Journal of Medicinal Chemistry
Article
as the mobile phase at 5 mL/min. Postanalysis of each isolated
6.6 Hz, 1H), 6.83 (tdd, J = 8.4, 2.6, 0.9 Hz, 1H), 3.29−3.22 (m, 1H),
3.04−2.83 (m, 3H), 2.40 (dd, J = 16.3, 9.1 Hz, 1H), 2.21−2.08 (m,
enantiomer was performed on a Chiralcel OD-H column (250 × 4.6
2
13
mm ID, particle size: 5 μm) using 0.1% TEA heptane−EtOH (95:5)
1H), 1.77 (dtd, J = 12.8, 10.3, 6.2 Hz, 1H). C NMR (101 MHz,
as the mobile phase at 1 mL/min. The chiral structure of enantiomers
CD OD) δ 164.21 (CF, d, J = 241.9 Hz), 163.95 (C), 159.68 (C),
3
CF
3
and 4 was arbitrarily assigned.
150.93 (CH), 149.77 (CH), 137.16 (CH), 135.75 (C), 130.75 (CH,
d, JCF = 9.3 Hz), 125.04 (CH), 118.43 (CH, d, JCF = 2.6 Hz), 112.15
(C), 110.71 (CH, d, JCF = 21.4 Hz), 109.86 (CH, d, JCF = 26.0 Hz),
47.71 (CH), 31.91 (CH ), 31.62 (CH ), 31.25 (CH ).
Synthesis of Compound 6: N -(3-Fluorophenyl)-2-(2-pyridyl)-
5,6,7,8-tetrahydroquinazoline-4,6-diamine. Step 1: Synthesis of 6-
(Dibenzylamino)-2-(2-pyridyl)-5,6,7,8-tetrahydro-3H-quinazolin-4-
one (Compound F1, Scheme 1c). This compound was obtained
using 5-(dibenzylamino)-2-oxo-cyclohexanecarboxylate (335.0 mg,
4
(
6R)-N -(3-Fluorophenyl)-2-(4-pyridyl)-5,6,7,8-tetrahydroquina-
zoline-4,6-diamine (3, Scheme 1d). Enantiomeric purity of 95.2%
enantiomeric excess (ee) was obtained at 290 nm of the first eluting
enantiomer at R = 63.3 min in a Chiralcel OD-H column. R = 1.53
2
2
2
4
t
t
+
+
min (gradient 1); MS (ESI) m/z: 336.2 [M − H] , [M − H] calcd:
+
3
36.2. HRMS m/z: 336.1623, calcd for C H FN : 336.1624. QC
19 19 5
+
analysis: R = 2.57 min, m/z: 336.11 [M − H] , UV (215 nm):
t
1
>
99.5%. H NMR (400 MHz, DMSO-d ) δ 8.73 (s, 1H), 8.72−8.67
6
0
4
.95 mmol) and pyridine-2-carboxamidine hydrochloride (774 mg,
.77 mmol) following the general procedure F previously described
(
(
m, 2H), 8.16−8.05 (m, 2H), 7.75 (dt, J = 12.1, 2.3 Hz, 1H), 7.64
dd, J = 8.0, 1.9 Hz, 1H), 7.41 (td, J = 8.2, 6.9 Hz, 1H), 6.90 (td, J =
and affording a pure white solid (300 mg, yield 74%). R = 1.89 min
8
3
5
.4, 2.6 Hz, 1H), 3.27 (s, 3H), 2.89 (dddd, J = 19.8, 15.1, 8.6, 5.4 Hz,
H), 2.46−2.35 (m, 1H), 2.09−1.89 (m, 1H), 1.70 (dtd, J = 12.6, 9.5,
t
+
+
(
gradient 2); MS (ESI) m/z: 423.5 [M − H] , [M − H] calcd:
1
.9 Hz, 1H). 13C NMR (101 MHz, DMSO-d ) δ 163.08 (C), 162.05
6
4
4
1
23.2. H NMR (400 MHz, DMSO-d ) δ 11.81 (s, 1H), 8.70 (dt, J =
6
.6, 1.3 Hz, 1H), 8.23 (d, J = 7.9 Hz, 1H), 7.99 (td, J = 7.8, 1.7 Hz,
H), 7.60 (ddd, J = 7.7, 4.7, 1.2 Hz, 1H), 7.43−7.36 (m, 4H), 7.31
(
CF, d, JCF = 240.7 Hz), 158.61 (C), 157.26 (C), 150.24 (CH),
45.23 (C), 141.69 (C, d, JCF = 11.1 Hz), 129.86 (CH, d, JCF = 9.6
Hz), 121.29 (CH), 117.23 (CH, d, JCF = 1.5 Hz), 112.76 (C), 109.11
CH, d, JCF = 21.0 Hz), 108.11 (CH, d, JCF = 25.9 Hz), 46.01 (CH),
1.84 (CH ), 30.60 (CH ), 30.35 (CH ).
1
(
dd, J = 8.3, 6.8 Hz, 4H), 7.25−7.15 (m, 2H), 3.73 (d, J = 14.3 Hz,
2
2
1
H), 3.65 (d, J = 14.2 Hz, 2H), 2.91−2.76 (m, 1H), 2.73 (s, 1H),
.70−2.54 (m, 2H), 2.12−2.05 (m, 1H), 1.77 (qd, J = 12.0, 5.2 Hz,
H).
(
3
2
2
2
4
(
6S)-N -(3-Fluorophenyl)-2-(4-pyridyl)-5,6,7,8-tetrahydroquina-
zoline-4,6-diamine (4, Scheme 1d). Enantiomeric purity was >99.5%
ee at 290 nm of the second eluting enantiomer at R = 67. 6 min in the
Chiralcel OD-H column. R = 1.53 min (gradient 1); MS (ESI) m/z:
Step 2: Synthesis of N,N-Dibenzyl-4-chloro-2-(2-pyridyl)-5,6,7,8-
tetrahydroquinazolin-6-amine (Compound G1, Scheme 1c). This
compound was obtained using compound F1 (300.0 mg, 0.71 mmol)
following the general procedure G previously described. Normal
t
t
+
+
3
36.2 [M − H] , [M − H] calcd: 336.2. HRMS m/z: 336.1623,
+
phase purification (CHCl /CHCl :MeOH 4:1 from 100/0 to 50/50)
calcd for C H FN : 336.1624. QC analysis: R = 2.56 min, m/z:
3
3
19
19
5
t
+
1
afforded the pure title compound (275 mg, yield 88%). R = 2.29 min
3
36.14 [M − H] , UV (215 nm): >99.5%. H NMR (400 MHz,
t
+
+
(
4
gradient 2); MS (ESI) m/z: 441/443 [M − H] , [M − H] calcd:
41/443. H NMR (400 MHz, CDCl ) δ 8.82 (ddd, J = 4.7, 1.8, 0.9
DMSO-d ) δ 8.73 (s, 1H), 8.72−8.67 (m, 2H), 8.16−8.05 (m, 2H),
6
1
7
.75 (dt, J = 12.1, 2.3 Hz, 1H), 7.64 (dd, J = 8.0, 1.9 Hz, 1H), 7.41
3
Hz, 1H), 8.44 (dt, J = 8.0, 1.1 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H),
.46−7.39 (m, 4H), 7.37 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 7.35−7.28
(
2
2
(
td, J = 8.2, 6.9 Hz, 1H), 6.90 (td, J = 8.4, 2.6 Hz, 1H), 3.27 (s, 3H),
7
.89 (dddd, J = 19.8, 15.1, 8.6, 5.4 Hz, 3H), 2.46−2.35 (m, 1H),
13
.09−1.89 (m, 1H), 1.70 (dtd, J = 12.6, 9.5, 5.9 Hz, 1H). C NMR
(m, 4H), 7.25−7.20 (m, 2H), 3.83 (d, J = 14.0 Hz, 2H), 3.70 (d, J =
14.1 Hz, 2H), 3.28 (ddd, J = 18.3, 5.0, 2.5 Hz, 1H), 3.16−3.00 (m,
2H), 2.98−2.79 (m, 2H), 2.29 (ddd, J = 12.5, 5.4, 2.6 Hz, 1H), 1.85
(qd, J = 12.3, 5.0 Hz, 1H).
101 MHz, DMSO-d ) δ 163.08 (C), 162.05 (CF, d, J = 240.7 Hz),
6
C
F
1
=
58.61 (C), 157.26 (C), 150.24 (CH), 145.23 (C), 141.69 (C, d, JCF
11.1 Hz), 129.86 (CH, d, JCF = 9.6 Hz), 121.29 (CH), 117.23 (CH,
d, JCF = 1.5 Hz), 112.76 (C), 109.11 (CH, d, JCF = 21.0 Hz), 108.11
CH, d, JCF = 25.9 Hz), 46.01 (CH), 31.84 (CH2), 30.60 (CH2),
6
6
4
Step 3: Synthesis of N ,N -Dibenzyl-N -(3-fluorophenyl)-2-(2-
pyridyl)-5,6,7,8-tetrahydroquinazoline-4,6-diamine (Compound
H1, Scheme 1c). This compound was obtained using compound
G1 (135 mg, 0.31 mmol) and 3-fluoroaniline (0.036 mL, 0.37 mmol)
following the general procedure H previously described for 1 h. Final
normal phase purification (cyclohexane/EtOAc from 40/60 to 60/
(
3
0.35 (CH2).
4
Synthesis of Compound 5: N -(3-Fluorophenyl)-2-(3-pyridyl)-
5
,6,7,8-tetrahydroquinazoline-4,6-diamine. Step 1: Synthesis of
6
6
4
N ,N -Dibenzyl-N -(3-fluorophenyl)-2-(3-pyridyl)-5,6,7,8-tetrahy-
droquinazoline-4,6-diamine (Compound D1.2, Scheme 1b). This
compound was obtained using compound C1.1 (55 mg, 0.12 mmol)
and pyridine-3-boronic acid (19.2 mg, 0.14 mmol) following the
general procedure D previously described. Final normal phase
purification (cyclohexane/TBME from 80/20 to 50/50) afforded
40) afforded the pure title compound (131.1 mg, yield 83%). R =
t
+
+
2.26 min (gradient 1); MS (ESI) m/z: 516.5 [M − H] , [M − H]
1
calcd: 516.2. H NMR (400 MHz, DMSO-d ) δ 8.69 (ddd, J = 4.7,
6
1.8, 0.9 Hz, 1H), 8.63 (s, 1H), 8.20 (dt, J = 8.0, 1.1 Hz, 1H), 8.06 (dt,
J = 12.5, 2.3 Hz, 1H), 7.90 (td, J = 7.7, 1.8 Hz, 1H), 7.70 (ddd, J =
8.3, 2.0, 0.9 Hz, 1H), 7.48−7.41 (m, 5H), 7.38 (td, J = 8.3, 7.0 Hz,
1H), 7.32 (t, J = 7.6 Hz, 4H), 7.26−7.18 (m, 2H), 6.86 (tdd, J = 8.4,
2.6, 0.9 Hz, 1H), 3.80 (d, J = 14.2 Hz, 2H), 3.70 (d, J = 14.2 Hz, 2H),
3.06−2.86 (m, 3H), 2.85−2.69 (m, 1H), 2.25−2.10 (m, 1H), 1.85
(qd, J = 12.2, 5.0 Hz, 1H).
the pure title compound (58.0 mg, yield 96%). R = 3.0 min (gradient
t
+
+
1
2
); MS (ESI) m/z: 516.4 [M − H] , [M − H] calcd: 516.2. H
NMR (400 MHz, CDCl ) δ 9.54 (dd, J = 2.2, 0.9 Hz, 1H), 8.65 (dd, J
3
=
4.8, 1.7 Hz, 1H), 8.58 (dt, J = 7.9, 2.0 Hz, 1H), 7.68 (dt, J = 11.2,
2.3 Hz, 1H), 7.46 (d, J = 7.8 Hz, 5H), 7.41−7.29 (m, 7H), 7.26 (s,
2H), 6.81 (tdd, J = 8.3, 2.6, 1.2 Hz, 1H), 6.49 (s, 1H), 3.91 (d, J =
13.7 Hz, 2H), 3.71 (d, J = 14.0 Hz, 2H), 3.29−3.10 (m, 1H), 3.11−
2.98 (m, 1H), 2.80 (ddd, J = 17.9, 12.2, 5.4 Hz, 1H), 2.65 (d, J = 8.3
4
Step 4: Synthesis of N -(3-Fluorophenyl)-2-(2-pyridyl)-5,6,7,8-
tetrahydroquinazoline-4,6-diamine (Compound 6, Scheme 1c).
This compound was obtained using compound H1 (131 mg, 0.25
mmol) following the general procedure I previously described for 4 h.
Hz, 2H), 2.46−2.22 (m, 1H), 1.84 (qd, J = 12.2, 4.8 Hz, 1H).
4
Step 2: Synthesis of N -(3-Fluorophenyl)-2-(3-pyridyl)-5,6,7,8-
Final normal phase purification (DCM/DCM:NH 1 N MeOH 4:1
3
tetrahydroquinazoline-4,6-diamine (Compound 5, Scheme 1b).
This compound was obtained using compound D1.2 (58.0 mg, 0.11
mmol) following the general procedure E previously described for 4 h.
Final normal phase purification (DCM/DCM:NH 1 N MeOH 4:1
from 95/5 to 75/25) afforded the pure title compound (12.2 mg,
from 90/10 to 60/40) afforded the pure title compound (51.1 mg,
yield 60%). R = 1.57 min (gradient 1); MS (ESI) m/z: 336.1 [M −
t
+
+
H] , [M − H] calcd: 336.2. HRMS m/z: 336.1623, calcd for
C H FN : 336.1624. QC analysis: R = 2.70 min, m/z: 336.50 [M
− H] , UV (215 nm): 97%. H NMR (400 MHz, DMSO-d ) δ 8.71
+
3
19 19
5
t
+
1
6
yield 33%). R = 1.71 min (gradient 1); MS (ESI) m/z: 336.1 [M −
(ddd, J = 4.7, 1.8, 0.9 Hz, 1H), 8.58 (s, 1H), 8.23 (dt, J = 8.0, 1.1 Hz,
1H), 8.10 (dt, J = 12.6, 2.3 Hz, 1H), 7.92 (td, J = 7.7, 1.8 Hz, 1H),
7.78−7.68 (m, 1H), 7.46 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 7.35 (td, J =
8.2, 7.0 Hz, 1H), 6.90−6.79 (m, 1H), 3.18 (tdd, J = 8.4, 5.0, 3.0 Hz,
1H), 2.96−2.71 (m, 3H), 2.35 (dd, J = 17.0, 8.3 Hz, 1H), 2.00−1.89
t
+
+
H] , [M − H] calcd: 336.2. HRMS m/z: 336.1620, calcd for C H
1
9
19
+
5
+
FN : 336.1624. QC analysis: R = 2.67 min, m/z: 336.10 [M − H] ,
t
1
UV (215 nm): 95%. H NMR (400 MHz, CD OD) δ 9.45−9.32 (m,
3
1
7
H), 8.64 (dt, J = 8.0, 1.9 Hz, 1H), 8.58 (dd, J = 4.9, 1.7 Hz, 1H),
.70 (dt, J = 11.7, 2.3 Hz, 1H), 7.56−7.44 (m, 2H), 7.35 (td, J = 8.2,
1
3
(m, 1H), 1.64 (dtd, J = 12.7, 9.6, 5.8 Hz, 1H). C NMR (101 MHz,
H
J. Med. Chem. XXXX, XXX, XXX−XXX