2 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H),
5.36 (s, 1H), 5.08 – 4.97 (m, 2H), 4.74 – 4.61 (m, 1H), 4.54 – 4.43 (m,
9