Journal of Medicinal Chemistry
Article
N-Cyclopropyl-5-(2-(2-methyl-5-(6-((4-methylpiperazin-1-yl)-
methyl)-1H-benzo[d]imidazol-2-yl)phenyl)ethynyl)pyrimidin-2-
amine (2e). In a similar manner to 2a, compound 2e was prepared
from 16a and 17e (30 mg, a brown solid, 23%). mp: 136−137 °C. 1H
NMR (300 MHz, CDCl3): δ 8.40 (2 H, s), 8.21 (1 H, s), 7.98 (1 H,
d, J = 8.1 Hz), 7.55−7.48 (2 H, m), 7.23−7.15 (2 H, m), 5.81 (1 H,
s), 5.28 (1 H, s), 3.57 (2 H, s), 2.79−2.77 (1 H, m), 2.55 (8 H, brs),
2.46 (3 H, s), 2.32 (3 H, s), 0.87−0.83 (2 H, m), 0.56 (2 H, brs). 13C
NMR (150 MHz, CDCl3): δ 161.58, 160.20, 151.64, 141.87, 131.17,
130.90, 130.29, 129.87, 128.89, 128.81, 127.61, 126.43, 125.04,
124.32, 123.69, 108.36, 90.78, 88.66, 62.55, 54.04, 51.12, 44.73, 23.99,
20.75, 7.44. HR-MS (ESI-TOF+): m/z [M + H]+ calcd for C29H32N7
478.2714, found 478.2718.
H, d, J = 9.3 Hz), 7.54−7.46 (3 H, m), 7.19 (1 H, d, J = 7.8 Hz), 7.11
(1 H, d, J = 4.5 Hz), 3.60 (2 H, s), 2.61 (8 H, brs), 2.31 (3 H, s). 13
NMR (150 MHz, CDCl3): δ 150.51, 144.10, 139.92, 139.86, 138.81,
138.72, 137.06, 131.16, 130.45, 130.11, 128.93, 128.07, 125.76,
123.17, 123.11, 118.25, 118.09, 117.68, 112.90, 94.94, 81.51, 62.76,
54.36, 51.64, 45.08. HR-MS (ESI-TOF+): m/z [M + H]+ calcd for
C27H25ClN7 482.1854, found 482.1841.
C
6-(2-(2-Chloro-5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo-
[d]imidazol-2-yl)phenyl)ethynyl)-N-cyclobutylpyridazin-3-amine
(2h). In a similar manner to 2a, compound 2g was prepared from 17b
1
and 16b (70 mg, a pale yellow solid, 64%). mp: 161−163 °C. H
NMR (300 MHz, CDCl3): δ 8.14 (1 H, d, J = 7.2 Hz), 7.95 (1 H, s),
7.65−7.62 (2 H, m), 7.38 (1 H, d, J = 8.7 Hz), 7.31 (1 H, d, J = 9.0
Hz), 7.19 (1 H, d, J = 8.1 Hz), 6.65 (1 H, d, J = 9.3 Hz), 5.80 (1 H, d,
J = 5.7 Hz), 4.30−4.28 (1 H, m), 3.63 (2 H, s), 2.63−2.40 (13 H, m),
2.02−1.96 (2 H, m), 1.81−1.79 (2 H, m). 13C NMR (100 MHz,
CDCl3): δ 157.22, 150.53, 138.33, 136.91, 132.49, 131.47, 131.26,
130.01, 129.87, 129.56, 129.19, 129.06, 128.51, 128.02, 124.56,
122.41, 112.27, 91.11, 87.86, 63.23, 54.85, 52.63, 47.08, 45.73, 30.94,
15.29. HR-MS (ESI-TOF+): m/z [M + H]+ calcd for C29H31ClN7
512.2324, found 512.2303.
4-(4-Methyl-1H-imidazol-1-yl)-2-nitroaniline (19). A suspension
of 4-bromo-2-nitroaniline 18 (4.34 g, 20 mmol), 4-methylimidazole
(1.97 g, 24 mmol), K2CO3 (3.04 g, 22 mmol), CuI (0.57 g, 3 mmol)
and 8-hydroxyquinoline (0.44 g, 3 mmol) in 20 mL of DMSO was
stirred at 120 °C in a sealed tube under Ar2 for 29 h. The mixture was
cooled to rt, and 28% aqueous ammonia (10 mL) was added. To the
mixture were added H2O and EtOAc. The aqueous layer was
extracted with EtOAc (80 mL × 3), and the organic layers were
washed with brine, dried over Na2SO4, and filtered. The filtrate was
evaporated in a vacuum, and the residue was washed with PE/EtOAc
6-(2-(2-Chloro-5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo-
[d]imidazol-2-yl)phenyl)ethynyl)-N-cyclopropylpyridazin-3-amine
(2i). In a similar manner to 2a, compound 2i was prepared from 17c
1
to give 2.47 g of the product as a red solid (57%). H NMR (300
1
and 16b (30 mg, a khaki solid, 28%). mp: 130−131 °C. H NMR
MHz, DMSO-d6): δ 8.06−8.02 (2 H, m), 7.68 (1 H, dd, J = 2.7 and
9.0 Hz), 7.56 (2 H, s), 7.36 (1 H, s), 7.15 (1 H, d, J = 9.3 Hz), 2.15 (3
H, s). LC-MS: m/z [M + H]+ 219.0895.
(300 MHz, CDCl3): δ 8.12 (1 H, d, J = 8.1 Hz), 7.86 (1 H, s), 7.64−
7.55 (2 H, m), 7.45−7.39 (2 H, m), 7.22 (1 H, s), 7.02 (1 H, d, J =
9.3 Hz), 6.00 (1 H, s), 3.61 (2 H, s), 2.60−2.44 (9 H, m), 2.27 (3 H,
s), 0.89−0.87 (2 H, m), 0.65 (2 H, brs). 13C NMR (150 MHz,
DMSO-d6): δ 159.75, 149.77, 144.31, 143.38, 137.73, 135.89, 131.25,
130.68, 130.01, 128.60, 124.79, 123.74, 122.66, 119.60, 119.01,
112.18, 111.55, 93.32, 86.35, 62.88, 55.24, 52.98, 46.19, 23.99, 7.20.
HR-MS (ESI-TOF+): m/z [M + H]+ calcd for C28H29ClN7 498.2167,
found 498.2150.
2-Amino-4-(4-methyl-1H-imidazol-1-yl)aniline (20). Compound
19 (0.22 g, 1 mmol) was suspended in 20 mL of anhydrous methanol.
The mixture was hydrogenated with 0.11 g of Raney Ni at 40 psi for 7
h. Then, the Raney Ni was removed by filtration. The filtrate was
evaporated to give 0.18 g of the title compound as a yellow solid
(96%), which was used immediately without any further purification.
N-(2-Amino-4-(4-methyl-1H-imidazol-1-yl)phenyl)-3-iodo-4-
methylbenzamide (21). A solution of 3-iodo-4-methylbenzoic acid
(0.26 g, 1 mmol) in SOCl2 (5 mL) was refluxed for 2 h and then
evaporated in a vacuum to remove the residual SOCl2. The residue
was dissolved in 5 mL of anhydrous THF and added dropwise to a
solution of triethylamine (0.12 g, 1.2 mmol), compound 20 (0.18 g, 1
mmol), and DMAP (24 mg) in 5 mL of anhydrous THF. The result
mixture was stirred at rt for 20 h and then evaporated in a vacuum.
The residue was purified by chromatography on silica gel (CH2Cl2/
CH3OH = 97:3) to give 0.16 g of the product as a pale yellow solid
(37%). LC-MS: m/z [M + H]+ 433.0520.
2-(3-Iodo-4-methylphenyl)-6-(4-methyl-1H-imidazol-1-yl)-1H-
benzo[d]imidazole (22). A solution of compound 21 (0.16 g, 0.37
mmol) in 5 mL of glacial acetic acid was refluxed for 8 h. Then, the
mixture was evaporated in a vacuum, and the residue was purified by
chromatography on silica gel (CH2Cl2/CH3OH = 97:3 to 94:6) to
give 0.1 g of the product as a pale yellow solid (65%). 1H NMR (300
MHz, DMSO-d6): δ 8.65 (1 H, s), 8.13−8.11 (2 H, m), 7.71 (1 H, d,
J = 8.4 Hz), 7.55−7.51 (2 H, m), 7.45−7.39 (3 H, m), 2.45 (3 H, s),
2.19 (3 H, s). LC-MS: m/z [M + H]+ 415.0409.
6-(2-(2-Chloro-5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo-
[d]imidazol-2-yl)phenyl)ethynyl)-N-isopropylpyridazin-3-amine
(2j). In a similar manner to 2a, compound 2j was prepared from 17d
1
and 16b (70 mg, a khaki solid, 65%). mp: 127−128 °C. H NMR
(300 MHz, CDCl3): δ 8.12 (1 H, d, J = 7.5 Hz), 7.82 (1 H, s), 7.64−
7.53 (3 H, m), 7.36 (1 H, d, J = 8.4 Hz), 7.30 (1 H, d, J = 9.3 Hz),
6.68 (1 H, d, J = 9.3 Hz), 5.22 (1 H, d, J = 6.6 Hz), 4.14−4.12 (1 H,
m), 3.62 (2 H, s), 2.51 (8 H, brs), 2.31 (3 H, s), 1.30 (6 H, d, J = 6.0
Hz). 13C NMR (100 MHz, CDCl3): δ 162.61, 157.33, 150.63, 138.26,
136.97, 131.33, 131.24, 129.82, 129.58, 129.23, 129.15, 128.56,
128.03, 124.53, 123.48, 122.37, 112.98, 91.14, 87.85, 63.31, 55.03,
52.84, 45.89, 43.45, 22.73. HR-MS (ESI-TOF+): m/z [M + H]+ calcd
for C28H31ClN7 500.2324, found 500.2313.
5-(2-(2-Chloro-5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo-
[d]imidazol-2-yl)phenyl)ethynyl)-N-cyclopropylpyrimidin-2-amine
(2k). In a similar manner to 2a, compound 2k was prepared from 17e
1
and 16b (10 mg, a brown solid, 9%). mp: 160−162 °C. H NMR
(300 MHz, CDCl3): δ 8.44 (2 H, d, J = 4.5 Hz), 8.13 (1 H, d, J = 7.8
Hz), 7.59 (1 H, d, J = 7.5 Hz), 7.52 (1 H, s), 7.46 (1 H, d, J = 8.7
Hz), 7.39 (1 H, d, J = 8.4 Hz), 7.16 (1 H, d, J = 7.5 Hz), 5.80 (1 H,
s), 3.60 (2 H, s), 3.12−2.81 (9 H, m), 2.59 (3 H, s), 0.88−0.82 (2 H,
m), 0.61−0.58 (2 H, m). 13C NMR (150 MHz, DMSO-d6): δ 162.27,
160.69, 150.22, 135.87, 135.60, 134.96, 130.98, 130.71, 130.56,
129.84, 129.50, 128.87, 128.69, 128.11, 123.31, 105.93, 91.36, 88.80,
63.27, 52.90, 49.61, 45.79, 24.41, 6.78. HR-MS (ESI-TOF+): m/z [M
+ H]+ calcd for C28H29ClN7 498.2167, found 498.2163.
3-((2-Methyl-5-(5-(4-methyl-1H-imidazol-1-yl)-1H-benzo[d]-
imidazol-2-yl)phenyl)ethynyl)imidazo[1,2-b]pyridazine (2f). In a
similar manner to 2a, compound 2f was prepared from 17a and 22
1
(80 mg, a pale yellow solid, 63%). mp: 182−184 °C. H NMR (400
MHz, CD3OD): δ 8.57 (1 H, d, J = 3.6 Hz), 8.36 (1 H, s), 8.24 (1 H,
s), 8.05−7.98 (3 H, m), 7.70 (1 H, s), 7.67 (1 H, d, J = 9.0 Hz),
7.47−7.40 (3 H, m), 7.30 (1 H, dd, J = 4.2 and 9.2 Hz), 2.59 (3 H, s),
2.28 (3 H, s). 13C NMR (150 MHz, CD3OD): δ 153.42, 144.66,
142.71, 139.83, 136.69, 134.16, 134.04, 131.52, 130.27, 129.41,
126.93, 126.81, 124.99, 123.15, 119.10, 117.19, 116.93, 112.97, 96.26,
80.08, 19.47, 9.94. HR-MS (ESI-TOF+): m/z [M + H]+ calcd for
C26H20N7 430.1775, found 430.1778.
Synthesis of Compounds 3a−e. 3,3-Difluoro-1-(4-methylpiper-
azin-1-yl)-2,3-dihydro-1H-inden-5-amine (24). Compound 23 (0.15
g, 0.5 mmol) was dissolved in MeOH (20 mL) and agitated with 10%
Pd/C (15 mg) under an atmosphere of H2 for 12 h. The reaction was
monitored by TLC. The mixture was then filtered and evaporated to
give a gray solid, which was used immediately without any further
purification.
N-(3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-
inden-5-yl)-3-iodo-4-methylbenzamide (25a). 3-Iodo-4-methylben-
zoyl chloride, which was prepared from the reaction of 3-iodo-4-
methylbenzoic acid (79 mg, 0.3 mmol) and SOCl2, was added to a
3-(2-(2-Chloro-5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo-
[d]imidazol-2-yl)phenyl)ethynyl)imidazo[1,2-b]pyridazine (2g). In a
similar manner to 2a, compound 2g was prepared from 17a and 16b
(80 mg, a khaki solid, 78%). mp: 156−157 °C. 1H NMR (300 MHz,
CDCl3): δ 8.43 (1 H, s), 8.36 (1 H, s), 8.14−8.11 (2 H, m), 7.93 (1
7447
J. Med. Chem. 2021, 64, 7434−7452