Journal of Medicinal Chemistry
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purified by flash column chromatography to afford the title compound
(63 mg, 0.15 mmol, and 75%) (Scheme 27). The product was
Scheme 24. Preparation of (R)-2-Amino-N-methyl-N,3-
diphenylpropanamide (AP-5-8)
1H NMR (400 MHz, DMSO): δ 10.35 (s, 1H), 8.19 (d, J = 7.7 Hz,
1H), 7.53−7.30 (m, 3H), 7.26−7.03 (m, 5H), 6.96 (s, 1H), 6.79 (d, J =
3.6 Hz, 2H), 6.68−6.54 (m, 2H), 6.38−6.06 (m, 1H), 4.93 (s, 2H), 4.44
(d, J = 4.4 Hz, 1H), 3.51−3.34 (m, 2H), 3.13 (s, 3H), 2.81 (dd, J = 13.3,
4.4 Hz, 1H), 2.71−2.55 (m, 1H). Mass m/z: calcd for C26H27N4O2+ [M
+ H]+, 427.2; found, 427.3.
Synthesis of R-CX15. Preparation of (R)-N-Methyl-2-(2-(7-nitro-
1H-indol-3-yl)acetamido)-N,3-diphenylpropanamide (AP-5-46). To
a stirred solution of 2-(7-nitro-1H-indol-3-yl)acetic acid (100 mg, 0.45
mmol) and (R)-2-amino-N-methyl-N,3-diphenylpropanamide 2,2,2-
trifluoroacetate (184 mg, 0.5 mmol) in 20 mL of dry CH2Cl2 at 0 °C
were added diisopropyl ethyl amine (175 mg, 1.36 mmol) and T3P 50%
solution in CH2Cl2 by weight (376 mg, 1.36 mmol) dropwise
simultaneously. The reaction mixture was allowed to stir for 1 h at 0
°C. Completion of the reaction was confirmed by LC−MS. The
reaction mixture was quenched with cold water, and the product was
extracted with CH2Cl2 and dried over anhydrous Na2SO4. The solvent
was evaporated under reduced pressure, and the crude product was
purified by flash column chromatography to afford 9 (144 mg, 0.32
trifluoroacetate (214 mg, 0.58 mmol) in 6 mL of dry CH2Cl2 at 0 °C
were added diisopropyl ethyl amine (171 mg, 1.32 mmol) and T3P 50%
solution in CH2Cl2 by weight (438 mg, 0.69 mmol) dropwise
simultaneously. The reaction mixture was allowed to stir for 30 min
at 0 °C. Completion of the reaction was confirmed by LC−MS. The
reaction mixture was quenched with cold water, and the product was
extracted with CH2Cl2 and dried over anhydrous Na2SO4. The solvent
was evaporated under reduced pressure, and the crude product was
purified by flash column chromatography to afford the title compound
(184 mg, 0.43 mmol, and 82%) (Scheme 25). The product was
1
1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.41−7.31 (m, 4H),
7.29 (d, J = 8.0 Hz, 1H), 7.18−7.11 (m, 2H), 7.11−7.03 (m, 3H), 6.93
(d, J = 5.7 Hz, 2H), 6.66 (d, J = 7.1 Hz, 2H), 6.18 (d, J = 8.3 Hz, 1H),
4.78 (dd, J = 15.2, 7.1 Hz, 1H), 3.67−3.46 (m, 2H), 3.16 (s, 3H), 2.72
(dd, J = 13.3, 6.9 Hz, 1H), 2.52 (dd, J = 13.3, 7.0 Hz, 1H), 2.31 (s, 3H).
Mass m/z: calcd for C27H27N3NaO2+ [M + Na]+, 448.2; found, 448.2.
Synthesis of S-CX15. Preparation of (S)-N-Methyl-2-(2-(7-nitro-
1H-indol-3-yl)acetamido)-N,3-diphenylpropanamide (AP-5-47). To
a stirred solution of 2-(7-nitro-1H-indol-3-yl)acetic acid (100 mg, 0.5
mmol) and (S)-2-amino-N-methyl-N,3-diphenylpropanamide 2,2,2-
trifluoroacetate (184 mg, 0.55 mmol) in 20 mL of dry CH2Cl2 at 0 °C
were added diisopropyl ethyl amine (193 mg, 1.5 mmol) and T3P 50%
solution in CH2Cl2 by weight (413 mg, 0.65 mmol) dropwise
simultaneously. The reaction mixture was allowed to stir for 30 min
at 0 °C. Completion of the reaction was confirmed by LC−MS. The
reaction mixture was quenched with cold water, and the product was
extracted with CH2Cl2 and dried over anhydrous Na2SO4. The solvent
was evaporated under reduced pressure, and the crude product was
purified by flash column chromatography to afford AP-5-47 (171 mg,
0.37 mmol, and 75%) (Scheme 26). The product was confirmed by 1H
NMR and MS.
mmol, and 70%) (Scheme 28). The product was confirmed by H
NMR and MS.
1H NMR (400 MHz, CDCl3): δ 9.85 (s, 1H), 8.17 (d, J = 8.0 Hz,
1H), 7.78 (d, J = 7.8 Hz, 1H), 7.43−7.28 (m, 3H), 7.21−7.12 (m, 2H),
7.08 (t, J = 7.2 Hz, 2H), 6.96 (t, J = 11.2 Hz, 2H), 6.72 (d, J = 7.0 Hz,
2H), 6.21 (d, J = 8.1 Hz, 1H), 4.83 (dd, J = 15.2, 7.3 Hz, 1H), 3.76−3.59
(m, 2H), 3.20 (s, 3H), 2.80 (dd, J = 13.4, 6.7 Hz, 1H), 2.59 (dd, J = 13.5,
7.4 Hz, 1H). Mass m/z: calcd for C26H25N4O4+ [M + H]+, 457.2; found,
457.3.
Preparation of (R)-2-(2-(7-Amino-1H-indol-3-yl)acetamido)-N-
methyl-N,3-diphenylpropanamide (R-CX15). To as stirred solution
of (R)-N-methyl-2-(2-(7-nitro-1H-indol-3-yl)acetamido)-N,3-diphe-
nylpropanamide (90 mg, 0.2 mmol) in EtOH (15 mL) at room
temperature Pd/C (10%, 30 mg) was added and stirred under a
hydrogen atmosphere at room temperature for 16 h. Completion of the
reaction was confirmed by LC−MS, the reaction was filtered over
Celite, and the filter bed was washed with EtOH (20 mL). The
combined organic portions were evaporated to afford the crude
product, which was purified by flash column chromatography to afford
the title compound (60 mg, 0.14 mmol, and 70%) (Scheme 29). The
product was confirmed by 1H NMR and MS (Figure S8).
1H NMR (400 MHz, DMSO): δ 10.35 (s, 1H), 8.19 (d, J = 7.8 Hz,
1H), 7.52−7.26 (m, 3H), 7.17 (dd, J = 26.0, 5.1 Hz, 5H), 6.97 (s, 1H),
6.79 (d, J = 3.6 Hz, 2H), 6.65 (dd, J = 7.6, 5.4 Hz, 2H), 6.28 (dd, J = 8.2,
4.4 Hz, 1H), 4.92 (s, 2H), 4.55−4.31 (m, 1H), 3.49−3.34 (m, 2H), 3.13
(s, 3H), 2.81 (dd, J = 13.3, 4.5 Hz, 1H), 2.64 (dd, J = 13.3, 9.5 Hz, 1H).
Mass m/z: calcd for C26H27N4O2+ [M + H]+, 427.3; found, 427.3.
Synthesis of S-CX16. Preparation of N-Methyl-1H-indazol-5-
amine (AP-5-69). To a stirred solution of tert-butyl 5-(2,2,2-trifluoro-
N-methylacetamido)-1H-indazole-1-carboxylate (prepared as reported
procedure JMC, 2016, 59, 3793−3807) (5.84 g, 17.01 mmol) in
methanol (90 mL) and water (45 mL) at room temperature, potassium
carbonate (11.75 g, 85.05 mmol) was added. The reaction was heated
to 85 °C and stirred overnight with a condenser. The reaction was
cooled down and neutralized with 1 N HCl. The aqueous layer was
extracted with ethyl acetate (2 × 100 mL), washed with aq NaCl (2 ×
100 mL), dried over Na2SO4, and concentrated. The crude product was
1H NMR (400 MHz, CDCl3): δ 9.85 (s, 1H), 8.17 (d, J = 8.0 Hz,
1H), 7.78 (d, J = 7.8 Hz, 1H), 7.42−7.31 (m, 3H), 7.21−7.12 (m, 2H),
7.08 (t, J = 7.2 Hz, 2H), 6.96 (t, J = 11.2 Hz, 2H), 6.72 (d, J = 7.0 Hz,
2H), 6.20 (d, J = 8.1 Hz, 1H), 4.83 (dd, J = 15.2, 7.3 Hz, 1H), 3.74−3.59
(m, 2H), 3.20 (s, 3H), 2.80 (dd, J = 13.5, 6.8 Hz, 1H), 2.80 (dd, J = 13.5,
6.8 Hz, 1H), 2.59 (dd, J = 13.5, 7.5 Hz, 1H). Mass m/z: calcd for
C26H25N4O4+ [M + H]+, 457.2; found, 457.3.
Preparation of (S)-2-(2-(7-Amino-1H-indol-3-yl)acetamido)-N-
methyl-N,3-diphenylpropanamide (S-CX15). At room temperature,
Pd/C (10%, 30 mg) was added to as stirred solution of (S)-N-methyl-2-
(2-(7-nitro-1H-indol-3-yl)acetamido)-N,3-diphenylpropanamide (90
mg, 0.2 mmol) in EtOH (15 mL) and stirred under a Hydrogen
atmosphere at room temperature for 16 h. Completion of the reaction
was confirmed by LC−MS, the reaction was filtered over Celite, and the
filter bed was washed with EtOH (20 mL). The combined organic
portions were evaporated to afford the crude product, which was
Scheme 25. Preparation of (R)-N-Methyl-2-(2-(2-methyl-1H-indol-3-yl)acetamido)-N,3-diphenylpropanamide (R-PF-74)
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J. Med. Chem. 2021, 64, 3747−3766