3532 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
Pei et al.
(m, 1H), 4.38-4.45 (m, 1H), 4.79-4.92 (m, 2H), 6.62 (d, J )
8.14 Hz, 1H), 6.78 (d, J ) 7.46 Hz, 1H), 7.06 (t, J ) 7.97 Hz, 1H)
ppm. Anal. (C23H28F3N3O4·0.4TFA) C, H, N.
H), 4.72 (dd, J ) 8.73, 5.93 Hz, 1 H), 4.84 (dd, J ) 7.96, 4.52 Hz,
1 H), 8.03 (d, J ) 1.56 Hz, 1 H), 8.60 (d, J ) 1.56 Hz, 1 H) ppm;
MS (ESI) m/z 379, 381 (M + H)+. Anal. (C19H20ClF3N4O6·
0.35TFA) C, H, N.
Method H. N-Oxide Synthesis. The precursor of 21ak with the
Boc group on (0.14 mmol) and mCPBA (96 mg, 77%, 0.35 mmol)
were mixed in 1.5 mL of CH2Cl2. The reaction was stirred overnight
and purified by reverse-phase HPLC to provide the corresponding
N-oxide (51 mg, 64%). The Boc group was then removed as
described in method A6.
Compound 21aa: 1H NMR (500 MHz, MeOH-d4) δ 1.42 (s, 9
H), 2.01-2.10 (m, 1 H), 2.12-2.37 (m, 5 H), 2.38-2.47 (m, 1 H),
2.54-2.64 (m, 1 H), 3.61-3.74 (m, 2 H), 4.24 (dd, J ) 8.89, 4.83
Hz, 1 H), 4.26-4.33 (m, 1 H), 4.49 (dd, J ) 10.29, 7.48 Hz, 1 H),
4.73 (dd, J ) 8.73, 5.30 Hz, 1 H), 4.85 (dd, J ) 7.95, 4.52 Hz, 1
H), 6.95 (t, J ) 7.49 Hz, 1 H), 7.05 (d, J ) 8.11 Hz, 1 H), 7.17-
7.23 (m, 1 H), 7.32 (dd, J ) 7.80, 1.25 Hz, 1 H) ppm; MS (ESI)
m/z 356 (M + H)+. Anal. (C23H30F3N3O4·0.6TFA) C, H, N.
Compound 21ab: 1H NMR (300 MHz, CDCl3) δ 1.2-1.9 (m,
2H), 2.22-2.45 (m, 6H), 3.51-3.71 (m, 2H), 3.99 (d, J ) 15.94
Hz, 1H), 4.01-4.07 (m, 1H), 4.04-4.16 (m, 1H), 4.24 (d, J )
15.94 Hz, 1H), 4.34-4.40 (m, 1H), 4.72-4.82 (m, 1H), 4.82-
4.88 (m, 1H), 6.85 (d, J ) 8.14 Hz, 1H), 7.03 (t, J ) 7.46 Hz,
1H), 7.09-7.14 (m, 3H), 7.19-7.24 (m, 3H), 7.27-7.3 (m, 1H)
ppm. Anal. (C26H28 F3N3O4·0.45 TFA) C, H, N.
Compound 21al: 1H NMR (500 MHz, MeOH-d4) δ ppm 1.80-
1.97 (m, 1 H), 1.98-2.11 (m, 4 H), 2.12-2.21 (m, 1 H), 2.22-
2.33 (m, 3 H), 4.01-4.16 (m, 1 H), 4.49-4.66 (m, 4 H), 4.84 (dd,
J ) 7.80, 4.99 Hz, 1 H), 7.57 (d, J ) 1.56 Hz, 1 H), 8.47 (d, J )
1.56 Hz, 1 H), 8.78 (bs, 1 H), 9.99 (bs, 1 H) ppm; MS (ESI) m/z
395, 397 (M + H)+. Anal. (C19H20ClF3N4O7·0.5TFA) C, H, N.
Compound 21am: 1H NMR (500 MHz, MeOH-d4) δ 2.03-
2.37 (m, 6 H), 2.37-2.46 (m, 1 H), 2.54-2.65 (m, 1 H), 3.13 (s,
3 H), 3.62-3.73 (m, 2 H), 4.23-4.32 (m, 1 H), 4.52-4.59 (m, 2
H), 4.72 (dd, J ) 8.85, 5.80 Hz, 1 H), 4.81-4.84 (m, 1 H), 7.37
(d, J ) 8.85 Hz, 1 H), 7.91 (dd, J ) 8.54, 2.14 Hz, 1 H), 8.00 (d,
J ) 2.44 Hz, 1 H) ppm; MS (ESI) m/z 412, 414 (M + H)+. Anal.
(C20H23ClF3N3O6S·0.3TFA) C, H, N.
1
Compound 21ac: H NMR (500 MHz, MeOH-d4) δ 1.45 (s, 9
H), 2.02-2.11 (m, 1 H), 2.13-2.38 (m, 5 H), 2.39-2.50 (m, 1 H),
2.55-2.65 (m, 1 H), 3.63-3.75 (m, 2 H), 4.24-4.32 (m, 1 H),
4.40 (dd, J ) 10.60, 4.68 Hz, 1 H), 4.59 (dd, J ) 10.60, 7.80 Hz,
1 H), 4.76 (dd, J ) 8.89, 5.15 Hz, 1 H), 4.78-4.89 (m, 1 H), 7.13
(d, J ) 8.42 Hz, 1 H), 7.92 (dd, J ) 8.42, 2.18 Hz, 1 H), 8.04 (d,
J ) 2.18 Hz, 1 H) ppm; MS (ESI) m/z 400 (M + H)+. Anal.
(C24H30F3N3O6·0.7TFA·0.7H2O) C, H, N.
Compound 21an: 1H NMR (400 MHz, MeOH-d4) δ 2.04-2.48
(m, 7 H), 2.54-2.65 (m, 1 H), 3.13 (s, 3 H), 3.64-3.74 (m, 2 H),
4.23-4.34 (m, 1 H), 4.52-4.61 (m, 2 H), 4.73 (dd, J ) 8.44, 5.98
Hz, 1 H), 4.82-4.87 (m, 1 H), 7.33 (d, J ) 8.90 Hz, 1 H), 7.95
(dd, J ) 8.75, 2.30 Hz, 1 H), 8.15 (d, J ) 2.46 Hz, 1 H) ppm; MS
(ESI) m/z 456, 458 (M + H)+. Anal. (C20H23BrF3N3O6S·0.4TFA·
0.4H2O) C, H, N.
Compound 21ad: 1H NMR (400 MHz, MeOH-d4) δ 1.23 (d, J
) 6.75 Hz, 3 H), 1.26 (d, J ) 6.75 Hz, 3 H), 2.24 (m, 7 H), 2.60
(m, 1 H), 3.51 (m, 1 H), 3.66 (m, 2 H), 4.22 (m, 1 H), 4.45 (d, J
) 5.22 Hz, 2 H), 4.73 (dd, J ) 8.90, 5.52 Hz, 1 H), 4.85 (m, 1 H),
7.05 (d, J ) 8.59 Hz, 1 H), 7.89 (dd, J ) 8.59, 2.15 Hz, 1 H), 7.94
(d, J ) 2.15 Hz, 1 H); MS (ESI) m/z 386 (M + H)+. Anal.
(C23H28F3N3O6·0.35TFA·0.2H2O) C, H, N.
Compound 21ao: 1H NMR (500 MHz, MeOH-d4) δ ppm 2.03
(dd, J ) 13.10, 8.42 Hz, 1 H), 2.12-2.40 (m, 6 H), 2.53-2.61 (m,
1 H), 3.62-3.74 (m, 2 H), 4.05-4.17 (m, 1 H), 4.23-4.34 (m, 2
H), 4.61 (dd, J ) 8.73, 6.24 Hz, 1 H), 4.84 (dd, J ) 7.80, 4.37 Hz,
1 H), 5.95-6.00 (s, 2 H), 6.85 (s, 1 H), 7.04 (s, 1 H) ppm; MS
(ESI) m/z 422, 424 (M + H)+. Anal. (C20H21BrF3N3O6·0.4TFA)
C, H, N.
Compound 21ae: 1H NMR (400 MHz, MeOH-d4) δ 2.23 (m, 7
H), 2.59 (m, 1 H), 3.68 (m, 2 H), 4.24 (m, 1 H), 4.53 (d, J ) 5.22
Hz, 2 H), 4.71 (dd, J ) 8.75, 5.98 Hz, 1 H), 4.83 (overlap with
solvent peak, 1H), 7.23 (d, J ) 8.59 Hz, 1 H), 7.98 (dd, J ) 8.59,
2.15 Hz, 1 H), 8.04 (d, J ) 2.15 Hz, 1 H) ppm; MS (ESI) m/z 378
(M + H)+. Anal. (C20H21ClF3N3O6·0.7TFA·0.4H2O) C, H, N.
Compound 21af: 1H NMR (500 MHz, MeOH-d4) δ 2.03 (m, 1
H), 2.27 (m, 6 H), 2.59 (m, 1 H), 3.68 (m, 2 H), 3.92 (s, 3 H), 4.18
(m, 1 H), 4.41 (m, 2 H), 4.69 (dd, J ) 8.73, 6.24 Hz, 1 H), 4.84
(dd, J ) 7.95, 4.52 Hz, 1 H), 7.11 (d, J ) 8.42 Hz, 1 H), 7.64 (d,
J ) 1.87 Hz, 1 H), 7.68 (dd, J ) 8.42, 1.87 Hz, 1 H) ppm; MS
(ESI) m/z 374 (M + H)+. Anal. (C21H24F3N3O7·0.3TFA·0.2H2O)
C, H, N.
Compound 21ap: 1H NMR (500 MHz, MeOH-d4) δ 2.21 (m, 7
H), 2.55 (m, 1 H), 3.70 (m, 2 H), 4.15 (m, 1 H), 4.65 (m, 2 H),
4.76 (m, 1 H), 4.86 (dd, J ) 7.96, 4.52 Hz, 1 H), 7.04 (d, J ) 8.24
Hz, 1 H), 7.56 (m, 1 H), 7.62 (m, 1 H), 8.26 (d, J ) 8.24 Hz, 1 H),
8.48 (d, J ) 7.93 Hz, 1 H), 9.01 (d, J ) 8.54 Hz, 1 H) ppm; MS
(ESI) m/z 394 (M + H)+. HRMS calcd for C22H24N3O4[M + H]+
394.1767, found 393.1764.
Compound 21aq: 1H NMR (400 MHz, MeOH-d4) δ 2.03-2.46
(m, 7 H), 2.54-2.65 (m, 1 H), 3.62-3.72 (m, 2 H), 4.18-4.33
(m, 1 H), 4.48-4.58 (m, 2 H), 4.72 (dd, J ) 8.59, 6.14 Hz, 1 H),
4.82-4.87 (m, 1 H), 7.77-7.83 (two overlapping singlets, 2 H)
ppm; MS (ESI) m/z 413, 415 (M + H)+. Anal. (C19H19Cl2F3N4O6·
0.45TFA) C, H, N.
1
Compound 21ag: H NMR (400 MHz, MeOH-d4) δ 2.25 (m,
7H), 2.62 (m, 1 H), 3.68 (m, 2 H), 4.24 (m, 1 H), 4.50 (m, 2 H),
4.70 (dd, J ) 8.59, 6.14 Hz, 1 H), 4.86 (m, 1 H), 7.53 (d, J ) 8.29
Hz, 1 H), 7.68 (dd, J ) 8.29, 1.84 Hz, 1 H), 7.75 (d, J ) 1.84 Hz,
1 H) ppm; MS (ESI) m/z 378, 380 (M + H)+. Anal. (C20H21-
ClF3N3O6·0.7TFA) C, H, N.
Method H1. Reduction of Nitro Group. Nitro 26a (0.14 mmol)
and NH4Cl (8 mg, 0.14 mmol) were mixed in EtOH/H2O (1 mL/
0.2 mL). Iron powder (25 mg, 0.98 mmol) was added to the mixture,
and the mixture was heated to 50 °C for 1 h. It was filtered and
ethyl acetate (25 mL) was added to the mixture. The solution was
washed with brine (2×), and then dried with Na2SO4. The solution
was then concentrated in vacuo to give aniline 27a (48 mg, 100%),
which was used in the next step without further purification.
Method H2. Aniline 27a (0.07 mmol) was dissolved in CH2Cl2
(1 mL) and pyridine (0.5 mL) in a microwave reaction tube.
Phenylsulfonyl chloride (6.0 µL, 0.21 mmol) was added. The
mixture was heated to 130 °C in a microwave reactor and kept
there for 20 min. The mixture was filtered and purified by reverse-
phase HPLC to provide the title compound (30 mg, 70%). The Boc
group was then removed according to method A6 to give 21ar.
Aniline 27b was acylated according to method B3, and then the
Boc group was removed to give 21as.
Compound 21ah: 1H NMR (400 MHz, MeOH-d4) δ 1.75-1.94
(m, 1 H), 2.06-2.48 (m, 6 H), 2.50-2.64 (m, 1 H), 3.60-3.75
(m, 2 H), 4.19-4.31 (m, 1 H), 4.52 (d, J ) 5.42 Hz, 2 H), 4.66-
4.73 (m, 1 H), 4.84-4.90 (m, 1 H), 7.20 (d, J ) 8.81 Hz, 1 H),
8.03 (dd, J ) 8.81, 2.03 Hz, 1 H), 8.21 (d, J ) 2.37 Hz, 1 H) ppm;
MS (ESI) m/z 422, 424 (M + H)+. Anal. (C20H21BrF3N3O6·0.5TFA)
C, H, N.
Compound 21ai: 1H NMR (400 MHz, MeOH-d4) δ 2.27 (m, 7
H), 2.59 (m, 1 H), 3.67 (m, 2 H), 4.26 (m, 1 H), 4.50 (m, 2 H),
4.71 (dd, J ) 8.75, 6.29 Hz, 1 H), 4.86 (m, 1 H), 7.60 (dd, J )
8.29, 1.53 Hz, 1 H), 7.71 (m, 2 H) ppm; MS (ESI) m/z 514, 516
(M + H)+. Anal. (C20H21BrF3N3O6·1.4TFA·0.15H2O) C, H, N.
Compound 21aj: 1H NMR (400 MHz, MeOH-d4) δ 2.22 (m, 7
H), 2.58 (m, 1 H), 3.65 (m, 2 H), 4.22 (m, 1 H), 4.68 (dd, J )
8.75, 5.98 Hz, 1 H), 4.85 (m, 3 H), 8.32 (d, J ) 2.15 Hz, 1 H),
8.73 (d, J ) 2.15 Hz, 1 H) ppm; MS (ESI) m/z 379 (M + H)+.
Anal. (C19H20ClF3N4O6·0.2TFA·0.45H2O) C, H, N.
Compound 21ar: 1H NMR (500 MHz, MeOH-d4) δ 2.01-2.08
(m, 1 H), 2.10-2.42 (m, 7 H), 2.52-2.62 (m, 1 H), 3.62-3.72
(m, 2 H), 4.13-4.22 (m, 1 H), 4.31-4.37 (m, 2 H), 4.66 (dd, J )
8.58, 6.08 Hz, 1 H), 4.83 (dd, J ) 7.96, 4.52 Hz, 1 H), 6.98-7.02
Compound 21ak: 1H NMR (500 MHz, MeOH-d4) δ ppm 2.25
(m, 7 H), 2.60 (m, 1 H), 3.68 (m, 2 H), 4.27 (m, 1 H), 4.56 (m, 2