2260 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7
McDonald et al.
7.76 (2H, m), 7.60 (1H, t, J ) 8.4 Hz), 7.40-7.33 (4H, m), 7.07
(1H, d, J ) 8.4 Hz), 4.92 (2H, s), 4.04 (1H, t, J ) 7.5 Hz), 3.11
(2H, m), 3.00 (1H, m), 2.82 (3H, s), 1.85 (1H, m), 1.75 (1H, m),
the method of preparation of 6 except that 21 and 3-imidazol-1-
yl-phenylamine (22h)31 were used in place of 19a and 22a,
respectively (71%). H NMR (CDCl3) 8.57 (1H, s), 7.86 (1H, s),
7.71 (1H, t, J ) 1.8 Hz), 7.52-7.28 (6H, m), 7.19 (1H, s), 7.11-
7.08 (1H, m), 7.04-7.01 (1H, m), 4.84 (1H, d, J ) 17.7 Hz), 4.58
(1H, d, J ) 17.7 Hz), 4.24-4.23 (2H, m), 2.83-2.77 (1H, m),
2.05-1.67 (6H, m), 1.38-1.19 (13H, m). Anal. (C31H36N6O3‚
0.5H2O) C, H, N.
1
1.66-1.50 (4H, m), 1.40-1.11 (13H, m). [R]25 -21.0° (c 1.0,
D
DMSO-d6). Anal. (C30H38N4O3‚HCl‚3.5H2O) C, H, N.
2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihy-
dro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(dimethylamino)-phen-
yl)-acetamide (28). Compound 28 was prepared using step A of
the method of preparation of 6 except that 21 and m-N,N-
dimethylaminoaniline (22b) were used in place of 19a and 22a,
respectively, in step A (39%). 1H NMR (CDCl3) 8.08 (1H, s), 7.50
(2H, m), 7.28 (1H, m), 7.10 (2H, m), 6.88 (1H, m), 6.64 (1H, m),
6.45 (1H, m), 4.69 (1H, d), 4.67 (1H, d), 4.36 (1H, d), 4.14 (1H,
d), 2.95 (6H, m), 2.74 (1H, m), 2.00-1.71 (6H, m), 1.36-1.17
(13H, m). The compound was further characterized as the HCl salt.
Anal. (C30H39N5O3‚HCl‚2.0H2O) C, H, N.
2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihy-
dro-3H-1,3,4-benzotriazepin-3-yl)-N-m-tolyl-acetamide (35). Com-
pound 35 was prepared using step A of the method of preparation
of 6 except that 21 and m-toluidine (22i) were used in place of
1
19a and 22a, respectively (79%). H NMR (CDCl3) 8.19 (1H, s),
7.48 (2H, m), 7.46 (2H, m), 7.28 (2H, m), 7.15 (1H, d), 6.87 (1H,
m), 4.72 (1H, d), 4.65 (1H, d), 4.28 (1H, d), 4.20 (1H, d), 2.80
(1H, m), 2.30 (3H, s), 1.76-1.70 (6H, m), 1.29-1.19 (13H, m).
Anal. (C29H36N4O3‚0.5H2O) C, H, N.
N-(3-Amino-phenyl)-2-(5-cyclohexyl-1-(3,3-dimethyl-2-oxo-
butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-acet-
amide (29). Compound 29 was prepared by the same method used
in the preparation of 6 except that 21 and 22c were used in place
2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihy-
dro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-methoxy-phenyl)-acet-
amide (36). Compound 36 was prepared using step A of the method
of preparation of 6 except that 21 and m-anisidine (22j) were used
1
of 19a and 22a, respectively, in step A (37%). H NMR (CDCl3)
1
11.28 (1H, br s), 8.85 (1H, s), 7.69 (1H, s), 7.57-7.27 (6H, m),
7.04 (1H, m), 4.76 (1H, d), 4.63 (1H, d), 4.21 (2H, m), 2.80 (1H,
m), 2.18-1.35 (6H, m), 1.32-1.22 (13H, m). The product was
further characterized as the HCl salt. Anal. (C28H35N5O3‚HCl‚
2.0H2O) C, H, N.
in place of 19a and 22a, respectively (79%). H NMR (CDCl3)
8.22 (1H, m), 7.45-7.30 (2H, m), 7.27 (1H, m), 7.20-7.12 (2H,
m), 7.03 (1H, d), 6.84 (1H, d), 6.63 (1H, d), 4.73 (1H, d), 4.64
(1H, d), 4.28 (1H, d), 4.19 (1H, d), 3.79 (3H, s), 2.80 (1H, m),
1.76-1.55 (6H, m), 1.36-1.24 (13H, m). Anal. (C29H36N4O4‚
0.5H2O) C, H, N.
2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihy-
dro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-pyrrolidin-1-yl-phenyl)-
acetamide (30). Compound 30 was prepared using step A of the
method of preparation of 6 except that 21 and 3-pyrrolidin-1-yl-
phenylamine (22d)30 were used in place of 19a and 22a, respectively
2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihy-
dro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-hydroxy-phenyl)-acet-
amide (37). Compound 37 was prepared using step A of the method
of preparation of 6 except that 21 and 3-aminophenol (22k) were
used in place of 19a and 22a, respectively (35%). 1H NMR (CDCl3)
8.31 (1H, s), 7.68 (1H, s), 7.30 (2H, m), 7.26 (1H, m), 7.08 (2H,
m), 6.60 (1H, m), 6.57 (1H, m), 6.41 (1H, m), 4.72 (1H, d), 4.65
(1H, d), 4.32 (1H, d), 4.22 (1H, d), 2.77 (1H, m), 1.98-1.69 (6H,
m), 1.27-1.24 (13H, m). Anal. (C28H34N4O4‚0.4H2O) C, H, N.
2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihy-
dro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-hydroxymethyl-phenyl)-
acetamide (38). Step A. (3-(2-(5-Cyclohexyl-1,2-dihydro-1-(3,3-
dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-
3-yl)acetamido)phenyl)methyl methyl carbonate was prepared using
step A of the method of preparation of 6 except that 21 and 22l
1
(63%). H NMR (CDCl3) 8.01 (1H, s), 7.49 (2H, m), 7.24 (1H,
m), 7.04 (2H, m), 6.72 (1H, s), 6.51 (1H, d), 6.26 (1H, d), 4.69
(2H, m), 4.42 (1H, d), 4.12 (1H, d), 3.25 (4H, m), 2.77 (1H, m),
2.00-1.69 (10H, m), 1.28-1.21 (13H, m). The compound was
further characterized as the HCl salt. Anal. (C32H41N5O9‚HCl) C,
H, N.
2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihy-
dro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-morpholin-4-yl-phenyl)-
acetamide (31). Compound 31 was prepared using step A of the
method of preparation of 6 except that 21 and 22e were used in
1
place of 19a and 22a, respectively (88%). H NMR (CDCl3) 8.22
1
(1H, br s), 7.50-7.44 (2H, m), 7.29-7.12 (3H, m), 7.03 (1H, d, J
) 8.1 Hz), 6.75 (1H, d, J ) 8.1 Hz), 6.63-6.60 (1H, m), 4.77
(1H, d, J ) 17.7 Hz), 4.65 (1H, d, J ) 17.7 Hz), 4.34 (1H, d, J )
16.8 Hz), 4.19 (1H, d, J ) 16.8 Hz), 3.84 (4H, t, J ) 4.8 Hz), 3.15
(4H, t, J ) 4.8 Hz), 2.82-2.75 (1H, m), 2.05-1.74 (6H, m), 1.36-
1.24 (13H, m). Anal. (C32H41N5O4‚0.3H2O) C, H, N.
were used in place of 19a and 22a, respectively (96%). H NMR
(CDCl3) 8.30 (1H, s), 7.51-7.39 (4H, m), 7.31-7.24 (2H, m), 5.11
(2H, s), 4.72 (1H, d), 4.64 (1H, d), 4.23 (1H, d), 4.14 (1H, d), 3.80
(3H, s), 2.89 (1H, m), 1.76-1.67 (6H, m), 1.29-1.24 (13H, m).
Step B. (3-(2-(5-Cyclohexyl-1,2-dihydro-1-(3,3-dimethyl-2-oxo-
butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)acetamido)-
phenyl)methyl methyl carbonate was dissolved in THF-MeOH
(1:1/40 mL), and 1% K2CO3 solution (30 mL) was added. The
mixture was stirred at ambient temperature for 2 h. Following
evaporation of the organic solvents, a precipitate formed which was
isolated by filtration and dried in vacuo to afford 38 as a yellow
2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihy-
dro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(2-ethoxy-ethylamino)-
phenyl)-acetamide (32). Compound 32 was prepared by the same
method used in the preparation of 6 except that 21 and 22f were
1
used in place of 19a and 22a, respectively, in step A (64%). H
1
NMR (CDCl3) 8.45 (1H, s), 7.61 (1H, s), 7.56-7.47 (2H, m), 7.36
(4H, m), 7.03 (1H, d), 4.70 (2H, dd), 4.26 (2H, dd), 3.73 (2H, br
s), 3.51 (4H, m), 2.82 (1H, br s), 2.05-1.65 (6H, m), 1.30-1.17
(16H, m). Anal. (C32H43N5O4‚HCl) C, H, N.
solid (790 mg, 89%). H NMR (CDCl3) 8.31 (1H, s), 7.51-7.45
(3H, m), 7.31-7.28 (3H, m), 7.26-7.10 (2H, m), 4.70 (1H, d),
4.67 (2H, s), 4.64 (1H, d), 4.26 (1H, d), 4.22 (1H, d), 2.89 (1H,
m), 1.85-1.55 (6H, m), 1.30-1.24 (13H, m). Anal. (C29H36N4O4‚
0.5H2O) C, H, N.
2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihy-
dro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(methyl-(2-methylamino-
ethyl)-amino)-phenyl)-acetamide (33). Compound 33 was pre-
pared by the same method used in the preparation of 6 except that
21 and 22g were used in place of 19a and 22a, respectively, in
step A (19%). 1H NMR (CDCl3) 8.09 (1H, s), 7.50-7.45 (2H, m),
7.29-7.24 (1H, m), 7.12-7.01 (3H, m), 6.53-6.46 (2H, m), 4.69-
4.67 (2H, m), 4.38 (1H, d, J ) 13.8 Hz), 4.17 (1H, d, J ) 13.8
Hz), 3.50-3.44 (2H, m), 2.93 (3H, s), 2.86-2.74 (3H, m), 2.49
(3H, s), 2.04-1.58 (7H, m), 1.31-1.19 (13H, m). Anal. (C32H44N6O3‚
0.5CH2Cl2) C, H, N.
3-(2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-di-
hydro-3H-1,3,4-benzotriazepin-3-yl)-acetylamino)-benzoic Acid
(39). Step A. 3-(2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-
oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-acetylamino)-ben-
zoic acid methyl ester was prepared using step A of the method of
preparation of 6 except that 21 and 3-amino-benzoic acid methyl
ester (27m) were used in place of 19a and 22a, respectively (71%).
1H NMR (CDCl3) 8.49 (1H, s), 7.92 (1H, m), 7.84 (1H, t), 7.74
(1H, dt), 7.48 (2H, m), 7.39-7.27 (2H, m), 7.03 (1H, d), 4.77 (1H,
d), 4.60 (1H, d), 4.25 (2H, s), 3.91 (3H, s), 2.80 (1H, m), 2.05-
1.73 (6H, m), 1.34-1.17 (13H, m).
2-(5-Cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihy-
dro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(1H-imidazol-1-yl)-phen-
yl)-acetamide (34). Compound 34 was prepared using step A of
Step B. Lithium hydroxide monohydrate (318 mg, 7.58 mmol)
was added to a solution of 3-(2-(5-cyclohexyl-1-(3,3-dimethyl-2-