J. Bao, et al.
BioorganicChemistryxxx(xxxx)xxxx
4.1.42. Tert-butyl 4-(4-((7-(3-(methylamino)phenyl)benzo[d]oxazol-2-yl)
amino)phenyl)piperazine-1- carboxylate (5l)
5a. 1H NMR (300 MHz, DMSO-d6): δ 1.42 (s, 9H), 2.91 (s, 4H), 3.47 (s,
4H), 3.47 (s, 4H), 7.01–7.23 (m, 2H), 7.35 (dd, J = 14.9, 8.2 Hz, 2H),
7.46 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 14.4 Hz, 1H), 11.01 (s, 1H). MS
Compound 5l was prepared from 4a and N-methyl-3-(4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolan -2-yl)aniline using the procedure de-
scribed in step 5 for 5a. 1H NMR (300 MHz, DMSO-d6): δ 1.43 (s, 9H),
2.75 (d, J = 4.9 Hz, 3H), 3.03 (s, 4H), 3.47 (s, 4H), 5.70 (d, J = 4.9 Hz,
1H), 6.60 (dd, J = 8.0, 1.5 Hz, 1H), 6.92 (s, 1H), 6.99 (dd, J = 7.4,
5.2 Hz, 3H), 7.15–7.30 (m, 3H), 7.35 (dd, J = 6.6, 2.3 Hz, 1H), 7.63 (d,
m/z: 491.2 [M+H]+
.
4.1.49. Tert-butyl 4-(4-((7-(3-carbamoylphenyl)benzo[d]oxazol-2-yl)amino)-
2-methylphenyl)piperazine-1-carboxylate (5s)
Compound 5s was prepared from 4g and (2-(methylcarbamoyl)
pyridin-4-yl)boronic acid using the procedure described in step 5 for
5a. 1H NMR (300 MHz, DMSO-d6): δ 1.43 (s, 9H), 2.28 (s, 3H), 2.75 (s,
4H), 3.46 (s, 4H), 7.06 (d, J = 9.4 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H),
7.30 (dd, J = 8.1, 0.9 Hz, 1H), 7.43 (dd, J = 7.7, 0.9 Hz, 1H), 7.53 (d,
J = 9.0 Hz, 2H), 10.35 (s, 1H). MS m/z: 498.6 [M+H]+
.
4.1.43. Tert-butyl4-(4-((7-(3-acetamidophenyl)benzo[d]oxazol-2-yl)
amino)phenyl)piperazine-1-carboxyl ate (5m)
Compound 5m was prepared from 4a and 3-(4,4,5,5-Tetramethyl-
1,3,2-dioxaborolan-2-yl)acetanilide using the procedure described in
step 5 for 5a. 1H NMR (300 MHz, DMSO-d6): δ 1.43 (s, 9H), 2.09 (s,
3H), 2.91–3.12 (m, 4H), 3.40–3.54 (m, 4H), 6.99 (d, J = 9.1 Hz, 2H),
7.17–7.24 (m, 1H), 7.30 (dd, J = 10.3, 5.1 Hz, 1H), 7.36–7.42 (m, 1H),
7.45 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.65 (t, J = 7.5 Hz,
J = 6.4 Hz, 2H), 10.75 (s, 1H). MS m/z: 487.2 [M+H]+
.
4.1.50. Tert-butyl
4-(4-((7-(3-carbamoylphenyl)benzo[d]oxazol-2-yl)
amino)-2-methoxyphenyl)piperazine-1-carboxylate (5t)
Compound 5t was prepared from 4h and (2-(methylcarbamoyl)
pyridin-4-yl)boronic acid using the procedure described in step 5 for
5a. 1H NMR (300 MHz, DMSO-d6): δ 1.42 (s, 9H), 2.86 (s, 4H), 3.45 (s,
4H), 3.81 (s, 3H), 6.92 (d, J = 8.6 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H),
7.23–7.33 (m, 2H), 7.38 (d, J = 2.3 Hz, 1H), 7.41 (dd, J = 7.7, 0.9 Hz,
3H), 7.98 (s, 1H), 10.03 (s, 1H), 10.40 (s, 1H). MS m/z: 528.6 [M+H]+
.
4.1.44. Tert-butyl 4-(4-((7-(1H-indol-4-yl)benzo[d]oxazol-2-yl)amino)phenyl)
piperazine-1-carboxylate (5n)
1H), 10.78 (s, 1H). MS m/z: 503.2 [M+H]+
.
Compound 5n was prepared from 4a and4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-1H-indole using the procedure described in
step 5 for 5a. 1H NMR (300 MHz, DMSO-d6): δ 1.43 (s, 9H), 3.02 (s,
4H), 3.47 (s, 4H), 6.43 (s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 7.24 (dd,
J = 15.1, 7.4 Hz, 2H), 7.31 (d, J = 4.5 Hz, 2H), 7.42 (t, J = 4.2 Hz, 2H),
7.48 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 10.36 (s, 1H), 11.28
4.1.51. Step 6 N-(4-(piperazin-1-yl)phenyl)-7-(1,2,3,6-tetrahydropyridin-
4-yl)benzo[d]oxazol-2-amine (T1)
To a solution of 5a (60 mg, 0.13 mmol) in dichloromethane (3 mL)
was added CF3COOH (0.3 mL) at room temperature. The reaction
mixture was stirred at room temperature for 6 h. Saturated aqueous
sodium bicarbonate was added to the reaction mixture until the pH of
solution was 7–8. The precipitated solid was collected on a filter and
was further purified by silica gel chromatography (Developing solvent:
dichloromethane/MeOH = 10/1) to give T1 (30 mg, yield 81.8%). 1H
NMR (300 MHz, DMSO-d6): δ 2.75–2.89 (m, 4H), 2.91–3.02 (m, 4H),
3.44 (s, 2H), 6.54 (s, 1H), 6.94 (d, J = 9.0 Hz, 2H), 7.02–7.09 (m, 1H),
7.16 (t, J = 7.7 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.60 (d, J = 9.0 Hz,
2H), 10.33 (s, 1H). HRMS-ESI m/z [M+H]+, calcd for C22H26N5O:
376.2137, found: 376.2133.
(s, 1H). MS m/z: 510.6 [M+H]+
.
4.1.45. Tert-butyl 4-(4-((7-(3-carbamoylphenyl)benzo[d]oxazol-2-yl)amino)
phenyl)piperazine-1-carboxylate (5o)
Compound 5o was prepared from 4a and 3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)benzamide using the procedure described in
step 5 for 5a. 1H NMR (300 MHz, DMSO-d6): δ 1.48 (s, 9H), 3.03–3.14
(m, 4H), 3.45–3.59 (m, 4H), 7.04 (d, J = 8.0 Hz, 2H), 7.41 (dt,
J = 21.6, 6.9 Hz, 4H), 7.52–7.54 (m, 1H), 7.67 (t, J = 9.4 Hz, 3H), 7.96
(d, J = 6.8 Hz, 1H), 8.05 (d, J = 6.7 Hz, 2H), 8.36 (s, 1H), 10.43 (s,
1H). MS m/z: 528.6 [M+H]+
.
4.1.52. 7-(3,6-Dihydro-2H-pyran-4-yl)-N-(4-(piperazin-1-yl)phenyl)benzo
[d]oxazol-2-amine (T2)
4.1.46. Tert-butyl 4-(4-((7-(3-(methylcarbamoyl)phenyl)benzo[d]oxazol-
2-yl)amino)phenyl)piperazine-1-carboxylate (5p)
Compound T2 was prepared from 5b using the procedure described
in step 6 for T1. 1H NMR (300 MHz, DMSO-d6): δ 2.58 (s, 2H),
2.75–2.88 (m, 4H), 2.88–3.03 (m, 4H), 3.88 (t, J = 5.4 Hz, 2H), 4.31 (d,
J = 2.5 Hz, 2H), 6.60 (s, 1H), 6.94 (d, J = 8.9 Hz, 2H), 7.09 (d,
J = 7.0 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 7.0 Hz, 1H), 7.59
(d, J = 9.0 Hz, 2H), 10.39 (s, 1H,). HRMS-ESI m/z [M+H]+, calcd for
C22H25N4O2: 377.1978, found: 377.1976.
Compound 5p was prepared from 4a and 3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)benzamide using the procedure described in
step 5 for 5a. 1H NMR (300 MHz, DMSO-d6): δ 1.43 (s, 9H), 2.83 (d,
J = 4.5 Hz, 3H), 2.98–3.08 (m, 4H), 3.46 (d, J = 4.8 Hz, 4H), 7.00 (d,
J = 9.0 Hz, 2H), 7.28–7.40 (m, 2H), 7.43 (d, J = 7.3 Hz, 1H), 7.63 (dd,
J = 12.5, 5.3 Hz, 3H), 7.87 (d, J = 7.9 Hz, 1H), 8.00 (d, J = 7.7 Hz,
1H), 8.26 (s, 1H), 8.57 (d, J = 4.5 Hz, 1H), 10.49 (s, 1H). MS m/z:
4.1.53. 7-Phenyl-N-(4-(piperazin-1-yl)phenyl)benzo[d]oxazol-2-amine
(T3)
528.6 [M+H]+
.
Compound T3 was prepared from 5c using the procedure described
in step 6 for T1. 1H NMR (300 MHz, DMSO-d6): δ 2.86–2.99 (s, 4H),
3.00–3.11 (s, 4H), 6.97 (d, J = 9.0 Hz, 1H), 7.24–7.36 (m, 1H),
7.37–7.48 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H),
7.87 (d, J = 7.4 Hz, 1H),10.47 (s, 1H). HRMS-ESI m/z [M+H]+, calcd
for C23H23N4O: 371.1872, found: 371.1871.
4.1.47. Tert-butyl
4-(4-((7-(2-(methylcarbamoyl)pyridin-4-yl)benzo[d]
oxazol-2-yl)amino)phenyl)piperazine-1-carboxylate (5q)
Compound 5q was prepared from 4a and (2-(methylcarbamoyl)
pyridin-4-yl)boronic acid using the procedure described in step 5 for
5a. 1H NMR (300 MHz, DMSO-d6): δ 1.43 (s, 9H), 2.88 (d, J = 4.8 Hz,
3H), 2.96–3.16 (m, 4H), 3.40–3.54 (m, 4H), 7.01 (d, J = 9.1 Hz, 2H),
7.37 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.1 Hz, 2H), 7.65 (d, J = 9.0 Hz,
2H), 8.06 (dd, J = 5.1, 1.8 Hz, 1H), 8.48 (d, J = 1.2 Hz, 1H), 8.77 (d,
J = 5.1 Hz, 1H), 8.86 (d, J = 4.8 Hz, 1H), 10.59 (s, 1H). MS m/z: 529.5
4.1.54. N-(4-(piperazin-1-yl)phenyl)-7-(pyridin-3-yl)benzo[d]oxazol-2-
amine (T4)
Compound T4 was prepared from 5d using the procedure described
in step 6 for T1. 1H NMR (300 MHz, DMSO-d6): δ 2.93–2.99 (m, 4H),
3.04–3.10 (m, 4H), 6.98 (d, J = 9.1 Hz, 2H), 7.33 (t, J = 7.7 Hz, 1H),
7.43 (ddd, J = 13.6, 7.7, 1.3 Hz, 2H), 7.54–7.60 (m, 1H), 7.63 (d,
J = 9.0 Hz, 2H), 8.37–8.17 (m, 1H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H),
9.09–9.12 (m, 1H), 10.50 (s, 1H). HRMS-ESI m/z [M+H]+, calcd for
[M+H]+
.
4.1.48. Tert-butyl 4-(4-((7-(3-carbamoylphenyl)benzo[d]oxazol-2-yl)amino)-
2-fluorophenyl)piperazine-1-carboxylate (5r)
Compound 5r was prepared from 4f and (2-(methylcarbamoyl)
pyridin-4-yl)boronic acid using the procedure described in step 5 for
C22H22N5O: 372.1824, found: 372.1820.
11