Journal of Medicinal Chemistry
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4H), 6.66 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.86−4.00 (m, 1H), 3.60
(ddd, J = 5.0, 8.3, 13.0 Hz, 1H), 2.95−3.13 (m, 1H), 2.74−2.90 (m,
1H), 1.29−1.43 (m, 3H). MS (ESI pos ion) m/z: calcd for
C26H23F3N2O3, 468.2; found, 469.0 (M + 1).
4H), 6.65 (s, 1H), 3.85−3.98 (m, 1H), 3.62 (ddd, J = 13.1, 8.3, 5.1 Hz,
1H), 2.98−3.11 (m, 1H), 2.83 (dt, J = 16.1, 5.5 Hz, 1H). MS (ESI pos
23
ion) m/z: calcd for C22H18F3N3O, 397.1; found, 398.1 (M + 1). [α]D
−98.4 (c 1.03, CHCl3).
Step 2: A mixture of (R)-ethyl 4-(1-(4-(trifluoromethyl)phenyl)-
1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoate (0.210 g,
0.448 mmol) and 5N NaOH (0.4 mL, 2 mmol) in EtOH (5 mL)
was stirred at room temperature for 24 h. The mixture was
concentrated, taken up in water, and neutralized with 10% aqueous
HCl, and the resulting solid was collected by filtration and dried under
vacuum to give (R)-4-(1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahy-
droisoquinoline-2-carboxamido)benzoic acid (20, 81.4 mg, 41.1%) as a
(R)-N-(Pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihy-
droisoquinoline-2(1H)-carboxamide (26). To a solution of (R)-1-
(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline ((R)-5a,
200 mg, 721 μmol) in MeCN (3 mL) was added 4-nitrophenyl
pyridin-4-ylcarbamate (561 mg, 2164 μmol). The resulting mixture
was heated at 55 °C overnight. The mixture was cooled to room
temperature, concentrated, and the residue purified by silica gel flash
column chromatography (solid loading, 0−100% EtOAc/hexanes) to
1
1
white solid. H NMR (300 MHz, MeOH-d4) δ 7.85−8.02 (m, J = 8.8
give the title compound (26, 45 mg, 16%) as a white solid. H NMR
Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.37−7.49
(m, J = 8.0 Hz, 2H), 7.15−7.37 (m, 4H), 6.66 (s, 1H), 3.84−4.02 (m,
1H), 3.60 (ddd, J = 5.0, 8.2, 13.0 Hz, 1H), 2.95−3.15 (m, 1H), 2.73−
2.92 (m, 1H). MS (ESI pos ion) m/z: calcd for C24H19F3N2O3, 440.1;
found, 441.0 (M + 1).
(400 MHz, MeOH-d4) δ 8.24−8.38 (m, 2H), 7.54−7.65 (m, 4H), 7.43
(d, J = 8.2 Hz, 2H), 7.16−7.35 (m, 4H), 6.66 (s, 1H), 3.87−4.02 (m,
1H), 3.60 (ddd, J = 5.0, 8.5, 13.2 Hz, 1H), 2.97−3.13 (m, 1H), 2.84
(td, J = 5.4, 16.2 Hz, 1H). MS (ESI pos ion) m/z: calcd for
C22H18F3N3O, 397.1; found, 398.1 (M + 1).
(R)-N-(2-Cyanophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-di-
hydroisoquinoline-2(1H)-carboxamide (21). Following the gen-
eral procedure for preparation of ureas from isocyanates, 21 was
obtained from amine (R)-5a and 2-isocyanatobenzonitrile in 37%
(R)-N-(tert-Butyl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroi-
soquinoline-2(1H)-carboxamide (27). Following the general
procedure for preparation of ureas from isocyanates, 27 was obtained
from amine (R)-5a and 2-isocyanato-2-methylpropane in 74% yield.
1H NMR (400 MHz, MeOH-d4) δ 7.57 (d, J = 8.2 Hz, 2H), 7.36 (d, J
1
yield. H NMR (400 MHz, MeOH-d4) δ 7.71 (dd, J = 1.3, 7.7 Hz,
1H), 7.56−7.67 (m, 3H), 7.48 (t, J = 9.2 Hz, 3H), 7.21−7.36 (m, 5H),
6.62 (s, 1H), 3.91 (td, J = 6.0, 12.6 Hz, 1H), 3.63 (ddd, J = 5.1, 8.0,
12.9 Hz, 1H), 3.08 (ddd, J = 5.6, 8.1, 16.0 Hz, 1H), 2.82 (td, J = 5.6,
16.1 Hz, 1H). MS (ESI pos ion) m/z: calcd for C24H18F3N3O, 421.1;
found, 422.1 (M + 1).
(R)-N-(3-Cyanophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-di-
hydroisoquinoline-2(1H)-carboxamide (22). Following the gen-
eral procedure for preparation of ureas from isocyanates, 22 was
obtained from amine (R)-5a and 3-isocyanatobenzonitrile in 37%
yield. 1H NMR (400 MHz, MeOH-d4) δ 7.88 (t, J = 1.7 Hz, 1H), 7.73
(td, J = 1.1, 8.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.40−7.49 (m, 3H),
7.34−7.39 (m, 1H), 7.19−7.32 (m, 4H), 6.65 (s, 1H), 3.85−3.97 (m,
1H), 3.61 (ddd, J = 5.1, 8.3, 13.1 Hz, 1H), 2.98−3.10 (m, 1H), 2.83
(td, J = 5.4, 16.1 Hz, 1H). MS (ESI pos ion) m/z: calcd for
C24H18F3N3O, 421.1; found, 422.1 (M + 1).
= 8.0 Hz, 2H), 7.16−7.30 (m, 4H), 6.47 (s, 1H), 3.64 (td, J = 6.2, 12.5
Hz, 1H), 3.47 (ddd, J = 5.3, 7.4, 12.5 Hz, 1H), 2.84−2.99 (m, 1H),
2.71 (td, J = 6.1, 16.0 Hz, 1H), 1.36 (s, 9H). MS (ESI pos ion) m/z:
calcd for C21H23F3N2O, 376.2; found, 377.1 (M + 1).
N-Isopropyl-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroiso-
quinoline-2(1H)-carboxamide (28). Following the general proce-
dure for preparation of ureas from isocyanates, 28 was obtained from
1
amine (R)-5a and 2-isocyanatopropane in 33% yield. H NMR (400
MHz, MeOH-d4) δ 7.57 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H),
7.13−7.31 (m, 4H), 6.52 (s, 1H), 3.89−4.05 (m, 1H), 3.67 (td, J = 6.1,
12.6 Hz, 1H), 3.43 (ddd, J = 5.1, 7.8, 12.8 Hz, 1H), 2.92 (ddd, J = 5.6,
7.9, 16.0 Hz, 1H), 2.72 (td, J = 5.8, 16.0 Hz, 1H), 1.16 (d, J = 6.7 Hz,
3H), 1.19 (d, J = 6.5 Hz, 3H). MS (ESI pos ion) m/z: calcd for
C20H21F3N2O, 362.2; found, 363.2 (M + 1).
(R)-1-(4-(Trifluoromethyl)phenyl)-N-((R)-1,1,1-trifluoropro-
pan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (30). A
mixture of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoqui-
noline ((R)-5a, 0.161 g, 0.582 mmol) and (R)-4-nitrophenyl (1,1,1-
trifluoropropan-2-yl)carbamate (0.155 g, 0.563 mmol) in 1,4-dioxane
(4 mL) was heated by a microwave reactor for 30 min at 160 °C. The
reaction was allowed to cool, concentrated, and purified by preparative
HPLC to give the title compound (30, 110 mg, 45.4%) as a white
solid. 1H NMR (300 MHz, MeOH-d4) δ 7.58 (d, J = 8.2 Hz, 2H), 7.35
(d, J = 8.2 Hz, 2H), 7.15−7.31 (m, 4H), 6.53 (s, 1H), 4.65 (td, J = 7.4,
14.9 Hz, 1H), 3.62−3.82 (m, 1H), 3.47 (ddd, J = 5.2, 7.8, 12.8 Hz,
1H), 2.87−3.03 (m, 1H), 2.73 (td, J = 5.9, 16.1 Hz, 1H), 1.35 (d, J =
7.0 Hz, 3H). MS (ESI pos ion) m/z: calcd for C20H18F6N2O, 416.1;
found, 417.2 (M + 1).
N-(4-Fluorophenyl)-1-methyl-1-(4-(trifluoromethyl)phenyl)-
3,4-dihydroisoquinoline-2(1H)-carboxamide (32). Following the
general procedure for preparation of ureas from isocyanates, 32 was
obtained from amine 6 and 4-fluorophenyl isocyanate in 79% yield. 1H
NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.51−7.59 (m, 4H), 7.29
(dd, J = 5.0, 9.0 Hz, 2 H), 7.20 (d, J = 7.0 Hz 1 H), 6.96−7.10 (m,
4H), 6.73 (d, J = 7.5 Hz, 1 H), 4.11−4.19 (m, 1H), 3.61 (t, J = 10.3
Hz, 1H), 3.23−3.29 (m, 1H), 3.92−3.02 (m, 1H), 2.13 (s, 3H). MS
(ESI pos ion) m/z: calcd for C24H20F4N2O, 428.2; found, 429.1 (M +
1).
(R)-N-(4-Cyanophenyl)-1-(4-(trifluoromethyl)phenyl)-3,4-di-
hydroisoquinoline-2(1H)-carboxamide (23). Following the gen-
eral procedure for preparation of ureas from isocyanates, 23 was
obtained from amine (R)-5a and 4-isocyanatobenzonitrile in 96%
yield. 1H NMR (400 MHz, MeOH-d4) δ 7.57−7.70 (m, 6H), 7.43 (d,
J = 8.2 Hz, 2H), 7.20−7.34 (m, 4H), 6.65 (s, 1H), 3.86−3.99 (m, 1H),
3.61 (ddd, J = 5.0, 8.4, 13.1 Hz, 1H), 2.97−3.11 (m, 1H), 2.83 (td, J =
5.4, 16.1 Hz, 1H). MS (ESI pos ion) m/z: calcd for C24H18F3N3O,
421.1; found, 422.1 (M + 1).
(R)-N-(Pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihy-
droisoquinoline-2(1H)-carboxamide (24). To a solution of (R)-1-
(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline ((R)-5a,
100 mg, 361 μmol) in MeCN (2 mL) was added 4-nitrophenyl
pyridin-2-ylcarbamate (467 mg, 1803 μmol). The resulting mixture
was stirred at 70 °C overnight. The mixture was concentrated, and the
residue was purified by silica gel flash column chromatography (solid
loading, 0−100% EtOAc/hexane) to give the title compound (24, 103
1
mg, 72%) as a white solid. H NMR (400 MHz, MeOH-d4) δ 8.24
(dd, J = 1.0, 4.9 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.70−7.78 (m, 1H),
7.57−7.65 (m, J = 8.4 Hz, 2H), 7.41−7.50 (m, J = 8.4 Hz, 2H), 7.21−
7.35 (m, 4H), 7.05 (ddd, J = 0.8, 5.1, 7.2 Hz, 1H), 6.65 (s, 1H), 3.91
(td, J = 6.1, 12.5 Hz, 1H), 3.66 (ddd, J = 5.1, 8.0, 12.9 Hz, 1H), 3.05
(ddd, J = 5.6, 8.1, 16.1 Hz, 1H), 2.84 (td, J = 5.8, 16.1 Hz, 1H). MS
(ESI pos ion) m/z: calcd for C22H18F3N3O, 397.1; found, 398.1 (M +
1).
4,4-Trifluoro-N-(4-fluorophenyl)-1-(4-(trifluoromethyl)-
phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (33). Fol-
lowing the general procedure for preparation of ureas from
isocyanates, 33 was obtained from amine 18 and 4-fluorophenyl
(R)-N-(Pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihy-
droisoquinoline-2(1H)-carboxamide (25). Following the general
procedure for preparation of ureas from isocyanates, 25 was obtained
1
1
isocyanate in 23% yield. H NMR (300 MHz, CDCl3) δ 7.82 (d, J =
from amine (R)-5a and 3-isocyanatopyridine in 90% yield. H NMR
4.7 Hz, 1H), 7.55−7.64 (m, J = 8.2 Hz, 2H), 7.45−7.55 (m, 2H),
7.36−7.45 (m, J = 8.2 Hz, 2H), 7.27−7.33 (m, 2H), 7.17 (d, J = 5.1
Hz, 1H), 6.93−7.08 (m, 2H), 6.83 (s, 1H), 6.53 (s, 1H), 4.04−4.23
(400 MHz, MeOH-d4) δ 8.64 (d, J = 2.5 Hz, 1H), 8.16−8.23 (m, 1H),
7.97 (dt, J = 8.4, 1.8 Hz, 1H), 7.56−7.66 (m, J = 8.4 Hz, 2H), 7.40−
7.47 (m, J = 8.2 Hz, 2H), 7.36 (dd, J = 8.3, 4.8 Hz, 1H), 7.19−7.32 (m,
3001
dx.doi.org/10.1021/jm401955h | J. Med. Chem. 2014, 57, 2989−3004