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W. Wang et al. / Bioorganic & Medicinal Chemistry xxx (2018) xxx–xxx
1H, NH), 5.47 (s, 2H), 4.38 (q, J = 6.6 Hz, 1H), 2.31 (s, 3H), 2.15 (s,
3H), 2.11–2.04 (m, 2H), 1.73–1.62 (m, 4H), 1.50–1.43 (m, 2H). 13C
NMR (150 MHz, CDCl3) d 168.3, 166.6, 159.3, 158.8, 139.9, 138.0,
134.4, 133.4, 132.0, 129.4, 128.8 (2C), 128.2, 127.5, 127.1 (2C),
125.7, 111.0, 54.4, 51.7, 33.2 (2C), 23.8 (2C), 12.0, 10.7. MS (ESI)
443.2 for [M+H]+.
128.9 (2C), 127.8, 127.5, 127.3, 125.5 (2C), 110.7, 54.2, 29.4, 11.9,
10.5. ESR (DMSO): g = 2.007. MS (ESI) 529.3 for [M+H]+.
4.1.4.8.
thalazin-2(1H)-yl)m
N-Cyclopropyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-1-oxoph-
ethyl)benzamide(12a). With 1-methyl-4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, a simi-
lar procedure as that described for 11a gave pure 12a (86%) as a
white solid. m.p.: 175–177 °C. 1H NMR (600 MHz, CDCl3) d 8.50
(d, J = 7.2 Hz, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.82–7.77
(m, 2H), 7.72 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H),7.51 (d, J = 8.4 Hz,
1H), 6.25 (s, 1H, NH), 5.45 (s, 2H), 4.01 (s, 3H), 2.87 (q, J = 3.6 Hz,
1H), 0.87–0.81 (m, 2H), 0.61–0.57 (m, 2H). 13C NMR (150 MHz,
CDCl3) d 168.5, 158.9, 140.5, 140.3, 139.2, 133.8, 133.2, 131.5,
130.3, 129.3, 128.7 (2C), 128.2, 127.4, 127.1 (2C), 126.0, 117.0,
54.4, 39.2, 23.1, 6.8 (2C). MS (ESI) 400.2 for [M+H]+.
4.1.4.3. N-Cyclohexyl-4-((4-(3,5-dimethylisoxazol-4-yl)-1-oxophtha-
lazin-2(1H)-yl)me thyl)benzamide (11c). With compound 10c, a
similar procedure as that described for 11a gave pure 11c (86%)
as a white solid. m.p.: 198–200 °C. 1H NMR (600 MHz, CDCl3) d
8.54–8.50 (m, 1H), 7.84–7.79 (m, 2H), 7.71 (d, J = 7.2 Hz, 2H),
7.52 (d, J = 8.4 Hz, 2H), 7.44–7.42 (m, 1H), 5.93 (d, J = 7.8 Hz, 1H,
NH), 5.47 (s, 2H), 3.95 (t, J = 3.6 Hz, 1H), 2.32 (s, 3H), 2.16 (s, 3H),
2.00 (d, J = 9.6 Hz, 2H), 1.75–1.72 (m, 2H), 1.66–1.63 (m, 1H),
1.45–1.37 (m, 2H), 1.25–1.17 (m, 3H). 13C NMR (150 MHz, CDCl3)
d 168.3, 166.1, 159.3, 158.8, 139.8, 138.0, 134.5, 133.4, 132.0,
129.4, 128.8 (2C), 128.1, 127.5, 127.1 (2C), 125.7, 111.0, 54.5,
48.7, 33.2 (2C), 25.5, 24.8 (2C), 12.0, 10.7. MS (ESI) 457.2 for
[M+H]+.
4.1.4.9.
N-Cyclopentyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-1-oxoph-
thalazin-2(1H)-yl) methyl)benzamide (12b). With compound 10b,
a similar procedure as that described for 12a gave pure 12b
(88%) as a white solid. m.p.: 184–186 °C. 1H NMR (600 MHz, CDCl3)
d 8.51 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H),7.82–
7.77 (m, 2H), 7.73 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz,
2H), 6.04 (d, J = 6.6 Hz, 1H, NH), 5.46 (s, 2H), 4.37 (q, J = 7.2 Hz, 1H),
4.01 (s, 3H), 2.09–2.03 (m, 2H), 1.72–1.61 (m, 4H), 1.49–1.43 (m,
2H). 13C NMR (150 MHz, CDCl3) d 166.8, 158.9, 140.3, 140.2,
139.2, 134.2, 133.2, 131.5, 130.3, 129.2, 128.7 (2C), 128.1, 127.4,
127.0 (2C), 125.9, 117.0, 54.4, 51.6, 39.2, 33.2 (2C), 23.7 (2C). MS
(ESI) 428.2 for [M+H]+.
4.1.4.4. 4-(3,5-Dimethylisoxazol-4-yl)-2-(4-(piperidine-1-carbonyl)
benzyl)phthalazin -1(2H)-one(11d). With compound 10d, a similar
procedure as that described for 11a gave pure 11d (78%) as a white
solid. m.p.: 188–190 °C. 1H NMR (600 MHz, CDCl3) d 8.53 (d, J = 7.8
Hz, 1H), 7.84–7.79 (m, 2H), 7.50 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.8
Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 5.46 (s, 2H), 3.68 (brs, 2H), 3.30
(brs, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 1.66 (s, 4H), 1.48 (s, 2H). 13C
NMR (150 MHz, CDCl3) d 169.9, 168.3, 159.4, 158.9, 137.9, 137.8,
136.1, 133.4, 132.0, 129.4, 128.8 (2C), 128.2, 127.6, 127.1 (2C),
125.7, 111.1, 54.5, 48.7, 43.1, 26.5, 25.6, 24.5, 12.0, 10.7. MS (ESI)
443.3 for [M+H]+.
4.1.4.10.
N-Cyclohexyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-1-oxoph-
thalazin-2(1H)-yl)m ethyl)benzamide (12c). With compound 10c, a
similar procedure as that described for 12a gave pure 12c (90%)
as a white solid. m.p.: 192–194 °C. 1H NMR (600 MHz, CDCl3) d
8.51 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.81–
7.77 (m, 2H), 7.73 (s, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.8
Hz, 2H), 5.91 (d, J = 6.6 Hz, 1H, NH), 5.46 (s, 2H), 4.01 (s, 3H),
3.96–3.94 (m, 1H), 1.99 (brs, 2H), 1.75–1.71 (m, 2H), 1.66–1.62
(m, 2H), 1.45–1.37 (m, 2H), 1.27–1.18 (m, 2H). 13C NMR (150
MHz, CDCl3) d 166.3, 158.9, 140.3, 140.2, 140.1, 139.2, 134.4,
133.1, 130.3, 129.2, 128.7 (2C), 128.1, 127.4, 127.0 (2C), 125.9,
117.0, 54.5, 48.6, 39.2, 33.1, 25.5 (2C), 24.9, 24.8. MS (ESI) 442.2
for [M+H]+.
4.1.4.5. 4-(3,5-Dimethylisoxazol-4-yl)-2-(4-(morpholine-4-carbonyl)
benzyl)phthalazin -1(2H)-one(11e). With compound 10e, a similar
procedure as that described for 11a gave pure 11e (79%) as a white
solid. Yield 79%. m.p.: 137–139 °C. 1H NMR (600 MHz, CDCl3) d
8.51 (d, J = 6.0 Hz, 1H), 7.83–7.78 (m, 2H), 7.52 (d, J = 8.4 Hz, 2H),
7.43 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.2 Hz, 2H), 5.45 (s, 2H), 3.76–
3.40 (m, 8H), 2.32 (s, 3H), 2.15 (s, 3H). 13C NMR (150 MHz, CDCl3)
d 169.7, 168.3, 159.3, 158.9, 138.5, 138.0, 134.8, 133.4, 132.0,
129.4, 128.9 (2C), 128.2, 127.5, 127.4 (2C), 125.7, 111.0, 66.8
(2C), 54.5, 48.6, 42.6, 12.0, 10.7. MS (ESI) 445.2 for [M+H]+.
4.1.4.11. 4-(1-Methyl-1H-pyrazol-4-yl)-2-(4-(piperidine-1-carbonyl)
benzyl)phthalazin -1(2H)-one(12d). With compound 10d, a similar
procedure as that described for 12a gave pure 12d (82%) as a white
solid. m.p.: 178–180 °C. 1H NMR (600 MHz, CDCl3) d 8.52 (d, J = 6.6
Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.83–7.79 (m, 2H), 7.75
(s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 5.45 (s, 2H),
4.02 (s, 3H), 3.68 (brs, 2H), 3.31 (brs, 2H), 1.65 (brs, 2H), 1.62 (brs,
2H), 1.47 (brs, 2H). 13C NMR (150 MHz, CDCl3) d 170.0, 158.9,
140.2, 139.2, 138.2, 135.8, 133.1, 131.5, 130.3, 129.3, 128.6 (2C),
128.2, 127.4, 127.1 (2C), 125.9, 117.1, 54.5, 48.7, 43.1, 39.2, 26.5,
25.6, 24.6. MS (ESI) 428.3 for [M+H]+.
4.1.4.6. 4-((4-(3,5-Dimethylisoxazol-4-yl)-1-oxophthalazin-2(1H)-yl)
methyl)-N-(1-met hylpiperidin-4-yl)benzamide (11f). With com-
pound 10f, a similar procedure as that described for 11a gave pure
11f (75%) as a white solid. m.p.: 207–209 °C. 1H NMR (600 MHz,
DMSO d6) d 8.46 (brs, 1H, NH), 8.37–8.35 (m, 1H), 7.93–7.90 (m,
2H), 7.82 (d, J = 7.8 Hz, 2H), 7.58–7.56 (m, 1H), 7.40 (d, J = 7.8 Hz,
2H), 5.42 (s, 2H), 3.96 (brs, 1H), 2.97 (brs, 2H), 2.64 (s, 3H), 2.30
(s, 3H), 2.07 (s, 3H), 1.94–1.84 (m, 4H), 1.22–1.18 (m, 2H). 13C
NMR (150 MHz, DMSO d6) d 168.3, 165.6, 159.0, 158.1, 140.3,
137.4, 134.0, 133.5, 132.4, 128.9, 127.6 (2C), 127.5, 127.4, 126.6
(2C), 126.3, 110.6, 53.6, 52.5, 44.1, 42.4, 29.0, 28.6, 26.5, 11.6,
10.1. MS (ESI) 472.3 for [M+H]+.
4.1.4.12.
4-(1-Methyl-1H-pyrazol-4-yl)-2-(4-(morpholine-4-car-
4.1.4.7. 4-((4-(3,5-Dimethylisoxazol-4-yl)-1-oxophthalazin-2(1H)-yl)
bonyl)benzyl)phthalazi n-1(2H)-one (12e). With compound 10e, a
similar procedure as that described for 12a gave pure 12e (81%)
as a white solid. m.p.: 170–172 °C. 1H NMR (600 MHz, CDCl3) d
8.51 (d, J = 9.0 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.80–
7.78 (m, 2H), 7.75 (s, 1H), 7.53 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 8.4
Hz, 2H), 5.45 (s, 2H), 4.02 (s, 3H), 3.74–3.40 (m, 8H). 13C NMR
(150 MHz, CDCl3) d 170.2, 158.9, 140.2, 139.2, 138.8, 134.6,
133.2, 131.5, 130.3, 129.3, 128.7 (2C), 128.2, 127.4 (3C), 125.9,
117.0, 66.8 (2C), 54.6, 48.2, 42.7, 39.3. MS (ESI) 430.2 for [M+H]+.
methyl)-N-[(2,2,
6,6-tetramethyl-1-oxyl)piperidin-4-yl]benzamide
(11g). With compound 10g, a similar procedure as that described
for 11a gave pure 11g (78%) as a pink solid. m.p.: 164–166 °C. 1H
NMR (600 MHz, CDCl3) (compound 11g is a free-radical, some sig-
nals appear broadened and other signals are missing) d 8.53 (brs,
1H), 7.84–7.74 (m, 3H), 7.59 (brs, 2H), 7.47 (brs, 1H), 7.18 (s, 1H),
5.49 (s, 2H), 2.33 (s, 3H), 2.16 (s, 3H). 13C NMR (150 MHz, CDCl3)
d 168.0, 166.5, 159.0, 158.6, 140.2, 137.8, 133.3, 131.9, 129.1,