H. B. Rode et al. / Bioorg. Med. Chem. 19 (2011) 429–439
437
4.1.9. N-(1-(3-Bromophenylamino)-4-cyanoisoquinolin-7-yl)-3-
(4-methylpiperazin-1yl)propanamide (11)
3-(4-Methylpiperazin-1-yl)propanoic acid (38 mg, 0.220 mmol)
was added in 2 mL THF and cooled to 0 °C under argon. Oxalyl
4.1.12. (S)-N-(1-(3-Bromophenylamino)-4-cyanoisoquinolin-7-
yl)-5-oxopyrrolidine-2-carboxamide (14)
From -pyroglutamic acid (30 mg, 0.232 mmol), oxalyl chloride
(20.70 L, 0.236 mmol), catalytic DMF in was dissolved in 1.5 mL
L
l
chloride (20
l
L, 0.228 mmol) was added dropwise followed by a
DCM and stirred for 2 h at 30 °C. 7-Amino-1-(3-bromophenylami-
no)isoquinoline-4-carbonitrile 7 (20 mg, 0.059 mmol in 0.2 mL of 1-
methyl-2-pyrrolidinone) was added and stirred for 2 h at room tem-
perature as described for 9. Preparative HPLC on the crude product
produced 7 mg (27%) of 14 as an off-white solid. 1H NMR (400 MHz,
DMSO-d6): 10.56 (s, 1H), 10.03 (s, 1H), 8.86 (s, 1H), 8.49 (s, 1H),
8.11–7.98 (m, 3H), 7.94 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H),
7.34 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.30 (dd, J = 8.3,
3.8 Hz, 1H), 2.46–2.35 (m, 1H), 2.31–2.14 (m, 2H), 2.13–2.03 (m,
1H); 13C NMR (101 MHz, DMSO-d6): 177.51, 171.85, 154.77, 147.38,
141.42, 138.26, 131.36, 130.36, 126.50, 125.95, 124.60, 124.35,
121.16, 120.97, 117.95, 117.52, 113.32, 95.45, 56.38, 29.24, 25.34;
HRMS (ESI-MS): Calcd for C21H1779BrN5O2 [M+H+]: 450.05601, for
drop of DMF. The reaction mixture was stirred at 40 °C for 3 h
(solution A). 7-Amino-1-(3-bromophenylamino)isoquinoline-4-
carbonitrile 7 (25 mg, 0.073 mmol) was dissolved in 1-methyl-2-
pyrrolidinone (0.5 mL) and added to pre-cooled solution A. The
reaction mixture was stirred overnight at room temperature and
then poured into saturated aq NaHCO3 solution, extracted with
EtOAc (3 Â 100 mL), washed with brine and concentrated under
high vacuum. The crude product was first purified by column chro-
matography (MeOH/DCM, 0:1 to 0.1:0.9) to obtain a hygroscopic
compound which was further purified by preparative HPLC to yield
14 mg (39%) of 11 as an off-white powder. 1H NMR (400 MHz,
DMSO-d6): 10.56 (s, 1H), 9.99 (s, 1H), 8.83 (s, 1H), 8.48 (s, 1H),
8.06 (t, J = 1.7 Hz, 1H), 7.99 (dd, J = 8.9, 1.4 Hz, 1H), 7.92 (d,
J = 8.8 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H),
7.30–7.26 (m, 1H), 2.68 (t, J = 6.8 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H),
2.50–2.34 (m, 8H), 2.21 (s, 3H); 13C NMR (101 MHz, DMSO-d6):
170.60, 154.72, 147.13, 141.50, 138.70, 131.05, 130.35, 126.29,
125.85, 124.50, 124.23, 121.17, 120.85, 118.04, 117.55, 112.76,
95.48, 54.48 (C Â 2), 53.57, 52.10 (C Â 2), 45.36, 34.03; HRMS
C
21H1781BrN5O2 [M+H+]: 452.05397. Found: 450.05572, 452.05360.
4.1.13. N-(1-(3-Bromophenylamino)-4-cyanoisoquinolin-7-
yl)furan-2-carboxamide (15)
7-Amino-1-(3-bromophenylamino)isoquinoline-4-carbonitrile
7 (20 mg, 0.059 mmol), furan-2-carboxylic acid chloride (6.2
lL,
0.064 mmol) and triethylamine (18 L, 0.128 mmol) in 2 mL THF
l
(ESI-MS): Calcd for
C
24H2679BrN6O [M+H+]: 493.13460, for
were stirred at 0 °C for 30 min. The reaction mixture was concen-
trated and the crude product was purified by preparative HPLC
to obtain 8 mg (32%) of 15 as an off-white solid. 1H NMR
(400 MHz, DMSO-d6): 10.72 (br s, 1H), 10.03 (br s, 1H), 8.98 (s,
1H), 8.51 (s, 1H), 8.19 (dd, J = 8.8, 1.5 Hz, 1H), 8.13–7.98 (m, 2H),
7.94 (d, J = 8.9 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 3.3 Hz,
1H), 7.32 (t, J = 8.0 Hz, 1H), 7.29-7.24 (m, 1H), 6.73 (m, 1H); 13C
NMR (101 MHz, DMSO-d6): 156.43, 154.71, 147.50, 147.13,
146.27, 141.40, 137.95, 131.44, 130.34, 127.47, 125.89, 124.31,
124.19, 121.18, 120.80, 117.81, 117.53, 115.38, 114.85, 112.34,
C
24H2681BrN6O [M+H+]: 495.13255. Found: 493.13409, 495.13197.
4.1.10. N-(1-(3-Bromophenylamino)-4-cyanoisoquinolin-7-yl)-
3-morpholinopropanamide (12)
From 3-morpholinopropanoic acid hydrochloride (46 mg,
0.235 mmol), oxalyl chloride (21
was dissolved in 1 mL DCM and heated for 2 h at 30 °C. 7-Amino-
1-(3-bromophenylamino)isoquinoline-4-carbonitrile (20 mg,
lL, 0.240 mmol), catalytic DMF
7
0.059 mmol in 0.2 mL of 1-methyl-2-pyrrolidinone) was added
and stirred at room temperature for 2 h as described in the
procedure for 9. The crude product was purified by preparative
HPLC, producing 11 mg (39%) of 12 as a white solid. 1H NMR
(400 MHz, DMSO-d6): 10.52 (br s, 1H), 9.99 (br s, 1H), 8.83 (s,
1H), 8.48 (s, 1H), 8.06 (t, J = 1.7 Hz, 1H), 7.99 (dd, J = 8.9, 1.5 Hz,
1H), 7.92 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.34 (t,
J = 8.0 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 3.58 (t, J = 4.4 Hz, 4H), 2.68
(t, J = 6.7, Hz, 2H), 2.59 (t, J = 6.7 Hz, 2H), 2.47–2.38 (m, 4H); 13C
NMR (151 MHz, DMSO-d6): 170.51, 154.73, 147.06, 141.46,
138.64, 131.03, 130.29, 126.31, 125.81, 124.42, 124.22, 121.11,
120.83, 118.00, 117.46, 112.79, 95.45, 66.14 (C Â 2), 54.05, 53.05
(C Â 2), 33.77; HRMS (ESI-MS): Calcd for C23H2379BrN5O2 [M+H+]:
95.43; HRMS (ESI-MS): Calcd for
C
21H1479BrN4O2 [M+H+]:
433.02946, for
C
21H1481BrN4O2 [M+H+]: 435.02742. Found:
433.02933, 435.02715.
4.1.14. N-(1-(3-Bromophenylamino)-4-cyanoisoquinolin-7-
yl)furan-3-carboxamide (16)
7-Amino-1-(3-bromophenylamino)isoquinoline-4-carbonitrile
7 (20 mg, 0.059 mmol), furan-3-carboxylic acid chloride (8.4 mg,
0.064 mmol) and triethylamine (18 lL, 0.128 mmol) were added
to THF at room temperature and the reaction mixture was stirred
for 30 min. The solvent was evaporated under high vacuum and
the crude was purified by preparative HPLC and crystallization, fur-
nishing 7 mg (28%) of 16 as a brown solid. 1H NMR (400 MHz,
DMSO-d6): 10.52 (br s, 1H), 10.02 (br s, 1H), 8.97 (s, 1H), 8.54–
8.49 (m, 2H), 8.21 (dd, J = 8.8, 1.7 Hz, 1H), 8.13 (t, J = 1.9 Hz, 1H),
7.96 (d, J = 8.9 Hz, 1H), 7.88–7.82 (m, 2H), 7.34 (t, J = 8.0 Hz, 1H),
7.30–7.26 (m, 1H), 7.09 (s, 1H); 13C NMR (101 MHz, DMSO-d6):
160.63, 154.67, 147.35, 146.26, 144.48, 141.41, 138.36, 131.27,
130.34, 127.20, 125.83, 124.33, 124.11, 122.61, 121.15, 120.67,
117.85, 117.47, 114.40, 109.13, 95.41; HRMS (ESI-MS): Calcd for
480.10296, for
480.10257, 482.10048.
C
23H2381BrN5O2 [M+H+]: 482.10092. Found:
4.1.11. Ethyl 1-(3-Bromopheylamino)-4-cyanoisoquinolin-7-
ylcarbamate (13)
7-Amino-1-(3-bromophenylamino)isoquinoline-4-carbonitrile
7 (10 mg, 0.030 mmol), ethyl chloroformate (3.37
lL, 0.035 mmol)
and triethylamine (9 L, 0.065 mmol) were added to pre-cooled
l
THF. The reaction mixture was stirred at room temperature for
6 days. Upon completion, the reaction mixture was concentrated
and purified by preparative HPLC to obtain 6 mg (50%) of 13 as a
white solid. 1H NMR (400 MHz, DMSO-d6): 10.13 (s, 1H), 9.95 (br
s, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 8.05 (s, 1H), 7.90–7.86 (m, 2H),
7.77 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.30–7.25 (m, 1H),
4.21 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR
(101 MHz, DMSO-d6): 154.57, 153.73, 146.92, 141.50, 138.95,
138.83, 130.63, 130.34, 125.82, 124.48, 124.18, 121.16, 120.87,
118.13, 117.53, 111.73, 95.42, 60.63, 14.56; HRMS (ESI-MS): Calcd
C
21H1479BrN4O2 [M+H+]: 433.02946, for C21H1481BrN4O2 [M+H+]:
435.02742. Found: 433.02921, 435.02702.
4.1.15. N-(1-(3-Bromophenylamino)-4-cyanoisoquinolin-7-yl)-
3-(1H-indol-3-yl)propanamide (17)
Indole-3-propionic acid (44 mg, 0.232 mmol), oxalyl chloride
(20.7 lL, 0.236 mmol), catalytic DMF in 1 mL DCM was stirred for
2 h at 30 °C before and 7-amino-1-(3-bromophenylamino)isoquin-
oline-4-carbonitrile 7 (20 mg, 0.059 mmol in 0.2 mL of 1-methyl-
2-pyrrolidinone) as added and stirred for additional 2 h at room
temperature as described in the procedure for 9. Column chroma-
tography of the crude product (EtOAc/petroleum ether, 0.1:0.9 to
for
C
19H1679BrN4O2 [M+H+]: 411.04511, for C19H1681BrN4O2
[M+H+]: 413.04307. Found: 411.04492, 413.04236.