1
Light yellow solid, 85% yield. H-NMR (600 MHz, CDCl
3
) δ (ppm): 8.90 (t, J = 8.2 Hz, 1H), 7.64 (t, J = 9.0 Hz, 2H), 7.39 (s, 1H),
4
6
.67 (m, 1H), 4.41-4.23 (m, 2H), 4.19 (d, J = 8.1 Hz, 1H), 3.05 (s, 3H), 2.82 (t, J = 7.7 Hz, 2H), 2.62 (t, J = 7.2 Hz, 2H), 2.17-2.13 (m,
H), 2.05 (m, 2H), 1.87 (m, 2H), 1.49 (s, 9H). HRMS-TOF (m/z) calcd for C26H34FN O S [M-H] : 530.2238, found 530.2084. HPLC
5 4
-
purity, 98.5%.
.1.14 tert-butyl 4-((2-((4-cyano-2-fluorophenyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)piperidine-1-
carboxylate (18)
Light yellow solid, 52% yield. H-NMR (600 MHz, CDCl
1.0, 1.3 Hz, 1H), 7.33 (d, J = 3.3 Hz, 1H), 4.29 (d, J= 7.5 Hz, 1H), 4.17-4.11 (m, 1H), 2.96 (m, 2H), 2.86 (t, J = 7.7 Hz, 2H), 2.64 (t, J
7.1 Hz, 2H), 2.15 (q, J = 7.7 Hz, 2H), 2.12-2.10 (m, 2H), 1.50 (s, 9H), 1.47-1.42 (m, 4H). HRMS-TOF (m/z) calcd for C24
4
1
3
) δ (ppm): 8.83 (t, J = 8.4 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.36 (dd, J =
1
=
6 2
H29FN O
-
[M-H] : 451.2258, found 451.2108. HPLC purity, 95.6%.
4.1.15 tert-butyl (endo)-3-((2-((4-cyano-2-fluorophenyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-8-
azabicyclo[3.2.1]octane-8-carboxylate (19)
1
Light yellow solid, 86% yield. H-NMR (600 MHz, CDCl
3
) δ (ppm): 8.80 (t, J = 8.5 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.36-7.34 (m,
2
2
1
H), 4.78 (d, J = 6.5 Hz, 1H), 4.35 (m, 1H), 4.32-4.23 (m, 2H), 2.86 (t, J = 7.6 Hz, 2H), 2.64 (t, J = 7.0 Hz, 2H), 2.42-2.28 (m, 1H),
13
.17 (q, J = 7.7 Hz, 2H), 2.14-2.12 (m, 3H), 1.89-1.86 (m, 4H), 1.52 (s, 9H). C-NMR (150 MHz, CDCl
3
) δ (ppm): 167.8, 163.8, 154.5,
49.4, 146.5, 130.1, 126.9, 125.4, 115.0, 114.7, 113.9, 105.4, 75.7, 64.2, 48.9, 48.1, 39.4, 34.7, 32.0, 31.3, 30.2, 24.6 (x3), 22.2, 17.7.
-
HRMS-TOF (m/z) calcd for C26
.1.16 tert-butyl (exo)-3-((2-((4-cyano-2-fluorophenyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-8-
azabicyclo[3.2.1]octane-8-carboxylate (20)
6 2
H31FN O [M-H] : 477.2415, found 477.2255. HPLC purity, 97.4%.
4
1
Yellow solid, 80% yield. H-NMR (600 MHz, CDCl
3
) δ (ppm): 8.78 (t, J = 8.2 Hz, 1H), 7.35-7.29 (m, 3H), 4.57 (m, 1H), 4.26-4.13
(
m, 3H), 2.79 (m, 2H), 2.55 (t, J = 7.0 Hz, 2H), 2.09-2.00 (m, 8H), 1.79 (m, 2H), 1.45 (s, 9H). HRMS-TOF (m/z) calcd for
-
C26H31FN6O2 [M-H] : 477.2415, found 477.2259. HPLC purity, 94.2%.
4
.1.17 5, 6, 7, 8-tetrahydroquinazoline-2,4-diol (21)
Follow the similar synthetic procedure of compounds 7. Yellow solid, 38% yield. H-NMR (600 MHz, CDCl
1
3
) δ (ppm): 7.98 (s, 1H),
-
7
.84 (s, 1H), 2.39 (m, 4H), 1.82 (m, 2H), 1.75 (m, 2H). MS-ESI: [M-H] :165.3.
4.1.18 2, 4-dichloro-5, 6, 7, 8-tetrahydroquinazoline (22)
1
Follow the similar synthetic procedure of compounds 7. Yellow solid, 50% yield. H-NMR (600 MHz, CDCl
3
) δ (ppm): 2.78 (m, 4H),
-
1
.9 (m, 2H), 1.79 (m, 2H). MS-ESI: [M-H] :201.4.
4.1.19 tert-butyl 4-((2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)amino)piperidine-1-carboxylate(23)
To the solution of compounds 22 (0.3 g, 1.5 mmol) in DMF were added K
2 3
CO (1.95 mmol) and 4-amino-1-Boc-piperidine (2.7
mmol). The reaction was stirred at 80℃ for 8 h. Then the mixture was extracted with ethyl acetate, washed with brine, dried over
1
MgSO
MHz, CDCl
Hz, 2H), 2.14-2.00 (m, 2H), 1.94-1.77 (m, 4H), 1.49 (s, 9H), 1.41-1.30 (m, 2H). MS-ESI: [M+H] : 367.1
4
, and evaporated. The residue was purified by column chromatography to give the product (0.5 g, 92% yield). H-NMR (600
3
) δ (ppm): 4.47 (d, J = 7.7 Hz, 1H), 4.31-4.17 (m, 1H), 4.07 (ds, 2H), 2.95 (ds, 2H), 2.70 (t, J = 6.1 Hz, 2H), 2.26 (t, J = 6.1
+
4
.1.20 tert-butyl 3-((2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate(24)
Follow the similar synthetic procedure of compounds 23 .Yellow solid, 70% yield. H-NMR (600 MHz, CDCl ) δ (ppm): 4.41 (m,
3
+
1
1H), 4.22 (m, 3H), 3.00 (m, 2H), 2.70 (m, 2H), 2.26 (m, 2H), 2.03 (m, 2H), 1.95-1.79 (m, 8H), 1.49 (m, 9H). MS-ESI: [M+H] : 393.3.
4
.1.21 tert-butyl 4-((2-((4-cyano-2-fluorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)piperidine-1-carboxylate (25)
1
Follow the similar synthetic procedure of compounds 12-20. Yellow solid, 55% yield. H-NMR (600 MHz, CDCl
3
) δ (ppm): 8.84 (t,
J = 8.4 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.34 (dd, J = 11.0, 1.7 Hz, 1H), 7.24 (s, 1H), 4.44 (d, J = 7.2 Hz, 1H), 4.17-4.11 (m, 3H), 2.97
1
3
(
(
2
9
4
8
m, 2H), 2.66 (t, J = 6.1 Hz, 2H), 2.28 (t, J = 6.2 Hz, 2H), 2.09 (m, 2H), 1.88-1.84 (m, 4H), 1.50 (s, 9H), 1.45 (m, 2H). C-NMR
150MHz, CDCl ) δ (ppm): 158.8, 156.3, 152.1, 150.8, 146.5, 130.3, 125.3, 114.9, 114.8, 114.0, 113.8, 101.6, 75.9, 44.4, 39.0, 38.6,
8.3, 27.9, 25.7, 24.5, 18.4, 18.3, 18.0. HRMS-TOF (m/z) calcd for C25 [M-H]- : 465.2415, found 465.2250. HPLC purity,
7.0%.
3
6 2
H31FN O
.1.22 tert-butyl (endo)-3-((2-((4-cyano-2-fluorophenyl)amino)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)-8-azabicyclo[3.2.1]octane-
-carboxylate (26)
1
Follow the similar synthetic procedure of compounds 12-20. Light yellow solid, 60% yield. H-NMR (600 MHz, CDCl
3
) δ (ppm):
8
2
1
2
4
.80 (t, J = 8.3 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.34 (m, 2H), 5.00 (d, J = 5.9 Hz, 1H), 4.36 (m, 2H), 4.26 (s, 1H), 2.66 (t, J = 6.2 Hz,
13
H), 2.30 (t, J = 6.3 Hz, 2H), 2.14 (m, 2H), 1.92-1.84 (m, 10H), 1.52 (s, 9H). C-NMR (150 MHz, CDCl
53.3, 151.3, 134.2, 129.3, 119.0, 118.7, 117.9, 117.8, 105.2, 79.6, 53.4, 52.8, 52.0, 35.7, 35.3, 29.3, 28.6 (x3), 28.2, 28.0, 22.4, 22.2,
1.8. HRMS-TOF (m/z) calcd for C27 [M-H]- : 491.2571, found 491.2431. HPLC purity, 95.7%.
.1.23 tert-butyl 4-((2-((2-fluoro-4-(methylsulfonyl)phenyl)amino)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)piperidine-1-carboxylate
3
) δ (ppm): 162.4, 160.2, 156.1,
H
6 2
33FN O
(
27)
Follow the similar synthetic procedure of compounds 12-20. Yellow solid, 56% yield. H-NMR (600 MHz, CDCl
J = 8.4 Hz, 1H), 7.68 (dd, J = 8.7, 1.7 Hz, 1H), 7.64 (dd, J = 10.6, 2.1Hz, 1H), 7.35 (s, 1H), 4.45 (d, J = 7.4 Hz, 1H), 4.19-4.12 (m, 3H),
1
3
) δ (ppm): 8.92 (t,
3
.07 (s, 3H), 2.97 (m, 2H), 2.67 (t, J = 6.1 Hz, 2H), 2.29 (t, J = 6.2 Hz, 2H), 2.11 (m, 2H), 1.90-1.84 (m, 4H), 1.51 (s, 9H), 1.43 (m, 2H).
13
C-NMR (150 MHz, CDCl
3
) δ (ppm): 158.8, 156.3, 152.1, 150.8, 146.6, 130.9, 126.9, 120.3, 114.5, 110.0, 109.9, 101.5, 75.9, 44.5,
S [M-H]- : 519.2316, found 519.2162.
40.9, 39.2, 38.6, 28.4, 27.9, 25.7, 24.5, 18.4, 18.3, 18.0. HRMS-TOF (m/z) calcd for C25H34FN O
5 4
HPLC purity, 97.4%.
.1.24 tert-butyl (endo)-3-((2-((2-fluoro-4-(methylsulfonyl)phenyl)amino)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)-8-
azabicyclo[3.2.1]octane-8-carboxylate (28)
Follow the similar synthetic procedure of compounds 12-20. Yellow solid, 58% yield. H-NMR (600 MHz, CDCl
J = 8.4 Hz, 1H), 7.69-7.63 (m, 2H), 7.46 (s, 1H), 5.01 (s, 1H), 4.36-4.27 (m, 3H), 3.05 (s, 3H), 2.65 (m, 2H), 2.28 (m, 2H), 2.13 (m, 2H),
4
1
3
) δ (ppm): 8.87 (t,
3
1
1
5
3
.88 (m, 10H), 1.50 (s, 9H). C-NMR (150 MHz, CDCl ) δ (ppm): 167.1, 160.8, 156.2, 149.3, 147.7, 130.9, 127.9, 120.5, 114.7, 109.8,
01.3, 75.7, 49.0, 47.8, 40.9, 39.7, 33.6, 32.1; 31.3, 30.2, 24.5 (x3), 22.2, 17.8. HRMS-TOF (m/z) calcd for C27
44.2394, found 544.2220. HPLC purity, 93.4%.
5 4
H36FN O S [M-H]- :