Journal of Medicinal Chemistry
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1.78 (dt, J = 11.24, 5.75 Hz, 4 H), 1.54−1.59 (m, 2 H). MS [M + 1] =
401.
6.95, 1.64 Hz, 1 H), 8.26 (s, 1 H), 8.14 (d, J = 8.59 Hz, 1 H), 8.06 (d, J
= 8.59 Hz, 1 H), 7.66−7.72 (m, 1 H), 7.54−7.63 (m, 1 H), 6.92 (t, J =
7.07 Hz, 1 H), 3.62−3.73 (m, 2 H), 2.46−2.52 (m, 2 H), 2.32 (s, 6 H),
1.59−1.91 (m, 4 H). MS [M + 1] = 389.
12-Oxo-N-(2-pyrrolidin-1-ylethyl)-12H-benzo[g]pyrido[2,1-b]-
quinazoline-4-carboxamide (9). This compound was synthesized
from 6a (50 mg, 0.17 mmol) and 2-pyrrolidin-1-ylethanamine (21.8
μL, 0.17 mmol) according to method A to give 12-oxo-N-(2-
pyrrolidin-1-ylethyl)-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carbox-
amide (32.4 mg, 0.084 mmol, 48.7% yield) as a yellow-orange solid.
1H NMR (400 MHz, CDCl3) δ ppm 11.65 (br s, 1 H), 9.11 (s, 1 H),
8.96 (dd, J = 7.20, 1.64 Hz, 1 H), 8.71−8.77 (m, 1 H), 8.37 (s, 1 H),
8.13 (d, J = 8.34 Hz, 1 H), 8.02 (d, J = 7.83 Hz, 1 H), 7.64−7.72 (m, 1
H), 7.54−7.63 (m, 1 H), 6.87−6.94 (m, 1 H), 3.79−3.88 (m, 2 H),
2.96−3.03 (m, 2 H), 2.89 (m, 2 H), 2.78 (m, 2 H), 2.00 (m, 4 H). MS
[M + 1] = 387.
N-[2-(Dimethylamino)ethyl]-11-oxopyrido[2,1-b]quinazoline-6-
carboxamide (15). This compound was synthesized from 6b (40 mg,
0.17 mmol) and N,N-dimethylethylenediamine (14.7 mg, 0.17 mmol)
according to method A to give N-[2-(dimethylamino)ethyl]-11-oxo-
pyrido[2,1-b]quinazoline-6-carboxamide (19.8 mg, 0.064 mmol, 38%
1
yield) as a yellow-orange solid. H NMR (400 MHz, MeOD) δ ppm
9.32 (d, J = 7.33 Hz, 1 H), 8.91 (d, J = 7.58 Hz, 1 H), 8.51 (d, J = 7.58
Hz, 1 H), 8.07 (d, J = 7.07 Hz, 1 H), 7.99−8.03 (m, 2 H), 7.71 (t, J =
7.45 Hz, 1 H), 3.98 (t, J = 5.81 Hz, 2 H), 3.53 (t, J = 5.81 Hz, 2 H),
3.06 (s, 6 H). MS [M + 1] = 311.
N-[2-(Diethylamino)ethyl]-12-oxo-12H-benzo[g]pyrido[2,1-b]-
quinazoline-4-carboxamide (10). This compound was synthesized
from 6a (50 mg, 0.17 mmol) and N′,N′-diethylethane-1,2-diamine
(24.3 μL, 0.17 mmol) according to method A to give N-[2-
(diethylamino)ethyl]-12-oxo-12H-benzo[g]pyrido[2,1-b]quinazoline-
4-carboxamide (18.2 mg, 0.047 mmol, 27% yield) as a yellow-orange
N-[2-(Diethylamino)ethyl]-11-oxopyrido[2,1-b]quinazoline-6-car-
boxamide (16). This compound was synthesized from 6b (40 mg,
0.17 mmol) and N′,N′-diethylethane-1,2-diamine (19.4 mg, 0.17
mmol) according to method A to give N-[2-(diethylamino)ethyl]-11-
oxo-pyrido[2,1-b]quinazoline-6-carboxamide (25.2 mg, 0.075 mmol,
1
44.7% yield) as a yellow solid. H NMR (400 MHz, CDCl3) δ ppm
1
solid. H NMR (400 MHz, CDCl3) δ ppm 11.56−11.65 (m, 1 H),
11.44 (br s, 1 H), 9.06 (dd, J = 7.07, 1.77 Hz, 1 H), 8.83 (dd, J = 6.82,
1.77 Hz, 1 H), 8.45−8.51 (m, 1 H), 7.87−7.94 (m, 2 H), 7.54 (ddd, J
= 8.08, 5.68, 2.40 Hz, 1 H), 7.04 (t, J = 7.07 Hz, 1 H), 3.71 (q, J = 5.81
Hz, 2 H), 2.69−2.84 (m, 6 H), 1.13 (t, J = 7.20 Hz, 6 H). MS [M + 1]
= 339.
9.12 (s, 1 H), 8.94−8.99 (m, 1 H), 8.75 (d, J = 7.07 Hz, 1 H), 8.41 (s,
1 H), 8.14 (d, J = 8.08 Hz, 1 H), 8.01 (d, J = 7.83 Hz, 1 H), 7.68 (t, J =
7.58 Hz, 1 H), 7.51−7.62 (m, 1 H), 6.91 (t, J = 7.07 Hz, 1 H), 3.77 (br
s, 2 H), 2.83 (m, 6 H), 1.21 (t, J = 7.20 Hz, 6 H). MS [M + 1] = 389.
N-[2-(Dimethylamino)-1-methylethyl]-12-oxo-12H-benzo[g]-
pyrido[2,1-b]quinazoline-4-carboxamide (11). This compound was
synthesized from 6a (50 mg, 0.17 mmol) and N1,N1-dimethylpro-
pane-1,2-diamine (22.2 μL, 0.17 mmol) according to method A to give
N-[2-(dimethylamino)-1-methyl-ethyl]-12-oxo-12H-benzo[g]pyrido-
[2,1-b]quinazoline-4-carboxamide hydrochloride (38.7 mg, 0.103
mmol, 60% yield) as a yellow-orange solid. 1H NMR (400 MHz,
CDCl3) δ ppm 9.12 (s, 1 H), 8.82 (td, J = 6.63, 1.64 Hz, 1 H), 8.31−
8.35 (m, 1 H), 8.12 (d, J = 8.59 Hz, 1 H), 8.03 (d, J = 8.08 Hz, 1 H),
7.62−7.68 (m, 1 H), 7.53−7.58 (m, 1 H), 6.74−6.80 (m, 1 H), 3.47
(br s, 1 H), 2.91 (br s, 1 H), 2.43−2.49 (m, 1 H), 2.39 (s, 3 H), 2.20
(s, 3 H), 1.96 (br s, 3 H). MS [M + 1] = 375.
2-(Dimethylamino)ethyl 12-Oxo-12H-benzo[g]pyrido[2,1-b]-
quinazoline-4-carboxylate (17). This compound was synthesized
from 6a (50 mg, 0.17 mmol) and 2-dimethylaminoethanol (41.6 μL,
0.41 mmol) according to method A to give 2-(dimethylamino)ethyl
12-oxo-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carboxylate (47 mg,
1
0.13 mmol, 47.2 % yield) as an orange solid. H NMR (400 MHz,
CDCl3) δ ppm 9.10 (s, 1 H), 8.87 (dd, J = 7.45, 1.64 Hz, 1 H), 8.36 (s,
1 H), 8.11 (d, J = 8.34 Hz, 1 H), 8.02 (d, J = 8.34 Hz, 1 H), 7.78 (dd, J
= 6.69, 1.64 Hz, 1 H), 7.64 (ddd, J = 8.27, 6.76, 1.14 Hz, 1 H), 7.52−
7.57 (m, 1 H), 6.72 (dd, J = 7.33, 6.57 Hz, 1 H), 4.58 (t, J = 5.81 Hz, 2
H), 2.80 (t, J = 5.68 Hz, 2 H), 2.38 (s, 6 H). MS [M + 1] = 362.
N-[2-(Dimethylamino)ethyl]-N-methyl-12-oxo-12H-benzo[g]-
pyrido[2,1-b]quinazoline-4-carboxamide (18). This compound was
synthesized from 6a (50 mg, 0.17 mmol) and N,N,N′-trimethylethy-
lenediamine (21.3 μL, 0.17 mmol) according to method A to give N-
[2-(dimethylamino)ethyl]-N-methyl-12-oxo-12H-benzo[g]pyrido[2,1-
b]quinazoline-4-carboxamide trifluoroacetate (18.8 mg, 0.050 mmol,
N-(Azetidin-3-yl)-12-oxo-12H-benzo[g]pyrido[2,1-b]quinazoline-
4-carboxamide (12). A solution of 30 (76 mg, 0.17 mmol) in
chloroform (1 mL) was treated with trifluoroacetic acid (1.5 mL, 19.6
mmol) at room temperature for 24 h (for convenience). The solvents
were removed in vacuo to give N-(azetidin-3-yl)-12-oxo-12H-benzo-
[g]pyrido[2,1-b]quinazoline-4-carboxamide trifluoroacetate (76.1 mg,
0.17 mmol, 99% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3)
δ ppm 9.14−9.20 (m, 1 H), 9.10 (d, J = 5.81 Hz, 1 H), 8.67−8.74 (m,
1 H), 8.46 (s, 1 H), 8.20−8.27 (m, 1 H), 8.12 (s, 1 H), 7.92 (s, 1 H),
7.75 (d, J = 7.83 Hz, 1 H), 7.65 (d, J = 6.82 Hz, 1 H), 7.11 (t, J = 7.20
Hz, 1 H), 4.67 (dd, J = 7.07, 4.55 Hz, 1 H), 4.53 (d, J = 7.33 Hz, 2 H),
2.83 (br.s., 3 H). MS [M + 1] = 345.
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29.1% yield) as an orange solid. H NMR (400 MHz, CDCl3) δ ppm
9.14 (s, 1 H), 8.93 (d, J = 7.33 Hz, 1 H), 8.28 (s, 1 H), 8.14 (d, J =
8.34 Hz, 1 H), 8.04 (d, J = 8.84 Hz, 1 H), 7.93 (d, J = 6.82 Hz, 1 H),
7.67−7.74 (m, 1 H), 7.58−7.64 (m, 1 H), 6.97 (t, J = 7.07 Hz, 1 H),
4.12 (t, J = 5.94 Hz, 2 H), 3.57 (t, J = 6.19 Hz, 2 H), 3.12 (s, 6 H),
3.10 (s, 3 H). MS [M + 1] = 375.
N-[2-(Dimethylamino)ethyl]-N-ethyl-12-oxo-12H-benzo[g]-
pyrido[2,1-b]quinazoline-4-carboxamide (19). This compound was
synthesized from 6a (50 mg, 0.17 mmol) and N,N-dimethyl-N′-
ethylethylenediamine (27.1 μL, 0.17 mmol) according to method A to
give N-[2-(dimethylamino)ethyl]-N-ethyl-12-oxo-12H-benzo[g]-
pyrido[2,1-b]quinazoline-4-carboxamide trifluoroacetate (36.1 mg,
0.093 mmol, 54% yield) as a yellow-orange solid. 1H NMR (400
MHz, CDCl3) δ ppm 9.13 (s, 1 H), 8.87 (d, J = 7.33 Hz, 1 H), 8.21 (s,
1 H), 8.13 (d, J = 8.34 Hz, 1 H), 8.03 (d, J = 8.59 Hz, 1 H), 7.65−7.71
(m, 1 H), 7.56−7.62 (m, 2 H), 6.84 (t, J = 7.07 Hz, 1 H), 4.06 (m, 2
H), 3.62 (t, J = 6.69 Hz, 2 H), 3.39 (q, J = 7.24 Hz, 2 H), 3.12 (s, 6 H),
1.20 (t, J = 7.07 Hz, 3 H). MS [M + 1] = 389.
N-(2-Imidazol-1-ylethyl)-12-oxo-12H-benzo[g]pyrido[2,1-b]-
quinazoline-4-carboxamide (20). This compound was synthesized
from 6a (50 mg, 0.17 mmol) and 2-imidazol-1-ylethanamine (16.6 μL,
0.17 mmol) according to method A to give N-(2-imidazol-1-ylethyl)-
12-oxo-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carboxamide (28.5
mg, 0.074 mmol, 43% yield) as a yellow-orange solid. 1H NMR
(400 MHz, CDCl3) δ ppm 11.57 (br s, 1 H), 9.08 (s, 1 H), 8.98 (dd, J
= 7.07, 1.77 Hz, 1 H), 8.73 (dd, J = 7.07, 1.77 Hz, 1 H), 8.10 (t, J =
8.34 Hz, 3 H), 7.94 (s, 1 H), 7.66−7.72 (m, 3 H), 7.55−7.60 (m, 2 H),
N-[2-(Dimethylamino)propyl]-12-oxo-12H-benzo[g]pyrido[2,1-
b]quinazoline-4-carboxamide (13). This compound was synthesized
from 6a (50 mg, 0.17 mmol) and 2-(dimethylamino)propan-1-amine
(21.1 mg, 0.21 mmol) according to method A to give N-[2-
(dimethylamino)propyl]-12-oxo-12H-benzo[g]pyrido[2,1-b]-
quinazoline-4-carboxamide (52 mg, 0.139 mmol, 80.6 % yield) as a
1
yellow solid. H NMR (400 MHz, CDCl3) δ ppm 11.70 (br s, 1 H),
9.09 (s, 1 H), 8.94 (dd, J = 7.33, 1.77 Hz, 1 H), 8.73 (dd, J = 6.82, 1.77
Hz, 1 H), 8.27 (s, 1 H), 8.12 (d, J = 8.59 Hz, 1 H), 7.99 (d, J = 8.59
Hz, 1 H), 7.66 (dd, J = 7.96, 6.95 Hz, 1 H), 7.53−7.58 (m, 1 H), 6.89
(t, J = 7.07 Hz, 1 H), 3.77 (dt, J = 14.02, 5.62 Hz, 1 H), 3.40−3.48 (m,
1 H), 2.95−3.05 (m, 1 H), 2.51 (s, 6 H), 1.15 (d, J = 6.32 Hz, 3 H).
MS [M + 1] = 375.
N-[4-(Dimethylamino)butyl]-12-oxo-12H-benzo[g]pyrido[2,1-b]-
quinazoline-4-carboxamide (14). This compound was synthesized
from 6a (50 mg, 0.17 mmol) and N′,N′-dimethylbutane-1,4-diamine
(24.5 μL, 0.17 mmol) according to method A to give N-[4-
(dimethylamino)butyl]-12-oxo-12H-benzo[g]pyrido[2,1-b]-
quinazoline-4-carboxamide (22.1 mg, 0.057 mmol, 33% yield) as a
yellow-orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.35−11.41
(m, 1 H), 9.13 (s, 1 H), 8.98 (dd, J = 7.20, 1.64 Hz, 1 H), 8.76 (dd, J =
I
dx.doi.org/10.1021/jm5004842 | J. Med. Chem. XXXX, XXX, XXX−XXX