Journal of Medicinal Chemistry
Article
1
=
H), 6.83 (dd, J = 7.2, 7.6 Hz, 2H), 6.97 (t, J = 7.8 Hz, 1H), 7.16 (d, J
7.6 Hz, 3H), 7.26 (t, J = 7.6 Hz, 2H), ppm. The free base was
6.37 (s, 1H), 6.44 (d, J = 8.4 Hz, 1H), 6.82 (t, J = 7.6 Hz, 2H), 6.96 (t,
J = 8.6 Hz, 2H), 9.03 (br s, 1H), ppm. 13C NMR (100 MHz, CDCl ) δ
3
13
converted into the oxalate salt (white solid). C NMR (100 MHz,
CD OD) δ 25.50, 26.14, 26.29, 27.83, 28.15, 28.84, 29.14, 30.53,
24.57, 25.13, 26.30, 31.05, 31.07, 34.09, 40.82, 42.89, 53.23, 67.34,
102.12, 105.72, 108.76, 115.74, 117.32, 119.82, 121.17, 126.15, 127.57,
128.61, 138.16, 153.63, 158.45, 171.57, ppm. The free base was
converted into the maleate salt (white solid). HRMS (ESI) calculated
3
3
1
5.18, 39.27, 40.91, 52.34, 70.24, 70.28, 106.88, 113.56, 119.95,
22.15, 125.07, 125.28, 127.85, 127.97, 142.27, 153.59, 164.76, ppm.
2
3
+
23
HPLC-DAD (R : 5.733 min; purity 98.00%); mp 119−121 °C; [α]
−
H, N.
421.2234, found 421.2241 (M + H ); mp 144−145 °C (dec); [α]
t
D
D
7.0 (MeOH, c 0.06). Anal. (C H N O ·1.6H C O ·0.4NH OH) C,
−6.7 (MeOH, c 0.18). Anal. (C H N O ·H C O ·H O) C, H, N.
27
37
3
2
2
2
4
4
24 28
4
3
4
4
4
2
(R)-5-(Methylamino)-1-(12-((2-oxo-1,2,3,4-tetrahydroquinolin-7-
yl)oxy)dodecyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one
(12). The reaction followed the procedure described for 4 starting
(
R)-5-(Methylamino)-1-(8-(4-phenylbutoxy)octyl)-5,6-dihydro-
4
H-imidazo[4,5,1-ij]quinolin-2(1H)-one (8). The reaction followed
45
45
the procedure described for 4 starting from 1 (0.20 g; 0.0009 mol)
and 26 (0.34 g; 0.0009 mol). The crude compound was purified via
flash chromatography, eluting with 1% CMA to give the pure product
in a 24% yield. H NMR (400 MHz, CDCl ) δ 1.30−1.76 (m, 16H),
from 1 (0.10 g; 0.0005 mol) and 39 (0.20 g; 0.0005 mol). The crude
compound was purified via flash chromatography, eluting with 5%
1
CMA to give the pure product as a yellow oil in 34% yield. H NMR
1
(400 MHz, CDCl ) δ 1.24−1.43 (m, 18H), 1.69−1.76 (m, 2H), 2.53
3
3
2
3
.54 (s, 3H), 2.63 (t, J = 7.4 Hz, 2H), 2.78 (dd, J = 7.6, 7.6 Hz, 1H),
.06 (dd, J = 4.0, 4.0 Hz, 1H), 3.22 (m, 1H), 3.35−3.42 (m, 4H), 3.64
(s, 3H), 2.58 (t, J = 7.4 Hz, 2H), 2.76−2.88 (m, 3H), 3.06 (dd, J = 4.0,
4.0 Hz, 1H), 3.23 (m, 1H), 3.56−3.67 (m, 2H), 3.77−3.89 (m, 3H),
4.03 (dd, J = 4.0, 4.2 Hz, 1H), 6.36 (s, 1H), 6.48 (d, J = 8.4 Hz, 1H),
(
dd, J = 7.6, 7.2 Hz, 1H), 3.81−3.86 (m, 2H), 4.05 (dd, J = 4.0, 4.0 Hz,
1
3
1
H), 6.83 (dd, J = 7.2, 7.6 Hz, 2H), 6.98 (t, J = 7.6 Hz, 1H), 7.15 (d, J
6.82 (dd, J = 7.2, 7.2 Hz, 2H), 7.00 (m, 2H), 8.54 (br s, 1H), ppm.
C
=
7.2 Hz, 3H), 7.26 (m, 2H), ppm. 13C NMR (100 MHz, CDCl ) δ
NMR (100 MHz, CDCl ) δ 24.57, 25.97, 26.82, 28.64, 29.20, 29.22,
3
3
2
3
1
6.13, 26.83, 28.09, 28.68, 29.26, 29.34, 29.41, 29.70, 29.74, 31.17,
4.15, 35.74, 41.39, 42.87, 53.29, 70.67, 70.94, 105.70, 117.19, 119.62,
21.06, 125.65, 126.14, 127.75, 128.25, 128.42, 142.52, 153.55, ppm.
29.80, 29.39, 29.41, 29.44, 30.95, 31.09, 33.96, 41.39, 42.74, 53.24,
68.16, 102.25, 105.71, 108.64, 115.53, 117.07, 119.61, 121.06, 126.12,
127.76, 128.52, 138.19, 153.54, 158.76, 171.87, ppm. The free base was
2
3
The free base was converted into the oxalate salt (white solid); mp
1
H C O ·0.5H O) C, H, N.
converted into the oxalate salt (white solid); mp 147−148 °C; [α]
D
2
3
33−134 °C; [α] −7.1 (MeOH, c 0.45). Anal. (C H N O ·
−6.5 (MeOH, c 0.20). Anal. (C32H N O ·1.25H C O ·1.25H O) C,
44 4 3 2 2 4 2
D
29 41
3
2
H, N.
2
2
4
2
(
R)-5-(Methylamino)-1-(10-(4-phenylbutoxy)decyl)-5,6-dihydro-
(R)-N-(4-(2-Oxo-5-(propylamino)-5,6-dihydro-4H-imidazo[4,5,1-
4
H-imidazo[4,5,1-ij]quinolin-2(1H)-one (9). The reaction followed
ij]quinolin-1(2H)-yl)butyl)-1H-indole-2-carboxamide (13). A solution
45
46
the procedure described for 4 starting from 1 (0.20 g; 0.0009 mol)
of 2 (0.08 g; 0.0003 mol), 45 (0.10 g; 0.0003 mmol), and K CO
2 3
and 27 (0.33 g; 0.0009 mol). The crude compound was purified via
flash chromatography, eluting with 1% CMA to give the pure product
(0.09 g; 0.0007 mmol) in DMF (2 mL) was stirred overnight at 60 °C,
filtered, and evaporated to yield a crude product. The crude compound
was purified via preparative TLC, eluting with 10% CMA to give the
1
in a 24% yield. H NMR (400 MHz, CDCl ) δ 1.26−1.86 (m, 20H),
3
1
2
.55 (s, 3H), 2.60−2.63 (m, 2H), 2.82 (dd, J = 8.0, 8.0 Hz, 1H), 3.08
pure product as a white solid in 14% yield. H NMR (400 MHz,
(
=
(
dd, J = 4.2, 4.2 Hz, 1H), 3.22 (m, 1H), 3.37−3.41 (m, 4H), 3.66 (t, J
CDCl ) δ 0.92 (t, J = 7.4 Hz, 3H), 1.50 (m, 2H), 1.70 (t, J = 6.8 Hz,
3
9.6 Hz, 1H), 3.81−3.86 (m, 2H), 4.07 (dd, J = 4.2, 4.2 Hz, 1H), 6.83
2H), 1.89 (t, J = 7.0 Hz, 2H), 2.67−2.81 (m, 3H), 3.08 (dd, J = 4.4, 4.0
Hz, 1H), 3.32 (m, 1H), 3.54−3.63 (m, 3H), 3.95 (dt, J = 6.8, 6.8 Hz,
2H), 4.12 (dd, J = 3.2, 3.6 Hz, 1H), 6.86 (dd, J = 7.2, 7.6 Hz, 2H), 6.97
(d, J = 7.6 Hz, 1H), 7.00 (m, 1H), 7.15−7.09 (m, 2H), 7.26 (m, 1H),
dd, J = 7.6 Hz, 8.0 Hz, 2H), 6.99 (t, J = 7.8 Hz, 1H), 7.15−7.19 (m,
3
2
3
1
H), 7.28 (m, 2H), ppm. 13C NMR (100 MHz, CDCl ) δ 26.16,
3
6.87, 28.09, 28.68, 29.26, 29.29, 29.42, 29.43, 29.52, 29.75, 31.03,
4.03, 35.75, 41.41, 42.74, 53.28, 53.76, 70.67, 71.00, 105.75, 117.20,
19.61, 121.08, 125.65, 128.24, 128.42, 142.53, 153.53, ppm. The free
7
.42 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 9.76 (br s, 1H),
13
ppm. C NMR (100 MHz, CDCl
) δ 11.71, 23.42, 25.66, 26.59,
1.52, 39.55, 40.74, 43.68, 49.32, 51.57, 102.79, 105.71, 111.71,
17.76, 119.98, 120.41, 121.36, 121.98, 124.23, 126.21, 127.34, 127.73,
3
3
1
1
base was converted into the oxalate salt (white solid); mp 114−115
°
1
C; [α]2 − 2.8 (MeOH, c 0.15). Anal. (C H N O ·1.5H C O ·
3
D
31 45
3
2
2
2
4
2
3
31.02, 136.33, 153.89, 161.81, ppm; mp 201−204 °C (dec); [α]
.25H O) C, H, N.
D
2
(
R)-5-(Methylamino)-1-(12-(4-phenylbutoxy)dodecyl)-5,6-dihy-
−0.3 (CHCl , c 0.40). Anal. (C26H N O ·0.5H O) C, H, N.
3 31 5 2 2
(R)-N-(4-(5-(Dipropylamino)-2-oxo-5,6-dihydro-4H-imidazo-
dro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (10). The reaction fol-
45
[
4,5,1-ij]quinolin-1(2H)-yl)butyl)-1H-indole-2-carboxamide (14).
lowed the procedure described for 4 starting from 1 (0.20 g; 0.0009
mol) and 28 (0.39 g; 0.0009 mol). The crude compound was purified
The reaction followed the procedure described for 13 starting from
5
2 (0.04 g; 0.0001 mol). The crude compound was purified via
via flash chromatography, eluting with 1% CMA to give the pure
1
preparative TLC, eluting with 10% CMA to give the pure product a
product in a 24% yield. H NMR (400 MHz, CDCl ) δ 1.24−1.87 (m,
3
1
white solid in 17% yield. H NMR (400 MHz, CDCl ) δ 0.89 (t, J =
2
8
4
4
1
4H), 2.55 (s, 3H), 2.61−2.65 (t, J = 7.4 Hz, 2H), 2.79 (dd, J = 8.0,
.0 Hz, 1H), 3.07 (dd, 4.0, 4.0 Hz, 1H), 3.24 (m, 1H), 3.38−3.41 (m,
H), 3.65 (dd, J = 7.2, 6.8 Hz, 1H), 3.81−3.86 (m, 2H), 4.07 (dd, J =
.6, 4.6 Hz, 1H), 6.84 (dd, J = 7.6, 8.0 Hz, 2H), 6.99 (t, J = 7.6 Hz,
H), 7.19 (d, J = 7.6 Hz, 3H), 7.25 (m, 2H), ppm. The free base was
3
7
.4 Hz, 6H), 1.46 (m, 4H), 1.70 (m, 2H), 1.90 (m, 2H), 2.46−2.60
m, 4H), 2.82−2.94 (m, 2H), 3.31 (m, 1H), 3.48 (t, J = 11.4 Hz, 1H),
.57 (q, J = 6.4 Hz, 2H), 3.96 (t, J = 6.6 Hz, 2H), 4.20 (dd, J = 4.4, 4.8
Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.96−7.01
m, 2H), 7.09−7.14 (m and br s, 2H), 7.26 (dt, J = 4.0 Hz, 3.6 Hz,
H), 7.42 (d, J = 8.0, 1H), 7.64 (d, J = 8.0 Hz, 1H), 9.62 (br s, 1H).
(
3
13
(
1
converted into the oxalate salt (white solid). C NMR (100 MHz,
CD OD) δ 25.85, 26.29, 26.38, 27.89, 28.21, 28.86, 28.95, 29.11,
3
13
C NMR (100 MHz, CDCl ) δ 11.68, 22.32, 25.58, 26.57, 26.87,
2
7
1
9.20, 29.23, 29.28, 29.30, 30.51, 35.22, 39.28, 40.98, 52.31, 70.23,
0.47, 106.85, 113.68, 119.96, 122.12, 125.08, 125.30, 127.87, 127.93,
3
39.57, 40.68, 52.82, 54.68, 102.80, 105.42, 111.88, 119.31, 119.84,
120.42, 121.15, 121.99, 124.24, 126.25, 127.33, 127.75, 131.01, 136.30,
153.89, 161.78, ppm. HRMS (ESI) calculated 488.3020, found
23
27.99, 142,29, 153.57, 164.77, ppm; mp 142−143 °C; [α] −0.9
D
(
MeOH, c 0.23). Anal. (C H N O ·H C O ·2H O) C, H, N.
33 49 3 2 2 2 4 2
+
23
(
R)-5-(Methylamino)-1-(4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-
yl)oxy)butyl)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one
11). The reaction followed the procedure described for 4, starting
488.3016 (M + H ); mp 197−199 °C; [α]
D
−5.7 (MeOH, c 0.07).
Anal. (C H N O ·0.15CHCl ) C, H, N.
29
37
5
2
3
(
(R)-5-(Methylamino)-1-(2-(2-(4-phenylbutoxy)ethoxy)ethyl)-5,6-
dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (15). 32 (0.27 g;
0.0009 mol) was added portionwise to a solution of 1 (0.20 g;
45
from 1 (0.10 g; 0.0005 mol) and 38 (0.15 g; 0.0005 mol). The crude
45
compound was purified via flash chromatography, eluting with 5%
1
CMA to give the pure product as a yellow oil in 38% yield. H NMR
0.0009 mol) and K CO (0.62 g; 0.005 mol) in acetone (50 mL). The
2
3
(
3
400 MHz, CDCl ) δ 1.78−1.80 (m, 2H), 1.81−1.94 (m, 2H), 2.50 (s,
reaction mixture was stirred at reflux overnight and filtered, and the
solvent was evaporated. The crude compound was purified via flash
3
H), 2.56 (t, J = 12.0 Hz, 2H), 2.75 (dd, J = 7.6, 7.6 Hz, 1H), 2.84 (t, J
=
=
7.4 Hz, 2H), 3.02 (dd, J = 4.0, 4.0 Hz, 1H), 3.19 (m, 1H), 3.63 (dd, J
7.2, 7.2 Hz, 1H), 3.88−3.95 (m, 4H), 4.02 (dd, J = 3.6, 3.2 Hz, 1H),
chromatography, eluting with 10% CMA to give the pure product as a
1
yellow oil in 49% yield. H NMR (400 MHz, CDCl ) δ 1.58−1.69 (m,
3
L
J. Med. Chem. XXXX, XXX, XXX−XXX