652
W. Peng et al. / European Journal of Medicinal Chemistry 108 (2016) 644e654
9
.07 (s, 1H), 8.53 (d, J ¼ 2.4 Hz, 1H), 8.29e8.20 (m, 1H), 7.88 (d,
5.1.24. 2-(2-Aminopyrimidin-5-yl)-4-morpholino-N-
phenylquinazolin-8-amine (18b)
To a round-bottom flask was added 16 (105 mg, 0.25 mmol),
2 3
NaOt-Bu (72 mg, 0.75 mmol), Pd (dba) (11 mg, 0.0125 mmol),
J ¼ 9.0 Hz, 1H), 7.79e7.71 (m, 1H), 7.40 (dd, J ¼ 8.2, 4.7 Hz, 1H), 7.26
(
d, J ¼ 2.2 Hz, 1H), 7.17 (dd, J ¼ 9.0, 2.3 Hz, 1H), 7.12 (s, 2H), 3.82 (t,
13
J ¼ 4.3 Hz, 4H), 3.73 (t, J ¼ 3.9 Hz, 4H). C NMR (100 MHz, DMSO-
d
6
)
d: 164.1, 163.5, 158.1, 156.5, 153.9, 147.4, 142.8, 141.6, 138.0, 126.7,
XantPhos (21 mg, 0.0375 mmol), 1-chloro-3-iodobenzene(119 mg,
0.5 mmol) in dioxane (10 mL). The reaction mixture was heated at
125.8, 124.0, 120.2, 116.5, 108.1, 107.0, 66.0, 49.7. HRMS (ESI) m/z:
ꢀ
ꢁ
calcd. for C21
H
19
N
8
O [MꢀH] : 399.1687; found 399.1691.
90 C for 12 h (monitored by TLC), then purified by column chro-
matography on silica gel to give Boc-protected product. Then the
Boc-protected product was mixed with CF
3 mL), the reaction was stirred for 2 h. Then the organic solvent
was removed, saturated Na CO was added to neutralize the solu-
tion. Then MeOH/CH Cl (1:9) was added, the organic layer was
3 2 2
COOH (3 mL) and CH Cl
5
.1.20. N-(2-(2-Aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-
(
yl)nicotinamide (17d)
Compound 17d was prepared from intermediate 15. Yield 37%.
2
3
1
H NMR (400 MHz, D
2
O)
d: 9.14 (s, 1H), 8.88 (d, J ¼ 5.6 Hz, 1H), 8.82
2
2
separated and concentrated. The residue was purified by silica gel
chromatography with 1:20 MeOH/CH Cl to give product 18b
(
d, J ¼ 8.1 Hz,1H), 8.75 (s, 2H), 8.14 (s,1H), 8.11e7.94 (m,1H), 7.85 (d,
13
J ¼ 9.1 Hz, 1H), 7.47 (d, J ¼ 9.1 Hz, 1H), 4.14 (s, 4H), 3.81 (s, 4H).
C
2
2
1
(
(
7
49 mg, 49% yield, R
400 MHz, DMSO-d
.41e7.33 (m, 2H), 7.33e7.23 (m, 2H), 7.10 (s, 2H), 7.02 (t, J ¼ 7.0 Hz,
f
¼ 0.43 in 1:20 MeOH/CH
2 2
Cl ). H NMR
2
NMR (100 MHz, D O) d: 163.1, 162.7, 160.8, 159.1, 151.9, 145.4, 143.9,
) d: 9.40 (s, 2H), 8.57 (s, 1H), 7.51e7.41 (m, 3H),
143.5, 142.5, 142.0, 132.4, 128.0, 127.3, 119.4, 113.8, 108.1, 107.7, 66.3,
6
4
9.5. TFA
d
163.2, 162.9, 162.5, 162.2 (CF
3
COOH), 120.7, 117.8, 114.9,
13
þ
1H), 3.92e3.81 (m, 4H), 3.81e3.69 (m, 4H). C NMR (100 MHz,
DMSO-d : 164.1, 164.0, 158.6, 154.4, 142.0, 141.7, 139.9, 129.1,
112.0 (CF
3
COOH). HRMS (ESI) m/z: calcd. for C22
29.1782; found 429.1802.
H
21
N
8
O
2
[MþH] :
6
) d
4
1
25.1, 121.8, 120.3,120.0, 114.7, 113.6, 111.1, 66.0, 49.8. HRMS (ESI) m/
þ
z: calcd. for C22
22
H N
7
O [MþH] : 400.1880; found 400.1887.
5.1.21. 3-((2-(2-Aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-
yl)amino)pyridine 1-oxide (17e)
5
.1.25. 2-(2-Aminopyrimidin-5-yl)-4-morpholino-N-(4-
Compound 17e was prepared from intermediate 15 (105 mg,
nitrophenyl)quinazolin-8-amine (18c)
0
.25 mmol) and 3-bromopyridine 1-oxide (43 mg, 0.25 mmol)
following a similar procedure (29 mg, 29% yield, R
¼ 0.32 in 1:10
: 9.26 (s, 1H), 9.16 (s,
H), 8.14 (s, 1H), 7.92 (d, J ¼ 9.0 Hz, 1H), 7.87 (d, J ¼ 6.2 Hz, 1H),
Compound 18c was prepared from intermediate 16 (31 mg, 28%
f
1
yield, R
f
¼ 0.38 in 1:20 MeOH/CH
2
Cl
2
). H NMR (400 MHz, DMSO-
1
2 2 6
MeOH/CH Cl ). H NMR (400 MHz, DMSO-d ) d
2
d
6
)
d
: 9.35 (s, 1H), 9.28 (s, 2H), 8.14 (d, J ¼ 9.2 Hz, 2H), 7.78 (d,
J ¼ 7.4 Hz,1H), 7.62 (d, J ¼ 8.1 Hz,1H), 7.51e7.36 (m, 3H), 7.12 (s, 2H),
7
3
.42e7.25 (m, 3H), 7.18 (dd, J ¼ 9.0, 2.3 Hz, 1H), 7.13 (s, 2H),
13
3
6
.82 (s, 8H). C NMR (100 MHz, DMSO-d ) d: 164.2, 164.0, 158.7,
13
.88e3.78 (m, 4H), 3.78e3.69 (m, 4H). C NMR (100 MHz, DMSO-
: 164.3, 162.0, 158.6, 158.6, 158.3, 154.5, 146.9, 140.6, 132.4,
155.1,149.8,144.2,138.9,136.4,125.6,124.6,119.8,118.9,118.6,115.7,
d
6
)
d
ꢀ
114.9, 66.0, 49.7. HRMS (ESI) m/z: calcd. for C22
H
19
N
8
O
3
[MꢀH] :
129.8,127.6,126.5,118.5,117.1,115.8,115.5, 66.0, 49.4. HRMS (ESI) m/
4
43.1586; found 443.1575.
þ
21
z: calcd. for C21H N
8
O
2
[MþH] : 417.1782; found 417.1799.
5
.1.26. 2-(2-Aminopyrimidin-5-yl)-N-(3-chlorophenyl)-4-
5
.1.22. 3-((2-(2-Aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-
morpholinoquinazolin-8-amine (18d)
Compound 18d was prepared from intermediate 16 (35 mg, 32%
yl)amino)picolinonitrile (17f)
To a solution of intermediate 15 (105 mg, 0.25 mmol) and so-
dium tert-butoxide (48 mg, 0.5 mmol) in 5 mL DMF was added 3-
fluoropicolinonitrile (37 mg, 0.3 mmol) at 0 C. The mixture was
stirred at room temperature for 1.5 h. The Boc-protected product
1
yield, R
: 9.38 (s, 2H), 8.69 (s, 1H), 7.51 (d, J ¼ 7.0 Hz, 1H), 7.46 (t,
J ¼ 1.9 Hz, 1H), 7.42e7.23 (m, 4H), 7.11 (s, 2H), 6.99 (d, J ¼ 7.7 Hz,
f
¼ 0.46 in 1:20 MeOH/CH
2 2
Cl ). H NMR (400 MHz, DMSO-
6
d ) d
ꢁ
13
1
H), 3.86e3.72 (m, 8H). C NMR (100 MHz, DMSO-d
6
) d: 164.1,
was purified by column chromatography on silica gel. Then the Boc-
164.0, 158.6, 154.6, 143.7, 142.4, 138.7, 133.5, 130.5, 124.9, 120.8,
protected product was mixed with CF
3 mL), the reaction was stirred for 2 h. Then the organic solvent
was removed, saturated solution was added to neutralize the so-
lution. Then MeOH/CH Cl (1:9) was added, the organic layer was
separated and concentrated. The residue was purified by silica gel
chromatography with 1:20 MeOH/CH Cl to give product 17f
¼ 0.28 in 1:20 MeOH/CH
: 9.31 (s, 1H), 9.16 (s, 2H), 8.42 (d, J ¼ 4.3 Hz,
H), 8.07 (d, J ¼ 10.8 Hz,1H), 7.94 (d, J ¼ 9.6 Hz,1H), 7.68 (dd, J ¼ 8.5,
.5 Hz, 1H), 7.32e7.21 (m, 2H), 7.11 (s, 2H), 3.88e3.79 (m, 4H),
.79e3.72 (m, 4H). 13C NMR (100 MHz, DMSO-d
: 164.1, 163.5,
58.1, 156.7, 153.7, 146.2, 145.1, 142.5, 129.2, 128.3, 126.9, 124.6,
3 2 2
COOH (3 mL) and CH Cl
120.0, 119.0, 117.3, 114.9, 114.7, 112.8, 66.0, 49.8. HRMS (ESI) m/z:
(
þ
calcd. for C22
H
20
N
7
OClNa [MþNa] : 456.1310; found 456.1290.
2
2
5
.1.27. 2-(2-Aminopyrimidin-5-yl)-4-morpholino-N-(pyridin-2-yl)
quinazolin-8-amine (18e)
2
2
Compound 18e was prepared from intermediate 16 (46 mg, 46%
1
(
(
48 mg, 37% yield, R
6
400 MHz, DMSO-d ) d
f
2
Cl
2
). H NMR
1
yield, R
: 9.42 (s, 2H), 9.31 (s, 1H), 8.92 (d, J ¼ 7.3 Hz, 1H), 8.28 (d,
J ¼ 3.5 Hz, 1H), 7.78e7.61 (m, 1H), 7.52e7.32 (m, 3H), 7.15 (s, 2H),
f
¼ 0.42 in 1:20 MeOH/CH
2 2
Cl ). H NMR (400 MHz, DMSO-
6
d ) d
1
4
3
13
6
.96e6.78 (m, 1H), 3.82 (d, J ¼ 5.6 Hz, 8H). C NMR (100 MHz,
6
) d
DMSO-d : 164.1, 164.0, 158.7, 155.0, 154.6, 146.9, 142.0, 137.3,
6
) d
1
136.7, 125.0, 119.9, 116.6, 115.4, 115.3, 114.1, 112.9, 66.0, 49.8. HRMS
120.2, 117.0, 116.5, 110.2, 109.2, 66.0, 49.7. HRMS (ESI) m/z: calcd. for
þ
(ESI) m/z: calcd. for C21
20
H N
8
ONa [MþNa] : 423.1652; found
ꢀ
C
H
22 18
N
9
O [MꢀH] : 424.1640; found 424.1648.
4
23.1639.
5
.1.23. 2-(2-Aminopyrimidin-5-yl)-4-morpholinoquinazolin-8-
amine (18a)
Yield 90%, R
DMSO-d
: 9.30 (s, 2H), 7.17 (t, J ¼ 7.9 Hz, 1H), 7.13e7.07 (m, 2H),
5.1.28. 2-(2-Aminopyrimidin-5-yl)-4-morpholino-N-(pyridin-3-yl)
quinazolin-8-amine (18f)
f
¼ 0.39 in 1:20 MeOH/CH
2
Cl
2
. 1H NMR (400 MHz,
Compound 18f was prepared from intermediate 16. Yield 51%,
1
6
)
d
R
f
¼ 0.29 in 1:20 MeOH/CH
2
Cl
2
. H NMR (400 MHz, DMSO-d
6
)
d:
7
3
.05 (d, J ¼ 8.2 Hz, 1H), 6.89 (d, J ¼ 7.5 Hz, 1H), 6.05 (s, 2H),
9.42 (s, 2H), 8.71 (d, J ¼ 7.7 Hz, 2H), 8.22 (d, J ¼ 3.6 Hz, 1H), 7.83 (d,
13
.94e3.77 (m, 4H), 3.75e3.65 (m, 4H). C NMR (100 MHz, DMSO-
J ¼ 7.6 Hz, 1H), 7.45 (d, J ¼ 7.4 Hz, 1H), 7.36 (d, J ¼ 7.7 Hz, 2H), 7.29 (t,
13
d
6
)
d
: 164.7, 164.5, 158.6, 153.9, 145.7, 141.2, 126.2, 120.8, 115.3, 112.1,
J ¼ 7.8 Hz, 1H), 7.16 (s, 2H), 3.98e3.67 (m, 8H). C NMR (100 MHz,
þ
110.9, 66.5, 50.3. HRMS (ESI) m/z: calcd. for C22
22
H N
7
O [MþH] :
DMSO-d
6
) d: 164.6, 164.5, 159.2, 155.0, 143.1, 143.0, 142.8, 139.7,
3
24.1567; found 324.1563.
139.0, 126.9, 125.5, 124.2, 120.5, 115.3, 115.1, 112.3, 66.5, 50.3. HRMS