18
L.-G. Yu et al. / European Journal of Medicinal Chemistry 90 (2015) 10e20
6.11.1. Compound 40
3 H); 13C NMR (100 MHz, CDCl3)
d 154.36, 150.52, 147.53, 133.32,
Light yellow solid; yield: 68% (over three steps); mp:
133.02, 129.70, 112.89, 109.79, 109.37, 56.49, 49.93, 39.65, 35.67,
33.96, 31.54, 30.51, 24.78, 23.61, 19.88; HRMS(ESI): calcd for
C
156e160 ꢀC. 1H NMR (500 MHz, DMSO-d6)
d
12.43 (s, 1 H), 7.42 (s,
1 H), 7.29 (s, 1 H), 7.21 (s, 1 H), 3.91 (s, 3 H), 3.28 (s, 1 H), 2.89 (dd,
J ¼ 16.6, 3.9 Hz, 1 H), 2.75e2.65 (m, 1 H), 2.35 (d, J ¼ 14.6 Hz, 1 H),
1.94e1.88 (m, 1 H), 1.76e1.51 (m, 2 H), 1.29 (s, 3 H), 1.19 (s, 3 H), 1.13
19H24BrN2O[M þ H]þ; 375.1072; found 375.1054.
6.11.7. Compound 46
(s, 3 H); 13C NMR (100 MHz, DMSO-d6)
d
158.93, 154.70, 133.57,
Light yellow solid; yield: 74% (over three steps); mp: 114e117 ꢀC.
128.44, 116.56, 111.11, 109.61, 98.09, 56.18, 49.23, 34.60, 33.37, 31.01,
1H NMR (400 MHz, CDCl3)
d 7.53 (s, 1 H), 7.41 (s, 1 H), 6.95 (s, 1 H),
29.70, 23.91, 23.14, 18.95; HRMS(ESI): calcd for
C
20H24N3O
4.35 (q, J ¼ 7.1 Hz, 2 H), 3.91 (s, 3 H), 3.16 (d, J ¼ 14.7 Hz, 1 H),
3.03e2.70 (m, 2 H), 2.56 (d, J ¼ 14.7 Hz, 1 H), 1.96 (dd, J ¼ 12.6,
5.5 Hz, 1 H), 1.90e1.61 (m, 2 H), 1.41 (s, 3 H), 1.37 (t, J ¼ 7.1 Hz, 3 H),
[M þ H]þ; 322.1919, found 322.1938.
6.11.2. Compound 41
1.33 (s, 3 H), 1.20 (s, 3 H); 13C NMR (100 MHz, CDCl3)
d 166.24,
Light yellow solid; yield: 86% (over three steps); mp:
157.64, 152.81, 150.40, 133.32, 132.13, 127.69, 118.45, 112.72, 109.85,
60.83, 56.34, 49.88, 40.01, 35.56, 33.98, 31.55, 30.58, 24.68, 23.66,
19.93, 14.47; HRMS(ESI): calcd for C22H29N2O3[M þ H]þ; 369.2178;
found 369.2141.
175e178 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.42 (s, 1 H), 6.87 (s, 1 H),
6.82 (s, 1 H), 3.85 (d, J ¼ 6.2 Hz, 3 H), 3.16 (d, J ¼ 14.8 Hz, 1 H),
2.98e2.70 (m, 2 H), 2.70e2.44 (m, 3 H), 2.02e1.62 (m, 3 H), 1.42 (s,
3 H), 1.36e1.30 (m, 3 H), 1.24e1.19 (m; 6 H); 13C NMR (100 MHz,
CDCl3)
d
156.09, 150.51, 145.23, 133.40, 130.63, 129.25, 127.38,
6.11.8. Compound 47
113.27, 107.68, 55.62, 50.24, 39.47, 35.76, 33.94, 31.58, 30.84, 24.79,
Light yellow solid; yield: 85% (over three steps). 1H NMR
23.63, 22.85, 20.16, 14.21; HRMS(ESI): calcd for
C
21H29N2O
(400 MHz, DMSO-d6) d 7.44e7.30 (m, 6 H), 6.93 (s, 1 H), 6.68 (s, 1 H),
[M þ H]þ; 325.2280; found 325.2294.
5.01 (s, 2 H), 3.75 (s, 3 H), 3.17 (d, J ¼ 14.7 Hz, 1 H), 2.84e2.60 (m,
2 H), 2.30 (d, J ¼ 14.7 Hz,1 H), 1.91e1.78 (m,1 H), 1.68e1.56 (m, 2 H),
1.28 (s, 3 H), 1.18 (s, 3 H), 1.08 (s, 3 H).
6.11.3. Compound 42
Light yellow solid; yield: 48% (over three steps); mp:
177e181 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.47 (s, 1 H), 6.85 (s, 1 H),
6.11.9. Compound 48
6.79 (s, 1 H), 3.83 (s, 3 H), 3.17 (d, J ¼ 14.9 Hz, 1 H), 2.94e2.71 (m,
2 H), 2.63e2.45 (m, 3 H), 1.95 (dd, J ¼ 12.5, 5.4 Hz, 1 H), 1.85 (d,
J ¼ 12.5 Hz, 1 H), 1.79e1.67 (m, 1 H), 1.67e1.53 (m, 2 H), 1.46 (s, 2 H),
1.38 (s, 3 H),1.20 (s, 3 H), 0.97 (t, J ¼ 7.3 Hz, 3 H); 13C NMR (100 MHz,
Light yellow solid; yield: 45% (over three steps); mp:
106e109 ꢀC. 1H NMR (500 MHz, CDCl3)
d 7.37 (s, 1 H), 7.18 (s, 1 H),
6.98 (dd, J ¼ 17.7, 11.1 Hz, 1 H), 6.85 (s, 1 H), 5.72 (d, J ¼ 17.7 Hz, 1 H),
5.23 (d, J ¼ 11.2 Hz,1 H), 3.85 (d, J ¼ 10.8 Hz, 3 H), 3.15 (d, J ¼ 14.7 Hz,
1 H), 2.98e2.74 (m, 2 H), 2.55 (d, J ¼ 14.7 Hz, 1 H), 1.95 (dd, J ¼ 12.8,
5.6 Hz, 1 H), 1.86e1.68 (m, 2 H), 1.38 (s, 3 H), 1.30 (s, 3 H), 1.21 (s,
CDCl3) d 156.17, 150.50, 145.24, 133.33, 130.11, 129.20, 127.23, 113.29,
107.72, 55.62, 50.20, 39.46, 35.74, 33.93, 32.01, 31.57, 30.80, 24.80,
23.62, 23.17, 20.15, 14.41; HRMS(ESI): calcd for C22H31N2O[M þ H]þ;
339.2431; found 339.2470.
3 H); 13C NMR (100 MHz, CDCl3)
d 155.53, 150.59, 147.77, 133.23,
131.56, 127.78, 126.98, 125.02, 114.23, 113.15, 108.47, 55.86, 50.15,
39.69, 35.71, 33.97, 31.58, 30.84, 24.73, 23.65, 20.11; HRMS(ESI):
calcd for C21H27N2O[M þ H]þ; 323.2123; found 323.2147.
6.11.4. Compound 43
Light yellow solid; yield: 54% (over three steps); mp:
157e159 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.43 (s, 1 H), 6.84 (d,
6.11.10. Compound 49
J ¼ 12.7 Hz, 2 H), 3.85 (s, 3 H), 3.17 (d, J ¼ 14.8 Hz, 1 H), 3.00e2.69
(m, 2 H), 2.66e2.46 (m, 3 H), 1.95 (dd, J ¼ 12.4, 5.1 Hz, 1 H),
1.89e1.66 (m, 2 H), 1.63e1.52 (m, 2 H), 1.43 (s, 3 H), 1.35 (s, 3 H), 1.22
Light yellow solid; yield: 75% (over three steps); mp:
104e107 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.36 (br.s,1 H), 7.43 (s,1 H),
6.89 (d, J ¼ 25.5 Hz, 2 H), 5.11 (d, J ¼ 16.9 Hz, 2 H), 3.85 (s, 3 H), 3.17
(d, J ¼ 14.7 Hz, 1 H), 2.99e2.69 (m, 2 H), 2.58 (d, J ¼ 14.7 Hz, 1 H),
2.13 (s, 3 H), 1.96 (dd, J ¼ 12.3, 4.8 Hz, 1 H), 1.89e1.66 (m, 2 H), 1.43
(s, 3 H), 1.34 (s, 3 H), 1.23 (s, 3 H); 13C NMR (100 MHz, CDCl3)
(s, 3 H), 0.95 (t, J ¼ 7.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
d 156.04,
150.25, 145.11, 133.45, 129.90, 129.29, 127.15, 113.12, 107.63, 55.53,
50.11, 39.36, 35.65, 33.81, 32.17, 31.46, 30.71, 29.72, 29.46, 24.70,
23.50, 22.83, 20.05, 14.08; HRMS(ESI): calcd for
C
23H33N2O
d
155.35, 150.61, 146.94, 143.97, 133.22, 130.83, 129.69, 127.60,
[M þ H]þ; 353.2587; found 353.2593.
115.04, 113.21, 108.57, 55.85, 50.16, 39.56, 35.69, 33.96, 31.58, 30.75,
24.76, 23.65, 23.40, 20.11. HRMS(ESI): calcd for
C22H29N2O
6.11.5. Compound 44
[M þ H]þ; calcd 337.228; found 337.2254.
Light yellow solid; yield: 54% (over three steps); mp:
127e131 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.52 (s, 1 H), 7.44 (s, 1 H),
6.12. Synthesis of compound 50
6.85 (s,1 H), 6.80 (s,1 H), 3.84 (d, J ¼ 6.4 Hz, 3 H), 3.16 (d, J ¼ 14.9 Hz,
1 H), 2.96e2.71 (m, 2 H), 2.67e2.34 (m, 3 H), 2.02e1.64 (m, 3 H),
1.57 (dt, J ¼ 15.1, 7.4 Hz, 2 H), 1.46e1.40 (m, 3 H), 1.35 (s, 3 H),
1.33e1.24 (m, 10 H), 1.21 (s, 4 H), 0.89 (t, J ¼ 6.7 Hz, 4 H); 13C NMR
To a solution of compound 46 (90 mg, 0.24 mmol) in THF (10 mL)
was added NaOH(50 mg,1.25 mmol)at 0 ꢀC. The reaction mixture
was heated to reflux for 3 h then poured into hydrochloric acid
(20 mL, 0.1 M), extracted with AcOEt (10 mL ꢂ 3). The combined
organic extract was washed with brine, dried over Na2SO4 and
concentrated to give compound 50 (78 mg, 90%) as a light yellow
(100 MHz, CDCl3)
d 156.14, 150.50, 145.19, 133.35, 129.99, 129.47,
127.26, 113.28, 107.73, 55.63, 50.21, 39.46, 35.75, 33.93, 32.07, 31.57,
30.81, 30.08, 29.92, 29.87, 29.65, 29.43, 24.80, 23.62, 22.83, 20.16,
14.26; HRMS(ESI): calcd for C27H41N2O [M þ H]þ; 409.3219; found
409.3210.
solid; mp: 262e263 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d 7.37 (s, 1 H),
7.32 (s, 1 H), 7.08 (s, 1 H), 3.82 (s, 3 H), 3.26 (d, J ¼ 14.8 Hz, 1 H), 2.87
(dd, J ¼ 16.2, 3.6 Hz, 1 H), 2.78e2.63 (m, 1 H), 2.36 (d, J ¼ 14.7 Hz,
1 H),1.92e1.85 (m,1 H),1.75e1.53 (m, 2 H),1.30 (s, 3 H),1.20 (s, 3 H),
6.11.6. Compound 45
Light yellow solid; yield: 43% (over three steps); mp:
1.13 (s, 3 H); 13C NMR (100 MHz, DMSO-d6)
d167.12, 156.69, 152.37,
212e216 ꢀC. 1H NMR (400 MHz, CDCl3)
d
7.60 (br.s,1 H), 7.43 (s, 1 H),
148.51, 133.07, 131.22, 127.04, 118.84, 111.51, 109.96, 55.90, 49.52,
34.89, 33.43, 31.06, 30.46, 29.98, 24.15, 23.18, 21.10, 19.31;
7.27 (s, 1 H), 6.87 (s, 1 H), 3.91 (d, J ¼ 6.2 Hz, 3 H), 3.15 (d, J ¼ 14.8 Hz,
1 H), 2.96e2.69 (m, 2 H), 2.55 (d, J ¼ 14.7 Hz, 1 H), 1.94 (dd, J ¼ 12.2,
5.0 Hz, 1 H), 1.87e1.62 (m, 2 H), 1.42 (s, 3 H), 1.33 (s, 3 H), 1.19 (s,
HRMS(ESI): calcd for
341.1861.
C
20H25N2O3 [M þ H]þ; 341.1865; found