Journal of Medicinal Chemistry
ARTICLE
(10.0 g, 41.1 mmol, 71% yield) and N-[(1S)-1-cyclopropyl-2,2,2-tri-
fluoroethyl]-(S)-2-Methylpropane-2-sulfinamide (960 mg, 3.95 mmol,
7% yield) as white solids. N-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-
1-[(Dicyclopropylmethyl)amino]-7-(1-methyl-1H-pyra-
zol-4-yl)-5H-pyrido[4,3-b]indole-4-carboxamide (52). Step 1.
To a stirred slurry of 6b (2.5 g, 9.54 mmol) in dioxane (70 mL) in a
pressure vessel were added dicyclopropylmethanaminium chloride
(5.07 g, 34.3 mmol) and diisopropylethylamine (7.66 mL, 43.9 mmol).
The reaction mixture was heated to 145 ꢀC for 3 days, treated with
additional dicyclopropylmethanaminium chloride (2.0 g, 13.5 mmol)
and diisopropylethylamine (3.0 mL, 17 mmol), and heated to 145 ꢀC for
4 days. The reaction mixture was cooled to room temperature and
concentrated. The residue was diluted with ethyl acetate and saturated
NaHCO3 solution. The aqueous layer was extracted with ethyl acetate
(3Â). The combined organics were washed with brine, dried over
sodium sulfate, concentrated, and purified by flash chromatography to
afford 7-chloro-1-[(dicyclopropylmethyl)amino]-5H-pyrido[4,3-b]indole-
4-carbonitrile (2.30 g, 6.82 mmol, 72% yield). LRMS (ESI) calcd for
1
(S)-2-methylpropane-2-sulfinamide: H NMR (600 MHz, CDCl3) δ
3.32 (d, J = 5.7 Hz, 1H), 2.94À2.87 (m, 1H), 1.22 (s, 9H), 1.10À1.01
(m, 1H), 0.82À0.76 (m, 1H), 0.72À0.66 (m, 1H), 0.66À0.60 (m, 1H),
0.52À0.47 (m, 1H). N-[(1S)-1-Cyclopropyl-2,2,2-trifluoroethyl]-(S)-2-
methylpropane-2-sulfinamide: 1H NMR (600 MHz, CDCl3) δ 3.62 (d, J =
5.2 Hz, 1H), 3.02À2.94 (m, 1H), 1.24 (s, 9H), 1.10À0.98 (m, 1H),
0.82À0.78 (m, 2H), 0.72À0.66 (m, 1H), 0.66À0.60 (m, 1H), 0.51À
0.46 (m, 1H).
Step 2. N-[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]-(S)-2-methyl-
propane-2-sulfinamide (16.55 g, 68.0 mmol) was dissolved in MeOH
(34 mL), and 4 M HCl in dioxane (34.0 mL, 136 mmol) was added. The
reaction mixture was allowed to stir for 30 min and concentrated to half
the volume. Ether was added to the mixture, and the resultant precipitate
was filtered to afford (1R)-1-cyclopropyl-2,2,2-trifluoroethanaminium
chloride (10.8 g, 61.5 mmol, 90% yield) as a white solid. 1H NMR (500
MHz, D2O) δ 3.44 (m, 1H), 1.27 (m, 1H), 0.85À0.98 (m, 2H), 0.75 (m,
1H), 0.58 (m, 1H).
1
(C19H18ClN4) [M + H]+ 337.1, found 337.1. H NMR (600 MHz,
DMSO-d6) δ 12.45 (brs, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.33 (s, 1H), 7.54
(d, J = 2.1 Hz, 1H), 7.36 (dd, J = 2.1, 8.5 Hz, 1H), 7.05 (d, J = 8.8 Hz,
1H), 3.54 (m, 1H), 1.37 (m, 2H), 0.53 (m, 2H), 0.38 (m, 2H), 0.35 (m,
2H), 0.29 (m, 2H).
Step 2. To a stirred solution of 7-chloro-1-[(dicyclopropylmethyl)-
amino]-5H-pyrido[4,3-b]indole-4-carbonitrile (2.47 g, 7.33 mmol) in
DMSO (73 mL) were added potassium carbonate (6.08 g, 44.0 mmol)
and 30% H2O2 (8.99 mL, 88.0 mmol). The reaction mixture was heated
to 85 ꢀC for 5 h, cooled to room temperature, and diluted with ethyl
acetate and water. The mixture was extracted with ethyl acetate (3Â).
The combined organics were washed with brine, dried over sodium
sulfate, concentrated, and purified by flash chromatography to afford
7-chloro-1-[(dicyclopropylmethyl)amino]-5H-pyrido[4,3-b]indole-4-
carboxamide (2.59 g, 7.30 mmol, 100% yield). LRMS (ESI) calcd for
1-{[(1S)-1-Cyclopropylethyl]amino}-7-(1-methyl-1H-pyr-
azol-4-yl)-5H-pyrido[4,3-b]indole-4-carboxamide (48). Step 1.
A mixture of 6b (150 mg, 0.572 mmol), (1S)-1-cyclopropylethanami-
nium chloride (209 mg, 1.72 mmol), and diisopropylethylamine (400
μL, 2.29 mmol) in dioxane (7.2 mL) was heated to 140 ꢀC for 3 days.
The mixture was diluted with ethyl acetate and washed with 50% brine.
The organic layer was dried over sodium sulfate, concentrated, and
purified by flash chromatography to afford 7-chloro-1-{[(1S)-1-cyclo-
propylethyl]amino}-5H-pyrido[4,3-b]indole-4-carbonitrile (133 mg, 0.43
mmol, 75% yield). LRMS (ESI) calcd for (C17H16ClN4) [M + H]+ 311.1,
found 311.0. 1H NMR (600 MHz, CDCl3) δ 8.98 (brs, 1H), 8.38 (s, 1H),
7.70 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 1.8, 8.2 Hz,
1H), 5.33 (d, J = 7.3 Hz, 1H), 3.98 (m, 1H), 1.43 (d, J = 6.5 Hz, 3H), 1.09
(m, 1H), 0.63 (m, 1H), 0.56 (m, 1H), 0.46 (m, 1H), 0.39 (m, 1H).
Step 2. 7-Chloro-1-{[(1S)-1-cyclopropylethyl]amino}-5H-pyrido-
[4,3-b]indole-4-carbonitrile (2.10 g, 6.76 mmol) and potassium carbo-
nate (4.67 g, 33.8 mmol) were placed in a flask. DMSO (67.6 mL) and
hydrogen peroxide (30%, 6.91 mL, 67.6 mmol) were added, and the
solution was heated at 85 ꢀC overnight. The reaction mixture was cooled
to room temperature, diluted with ethyl acetate, and washed with water
and brine. The organic layer was dried with magnesium sulfate,
concentrated, and purified by HPLC to afford 7-chloro-1-{[(1S)-1-
cyclopropylethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (1.87
g, 5.69 mmol, 84% yield). LRMS (ESI) calcd for (C17H18ClN4O) [M +
1
(C19H20ClN4O) [M + H]+ 355.1, found 355.1. H NMR (500 MHz,
DMSO-d6) δ 11.67 (s, 1H), 8.47 (s, 1H), 8.41 (d, J = 8.2 Hz, 1H), 7.83
(brs, 1H), 7.78 (s, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.18 (brs, 1H), 6.57 (d, J
= 8.5 Hz, 1H), 3.61 (q, J = 8.5 Hz, 1H), 1.35 (m, 2H), 0.51 (m, 2H),
0.32À0.40 (m, 6H).
Step 3. A mixture of 7-chloro-1-[(dicyclopropylmethyl)amino]-5H-
pyrido[4,3-b]indole-4-carboxamide (53 mg, 0.15 mmol), 1-methyl-
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40.4 mg,
0.194 mmol), Pd2(dba)3 (13.7 mg, 0.015 mmol), tricyclohexylpho-
sphine (10.5 mg, 0.037 mmol), and potassium phosphate tribasic (1.27
M, 400 μL, 0.51 mmol) in dioxane (3 mL) was purged with nitrogen for
10 min and heated to 100 ꢀC for 3 h. The mixture was cooled to room
temperature, concentrated, and purified by flash chromatography to
afford 52 (43 mg, 0.11 mmol, 72% yield). LRMS (ESI) calcd for
1
(C23H25N6O) [M + H]+ 401.2, found 401.2. H NMR (600 MHz,
1
H]+ 329.1, found 329.1. H NMR (600 MHz, DMSO-d6) δ 11.67 (s,
DMSO-d6) δ 11.43 (s, 1H), 8.43 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 8.12
(s, 1H), 7.87 (d, J = 1.1 Hz, 1H), 7.84 (s, 1H), 7.81 (brs, 1H), 7.45 (dd, J
= 1.7, 8.0 Hz, 1H), 7.12 (brs, 1H), 6.42 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H),
3.63 (m, 1H), 1.37 (m, 2H), 0.51 (m, 2H), 0.34À0.38 (m, 6H).
1-{[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]amino}-7-(1-
methyl-1H-pyrazol-4-yl)-5H-pyrido[4,3-b ]indole-4-carbox-
amide (53). Step 1. To 6b (5.0 g, 19.1 mmol), Pd2(dba)3 (873 mg,
0.95 mmol), BINAP (1.78 g, 2.86 mmol), and sodium tert-butoxide
(9.17 g, 95.0 mmol) in DME (125 mL) was added (1R)-1-cyclopropyl-
2,2,2-trifluoroethanaminium chloride (5.02 g, 28.6 mmol). The slurry
was purged with nitrogen gas for 15 min. The mixture was heated at
85 ꢀC for 16 h. The mixture was cooled to room temperature, diluted
with ethyl acetate, and washed with water (2Â) and brine. The organic
layer was dried with magnesium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified by chromatography on silica
gel to afford 7-chloro-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-
amino}-5H-pyrido[4, 3-b ]indole-4-carbonitrile (4.24 g, 11.62 mmol,
61% yield) as an off white solid. LRMS (ESI) calcd for (C17H13ClF3N4)
[M + H]+ 365.1, found 365.0. 1H NMR (600 MHz, DMSO-d6) δ 12.62
1H), 8.53 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H), 7.87 (brs, 1H), 7.78 (d, J = 2.0
Hz, 1H), 7.26 (dd, J = 2.1, 8.5 Hz, 1H), 7.19 (brs, 1H), 6.50 (d, J = 8.3
Hz, 1H), 4.00 (m, 1H), 1.36 (d, J = 6.7 Hz, 3H), 1.28 (m, 1H), 0.49 (m,
1H), 0.40 (m, 1H), 0.36 (m, 1H), 0.26 (m, 1H).
Step 3. A mixture of 7-chloro-1-{[(1S)-1-cyclopropylethyl]amino}-
5H-pyrido[4,3-b]indole-4-carboxamide (45 mg, 0.14 mmol), 1-methyl-
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (34.2 mg,
0.164 mmol), Pd2(dba)3 (12.5 mg, 0.014 mmol), tricyclohexylpho-
sphine (9.60 mg, 0.034 mmol), and potassium phosphate tribasic (1.27
M, 367 μL, 0.466 mmol) in dioxane (2.7 mL) was purged with nitrogen
for 10 min and heated to 100 ꢀC for 3 h. The mixture was cooled to room
temperature, concentrated, and purified by flash chromatography to
afford 48 (49 mg, 0.13 mmol, 96%). LRMS (ESI) calcd for
1
(C21H23N6O) [M + H]+ 375.2, found 375.2. H NMR (600 MHz,
DMSO-d6) δ 11.43 (s, 1H), 8.48 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.11
(s, 1H), 7.87 (d, J = 1.4 Hz, 1H), 7.85 (brs, 1H), 7.32 (s, 1H), 7.44 (dd, J
= 8.2, 1.4 Hz, 1H), 7.13 (brs, 1H), 6.36 (d, J = 8.5 Hz, 1H), 4.02 (m, 1H),
3.90 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H), 1.29 (m, 1H), 0.50 (m, 1H), 0.41
(m, 1H), 0.37 (m, 1H), 0.27 (m, 1H).
7346
dx.doi.org/10.1021/jm200909u |J. Med. Chem. 2011, 54, 7334–7349