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2.01–2.08 (2H, m), 3.05 (3H, s), 3.24 (2H, t, J = 8.7 Hz), 3.29–3.38
(2H, m), 3.77–3.82 (2H, m), 4.32 (2H, t, J = 8.7 Hz), 5.25–5.30 (1H,
m), 6.27 (1H, d, J = 6.6 Hz), 7.70 (1H, s), 7.75–7.78 (1H, m), 8.27
(1H, d, J = 6.6 Hz), 8.41 (1H, d, J = 8.7 Hz). Anal. Calcd for C23H30
N4O5S: C, 58.21; H, 6.37; N, 11.81. Found: C, 58.30; H, 6.26; N, 11.82.
5.1.61. Propan-2-yl 4-({6-[5-(methylsulfonyl)-2,3-dihydro-1H-
indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (35)
Compound 35 was prepared from 34 in a manner similar to that
described for compound 31a. Colorless solid. Yield 48%. MS (ESI/
APCI) m/z 461 [M+H]+. 1H NMR (300 MHz, CDCl3) d 1.26 (6H, t,
J = 6.1 Hz), 1.61–1.84 (2H, m), 1.86–2.11 (2H, m), 2.89–3.12 (3H,
m), 3.21–3.47 (4H, m), 3.74–3.93 (2H, m), 4.07 (2H, t, J = 8.7 Hz),
4.94 (1H, q, J = 6.2 Hz), 5.33 (1H, tt, J = 8.0, 3.9 Hz), 5.98 (1H, s),
7.72 (1H, s), 7.79 (1H, dd, J = 8.7, 1.9 Hz), 8.51 (1H, s), 8.57 (1H,
s). 13C NMR (100.6 MHz, CDCl3) d 22.3, 27.0, 30.7, 41.1, 44.9,
49.1, 68.7, 71.2, 90.1, 115.6, 123.7, 128.2, 132.7, 132.9, 148.6,
155.2, 157.3, 160.7, 169.5. Mp 188–189 °C. Anal. Calcd for C22H28-
N4O5S: C, 57.37; H, 6.13; N, 12.17. Found: C, 57.27; H, 6.15; N,
12.09.
5.1.57. Propan-2-yl 4-({2-[5-(methylsulfonyl)-2,3-dihydro-1H-
indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (31c)
Compound 31c was prepared from 30c in a manner similar to
that described for compound 31a. Solid. Yield 52% over 2 steps.
MS (ESI/APCI) m/z 461 [M+H]+. 1H NMR (300 MHz, CDCl3) d 1.27
(6H, d, J = 6.4 Hz), 1.72–1.94 (2H, m), 1.96–2.12 (2H, m), 3.05
(3H, s), 3.25 (2H, t, J = 8.7 Hz), 3.31–3.48 (2H, m), 3.73–3.91 (2H,
m), 4.33 (2H, t, J = 8.9 Hz), 4.83–5.06 (1H, m), 5.22–5.42 (1H, m),
6.28 (1H, d, J = 5.7 Hz), 7.72 (1H, s), 7.74–7.85 (1H, m), 8.28 (1H,
d, J = 5.7 Hz), 8.43 (1H, d, J = 8.3 Hz). 13C NMR (100.6 MHz, CDCl3)
d 22.3, 26.7, 30.5, 41.0, 44.9, 49.4, 68.8, 71.4, 100.6, 114.5, 123.7,
128.0, 132.3, 133.5, 148.4, 155.2, 158.1, 158.6, 168.7. Mp 147–
149 °C. Anal. Calcd for C22H28N4O5S: C, 57.37; H, 6.13; N, 12.17.
Found: C, 57.48; H, 6.21; N, 11.96.
5.1.62. 1-(6-{[1-(5-Ethylpyrimidin-2-yl)piperidin-4-
yl]oxy}pyrimidin-4-yl)-5-(methylsulfonyl)-2,3-dihydro-1H-
indole (36)
Compound 36 was prepared from 34 in a manner similar to that
described for compound 20. Colorless solid. Yield 82%. MS (ESI/
APCI) m/z 481 [M+H]+. 1H NMR (300 MHz, CDCl3) d 1.13 (3H, t,
J = 7.6 Hz), 1.53–1.74 (2H, m), 1.95–2.14 (2H, m), 2.44 (2H, q,
J = 7.6 Hz), 3.15 (3H, s), 3.24–3.31 (2H, m), 3.37–3.54 (2H, m),
4.09 (2H, t, J = 8.7 Hz), 4.20–4.38 (2H, m), 5.28–5.43 (1H, m), 6.23
(1H, s), 7.66–7.82 (2H, m), 8.26 (2H, s), 8.48–8.65 (2H, m). 13C
NMR (100.6 MHz, CDCl3) d 15.6, 22.7, 27.0, 30.7, 41.5, 44.9, 49.1,
72.0, 90.1, 115.6, 123.7, 124.5, 128.2, 132.6, 132.8, 148.6, 157.2,
157.3, 160.7, 160.8, 169.6. Mp 206–209 °C. Anal. Calcd for C24H28-
N6O3S: C, 59.98; H, 5.87; N, 17.49. Found: C, 59.81; H, 5.98; N,
17.21.
5.1.58. 1-(6-Chloropyrimidin-4-yl)-5-(methylsulfonyl)-2,3-
dihydro-1H-indole (32)
A mixture of 4,6-dichloropyrimidine (4.10 g, 27.5 mmol), com-
pound 1 (5.00 g, 25.0 mmol), and EtOH (160 mL) was refluxed for
4 h. After the mixture was concentrated under reduced pressure,
to the residue was added aqueous NaHCO3 solution. The precipi-
tated solid was collected by filtration, washed with water, and
dried under reduced pressure to give the title compound as a col-
orless solid (5.50 g, 71%). 1H NMR (300 MHz, DMSO-d6) d 3.17 (3H,
s), 3.24–3.37 (2H, m), 4.16 (2H, t, J = 8.7 Hz), 7.09 (1H, s), 7.73–7.85
(2H, m), 8.57 (1H, d, J = 9.4 Hz), 8.68 (1H, s).
5.1.63. 5-(Methylsulfonyl)-1-[6-({1-[3-(propan-2-yl)-1,2,4-
oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]-2,3-dihydro-
1H-indole (37)
5.1.59. tert-Butyl 4-({6-[5-(methylsulfonyl)-2,3-dihydro-1H-
indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate (33)
To a stirred solution of compound 29 (20.8 g, 103 mmol) in THF
(200 mL) was added sodium hydride (60% oil dispersion, 4.12 g,
103 mmol) at 0 °C. After the mixture was stirred at room temper-
ature for 2 h, compound 32 (8.00 g, 25.8 mmol) was added to the
mixture. The resulting mixture was stirred at 50 °C for 2 h. The
reaction mixture was quenched with water and extracted with
AcOEt. The organic layer was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography (hexane/AcOEt = 80/20
to 50/50) to give the title compound as a solid (6.17 g, 50%). MS
(ESI/APCI) m/z 475 [M+H]+. 1H NMR (300 MHz, CDCl3) d 1.48 (9H,
s), 1.65–1.84 (2H, m), 1.93–2.10 (2H, m), 3.04 (3H, s), 3.19–3.39
(4H, m), 3.70–3.89 (2H, m), 4.07 (2H, t, J = 8.9 Hz), 5.25–5.38 (1H,
m), 5.98 (1H, s), 7.72 (1H, s), 7.78 (1H, dd, J = 8.5, 2.1 Hz), 8.51
(1H, s), 8.57 (1H, d, J = 8.7 Hz).
To a mixture of compound 37 (500 mg, 1.34 mmol), NaHCO3
(344 mg, 4.09 mmol), THF (30 mL), and water (10 mL) was added
cyanogen bromide (191 mg, 1.80 mmol) at 0 °C, and the mixture
was stirred at room temperature for 16 h. Aqueous NaHCO3 solu-
tion was added and the mixture was extracted with a mixed sol-
vent of AcOEt and THF. The organic layer was washed with
brine, dried over MgSO4, and concentrated under reduced pres-
sure. The residue was dissolved in AcOEt/THF (1:1, 200 mL),
and
then
N-hydroxy-2-methylpropanimidamide
(204 mg,
2.00 mmol) and zinc chloride (1 M Et2O solution, 2.0 mL,
2.0 mmol) were added. The resulting mixture was refluxed for
4 h. The precipitated solid was collected and washed with AcOEt.
The solid was dissolved in a mixture of EtOH (300 mL) and con-
centrated hydrochloric acid (1 mL) followed by stirring at 70 °C
for 24 h. The reaction mixture was concentrated under reduced
pressure and partitioned between AcOEt and aqueous NaHCO3
solution. The organic layer was washed with brine and dried
over MgSO4. The solvent was removed by evaporation to give
the title compound as a solid (560 mg, 86% over 2 steps). MS
5.1.60. 5-(Methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-
yl]-2,3-dihydro-1H-indole (34)
(ESI/APCI) m/z 485 [M+H]+. 1H NMR (300 MHz, DMSO-d6)
d
To a mixture of compound 33 (6.17 g, 13.0 mmol), AcOEt
(100 mL) and MeOH (100 mL) was added 4 M HCl in AcOEt
(15 mL), and the mixture was stirred at room temperature for
16 h. After the mixture was concentrated under reduced pressure,
the residue was diluted with AcOEt and basified with 1 M aqueous
NaOH solution. The organic layer was separated, washed with
water and brine, and dried over MgSO4. The solvent was removed
by evaporation to give the title compound as a solid (4.56 g, 94%).
This product was used for the next step without further purifica-
tion. MS (ESI/APCI) m/z 375 [M+H]+.
1.19 (6H, d, J = 6.8 Hz), 1.64–1.88 (2H, m), 2.02–2.21 (2H, m),
2.73–2.92 (1H, m), 3.15 (3H, s), 3.21–3.35 (2H, m), 3.42–3.59
(2H, m), 3.75–3.93 (2H, m), 4.09 (2H, t, J = 8.7 Hz), 5.25–5.47
(1H, m), 6.25 (1H, s), 7.68–7.81 (2H, m), 8.47–8.63 (2H, m).
13C NMR (100.6 MHz, CDCl3) d 20.4, 27.0, 27.1, 30.1, 43.3, 44.9,
49.1, 69.9, 90.0, 115.7, 123.7, 128.2, 132.7, 133.0, 148.5, 157.3,
160.8, 169.3, 170.9, 175.9. Mp 187–189 °C. Anal. Calcd for C23-
H28N6O4Sꢁ0.2AcOEt: C, 56.92; H, 5.94; N, 16.73. Found: C,
56.74; H, 5.76; N, 16.72.