54 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 1
Kaila et al.
that was purified by method B, 16%. 1H NMR (400 MHz, DMSO-
d6): δ 2.51-2.56 (m, 2 H), 3.37-3.42 (m, 2 H), 4.23 (s, 2 H),
4.33 (br s, 2 H), 7.18 (d, J ) 9.1 Hz, 1 H), 7.27-7.33 (m, 2 H),
7.33-7.39 (m, 2 H), 8.95 (br s, 2 H), 9.31 (d, J ) 9.1 Hz, 1 H).
HRMS (ESI+) calcd for C20H17ClN2O3 (MH+), 369.10005; found,
369.101. HPLC (method 1, 97%; method 2, 98%).
2-((1H-Indol-3-yl)methyl)-3-hydroxy-7,8,9,10-tetrahydroben-
zo[h]quinoline-4-carboxylic Acid (27): General procedure VI,
method 2, was used, and purification was done by trituration with
boiling ethanol, resulting in a yellow powder, 49%. 1H NMR (400
MHz, DMSO-d6): δ 1.65-1.93 (m, 4 H), 2.83 (br s, 2 H), 3.24
(br s, 2 H), 4.41 (s, 2 H), 6.90-7.08 (m, 2 H), 7.13-7.36 (m, 3
H), 7.75 (d, J ) 7.1 Hz, 1 H), 8.19 (s, 1 H), 10.84 (s, 1 H). Anal.
(C23H20N2O3) C, H, N. HRMS (ESI+) calcd for C23H21N2O3 (MH+),
373.1547; found, 373.1548.
(C2H5)3N) C, H, N. HRMS (ESI+) calcd for C22H18F3NO4 (MH+),
418.1257; found, 418.1261.
2-(4-Carbamoylbenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo-
[h]quinoline-4-carboxylic Acid (62): General procedure VI,
method 2, was used, and the product was purified by method B,
resulting in a yellow solid, 10%. 1H NMR (400 MHz, DMSO-d6):
δ 1.73-1.91 (m, 4 H), 2.84 (t, J ) 6.2 Hz, 2 H), 3.15 (t, J ) 6.3
Hz, 2 H), 4.41 (s, 2 H), 7.29 (d, J ) 9.1 Hz, 1 H), 7.46 (d, J ) 8.6
Hz, 2 H), 7.83-7.91 (d, J ) 8.9 Hz, 2 H), 8.49 (d, J ) 8.8 Hz, 1
H). HRMS (ESI+) calcd for C22H20N2O4 (MH+), 377.1496; found,
377.1497. HPLC (method 1, 95%; method 2, 98%).
2-(4-Carboxybenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h]-
quinoline-4-carboxylic Acid (63): General procedure VI, method
2, was used, and the product was purified by method B, resulting
in a yellow solid, 15%. 1H NMR (400 MHz, DMSO-d6): δ 1.68-
1.96 (m, 4 H), 2.84 (t, J ) 6.2 Hz, 2 H), 3.16 (t, J ) 5.8 Hz, 2 H),
4.39 (s, 2 H), 7.30 (d, J ) 8.8 Hz, 1 H), 7.42 (d, J ) 8.6 Hz, 2 H),
7.69-7.82 (d, J ) 8.6 Hz, 2 H), 8.43 (d, J ) 8.8 Hz, 1 H). HRMS
(ESI+) calcd for C22H19NO5 (MH+), 378.1336; found, 378.1343.
HPLC (method 1, 95%; method 2, 99%).
2-(4-Cyanobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h]-
quinoline-4-carboxylic Acid (64): General procedure VI, method
2, was used, and the product was purified by method B, resulting
in a yellow solid, 20%. 1H NMR (400 MHz, DMSO-d6): δ 1.68-
1.91 (m, 4 H), 2.83 (t, J ) 5.3 Hz, 2 H), 3.13 (t, J ) 5.7 Hz, 2 H),
4.40 (s, 2 H), 7.28 (d, J ) 9.1 Hz, 1 H), 7.51 (d, J ) 8.6 Hz, 2 H),
7.66-7.80 (d, J ) 8.5 Hz, 2 H), 8.23 (d, J ) 8.8 Hz, 1 H). HRMS
(ESI+) calcd for C22H18N2O3 (MH+), 359.1390; found, 359.1391.
HPLC (method 1, 95%; method 2, 99%).
2-(3-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h]-
quinoline-4-carboxylic Acid (67): General procedure VI, method
2, was used, and the product was purified by method B, resulting
in a bright yellow powder, 20%. 1H NMR (400 MHz, DMSO-d6):
δ 1.74-1.88 (m, 4 H), 2.83 (t, J ) 4.3 Hz, 2 H), 3.15 (t, J ) 4.6
Hz, 2 H), 4.32 (s, 2 H), 7.24-7.35 (m, 4 H), 7.39 (s, 1 H), 8.20 (d,
J ) 8.8 Hz, 1 H). HRMS (ESI+) calcd for C21H19ClNO3 (MH+),
368.1048; found, 368.1046. HPLC (method 1, 96%; method 2,
100%).
2-(4-Chloro-benzyl)-3-hydroxy-7,8,9,10-tetrahydro-benzo[h]-
quinoline-4-carboxylic Acid (31): General procedure VI, method
1, was used, and purification was done by method A, resulting in
1
canary yellow crystals, 41%. H NMR (400 MHz, DMSO-d6): δ
1.82 (m, 4 H), 2.83 (t, J ) 5.6 Hz, 2 H), 3.16 (t, J ) 5.7 Hz, 2 H),
4.31 (s, 2 H), 7.29 (d, J ) 8.8 Hz, 1 H), 7.34 (s, 4 H), 8.18 (d,
J ) 8.8 Hz, 1 H). Anal. (C21H18ClNO3) C, H, N. HRMS (ESI+)
calcd for C21H18ClNO3 (MH+), 368.1048; found, 368.104.
3-Hydroxy-2-phenyl-7,8,9,10-tetrahydrobenzo[h]quinoline-4-
carboxylic Acid (49): General procedure VI, method 2, was used,
resulting in a yellow powder, 20%, which was purified by method
1
B. H NMR (400 MHz, DMSO-d6): δ 1.76-1.93 (m, 4 H), 2.86
(t, J ) 5.7 Hz, 2 H), 3.25 (t, J ) 5.8 Hz, 2 H), 7.33 (d, J ) 9.1 Hz,
1 H), 7.44-7.56 (m, 3 H), 8.09 (dd, J ) 8.1, 1.52 Hz, 2 H), 8.28
(d, J ) 8.8 Hz, 1 H). Anal. (C20H17NO3‚0.25H2O) C, H, N. HRMS
(ESI+) calcd for C20H17NO3 (MH+), 320.12812; found, 320.12807.
3-Hydroxy-2-phenylquinoline-4-carboxylic Acid (51): General
procedure VI, method 2, was used, and the product was purified
by trituration with boiling ethanol, resulting in a yellow powder,
19%. 1H NMR (400 MHz, DMSO-d6): δ 7.47-7.64 (m, 6 H), 7.99
(dd, J ) 8.1, 1.01 Hz, 1 H), 8.03-8.08 (m, 2 H). Anal. (C16H11-
NO3) C, H, N. HRMS (ESI+) calcd for C16H11NO3 (MH+),
266.08117; found, 266.08107.
Triethylammonium 3-Hydroxy-7,8-dimethyl-2-phenylquino-
line-4-carboxylic Acid (53): General procedure VI, method 1, was
used, and the product was purified by method A, resulting in a tan
2-(2-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h]-
quinoline-4-carboxylic Acid (69): General procedure VI, method
2, was used, and the product was purified by method B, resulting
in a bright yellow powder, 24%. 1H NMR (400 MHz, DMSO-d6):
δ 1.74 (br s, 4 H), 2.80 (br s, 2 H), 2.92 (br s, 2 H), 4.42 (s, 2 H),
7.22-7.32 (m, 4 H), 7.43-7.50 (m, 1 H), 8.23 (d, J ) 8.8 Hz, 1
H). HRMS (ESI+) calcd for C21H19ClNO3 (MH+), 368.1048; found,
368.1047. HPLC (method 1, 100%; method 2, 100%).
1
foam, 72%. H NMR (400 MHz, DMSO-d6): δ 1.18 (t, J ) 7.20
Hz, 9 H), 2.39 (s, 3 H), 2.68 (s, 3 H), 3.09 (q, J ) 7.3 Hz, 6 H),
7.25 (d, J ) 8.8 Hz, 1 H), 7.32-7.59 (m, 3 H), 8.12-8.40 (m, 2
H), 9.21 (d, J ) 8.8 Hz, 1 H). HRMS (ESI+) calcd for C18H15NO3
(MH+), 294.1125; found, 294.1123. HPLC (method 1, 98.3%;
method 2, 99%).
2-(3,4-Dichlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo-
[h]quinoline-4-carboxylic Acid (71): General procedure VI,
method 2, was used, and the product was purified by method B,
2-Benzyl-3-hydroxy-7,8,9,10-tetrahydrobenzo[h]quinoline-4-
carboxylic Acid (56): General procedure VI, method 2, was used,
and the product was purified by method B, resulting in a yellow
1
resulting in a bright yellow powder, 20%. H NMR (400 MHz,
1
solid, 35%. H NMR (400 MHz, DMSO-d6): δ 1.72-1.92 (m, 4
DMSO-d6): δ 1.73-1.86 (m, 4 H), 2.81 (t, J ) 6.1 Hz, 2 H), 3.12
(t, J ) 5.9 Hz, 2 H), 4.30 (s, 2 H), 7.28 (t, J ) 8.7 Hz, 2 H), 7.53
(d, J ) 8.1 Hz, 1 H), 7.59 (d, J ) 2.0 Hz, 1 H), 8.19 (d, J ) 8.6
Hz, 1 H). Anal. (C21H17Cl2NO3 + 0.25H2O) C, H, N. HRMS (ESI+)
calcd for C21H18Cl2NO3 (MH+), 402.0658; found, 402.0661.
3-Hydroxy-2-(thiophen-2-ylmethyl)-7,8,9,10-tetrahydrobenzo-
[h]quinoline-4-carboxylic Acid (73): General procedure VI,
method 2, was used, and the product was purified by method B,
H), 2.83 (t, J ) 6.1 Hz, 2 H), 3.18 (t, J ) 5.8 Hz, 2 H), 4.31 (s, 2
H), 7.14-7.21 (m, 1 H), 7.23-7.36 (m, 5 H), 8.24 (d, J ) 7.6 Hz,
1 H). HRMS (ESI+) calcd for C21H19NO3 (MH+), 334.1438; found,
334.1438. HPLC (method 1, 96%; method 2, 98%).
3-Hydroxy-2-phenethyl-7,8,9,10-tetrahydrobenzo[h]quinoline-
4-carboxylic Acid (58): General procedure VI, method 2, was used,
and the product was purified by method B, resulting in a yellow
1
1
solid, 15%. H NMR (500 MHz, D2O): δ 1.77-1.90 (m, 4 H),
resulting in a dark yellow powder, 4.8%. H NMR (400 MHz,
2.85 (t, J ) 6.0 Hz, 3 H), 3.16 (t, J ) 7.8 Hz, 2 H), 3.22 (t, J )
6.0 Hz, 2 H), 3.29 (t, J ) 7.8 Hz, 2 H), 7.18 (t, J ) 7.0 Hz, 1 H),
7.22-7.38 (m, 5 H), 8.24-8.32 (m, 1 H). Anal. (C22H21NO3) C,
H, N. HRMS (ESI+) calcd for C22H21NO3 (MH+), 348.15942;
found, 348.15933.
DMSO-d6): δ 1.75-1.88 (m, 4 H), 2.83 (t, J ) 5.7 Hz, 2 H), 3.17-
3.25 (m, 2 H), 4.49 (s, 2 H), 6.89-6.94 (m, 1 H), 6.94-6.98 (m,
1 H), 7.27 (d, J ) 9.1 Hz, 1 H), 7.32 (dd, J ) 5.3, 1.3 Hz, 1 H),
8.18 (d, J ) 8.8 Hz, 1 H). HRMS (ESI+) calcd for C19H18NO3S
(MH+), 340.1002; found, 340.1011. HPLC (method 1, 100%;
method 2, 100%).
3-Hydroxy-2-(4-(trifluoromethoxy)benzyl)-7,8,9,10-tetrahy-
drobenzo[h]quinoline-4-carboxylic Acid (60): General procedure
VI, method 1, was used, and the product was purified by method
3-Hydroxy-2-(thiophen-3-ylmethyl)-7,8,9,10-tetrahydrobenzo-
[h]quinoline-4-carboxylic Acid (75): General procedure VI,
method 2, was used, and the product was purified by method B,
1
A, resulting in a canary yellow solid, 27%. H NMR (400 MHz,
1
DMF): δ 1.75-1.88 (m, 4 H), 2.83 (t, J ) 5.3 Hz, 2 H), 3.15 (t,
J ) 5.6 Hz, 2 H), 4.34 (s, 2 H), 7.30-7.31 (m, 3 H), 7.44 (d, J )
8.6 Hz, 2 H), 8.21 (d, J ) 9.1 Hz, 1 H). Anal. (C22H18F3NO4‚0.1-
resulting in a bright yellow powder, 22%. H NMR (400 MHz,
DMSO-d6): δ 1.73-1.89 (m, 4 H), 2.83 (t, J ) 4.9 Hz, 2 H), 3.18
(t, J ) 5.7 Hz, 2 H), 4.32 (s, 2 H), 7.10 (d, J ) 4.8 Hz, 1 H), 7.23