7-Aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs as non-steroidal progesterone receptor antagonists

Article abstract of DOI:10.1016/j.bmc.2008.05.018

Novel 7-aryl benzo[1,4]oxazepin-2-ones were synthesized and evaluated as non-steroidal progesterone receptor (PR) modulators. The structure activity relationship of 7-aryl benzo[1,4]oxazepinones was examined using the T47D cell alkaline phosphatase assay. A number of 7-aryl benzo[1,4]oxazepinones such as 10j and 10v demonstrated good in vitro potency (IC₅₀ of 10-30 nM) and selectivity (over 100-fold) at PR over other steroidal receptors such as glucocorticoid and androgen receptors (GR and AR). Several 7-aryl benzo[1,4]oxazepinones were active in the rat uterine decidualization model. In this in vivo model, compounds 10j and 10u were active at 3 mg/kg when dosed orally.

Full text of DOI:10.1016/j.bmc.2008.05.018

Bioorganic & Medicinal Chemistry 16 (2008) 6589–6600
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
7-Aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs
as non-steroidal progesterone receptor antagonists
a
a
a
a
b
Puwen Zhang a, , Jeffrey C. Kern , Eugene A. Terefenko , Andrew Fensome , Ray Unwalla , Zhiming Zhang ,
*
Jeffrey Cohen b, Thomas J. Berrodin b, Matthew R. Yudt b, Richard C. Winneker b, Jay Wrobel a
a Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
b Women’s Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 February 2008
Revised 5 May 2008
Accepted 7 May 2008
Available online 10 May 2008
Novel 7-aryl benzo[1,4]oxazepin-2-ones were synthesized and evaluated as non-steroidal progesterone
receptor (PR) modulators. The structure activity relationship of 7-aryl benzo[1,4]oxazepinones was
examined using the T47D cell alkaline phosphatase assay. A number of 7-aryl benzo[1,4]oxazepinones
such as 10j and 10v demonstrated good in vitro potency (IC50 of 10–30 nM) and selectivity (over 100-
fold) at PR over other steroidal receptors such as glucocorticoid and androgen receptors (GR and AR). Sev-
eral 7-aryl benzo[1,4]oxazepinones were active in the rat uterine decidualization model. In this in vivo
model, compounds 10j and 10u were active at 3 mg/kg when dosed orally.
Keywords:
Progesterone receptor (PR)
PR agonists
Ó 2008 Elsevier Ltd. All rights reserved.
PR antagonists
Non-steroidal PR modulators
1. Introduction
tors. Herein, we report synthesis, in vitro SAR, and in vivo activity of
novel 7-aryl benzoxazepin-2-ones and analogs (10a–24) as PR antag-
The progesterone receptor (PR) is a member of the superfamily of
ligand-dependent transcription factors1 Progesterone, a natural PR
agonist, plays an important role in female reproduction. PR agonists,
both natural and synthetic, have been used extensively, often in com-
bination with an estrogen, as oral contraceptives and in post-meno-
pausal hormone therapy. In contrast, clinically successful PR
antagonists remain scarce and their therapeutic potential has not
yet been fully realized. Selective PR antagonists may be potentially
used in female contraception2 and for the treatment of various gyne-
cological and obstetric diseases including hormone dependent cancers
and non-malignant chronic conditions such as fibroids3 and endo-
metriosisp4,5 Mifepristone (1), the only FDA approved steroidal PR
antagonist that is in clinical use, demonstrated activity at other steroi-
dal receptors such as glucocorticoid (GR) and androgen receptors
(AR)6 Mifepristone was nearly equipotent as an antagonist for both
PR and GR and this potentially limits its chronic use. Clearly, the un-
met need of selective PR antagonists presents a good opportunity for
drug discovery in this area. To search for more selective PR antago-
nists, a number of non-steroidal PR antagonist templates have been
investigated and reported7–10 Recently, we have disclosed several ser-
ies of novel PR antagonists including 5-aryl oxindoles (e.g., 2), and 6-
aryl benzoxazinones (e.g., 3)11–13 In an expansion of our SAR effort, we
decided to examine 7-aryl benzo[1,4]oxazepin-2-ones as PR modula-
onists.
Me
N
O
F
Me
Me
OH
Me
NC
O
N
H
2
1
F
R2
R1
X
O
NC
O
N
N
O
O
H
H
10
3
2. Chemistry
The synthesis of 7-aryl benzoxazepin-2-ones and benzoxaze-
pine-2-thiones 10a–10ad is illustrated in Scheme 1. Treatment of
* Corresponding author. Tel.: +1 484 865 3856; fax: +1 484 865 9398.
E-mail address: Zhangp@wyeth.com (P. Zhang).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.05.018

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P. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 6589–6600
O
O
Br
Br
a
OH
NH2
R1
NH2
6
5
b
c
R1 R2
OH
NH
R1 R2
OH
Br
Br
d
NH2
8
Cl
7
O
e
R2
R2
R2
O
R1
R1
R1
Ar
O
Br
Ar
O
g
f
N
N
N
S
H
O
O
H
H
9
10
11
Scheme 1. Reagents and conditions: (a) R1Li, THF, 0°C, N2, 30–70%; (b) when R1 = R2, R1MgBr, diethyl ether, ꢀ78 °C–rt, N2, 30–60%; (c) R2MgBr or LiR2, THF, 0 °C–rt, N2, 25–
90%; (d) chloroacetyl chloride, Et3N, THF, 0 °C–rt, 50–70%; (e) NaH, THF, 0 °C to rt, N2, 80–99%; (f) ArB(OH)2, Pd(PPh3)4, Na2CO3, Glyme/H2O, 80–90 °C, 50–80%; (g) Lawesson’s
reagent, toluene, 110 °C.
anthranilic acid 5 with an appropriate organo-lithium agent affor-
ded (2-amino-5-bromophenyl) ketones 6. Conversion of ketones 6
to their corresponding carbinols 7 was readily furnished by the
addition of a Grignard or organo-lithium reagent. Anthranilic acid
5 could also be directly converted to carbinols 7 (R1 = R2) by the
addition of excess of an appropriate Grignard reagent. Acylation
of 7 with chloroacetyl chloride led to the formation of 8, which
upon ring closure with sodium hydride provided the key interme-
diate benzoxazepinones 9. The 7-aryl benzoxazepinones 10a–10ad
were obtained in good yields by coupling 9 and appropriate aryl
boronic acids via a standard Suzuki cross-coupling protocol. 7-Aryl
benzoxazepinones 10f and 10p were converted to their respective
benzoxazepine-2-thiones 11a and 11b by refluxing with Lawes-
son’s reagent in toluene.
Compounds 20a and 20b were prepared as shown in Scheme 2.
Aniline 12 was first protected using di-t-butyl pyrocarbonate to give
13. Ortho-directed lithiation of 13 followed by addition of ethyl pen-
tafluoropropionate afforded ketone 14. Removal of the Boc group
under acidic conditions gave 15 and subsequent bromination using
NBS provided compound 16. The ring closure and arylation at the 7-
position to deliver the desired target compounds 20a and 20b were
carried in a similar fashion as illustrated in Scheme 1.
4,5-Dihydro-1H-benzo[1,4]diazepin-2-one 24 was furnished via
the Scheme 3. Ring closure of 2-amino-5-bromoacetophenone 21
O
a
C2F5
b
d
NH2
NHBoc
O
NHBoc
12
13
14
c
O
O
C2F5
e
Br
Br
Br
C2F5
OH
C2F5
NH2
NH2
NH2
17
16
15
f
O
O
O
O
C2F5
C2F5
C2F5
Br
Ar
OH
O
h
g
NH
N
H
N
H
Cl
O
O
O
18
19
20
Scheme 2. Reagents and conditions: (a) Di-tert-butyl pyrocarbonate, DMAP, THF, 70 °C, N2, 81%; (b) ethyl pentafluoropropionate, t-BuLi, diethyl ether, ꢀ78 to ꢀ15 °C, N2,
28%; (c) TFA, CH2Cl2, rt, 80%; (d) NBS, CH2Cl2, rt, 94%; (e) furan, n-BuLi, THF, ꢀ78 to 0 °C, N2, >90%; (f) chloroacetyl chloride, Et3N, THF, 0 °C–rt, 60%; (g) NaH, THF, 0 °C–rt, N2,
50%; (h) ArB(OH)2, Pd(PPh3)4, Na2CO3, Glyme/H2O, 80 °C, 52%.

P. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 6589–6600
6591
Table 1
with glycine ethyl ester hydrochloride salt in refluxing pyridine
PR alkaline phosphatase activity of 7-aryl 5,5-dimethyl benzoxazepin-2-ones
formed 5-methyl-1H-benzo[e][1,4]diazepin-2(3H)-one 22. Cou-
pling 22 with 3-chloro-4-fluorophenyl boronic acid afforded com-
pound 23 following the standard Suzuki cross-coupling protocol.
Methylation of compound 23 at the 4-position followed by an
addition of methylmagnesium bromide afforded benzodiazepin-
2-one 24.
X
O
N
O
H
3. Results and discussion
a
Compound
X
T47D alkaline phosphatase IC50 (nM)
We have recently reported several series of non-steroidal PR
1
2
3
0.2
11–16
13.0
(90)b
62.1
14.9
100.0
15.7
29.3
30.0
30.1
15.0
29.1
25.0
34.6
modulators.
Among the antagonist scaffolds examined, the
6-aryl benzoxazin-2-ones were the most promising and rendered
the most potent and selective PR antagonists as demonstrated in
a number of in vitro and in vivo models12 In an expansion of our
SAR efforts on the benzoxazin-2-one template, we have examined
and disclosed the ring-contracted oxindole scaffold (e.g., 2). The
SAR effort led to several 5-aryl oxindoles that showed good in vitro
and in vivo PR antagonist potency11 To further exploit the SAR
uncovered from benzene-fused 5-membered ring oxindole and
6-membered ring benzoxazin-2-one scaffolds, we decided to
examine the benzoxazinone core ring expansion by inserting a
methylene moiety between the 2-position carbonyl group and
3-position oxygen atom. This modification led to 7-aryl benzoxaze-
pin-2-ones, a new class of PR modulators as demonstrated using
the T47D cell alkaline phosphatase assay17,18
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
2-F
3-F
4-F
2-F, 3-F
3-F, 4-F
3-F, 5-F
3-Cl, 4-F
3-Cl, 5-F
3-Cl, 5-Cl
3-CN, 5-F
3-CN, 5-Cl
a
Fifty percent inhibitory concentration of tested compounds on 1 nM proges-
terone induced alkaline phosphatase activity in the human T47D breast carcinoma
cell line.
b
The number in the parentheses is EC50 value and represents 50% effective
concentration of tested compounds on alkaline phosphatase activity in the human
T47D breast carcinoma cell line. Values represent the average of at least duplicate
determinations. The standard deviations for these assays were typically 20% of the
mean or less.
Using the 5,5-dimethylbenzoxazepinone as a core, a number of
novel 7-phenyl based benzoxazepinones were prepared to probe
the SAR of substitution on the 7-phenyl group (Table 1). 3-Fluoro-
phenyl analog 10b was more potent in the T47D alkaline phospha-
tase assay than its 2- and 4-fluoro congeners 10a and 10c. This
finding was consistent with the SAR trend observed from the ben-
zoxazinone and oxindole scaffolds in that an electron-withdrawing
group was preferred at the 3-position of the pendant phenyl
group11,12 Disubstituted analogs 10d–k had PR antagonist potency
in the 30 nM or lower range that was comparable to that of their
30-fluoro analog 10b. Overall, the ring-expanded benzoxazepinones
had similar in vitro potency compared to their benzoxazinone (3)
and oxindole (2) analogs in the T47D alkaline phosphatase
assay.11,12
in the same assay. Interestingly, both 3-cyano-5-fluoro and 3-
chloro-5-fluorophenyl substituted benzoxazepinones (10h, 10j)
elicited PR antagonist activity suggesting the same SAR trend to
their ring-contracted oxindole analogs.
Compounds 10l–ab and 20a,b (Table 2) were prepared to exam-
ine the SAR at the 5-position while maintaining the 7-(3-cyano-5-
fluorophenyl) and 7-(3-chloro-4-fluorophenyl) group constant.
Replacing one of methyl groups at the 5-position with a thien-2-
yl moiety (10l, IC50 = 65.5 nM) slightly decreased potency com-
pared to 5,5-dimethyl analog 10g (IC50 = 30.1 nM). Increasing the
size of alkyl group from methyl to propyl group (10m–q) caused
reduction in PR antagonist potency. Substitution of fur-2-yl and
thien-3-yl groups for thien-2-yl moiety (10r–u vs. 10m,n) in-
As previously disclosed,11,12 3-cyano-5-fluoro and 3-chloro-5-
fluorophenyl substituted benzoxazinones showed weak to moder-
ate PR agonist activity in T47D alkaline phosphatase assay while
the corresponding ring-contracted oxindoles were PR antagonists
Cl
F
O
Br
Br
N
b
N
a
NH2
N
N
O
H
O
H
21
22
23
c
Cl
F
N
N
O
H
24
Scheme 3. Reagents and conditions: (a) Glycine ethyl ester HCl salt, pyridine, reflux, 16%; (b) 3-Cl-4-F-phenyl boronic acid, Pd(PPh3)4, Na2CO3, Glyme/H2O, 80 °C, 73%; (c)
MeI, anhydrous acetonitrile, 50 °C; MeMgBr, ether, 5%.

6592
P. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 6589–6600
Table 2
PR alkaline phosphatase activity of different 5,5-disubstituted benzoxazepin-2-ones
Y
R1
R1
R2
R2
X
NC
O
O
N
N
O
H
O
H
a
Compound
R1
R2
X
T47D alkaline phosphatase IC50 (nM)
10l
CH3
C2H5
C2H5
n-C3H7
i-C3H7
i-C3H7
C2H5
C2H5
C2H5
Thien-2-yl
Thien-2-yl
Thien-2-yl
Thien-2-yl
Thien-2-yl
Thien-2-yl
Thien-3-yl
Thien-3-yl
Fur-2-yl
3-Cl, 4-F
3-Cl, 4-F
3-CN, 5-F
3-Cl, 4-F
3-Cl, 4-F
3-CN, 5-F
3-Cl, 4-F
3-CN, 5-F
3-Cl, 4-F
3-CN, 5-F
3-CN, 5-F
3-Cl, 4-F
3-CN, 5-F
3-Cl, 4-F
3-Cl, 4-F
3-Cl, 4-F
3-CN, 5-F
Y = O
65.5
207.7
100.0
349.4
365.7
138.3
116.7
59.2
62.5
11.8
13.3
22.5
26.6
65.2
88.0
1000.0
1000.0
29.9
107.6
82.4
10m
10n
10o
10p
10q
10r
10s
10t
10u
10v
10w
10x
10y
10z
10aa
10ab
10ac
10ad
20a
20b
C2H5
Fur-2-yl
Fur-2-yl
Fur-2-yl
Fur-2-yl
Fur-2-yl
Thien-2-yl
Thien-2-yl
Phenyl
50-Cl-thien-2-yl
50-Cl-thien-2-yl
C2H5
Thien-2-yl
Thien-2-yl
Phenyl
50-Cl-thien-2-yl
50-Cl-thien-2-yl
Fur-2-yl
Thien-2-yl
Fur-2-yl
Fur-2-yl
C2H5
C2F5
C2F5
Y = S
3-Cl, 4-F
3-CN, 5-F
34.1
a
% Inhibitory concentration of tested compounds on 1 nM progesterone induced alkaline phosphatase activity in the human T47D breast carcinoma cell line. Values
represent the average of at least duplicate determinations. The standard deviations for these assays were typically 20% of the mean or less.
creased PR antagonist potency. Increasing the lipophilicity by
replacing the ethyl group of compounds 10t,u with a pentafluoro-
ethyl group (20a,b) resulted in a slight reduction in potency. 5,5-
Difuryl, 5,5-dithienyl, and 5,5-diphenyl analogs 10v–z also showed
good PR antagonist potency. However, replacing thien-2-yl group
(10x,y) with 50-chlorothien-2-yl group (10aa,ab) at the 5-position
resulted in a greater than 15-fold loss in potency suggesting a size
limitation at this position. Compounds 10ac,ad also had good PR
antagonist potency suggesting that the phenyl-based aryl groups
at the 7-position can be replaced by an appropriate hetero aryl
moiety without losing PR antagonist potency.
As shown in Table 3, benzoxazepine-2-thione 11a became a PR
agonist with moderate potency when the 2-carbonyl group was re-
placed by a 2-thiocarbonyl moiety. However, 11a was over 20-fold
less potent than its corresponding benzoxazine-2-thione conge-
ner16 Interestingly, benzoxazepine-2-thione 11b with larger 5-sub-
stituents remained as a PR antagonist with a similar potency as
that of its parent compound 10p. Replacing the 4-oxygen by N-
methyl group led to 4,5-dihydrobenzodiazepin-2-one 24, which
was 3-fold less potent compared to 10g. In addition, benzodiaze-
pin-2-one 23, a precursor of 24, was PR antagonist with the mod-
erate potency.
Clearly, there appeared different SAR trends between 6-aryl
benzoxazinones and 7-aryl benzoxazepinones. In contrast to 6-aryl
benzoxazinones that showed both PR agonist and antagonist activ-
ities dependent on the nature of 6-aryl substitution, 7-aryl benzox-
azepinones demonstrated more consistent PR antagonist activity
regardless of 7-aryl substitutions. Furthermore, 7-aryl benzoxaze-
pine-2-thiones 11a and 11b were either less potent PR agonist or
remained a PR antagonist in contrast to the consistent agonism
of similar substituted 6-aryl benzoxazine-2-thiones.16 To under-
stand the binding mode of these 7-aryl benzoxazepinones within
the progesterone receptor, docking studies were carried out on
compound 10u using the recently published X-ray structure of
PR LBD with asoprisnil, a steroidal selective progesterone modula-
tor (SPRM). The PR/asoprisnil crystal structure showed helix-12 in
an antagonist conformation, which is different than the typical
agonist conformations seen in the PR/progesterone complex and
the non-steroidal PR agonist ligand tanaproget. Inspection of the
docked structure of 10u revealed that the nitrile group of the A-
ring makes
a network of hydrogen bond interactions with
Arg766 and Gln725 residues that are held in position by a water
molecule. The benzoxazepin-2-one ring lied in a similar orienta-
tion as seen in the benzoxazine-2-thione ring of tanaproget and
the NH group of the ligand made hydrogen bond interaction with
the carbonyl group of the Asn719 residue within helix-3. The larger
substituents on the 5-position, that is, ethyl and furan, were
accommodated in the pocket occupied by the Phe794 and
Leu797 residues. An overlay of the PR/asoprisnil complex structure
onto the PR/tanaproget structure showed backbone deviations of
0.7 Å in this region, which allowed residues Phe794, Leu797, and
Tyr890 to swing away from the ligand in the asoporisnil structure
and created more room for these groups to be accommodated. This
also explained why our earlier attempts to dock 10u into the
tanaproget binding site did not yield any reasonable low energy
bound pose for this ligand. Clearly the steric interactions with
the rotamers of these residues present in the tanaproget structure
did not allow these bulky groups to be accommodated. Taken to-
gether, docking studies suggested that the more bulky benzoxaze-
pin-2-ones preferred an antagonist conformation in the PR binding
pocket thus leading to more consistent PR antagonism (Fig. 1).
Compounds 10j, 10u, and 10v were evaluated for their selectiv-
ity against other steroidal receptors by using a Gal4-DNA binding
domain (DBD)-hormone receptor ligand binding domain (LBD)
one-hybrid assay for each receptor19 (Table 4). Compared to steroi-
dal PR antagonist mifepristone (1), these compounds are more
selective at PR over other hormone receptors. Both 10j and 10v
have 100-fold or greater selectivity at PR over other steroid recep-

P. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 6589–6600
6593
Table 3
In summary,
a
novel series of non-steroidal 7-aryl
PR alkaline phosphatase activity of 7-aryl benzoxazepine-2-thiones and benzodiaz-
epine-2-one
benzo[1,4]oxazepin-2-ones and analogs were evaluated as proges-
terone receptor (PR) modulators. The structure activity relation-
ship of 7-aryl benzo[1,4]oxazepinones was examined using the
CN
F
T47D cell alkaline phosphatase assay.
A number of 7-aryl
S
benzo[1,4]oxazepinones such as 10j and 10u demonstrated good
in vitro potency and selectivity at PR over other steroidal receptors
such as GR and AR. In addition, several 7-aryl benzo[1,4]oxazepi-
nones were active PR antagonists in the rat uterine decidualization
model.
O
O
F
F
N
N
H
S
S
H
11b
11a
4. Experimental
4.1. General
Cl
Cl
F
F
1H NMR spectra were recorded on a Bruker DPX300, Varian
INOVA 400, or Varian INOVA 500 instrument. Chemical shifts
are reported in d values (parts per million, ppm) relative to an
internal standard of tetramethylsilane in CDCl3 or DMSO-d6.
Electrospray (ESI) mass spectra were recorded using a Hewlett-
Packard 5989B MS engine or Waters Alliance-ZMD mass spec-
trometer. Electron Impact ionization (EI, EE = 70 eV) mass spectra
were recorded on a Finnigan Trace mass spectrometer. Elemental
analyses were carried out on a modified Perkin-Elmer model
2400 series II CHN analyzer or sent to Robertson Microlit. Ana-
lytical thin-layer chromatography (TLC) was carried out on pre-
coated plates (silica gel, 60 F-254), and spots were visualized
with UV light and stained in iodine. Preparative HPLC purifica-
tions were performed on a preparative Gilson HPLC system using
a CombiPrep Pro C18 column with acetonitrile (0.1% TFA) and
water (0.1% TFA) as solvents at a flow rate of 20 mL/min. Sol-
vents were purchased as anhydrous grade and were used with-
out further purification.
N
N
N
N
H
O
H
O
24
23
Compound
X
Y
T47D alkaline phosphatase
EC50 (nM)
T47D alkaline phosphatase
a
b
IC50 (nM)
11a
11b
23
35.8
78.2
676.7
104.7
24
a
Fifty percent effective concentration of tested compounds on alkaline phos-
phatase activity in the human T47D breast carcinoma cell line.
b
Fifty percent inhibitory concentration of tested compounds on 1 nM proges-
terone induced alkaline phosphatase activity in the human T47D breast carcinoma
cell line. Values represent the average of at least duplicate determinations. The
standard deviations for these assays were typically 20% of the mean or less.
4.1.1. 2-(2-Amino-5-bromophenyl)propan-2-ol (7a)
A solution of 2-amino-5-bromobenzoic acid (10.0 g, 46 mmol)
in dry THF (200 mL) was treated at ꢀ78 °C under nitrogen with a
solution of methylmagnesium bromide in ether (3.0 M, 90 mL,
270 mmol). The reaction mixture was slowly warmed to ambient
temperature, kept stirring for 48 h under nitrogen and then poured
into a cold 0.5 N aqueous hydrochloride solution (300 mL). The
mixture was neutralized with aqueous 1N sodium hydroxide solu-
tion and ethyl acetate (300 mL) was added. The organic layer was
separated and aqueous layer was extracted with ethyl acetate
(3 ꢂ 100 mL). The combined organic layers were washed with
brine and dried (MgSO4). After removal of solvent in vacuo, the res-
idue was purified by a silica gel flash chromatography (hexane–
ethyl acetate, 3:2) to give 2-(2-amino-5-bromophenyl)propan-2-
ol as off-white solid (6.0 g, 57%): mp 62–63 °C; MS (ESI) m/z 230
([M+H]+); 1H NMR (CDCl3): d 7.19 (d, 1H, J = 2.3 Hz), 7.12 (dd, 1H,
J = 8.4, 2.3 Hz), 6.51 (d, 1H, J = 8.4 Hz), 4.70 (s, 2H), 1.82 (s, 1H),
1.65 (s, 6H).
4.1.2. N-[4-Bromo-2-(1-hydroxy-1-methyl-ethyl)-phenyl]-2-
chloro-acetamide (8a)
Figure 1. Proposed binding mode of compound 10j (cyan) in PR/asoprisinil LBD
binding site. (Only key residues and a Connolly surface of the binding site are shown
for simplicity. Hydrogen bonds are shown as yellow dotted lines.)
To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (4.6 g,
20 mmol) in a mixture of anhydrous diethyl ether (100 mL) at 0 °C
under nitrogen was added triethyl amine (6.3 mL, 45 mmol) and
chloroacetyl chloride (1.8 mL, 22.6 mmol). After addition, the reac-
tion mixture was slowly warmed to rt, stirred for 3 h, and treated
with a cold 1N hydrogen chloride aqueous solution (70 mL). Ethyl
acetate (100 mL) was added and organic layer separated, dried
(Mg2SO4), concentrated to yield the title compound as an off-white
solid (4.5 g, 74%): mp 133–134 °C. MS (ESI) m/z 304 ([MꢀH]ꢀ); 1H
NMR (DMSO-d6): d 1.21 (s, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.46 (dd,
tors suggesting that these novel PR ligands might have less
potential AR- or GR-related side effects. Several 7-aryl benzoxaz-
epinones were also evaluated for their oral activity in the ovariec-
tomized mature female rat decidualization model.20 Both 10j
and 10u were PR antagonists in this in vivo model inhibiting pro-
gesterone induced decidualization by ꢁ50% when dosed orally at
3 mg/kg.

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P. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 6589–6600
Table 4
Antagonist cross-activities of 1, 10j, 10u, and 10v
a
b
b
b
b
Compound
PR IC50 (nM)
ER IC50 (nM)
AR IC50 (nM)
GR IC50 (nM)
MR IC50 (nM)
1
0.2
25.0
11.8
13.3
5000 (50)
NAc
NA
6.9 (95)
>3000 (57)
690 (82)
0.6 (97)
590 (96)
10j
10u
10v
>3000 (23)
190 (91)
1300 (82)
>3000 (32)
>3000 (82)
>3000 (60)
NA
>3000 (62)
a
Fifty percent inhibitory concentration of tested compounds on 1 nM progesterone induced alkaline phosphatase activity in the human T47D breast carcinoma cell line.
Values represent the average of at least duplicate determinations. The standard deviations for these assays were typically 20% of the mean or less.
b
Experimental values represented the average of at least duplicate determinations and values in the parentheses represented percentage of inhibition. The standard
deviation for these assays was typically 30% of mean or less. See Section 4 for details.
c
Not active up to 10 lM concentration.
J = 8.6, 2.3 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 6.28 (s, 1H), 4.43 (s, 2H),
1.53 (s, 6H).
4.1.7. 7-(2,3-Difluorophenyl)-5,5-dimethyl-1,5-dihydro-4,1-
benzoxazepin-2(H)-one (10d)
Prepared from 9a and 2,3-difluorophenyl boronic acid accord-
ing to the coupling procedure described in example 10b. 1H
NMR (DMSO-d6): d 10.04 (s, 1H), 7.2–7.45 (m, 6H), 4.28 (s,
2H), 1.59 (s, 6H); MS (ESI) m/z 304 ([M+H]+); MS (ESI) m/z 302
([MꢀH]ꢀ).
4.1.3. 7-Bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-
2(3H)-one (9a)
To a solution of N-[4-bromo-2-(1-hydroxy-1-methyl-ethyl)-
phenyl]-2-chloro-acetamide (3.0 g, 9.9 mmol) in anhydrous THF
(30 mL) was added sodium hydride (60% in mineral oil, 0.85 g,
21 mmol) at 0 °C under nitrogen. After addition, the reaction
mixture was stirred for 3 h, treated with an aqueous saturated
ammonium chloride solution (30 mL). Ethyl acetate (50 mL)
was added and organic layer separated, dried (Mg2SO4), and
concentrated to yield the title compound as an off-white solid
(2.7 g, 99%): mp 120–121 °C. MS (ESI) m/z 270 ([M+H]+); 1H
NMR (DMSO-d6): d 10.01 (s, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.37
(dd, J = 8.6, 2.3 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 4.23 (s, 2H),
1.53 (s, 6H).
4.1.8. 7-(3,4-Difluorophenyl)-5-ethyl-5-(2-furyl)-1,5-dihydro-
4,1-benzoxazepin-2(H)-one (10e)
Prepared from 9a and 3,4-difluorophenyl boronic acid using
the coupling procedure described in example 10b. 1H NMR
(DMSO-d6): d 9.98 (s, 1H), 7.76–7.83 (m, 1H), 7.60–7.67 (m,
1H), 7.49–7.56 (m, 3H), 7.17 (d, J = 8.32 Hz, 1H), 4.26 (s, 2H),
1.61 (s, 6H); MS (ESI) m/z 304 ([M+H]+); MS (ESI) m/z 302
([MꢀH]ꢀ).
4.1.9. 7-(3,5-Difluorophenyl)-5,5-dimethyl-1,5-dihydro-4,1-
benzoxazepin-2(3H)-one (10f)
4.1.4. 7-(3-Fluorophenyl)-5,5-dimethyl-1,5-dihydro-4,1-
benzoxazepin-2(H)-one (10b)
Prepared from 9a and 3,5-difluorophenyl boronic acid according
to the coupling procedure described in example 10b. 1H NMR
(DMSO-d6): d 10.04 (s, 1H), 7.61–7.57 (m, 2H), 7.52–7.45 (m, 2H),
7.23–7.17 (m, 2H), 4.72 (s, 2H), 1.60 (s, 6H); MS (FI) m/z 304
[M+H]+.
A
mixture of 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-ben-
zoxazepin-2(3H)-one (1.0 g, 3.7 mmol), 3-fluorophenyl boronic
acid (0.8 g, 5.7 mmol), tetrakis(triphenylphosphine) palladium
(0) (0.25 g, 0.22 mmol), sodium carbonate (1.2 g, 11.3 mmol) in
a mixture of DME and water (20 mL and 5 mL) was degassed to
remove air and then heated at 90 °C under nitrogen for 4 h. The
mixture was allowed to cool to rt, treated with a saturated aque-
ous ammonium sulfate solution (50 mL). Ethyl acetate (80 mL)
was added and organic layer separated, dried (Mg2SO4), and con-
centrated. The residue was purified by a flash chromatography on
a silica gel column (hexane–ethyl acetate, 3:1) to give the title
compound as an off-white solid: mp 196–197 °C; 1H NMR
(DMSO-d6): d 9.98 (s, 1H), 7.43–7.58 (m, 5H), 7.12–7.20 (m,
2H), 4.23 (s, 2H), 1.63 (s, 6H). MS (ESI) m/z 286 ([M+H]+); Anal.
4.1.10. 7-(3-Chloro-4-fluorophenyl)-5,5-dimethyl-1,5-dihydro-
4,1-benzoxazepin-2(H)-one (10g)
Prepared from 9a and 3-chloro-4-fluorophenyl boronic acid
according to the coupling procedure described in example 10b. A
white solid: mp 170–171 °C; 1H NMR (DMSO-d6): d 10.01 (s, 1H),
7.93 (dd, J = 8.1, 2.3 Hz, 1H), 7.68 (m, 1H), 7.44–7.59 (m, 3H),
7.18 (d, J = 8.4 Hz, 1H), 4.25 (s, 2H), 1.63 (s, 6H). MS (ESI) m/z 318
([MꢀH]ꢀ); Anal. Calcd for C17H15ClFNO2: C, 63.86; H, 4.73; N,
4.38. Found: C, 63.54; H, 4.72; N, 4.11.
Calcd for
C17H16FNO2: C, 71.56; H, 5.65; N:4.91. Found: C,
71.54; H, 5.77; N, 4.82.
4.1.11. 7-(3-Chloro-5-fluorophenyl)-5,5-dimethyl-1,5-dihydro-
4,1-benzoxazepin-2(H)-one (10h)
4.1.5. 7-(2-Fluorophenyl)-5,5-dimethyl-1,5-dihydro-4,1-
benzoxazepin-2(H)-one (10a)
Prepared from 10b and 5-chloro-3-fluoro phenyl boronic acid
according to the coupling procedure described in example 10b.
1H NMR (DMSO-d6): d 10.01 (s, 1H), 7.61–7.65 (m, 4H), 7.36–
7.39 (m, 1H), 7.18 (d, J = 8.54 Hz, 1H), 4.26 (s, 2H), 1.62 (s,
6H); MS (ESI) m/z 320/322 ([M+H]+); MS (ESI) m/z 318/320
([MꢀH]ꢀ).
Prepared from 9a and 2-fluorophenyl boronic acid according to
the coupling procedure described in example 10b. 1H NMR (DMSO-
d6): d 10.01 (s, 1H), 7.63 (m, 1H), 7.51–7.57 (m, 1H), 7.36–7.43 (m,
2H), 7.25–7.30 (m, 2H), 7.19 (d, J = 8.32 Hz, 1H), 4.27 (s, 2H), 1.59
(s, 6H); MS (ESI) m/z 286 ([M+H]+); MS (ESI) m/z 284 ([MꢀH]ꢀ).
4.1.12. 7-(3,5-Dichlorophenyl)-5,5-dimethyl-1,5-dihydro-4,1-
benzoxazepin-2(H)-one (10i)
4.1.6. 7-(4-Fluorophenyl)-5,5-dimethyl-1,5-dihydro-4,1-
benzoxazepin-2(H)-one (10c)
Prepared from 9a and 3,5-dichlorophenyl boronic acid
according to the coupling procedure described in example
10b. 1H NMR (DMSO-d6): d 10.02 (s, 1H), 7.76 (s, 2H), 7.55–
7.64 (m, 3H), 7.18 (d, J = 8.45 Hz, 1H), 4.26 (s, 2H), 1.62 (s
6H); MS (ESI) m/z 336/338 ([M+H]+); MS (ESI) m/z 334/336
([MꢀH]ꢀ).
Prepared from 9a and 4-fluorophenyl boronic acid according to
the coupling procedure described in example 10b. 1H NMR (DMSO-
d6): d 9.92 (s, 1H), 7.64–7.67 (m, 2H), 7.41–7.46 (m, 2H), 7.17–7.25
(m, 2H), 7.12 (s, J = 2.26 Hz, 1H), 4.21 (s, 2H), 1.57 (s, 6H); MS (ESI)
m/z 286 ([M+H]+); MS (ESI) m/z 284 ([MꢀH]ꢀ).

P. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 6589–6600
6595
4.1.13. 3-(5,5-Dimethyl-2-oxo-1,2,3,5-tetrahydro-4,1-
benzoxazepin-7-yl)-5-fluorobenzonitrile (10j)
4.1.19. 7-(3-Chloro-4-fluorophenyl)-5-methyl-5-thien-2-yl-1,5-
dihydro-4,1-benzoxazepin-2(H)-one (10l)
Prepared from 9a and 3-cyano-5-fluorophenyl boronic acid
according to the coupling procedure described in example 10b. A
white solid: mp 238–239 °C; 1H NMR (DMSO-d6): d 10.1 (s, 1H),
8.14 (t, J = 1.5 Hz, 1H), 7.98 (m, 1H), 7.80 (m, 1H), 7.69 (d,
J = 1.9 Hz, 1H), 7.64 (dd, J = 8.3, 2.0 Hz, 1H), 7.19 (d, J = 8.3 Hz,
1H), 4.27 (s, 2H), 1.63 (s, 6H). MS m/z 309 ([MꢀH]ꢀ); Anal. Calcd
for C18H15FN2O2: C, 69.67; H, 4.87; N, 9.03. Found: C, 69.51; H,
4.63; N, 9.07.
Prepared from 9b and 3-chloro-4-fluorophenyl boronic acid
according to the coupling procedure described in example 10b.
1H NMR (DMSO-d6): d 10.13 (s, 1H), 7.86 (dd, J = 6.8, 2.0 Hz, 1H),
7.64 (m, 2H), 7.55 (m, 2H), 7.48 (t, J = 8.8 Hz, 1H), 7.25 (d,
J = 8.3 Hz, 1H), 6.99 (dd, J = 4.9, 3.4 Hz, 1H), 6.91 (dd, J = 3.4,
1.0 Hz, 1H), 4.16 (d, J = 16.1 Hz, 1H), 4.06 (d, J = 16.1 Hz, 1H), 2.08
(s, 3H); MS (ES) m/z 388 ([M+H]+); Anal. Calcd for C20H15ClFNO2S:
C, 61.93; H, 3.90; N, 3.61. Found: C, 61.88; H, 3.99; N, 3.35.
4.1.14. 3-Chloro-5-(5,5-dimethyl-2-oxo-1,2,3,5-tetrahydro-4,1-
benzoxazepin-7-yl)benzonitrile (10k)
4.1.20. (2-Amino-5-bromophenyl)(2-thienyl)methanone (6b)
Prepared from 5-bromo anthranilic acid and 2-thenyllithium
using the procedure described in example 6a. 1H NMR (CDCl3): d
7.86 (d, J = 2.3 Hz, 1H), 7.71 (dd, J = 5.0, 1.0 Hz, 1H), 7.59 (dd,
J = 3.8, 1.0 Hz, 1H), 7.39 (dd, J = 8.8, 2.4 Hz, 1H), 7.19 (m, 1H),
6.66 (d, J = 8.8 Hz, 1H), 5.71 (s, 2H); MS (ES) m/z 280 ([MꢀH]ꢀ).
Prepared from 9a and 3-chloro-5-cyano phenyl boronic acid
according to example 10b. 1H NMR (DMSO-d6): d 10.03 (s, 1H),
8.22 (m, 1H), 8.14 (m, 1H), 7.97 (m, 1H), 7.69 (m, 1H), 7.64 (dd,
J = 8.54, 2.44 Hz, 1H), 7.20 (d, J = 8.54 Hz, 1H), 4.27 (s, 2H), 1.63
(s, 6H); MS (ESI) m/z 327/329 ([M+H]+); MS (ESI) m/z 325/327
([MꢀH]ꢀ).
4.1.21. N-[4-Bromo-2-(1-hydroxy-1-thien-2-ylpropyl)phenyl]-
2-chloroacetamide (8c)
4.1.15. 1-(2-Amino-5-bromo-phenyl)-ethanone (6a)
Prepared from 6b using the procedures described in examples
7b and 8a. 1H NMR (CDCl3): d 10.23 (s, 1H), 8.11 (d, J = 8.7 Hz,
1H), 7.46 (dd, J = 8.7, 2.3 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.29 (dd,
J = 5.1, 1.0 Hz, 1H), 6.97 (m, 1H), 6.90 (dd, J = 3.5, 1.0 Hz, 1H),
4.09 (m, 2H), 2.80 (s, 1H), 2.43 (m, 2H), 1.03 (t, J = 7.3 Hz, 3H);
MS (ES) m/z 386 ([MꢀH]ꢀ); Anal. Calcd for C15H15BrClNO2S: C,
46.35; H, 3.89; N, 3.60. Found: C, 46.67; H, 3.80; N, 3.52.
To a solution of 5-bromo anthranilic acid (50.0 g, 0.23 mol) in
anhydrous THF (500 mL) at 0 °C was added methyllithium (1.4 M
in diethyl ether, 661 mL, 0.93 mol) under nitrogen in a dropwise
manner. After addition, the reaction mixture was allowed to
slowly warm to rt, stirred overnight, and treated with a satu-
rated aqueous ammonium chloride solution (1000 mL). Ethyl
acetate (400 mL) was added and organic layer was separated.
The aqueous layer was extracted with ethyl acetate
(3 ꢂ 200 mL). The combined organic layers were dried (Mg2SO4)
and concentrated. The residue was purified by a flash chroma-
tography on silica gel (hexane:ethyl acetate/9:1) to afford the ti-
tle compound as a brown solid (29.3 g, 59%). MS (ES) m/z 214/
216 ([M+H]+).
4.1.22. 7-Bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-
benzoxazepin-2(3H)-one (9c)
Prepared from N-[4-bromo-2-(1-hydroxy-1-thien-2-ylpro-
pyl)phenyl]-2-chloroacetamide 8c using the procedure described
in example 9a. 1H NMR (CDCl3): d 7.80 (br s, 1H), 7.39 (m, 3H),
6.97 (m, 1H), 6.81 (m, 2H), 4.19 (d, J = 16.0 Hz, 1H), 4.05 (d,
J = 16.0 Hz, 1H), 2.58 (m, 1H), 2.31 (m, 1H), 0.87 (t, J = 7.2 Hz,
3H); MS (ES) m/z 350 ([MꢀH]ꢀ).
4.1.16. 1-(2-Amino-5-bromo-phenyl)-1-thiophen-2-yl-ethanol
(7b)
To a solution of 1-(2-amino-5-bromo-phenyl)-ethanone (3.0 g,
14 mmol) in anhydrous THF (50 mL) was added 2-thienyllithium
(1.0 M in THF, 28 mL, 28 mmol) at ꢀ78 °C under nitrogen. The reac-
tion mixture was allowed to slowly warm to ꢀ20 °C, treated with a
saturated aqueous ammonium chloride solution (50 mL). Ethyl
acetate (50 mL) was added and organic layer was separated, dried
(Mg2SO4), and concentrated to afford the title compound as clear
oil (3.9, 95%). 1H NMR (DMSO-d6): d 7.4 (d, J = 4.9 Hz, 1H), 7.07–
7.11 (m, 2H), 6.94 (m, 1H), 6.84 (dd, J = 3.5, 0.5 Hz, 1H), 6.55 (d,
J = 8.2 Hz, 1H), 6.36 (s, 1H), 5.31 (s, 2H), 1.85 (s, 3H).
4.1.23. 7-(3-Chloro-4-fluoro-phenyl)-5-ethyl-5-thiophen-2-yl-
1,5-dihydro-benzo[e][1,4]oxazepin-2-one (10m)
Prepared from 9c and 3-chloro-4-fluorophenyl boronic acid
using the coupling procedure described in example 10a. 1H NMR
(DMSO-d6): d 10.08 (s, 1H), 7.85 (dd, J = 7.1, 2.2 Hz, 1H), 7.65 (m,
2H), 7.57 (dd, J = 5.0, 1.0 Hz, 1H), 7.52 (m, 2H), 7.26 (d, J = 8.5 Hz,
1H), 7.01 (m, 2H), 4.11 (d, J = 15.4 Hz, 1H), 3.95 (d, J = 15.4 Hz,
1H), 2.41 (m, 2H), 0.78 (t, J = 7.0 Hz, 3H); MS (ES) m/z 400
([MꢀH]ꢀ).
4.1.24. 3-(5-Ethyl-2-oxo-5-thiophen-2-yl-1,2,3,5-tetrahydro-
benzo[e][1,4]oxazepin-7-yl)-5-fluoro-benzonitrile (10n)
Prepared from 9c and 5-fluoro-3-cyanophenyl boronic acid
using the coupling procedure described in example 10a. 1H NMR
(DMSO-d6): d 10.12 (s, 1H), 8.07 (s, 1H), 7.95 (dt, J = 10.3, 2.0 Hz,
1H), 7.81 (m, 2H), 7.69 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 5.0, 0.9 Hz,
1H), 7.29 (d, J = 8.5 Hz, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 4.10 (d,
J = 15.5 Hz, 1H), 4.01 (d, J = 15.5 Hz, 1H), 2.65 (m, 2H), 0.78 (t,
J = 7.0 Hz, 3H); MS (ES) m/z 391 ([MꢀH]ꢀ).
4.1.17. N-[4-Bromo-2-(1-hydroxy-1-thien-2-ylethyl)phenyl]-2-
chloroacetamide (8b)
Prepared from 7b and chloroacetyl chloride according to the
procedure described in example 8a. A white solid: 1H NMR
(DMSO-d6): d 10.78 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.51 (dd,
J = 8.7, 2.2 Hz, 1H), 7.43 (d, J = 5.0 Hz, 1H), 7.37 (m, 2H), 6.95
(m, 1H), 6.88 (dd, J = 3.4, 0.8 Hz, 1H), 4.26 (d, J = 6.9 Hz, 2H),
1.94 (s, 3H).
4.1.18. 7-Bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-
benzoxazepin-2(3H)-one (9b)
4.1.25. N-[4-Bromo-2-(1-hydroxy-1-thien-2-ylbutyl)phenyl]-2-
chloroacetamide (8d)
Prepared from 8b according to the procedure described in
example 9a. A white solid: 1H NMR (DMSO-d6): d 10.13 (s,
1H), 7.57 (dd, J = 5.0, 1.0 Hz, 1H), 7.47 (dd, J = 8.6, 1.4 Hz, 1H),
7.39 (d, J = 1.67 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.00 (m, 1H),
6.88 (dd, J = 2.6, 0.9 Hz, 1H), 4.18 (d, J = 15.8 Hz, 1H), 4.03 (d,
J = 16.3 Hz, 1H), 1.99 (s, 3H). MS (ES) m/z 338/340 ([M+H]+).
Prepared from the 5-bromoanthranilic acid according to the
procedures described in examples 6a, 7b, and 8a. 1H NMR
(DMSO-d6): d 10.93 (s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.47 (dd,
J = 8.8, 2.3 Hz, 1H), 7.41 (m, 2H), 7.15 (s, 1H), 6.94 (m, 2H), 4.28
(m, 2H), 2.15–2.40 (m, 2H), 1.25–1.40 (m, 2H), 0.88 (t, J = 7.3 Hz,
3H). MS (ESI) m/z 400/402 ([MꢀH]ꢀ). Anal. Calcd for

6596
P. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 6589–6600
C16H17BrClNO2S: C, 47.72; H, 4.25; N, 3.48. Found: C, 47.76; H,
4.39; N, 3.46.
1H), 7.04 (m, 2H), 4.20 (d, J = 14.4 Hz, 1H), 3.96 (d, J = 14.4 Hz,
1H), 2.90 (m, 1H), 0.92 (t, J = 6.4 Hz, 6H); MS (ES) m/z 407 ([M+H]+).
4.1.26. 7-Bromo-5-propyl-5-thien-2-yl-1,5-dihydro-4,1-
benzoxazepin-2(H)-one (9d)
4.1.32. N-[4-Bromo-2-(1-hydroxy-1-thien-3-ylpropyl)phenyl]-
2-chloroacetamide (8f)
Prepared from 8d according to the procedure described in
example 9a. A white solid: 1H NMR (DMSO-d6): d 10.06 (s, 1H),
7.58 (dd, J = 5.1, 1.1 Hz, 1H), 7.45 (dd, J = 8.7, 2.2 Hz, 1H), 7.36 (d,
J = 2.3 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 7.03 (dd, J = 5.1, 3.6 Hz,
1H), 6.92 (dd, J = 3.6, 1.1 Hz, 1H), 4.08 (d, J = 15.4 Hz, 1H), 3.91 (d,
J = 15.3 Hz, 1H), 2.32 (m, 2H), 1.43 (m, 1H), 0.92 (m, 1H), 08.84
(t, J = 7.2 Hz, 3H); MS (ESI) m/z 366/368 ([M+H]+); MS (ESI) m/z
364/366 ([MꢀH]ꢀ); Anal. Calcd for C16H16BrNO2S: C, 52.47; H,
4.40; N, 3.82. Found: C, 52.37; H, 4.21; N, 3.77.
Prepared from 1-(2-amino-5-bromophenyl)-propan-1-one
using the procedure described in examples 7b and 8a. 1H NMR
(DMSO-d6): d 10.95 (s, 1H), 8.05 (dd, J = 6.8, 2.9 Hz, 1H), 7.47
(m, 2H), 7.42 (m, 1H), 7.40 (m, 1H), 6.88 (dd, J = 4.9, 1.0 Hz,
1H), 6.74 (s, 1H), 4.32 (d, J = 31.7, 1H), 4.25 (d, J = 31.7 Hz, 1H),
2.30 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H); MS (ES) m/z 386
([M+H]+); Anal. Calcd for C15H15BrClNO2S: C, 46.35, H, 3.89, N,
3.60. Found: C, 46.03, H, 3.73, N, 3.55.
4.1.33. 7-Bromo-5-ethyl-5-thien-3-yl-1,5-dihydro-4,1-
benzoxazepin-2(3H)-one (9f)
4.1.27. 7-(3-Chloro-4-fluorophenyl)-5-propyl-5-thien-2-yl-1,5-
dihydro-4,1-benzoxazepin-2(H)-one (10o)
Prepared from 8f using the procedure described in example
Prepared from 9d and 3-chloro-4-fluorophenyl boronic acid
using the procedure described in example 10a. A white solid: mp
183–184 °C; 1H NMR (DMSO-d6): d 10.07 (s, 1H), 7.83 (dd, J = 7.1,
2.2 Hz, 1H), 7.51–7.68 (m, 4H), 7.47 (t, J = 9.0 Hz, 1H), 7.24 (d,
J = 8.5 Hz, 1H), 7.02 (t, J = 5.0 Hz, 1H), 6.96 (dd, J = 3.5, 1.0 Hz,
1H), 4.09 (d, J = 15.3 Hz, 1H), 3.90 (d, J = 15.3 Hz, 1H), 2.45 (m,
2H), 1.48 (m, 1H), 0.98 (m, 1H), 0.86 (t, J = 7.2 Hz, 3H). MS (ESI)
m/z 415/417 ([MꢀH]ꢀ).
9a. 1H NMR (DMSO-d6):
d 10.03 (s, 1H), 7.57 (dd, J = 4.9,
3.0 Hz, 1H), 7.45 (dd, J = 8.5, 2.2 Hz, 1H), 7.28 (d, J = 2.2 Hz,
1H), 7.26 (dd, J = 2.7, 1.4 Hz, 1H), 7.12 (dd, J = 5.2, 1.4 Hz, 1H),
7.10 (d, J = 8.5 Hz, 1H), 4.05 (d, J = 15.4 Hz, 1 H), 3.93 (d,
J = 15.4 Hz, 1H), 2.51 (m, 1H), 2.20 (m, 1H), 0.73 (t, J = 7.1 Hz,
3H); MS (ES) m/z 352 ([M+H]+); Anal. Calcd for C15H14BrNO2S:
C, 51.15, H, 4.01, N, 3.98. Found: C, 51.38, H, 4.09, N, 3.82.
4.1.34. 7-(3-Chloro-4-fluorophenyl)-5-ethyl-5-thien-3-yl-1,5-
dihydro-4,1-benzoxazepin-2(3H)-one (10r)
4.1.28. N-[4-Bromo-2-(1-hydroxy-2-methyl-1-thien-2-
ylpropyl)phenyl]-2-chloroacetamide (8e)
Prepared from 9f and 3-chloro-4-fluorophenyl boronic acid
using the coupling procedure described in example 10a. 1H NMR
(DMSO-d6): d 10.03 (s, 1H), 7.84 (dd, J = 6.9, 2.2 Hz, 1H), 7.62 (m,
2H), 7.56 (dd, J = 5.2, 3.0 Hz, 1H), 7.48 (m, 2H), 7.27 (m, 1H), 7.24
(d, J = 8.5 Hz, 1H), 7.16 (dd, J = 5.2, 1.4 Hz, 1H), 4.04 (d,
J = 15.4 Hz, 1H), 3.94 (d, J = 15.4 Hz, 1H), 2.53 (m, 1H), 2.35 (m,
1H), 0.75 (t, J = 7.1 Hz, 3H); MS (ES) m/z 402 ([M+H]+).
Prepared from (2-amino-5-bromophenyl)(2-thienyl)methanone
(6b) in two steps using the procedures described in examples 7b
and 8a. 1H NMR (DMSO-d6): d 11.25 (s, 1H), 8.14 (d, J = 8.8 Hz,
1H), 7.50 (d, J = 2.3 Hz, 1H), 7.46 (dd, J = 8.8, 2.3 Hz, 1H), 7.40 (dd,
J = 5.0, 1.1 Hz, 1H), 7.02 (d, J = 3.5, 1.1 Hz, 1H), 6.96 (m, 2H), 4.36
(d, J = 15.0 Hz, 1H), 4.30 (d, J = 15.0 Hz, 1H), 2.86 (m, 1H), 0.94
(dd, J = 22.0, 6.6 Hz, 6H); MS (ES) m/z 400 ([MꢀH]ꢀ); Anal. Calcd
for C16H17BrClNO2S: C, 47.72; H, 4.25; N, 3.48. Found: C, 47.89;
H, 4.14; N, 3.37.
4.1.35. 3-(5-Ethyl-2-oxo-5-thien-3-yl-1,2,3,5-tetrahydro-4,1-
benzoxazepin-7-yl)-5-fluorobenzonitrile (10s)
Prepared from 9f and 3-cyano-5-fluorophenyl boronic acid
using the coupling procedure described in example 10a. 1H NMR
(DMSO-d6): d 10.07 (s, 1H), 8.07 (t, J = 1.5 Hz, 1H), 7.94 (dt,
J = 10.3, 2.0 Hz, 1H), 7.80 (m, 1H), 7.73 (dd, J = 8.3, 2.0 Hz, 1H),
7.63 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 4.9, 2.9 Hz, 1H), 7.27 (m, 2H),
7.17 (dd, J = 4.9, 1.5 Hz, 1H), 4.02 (d, J = 15.6 Hz, 1H), 3.96 (d,
J = 15.6 Hz, 1H), 2.54 (m, 1H), 2.49 (m, 1H), 0.74 (t, J = 7.3 Hz,
3H); MS (ES) m/z 393 ([M+H]+).
4.1.29. 7-Bromo-5-isopropyl-5-thien-2-yl-1,5-dihydro-4,1-
benzoxazepin-2(3H)-one (9e)
Prepared from N-[4-bromo-2-(1-hydroxy-2-methyl-1-thien-2-
ylpropyl)phenyl]-2-chloroacetamide using the procedure de-
scribed in example 9a. 1H NMR (DMSO-d6): d 10.01 (s, 1H), 7.56
(dd, J = 4.9, 1.0 Hz, 1H), 7.52 (dd, J = 8.6, 2.2 Hz, 1H), 7.44 (d,
J = 2.2 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.03 (m, 2H), 4.22 (d,
J = 14.4 Hz, 1H), 3.87 (d, J = 14.4 Hz, 1H), 2.69 (m, 1H), 0.93 (dd,
J = 17.8, 6.8 Hz, 6H); MS (ES) m/z 364 ([MꢀH]ꢀ).
4.1.36. N-{4-Bromo-2-[1-(2-furyl)-1-hydroxypropyl]phenyl}-2-
chloroacetamide (8g)
4.1.30. 7-(3-Chloro-4-fluorophenyl)-5-isopropyl-5-thien-2-yl-
1,5-dihydro-4,1-benzoxazepin-2(3H)-one (10p)
Prepared from 1-(2-amino-5-bromophenyl)-propan-1-one in
two steps using the procedure described in examples 7b and
8a. 1H NMR (DMSO-d6 ): d 10.96 (s, 1H), 8.11 (d, J = 8.8 Hz,
1H), 7.60 (d, J = 1.0 Hz, 1H), 7.49 (dd, J = 8.8, 2.4 Hz, 1H), 7.11
(d, J = 2.0 Hz, 1H), 6.95 (s, 1H), 6.47 (m, 2H), 4.35 (s, 2H),
2.23 (q, 7.3 Hz, 2H), 0.82 (t, J = 7.3 Hz, 3H); MS (ES) m/z 372
([MꢀH]ꢀ).
Prepared from 9e and 3-chloro-4-fluorophenyl boronic acid
using the coupling procedure described in example 10a. 1H NMR
(DMSO-d6): d 10.02 (s, 1H), 7.83 (dd, J = 7.1, 2.2 Hz, 1H), 7.67 (dd,
J = 8.4, 2.0 Hz, 1H), 7.60 (m, 2H), 7.53 (m, 1H), 7.52 (m, 1H), 7.23
(d, J = 8.5 Hz, 1H), 7.05 (dd, J = 3.6, 1.3 Hz, 1H), 7.02 (dd, J = 5.0,
3.7 Hz, 1H), 4.21 (d, J = 14.4 Hz, 1H), 3.90 (d, J = 14.4 Hz, 1H), 2.81
(m, 1H), 0.91 (m, 6H); Anal. Calcd for C22H19ClFNO2S: C, 63.53; H,
4.60; N, 3.37. Found: C, 63.34; H, 4.92; N, 2.97.
4.1.37. 7-Bromo-5-ethyl-5-(2-furyl)-1,5-dihydro-4,1-
benzoxazepin-2(H)-one (9g)
Prepared from 8g using the procedure described in example
9a. 1H NMR (DMSO-d6): d 10.08 (s, 1H), 7.72 (t, J = 1.0 Hz, 1H),
7.47 (dd, J = 8.8, 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.12 (d,
J = 8.8 Hz, 1H), 6.48 (dd, J = 2.4, 1.0 Hz, 1H), 6.34 (d, J = 2.4 Hz,
1H), 4.21 (d, J = 15.1 Hz, 1H), 3.95 (d, J = 15.1 Hz, 1H), 2.45 (m,
1H), 2.10 (m, 1H), 0.73 (t, J = 7.3 Hz, 3H); MS (ES) m/z 336
([M+H]+).
4.1.31. 3-Fluoro-5-(5-isopropyl-2-oxo-5-thien-2-yl-1,2,3,5-
tetrahydro-4,1-benzoxazepin-7-yl)benzonitrile (10q)
Prepared from 9e and 3-cyano-5-fluorophenyl boronic acid
using the coupling procedure described in example 10a. 1H NMR
(DMSO-d6): d 10.07 (s, 1H), 8.03 (s, 1H), 7.90 (m, 1H), 7.84 (m,
1H), 7.77 (m, 2H), 7.51 (dd, J = 5.0, 1.2 Hz, 1H), 7.24 (d, J = 8.5 Hz,

P. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 6589–6600
6597
4.1.38. 7-(3-Chloro-4-fluorophenyl)-5-ethyl-5-(2-furyl)-1,5-
dihydro-4,1-benzoxazepin-2(H)-one (10t)
1H), 6.89 (d, J = 2.44 Hz, 1H), 6.51 (dd, J = 3.42, 1.95 Hz, 2H), 6.27
(dd, J = 3.42, 0.98 Hz, 2H), 4.17 (s, 2H); MS (ESI) m/z 422/424
([MꢀH]ꢀ).
Prepared from 9g and 3-chloro-4-fluorophenyl boronic acid
using the procedure described in example 10a. 1H NMR (DMSO-
d6): d 10.08 (s, 1H), 8.32 (s, 1H), 7.81 (dd, J = 7.1, 2.5 Hz, 1H), 7.72
(s, 1H), 7.63 (dd, J = 8.5, 2.2 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.33
(d, J = 2.2 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 6.47 (m, 1H), 6.32 (d,
J = 3.3 Hz, 1H), 4.19 (d, J = 15.4 Hz, 1H), 3.95 (d, J = 15.4 Hz, 1H),
2.52 (m, 1H), 2.26 (m, 1H), 0.75 (t, J = 7.1 Hz, 3H); MS (ES) m/z
386 ([M+H]+).
4.1.44. (2-Amino-5-bromophenyl)(dithien-2-yl)methanol (7c)
Prepared from methyl 2-amino-5-bromobenzoate and 2-thi-
enyllithium using the procedure similar to example 8h. 1H NMR
(CDCl3): d 7.35 (dd, J = 5.3, 1.1 Hz, 2H), 7.26 (dd, J = 8.4, 2.3 Hz,
1H), 6.98 (m, 2H), 6.82 (d, J = 2.3 Hz, 1H), 6.79 (m, 2H), 6.62 (d,
J = 8.4 Hz, 1H), 5.45 (br s, 1H), 3.86 (br s, 2H).
4.1.39. 3-[5-Ethyl-5-(2-furyl)-2-oxo-1,2,3,5-tetrahydro-4,1-
benzoxazepin-7-yl]-5-fluorobenzonitrile (10u)
4.1.45. 2-Bromo-N-{4-bromo-2-[hydroxy(dithien-2-
yl)methyl]phenyl}acetamide (8i)
Prepared from 9g and 3-cyano-5-fluorophenyl boronic acid
according to the coupling procedure described in example 10a.
1H NMR (DMSO-d6): d 10.13 (s, 1H), 8.03 (s, 1H), 7.90 (dt,
J = 10.5, 2.2 Hz, 1H), 7.80 (m, 1H), 7.74 (m, 2H), 7.52 (d, J = 2.2 Hz,
1H), 7.28 (d, J = 8.5 Hz, 1H), 6.46 (m, 1H), 6.29 (d, J = 3.3 Hz, 1H),
4.14 (d, J = 15.6 Hz, 1H), 3.96 (d, J = 15.6 Hz, 1H), 2.54 (m, 1H),
2.49 (m, 1H), 0.75 (t, J = 7.4 Hz, 3H); MS (ES) m/z 753 (2M+H)+.
Prepared from 7c and bromoacetyl chloride using the procedure
described in example 8a. 1H NMR (DMSO-d6): d 10.22 (s, 1H), 8.42
(s, 1H), 8.05 (d, J = 9.0 Hz, 1H) 7.59 (m, 3H), 7.05 (m, 2H), 6.87 (m,
2H), 6.78 (d, J = 3 Hz, 1H), 3.92 (s, 2H); MS (ES) m/z 484 ([MꢀH]ꢀ).
4.1.46. 7-Bromo-5,5-dithien-2-yl-1,5-dihydro-4,1-
benzoxazepin-2(3H)-one (9i)
Prepared from 8i using the similar procedure described in
example 9a. 1H NMR (CDCl3): d 8.08 (br s, 1H), 7.40 (d, J = 4.0 Hz,
2H), 7.37 (d, J = 2.1 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.99 (m, 2H),
6.89 (d, J = 3.6 Hz, 2H), 6.83 (d, J = 8.5 Hz, 1H), 4.35 (s, 1H); MS
(ES) m/z 404 ([MꢀH]ꢀ); Anal. Calcd for C17H12BrNO2S2: C, 50.25;
H, 2.98; N, 3.45. Found: C, 50.57; H, 3.01; N, 3.25.
4.1.40. N-[4-Bromo-2-[di(2-furyl)(hydroxy)methyl]phenyl]-2-
chloroacetamide (8h)
To a solution of furan (369.6 g, 5.4 mol) in anhydrous THF
(250 mL) was added at 0 °C n-butyllithium (2.5 M in hexane,
217 mL, 543 mmol) under nitrogen. The mixture was stirred for
30 min and treated with a solution of methyl 2-amino-5-bro-
mobenzoate (25.0 g, 108.7 mmol) in THF (150 mL). The mixture
was stirred for overnight and treated with an ice-cold saturated
aqueous ammonium chloride solution (200 mL). Ethyl acetate
(500 mL) was added and organic layer was separated, dried
(MgSO4) and concentrated. The residue was triturated in a mixture
of hexane and ethyl acetate to afford (2-amino-5-bromophe-
nyl)[di(2-furyl)]methanol as an orange solid (32.7 g, 90%). The title
compound was prepared according to the procedure described in
4.1.47. 3-Fluoro-5-(2-oxo-5,5-dithien-2-yl-1,2,3,5-tetrahydro-
4,1-benzoxazepin-7-yl)benzonitrile (10x)
Prepared from 9i and 3-cyano-5-fluorophenyl boronic acid
using the coupling procedure described in example 10a. 1H NMR
(DMSO-d6): d 10.32 (s, 1H), 7.81 (m, 3H), 7.63 (m, 3H), 7.30 (m,
2H), 7.05 (m, 4H), 4.21 (s, 2H); MS (ES) m/z 445 ([MꢀH]ꢀ).
4.1.48. 7-(3-Chloro-4-fluorophenyl)-5,5-dithien-2-yl-1,5-
dihydro-4,1-benzoxazepin-2(H)-one (10y)
example 8a. 1H NMR (DMSO-d6):
d 10.4 (s, 1H), 8.06 (d,
J = 8.79 Hz, 1H), 8.04 (s, 1H), 7.70–7.71 (m, 2H), 7.55 (dd, J = 8.79,
2.44 Hz, 1H), 6.67 (d, J = 2.44 Hz, 1H), 6.49–6.50 (m, 2H), 6.23–
6.24 (m, 2H), 4.23 (s, 2H); MS (ES) m/z 408/410 ([MꢀH]ꢀ).
Prepared from 9i and 3-chloro-4-fluorophenyl boronic acid
using the coupling procedure described in example 10a. 1H NMR
(DMSO-d6): d 10.27 (s, 1H), 7.68 (m, 4H), 7.48 (t, J = 8.8 Hz, 1H),
7.38 (m, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.04
(dd, J = 5.0, 3.6 Hz, 2H), 6.93 (dd, J = 3.6, 1.2 Hz, 2H), 4.22 (s, 2H);
MS (ES) m/z 456 ([M+H]+); Anal. Calcd for C23H15ClFNO2S2: C,
60.59; H, 3.32; N, 3.07. Found: C, 60.35; H, 3.28; N, 2.91.
4.1.41. 7-Bromo-5,5-di(2-furyl)-1,5-dihydro-4,1-benzoxazepin-
2(3H)-one (9h)
Prepared from 8h using the procedure described in example 9a.
1H NMR (DMSO-d6): d 10.27 (s, 1H), 7.78 (d, J = 0.98 Hz, 2H), 7.52
(dd, J = 8.79, 2.44 Hz, 1H), 7.18 (d, J = 8.79 Hz, 1 H), 6.73 (d,
J = 2.44 Hz, 1H), 6.51 (dd, J = 3.42, 1.95 Hz, 2H), 6.24 (dd, J = 3.42,
0.98 Hz, 2H), 4.1 (s, 2H); MS (ES) m/z 372/374 ([MꢀH]ꢀ); MS (ES)
m/z 374/376 ([M+H]+).
4.1.49. 7-(3-Chloro-4-fluorophenyl)-5,5-diphenyl-1,5-dihydro-
4,1-benzoxazepin-2(H)-one (10z)
Prepared from 7-bromo-5,5-diphenyl-1,5-dihydro-4,1-ben-
zoxazepin-2(3H)-one (9j, prepared in a similar manner as that for
compound 9i) and 3-chloro-4-fluoro benzeneboronic acid accord-
ing to the coupling procedure described in example 10a. 1H NMR
(DMSO-d6): d 10.17 (s, 1H), 7.65 (dd, J = 8.3, 2.44 Hz, 1H), 7.50
(dd, J = 7.32, 2.44 Hz, 1H), 7.34–7.43 (m, 7H), 7.25 (d, J = 8.3 Hz,
1H), 7.22–7.24 (m, 1H), 7.16–7.19 (m, 4H), 6.75 (d, 1.95 Hz, 1 H),
4.26 (s, 2H); MS (ESI) m/z 442/444 ([MꢀH]ꢀ); Anal. Calcd for
4.1.42. 3-[5,5-Di(2-furyl)-2-oxo-1,2,3,5-tetrahydro-4,1-
benzoxazepin-7-yl]-5-fluorobenzonitrile (10v)
Prepared from 9h and 3-cyano-5-fluorobenzeneboronic acid
according to the coupling procedure of example 10a. 1H NMR
(DMSO-d6): d 10.34 (s, 1H), 7.73–7.87 (m, 5H), 7.59 (dt, J = 10.25,
1.95 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 1.95 Hz, 1H), 1H,
6.52 (dd, J = 3.42, 1.95 Hz, 2H), 6.29 (dd, J = 3.42, 0.98 Hz, 2H),
4.16 (s, 2H); MS (ESI) m/z 415 ([M+H]+); MS (ESI) m/z 413
([MꢀH]ꢀ).
C27H19ClFNO2: C, 73.06; H, 4.31; N, 3.16. Found: C, 72.67; H,
4.36; N, 2.89.
4.1.50. 7-(3-Chloro-4-fluorophenyl)-5,5-bis(4-chlorophenyl)-
1,5-dihydro-4,1-benzoxazepin-2(H)-one (10aa)
4.1.43. 7-(3-Chloro-4-fluorophenyl)-5,5-di(2-furyl)-1,5-
dihydro-4,1-benzoxazepin-2(H)-one (10w)
Prepared from 7-bromo-5,5-bis(4-chlorophenyl)-1,5-dihydro-
4,1-benzoxazepin-2(H)-one (9k, prepared in a similar manner as
that for compound 9i) and 3-chloro-4-fluorobenzeneboronic acid
according to the coupling procedure described in example 10a.
1H NMR (DMSO-d6): d 10.17 (s, 1H), 7.69 (dd, J = 8.3, 2.4 Hz, 1H),
7.58 (dd, J = 6.8, 2.4 Hz, 1H), 7.46 (m, 5H), 7.31 (m, 1H), 7.24 (d,
J = 8.3 Hz, 1H), 7.22 (m, 4H), 6.78 (d, J = 2.0 Hz, 1H), 4.23 (s, 2H);
Prepared from 9h and 3-chloro-4-fluorophenyl boronic acid
according to the coupling procedure of example 10a. 1H NMR
(DMSO-d6): d 10.28 (s, 1H), 7.77 (dd, J = 1.95, 0.98 Hz, 2H), 7.66
(dd, J = 8.3, 1.95 Hz, 1H), 7.59 (dd, J = 7.32, 2.44 Hz, 1H), 7.45 (dd,
JHF = JHH = 8.79 Hz, 1H), 7.33–7.36 (m, 1H), 7.32 (d, J = 8.79 Hz,

6598
P. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 6589–6600
MS (ES) m/z 510 ([MꢀH]ꢀ); Anal. Calcd for C27H17Cl3FNO2: C,
0.71 mmol) at rt under nitrogen. The mixture was heated at
100 °C for 10 min, cooled to rt, and concentrated. The residue
was purified by a flash chromatography on silica gel column (hex-
ane:THF/4:1) to give the title compound as a yellowish solid
(0.25 g, 59%). 1H NMR (DMSO-d6): d 12.01 (s, 1H), 7.70–7.63 (m,
2H), 7.59–7.48 (m, 2H), 7.41 (d, J = 8.82 Hz, 1H), 7.28–7.18 (m,
1H), 4.51 (s, 2H), 1.62 (s, 6H); MS (FI) m/z 318 ([MꢀH]ꢀ).
63.24; H, 3.34; N, 2.73. Found: C, 62.75; H, 3.58; N, 2.72.
4.1.51. 3-[5,5-Bis(4-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepin-7-yl]-5-fluorobenzonitrile (10ab)
Prepared from 7-bromo-5,5-bis(4-chlorophenyl)-1,5-dihydro-
4,1-benzoxazepin-2(H)-one (9k) and 5-fluoro-3-cyanobenzenebo-
ronic acid according to the coupling procedure described in
example 10a. 1H NMR (DMSO-d6): d 10.24 (s, 1H), 7.79 (m, 3H),
7.59 (dt, J = 9.8, 2.0 Hz, 1H), 7.46 (m, 4H), 7.28 (d, J = 8.3 Hz, 1H),
7.26 (m, 4H), 6.93 (d, J = 2.0 Hz, 1H), 4.20 (s, 2H); MS (ES) m/z
501 ([MꢀH]ꢀ); Anal. Calcd for C28H17Cl2FN2O2: C, 66.81; H, 3.40;
N, 5.57. Found: C, 66.46; H, 3.43; N, 5.48.
4.1.55. 3-Fluoro-5-(5-isopropyl-5-thien-2-yl-2-thioxo-1,2,3,5-
tetrahydo-4,1-benzoxazepin-7-yl)benzonitrile (11b)
Prepared by heating a mixture of 3-fluoro-5-(5-isopropyl-2-
oxo-5-thien-2-yl-1,2,3,5-tetrahydro-4,1- benzoxazepin-7-yl)ben-
zonitrile (10q) and Lawesson’s reagent at reflux in toluene accord-
ing to example 11a. 1H NMR (DMSO-d6): d 12.09 (s, 1H), 8.1 (s, 1H),
7.96 (d, J = 10.1 Hz, 1H), 7.88 (m, 2H), 7.83 (dd, J = 8.5, 1.8 Hz, 1H),
7.48 (dd, J = 4.9, 0.66 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.03 (d,
J = 2.6 Hz, 1H), 7.00 (m, 1H), 4.48 (d, J = 14.1 Hz, 1H), 4.37 (d,
J = 14.1 Hz, 1H), 2.96 (m, 1H), 0.93 (d, J = 6.7 Hz, 3H), 0.87 (d,
J = 6.5 Hz, 3H); MS (ES) m/z 421 ([MꢀH]ꢀ).
4.1.52. 3-[5,5-Bis(4-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-
4,1-benzoxazepin-7-yl]-5-fluorobenzonitrile (10ac)
To a stirred solution of 7-bromo-5-ethyl-5-(2-furyl)-1,5-dihy-
dro-4,1-benzoxazepin-2(H)-one (9g, 5.0 g, 14.8 mmol) in DMF
(100 mL) were added potassium acetate (4.5 g, 44.4 mmol),
bis(pinacolato)diboron (7.5 g, 29.6 mmol), and [1,10-bis(diphenyl-
phosphino)-ferrocene]dichloropalladium (II) (0.6 g, 0.8 mmol) at
rt under nitrogen. The mixture was heated at reflux under nitrogen
overnight. The solution was allowed to cool to room temperature
and partitioned between ammonium chloride solution (sat.)
(100 mL) and ethyl acetate (150 mL). The aqueous layer was
extracted with ethyl acetate (3 ꢂ 50 mL). The organic layers
were combined, dried over magnesium sulfate, filtered through
silica gel and triturated with ether to give 5-ethyl-5-(2-fur-
yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-dihydro-
4,1-benzoxazepin-2(H)-one as a white solid (2.9 g, 50%). 1H NMR
(DMSO-d6): d 10.08 (s, 1H), 7.71 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H),
7.33 (s, 1H), 7.16 (d, J = 8.1 Hz, 1 H), 6.48 (d, J = 3.2 Hz, 1H), 6.30
(d, J = 3.2 Hz, 1H), 4.21 (d, J = 15.4 Hz, 1H), 4.04 (d, J = 15.4 Hz,
1H), 2.45 (m, 1H), 2.00 (m, 1H), 1.25 (s, 8H), 0.71 (t, J = 7.1 Hz,
3H); MS (ES) m/z 384 ([M+H]+).
The title compound 10ac was prepared from 5-ethyl-5-(2-fur-
yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,5-dihydro-
4,1-benzoxazepin-2(H)-one and 4-bromo-furan-2-carbonitrile
using the coupling procedure described in example 10a. 1H NMR
(DMSO-d6): d 10.02 (s, 1H), 8.55 (d, J = 2.2 Hz, 1H), 8.10 (d,
J = 2.0 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.58 (m, 1H), 7.41 (s, 1H),
7.24 (dd, J = 8.4, 2.7 Hz, 1H), 6.45 (s, 1H), 6.25 (d, J = 2.7 Hz, 1H),
4.11 (d, J = 15.6 Hz, 1H), 3.96 (d, J = 15.6 Hz, 1H), 2.50 (m, 1H),
2.33 (m, 1H), 0.75 (m, 3H); MS (ES) m/z 349 ([M+H]+); Anal. Calcd
for C20H16N2O4: C, 68.96; H, 4.63; N, 8.04. Found: C, 68.38; H, 4.73;
N, 7.84.
4.1.56. 1-(2-Amino-5-bromophenyl)-2,2,3,3,3-
pentafluoropropan-1-one (16)
A solution of BOC protected aniline (14.0 g, 72 mmol) in
anhydrous ether (150 mL) at ꢀ15 °C under nitrogen was treated
with a solution of tert-butyllithium (1.7 M in pentane, 106 mL,
183 mmol). The reaction mixture was stirred at ꢀ15 °C for 4 h,
cooled to ꢀ78 °C, and treated with ethyl pentafluoropropionate
(13 mL, 88 mmol). The mixture was allowed to slowly warm to
rt and brine (500 mL) was added. The organic layer was sepa-
rated, dried (MgSO4), and concentrated. The residue was taken
up in methylene chloride (100 mL) and treated with TFA
(5 mL) at 0 °C under nitrogen. After 1.5 h, the solution was trea-
ted with a cold sodium bicarbonate solution (3 N, 100 mL) and
organic layer was separated, dried (MgSO4), and concentrated.
The crude residue (5.0 g, 21 mmol) was then taken up in meth-
ylene chloride (80 mL) and treated with NBS (3.6 g, 20 mmol) in
portions at rt under nitrogen. After 1 h, the solution was washed
with aqueous 3 N sodium bicarbonate solution (3 ꢂ 20 mL), dried
(MgSO4), and concentrated to give 1-(2-amino-5-bromophenyl)-
2,2,3,3,3-pentafluoropropan-1-one as a yellow solid (6.0 g, 25%
in three steps). 1H NMR (DMSO-d6): d 7.97 (s, 2H), 7.67 (d,
J = 2.3 Hz, 1H), 7.56 (dd, J = 9.2, 2.2 Hz, 1H), 6.94 (d, J = 9.3 Hz,
1H); MS (ESI) m/z 318/320 ([M+H]+); MS (ESI) m/z 316/318
([MꢀH]ꢀ).
4.1.57. N-{4-Bromo-2-[2,2,3,3,3-pentafluoro-1-(2-furyl)-1-
hydroxypropyl]phenyl}-2-chloroacetamide (18)
4.1.53. 4-(5-Ethyl-2-oxo-5-thien-2-yl-1,2,3,5-tetrahydro-4,1-
benzoxazepin-7-yl)thiophene-2-carbonitrile (10ad)
To a solution of furan (13.0 g, 190 mmol) in anhydrous THF
(150 mL) was added n-butyllithium (2.5 M in hexane, 40 mL,
100 mmol) at 0 °C under nitrogen. The solution was stirred at
0 °C for 30 min, cooled to ꢀ78 °C, and treated with a solution
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-
benzoxazepin-2(3H)-one (9c) and 4-bromo-2-cyanothiophene
according to the procedures described in example 10ac. A yellow-
ish solid: mp 202–204 °C; 1H NMR (DMSO-d6): d 10.06 (s, 1H), 8.48
(s, 1H), 8.33 (s, 1H), 7.64–7.7 (m, 2H), 7.55 (d, J = 5.0 Hz, 1H), 7.23
(d, J = 8.48 Hz, 1H), 6.92–7.03 (m, 2H), 4.06 (d, J = 15.52 Hz, 1H),
3.94 (d, J = 15.44 Hz, 1H), 3.37 (m, 1H), 2.5 (m, 1H), 0.76 (t,
J = 6.79 Hz, 1H); MS (ESI) m/z 381 ([M+H]+); MS (ESI) m/z 379
([MꢀH]ꢀ); Anal. Calcd for C20H16N2O2S2: C, 63.14; H, 4.24; N,
7.36. Found: C, 62.53; H, 4.25; N, 7.12.
of
1-(2-amino-5-bromophenyl)-2,2,3,3,3-pentafluoropropan-1-
one. The mixture was allowed to warm to ꢀ30 °C, a saturated
ammonium chloride solution (100 mL) was added and mixture
was warmed to rt. Ethyl acetate (300 mL) was added and organic
layer separated, dried (MgSO4), and concentrated. The residue
was dissolved in anhydrous THF. The resultant solution was
cooled to 0 °C, treated with triethylamine followed by addition
of chloroacetyl chloride following the procedure described in
example 8a to give N-{4-bromo-2-[2,2,3,3,3-pentafluoro-1-(2-fur-
yl)-1-hydroxypropyl]phenyl}-2-chloroacetamide as a white solid.
1H NMR (DMSO-d6): d 10.54 (s, 1H), 9.11 (s, 1H), 8.18 (d,
J = 9.0 Hz, 1H), 7.79 (m, 1H), 7.64 (dd, J = 8.8, 2.4 Hz, 1H), 7.21
(d, J = 1.7 Hz, 1H), 6.71 (s, 1H), 6.58 (m, 1H), 4.35 (d, J = 1.5 Hz,
2H). MS (ESI) m/z 462/464 ([M+H]+); MS (ESI) m/z 460/462
([MꢀH]ꢀ).
4.1.54. 7-(3,5-Difluorophenyl)-5,5-dimethyl-1,5-dihydro-4,1-
benzoxazepin-2(3H)-thione (11a)
To a solution of 7-(3,5-difluorophenyl)-5,5-dimethyl-1,5-dihy-
dro-4,1-benzoxazepin-2(3H)-one (10f) (0.4 g, 1.3 mmol) in a mix-
ture of toluene (20 mL) and THF (10 mL, help to dissolve the
starting material) was added the Lawesson’s reagent (0.3 g,

P. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 6589–6600
6599
4.1.58. 7-Bromo-5-(2-furyl)-5-(pentafluoroethyl)-1,5-dihydro-
4,1-benzoxazepin-2(H)-one (19)
ane (0.13 mL, 2 mmol) in anhydrous acetonitrile (20 mL) was
heated at 50 °C under nitrogen for 24 h. The solvent was removed
and residue triturated in ethyl acetate to give 7-(3-chloro-4-fluoro-
phenyl)-4,5-dimethyl-2-oxo-2,3-dihydro-H-1,4-benzodiazepin-4-
ium as greenish solid (60 mg, 14%). 1H NMR (DMSO-d6): d 11.52 (s,
1H), 8.24 (d, J = 2.0 Hz, 1H), 8.13 (dd, J = 5.2, 2.2 Hz, 1H), 8.06 (dd,
J = 7.0, 2.3 Hz, 1 H), 7.81 (m, 1H), 7.58 (t, J = 9.0 Hz, 1H), 7.39 (d,
J = 8.7 Hz, 1H), 4.48 (bs, 2H), 3.84 (s, 3H), 2.98 (s, 3H). MS (ESI)
m/z 317/319 ([M]+).
Prepared from N-{4-bromo-2-[2,2,3,3,3-pentafluoro-1-(2-fur-
yl)-1-hydroxypropyl]phenyl}-2-chloroacetamide using the proce-
dure described in example 9a. 1H NMR (DMSO-d6): d 10.33 (s,
1H), 7.93 (s, 1H), 7.68 (dd, J = 8.6, 2.0 Hz, 1H), 7.49 (s, 1H), 7.20
(d, J = 8.7 Hz, 1H), 6.75 (d, J = 2.9 Hz, 1H), 6.64 (m, 1H), 4.49 (d,
J = 14.8 Hz, 1H), 4.14 (d, J = 14.9 hz, 1H); MS (ESI) m/z 426/428
([M+H]+); MS (ESI) m/z 424/426 ([MꢀH]ꢀ).
A mixture of 7-(3-chloro-4-fluorophenyl)-4,5-dimethyl-2-oxo-
2,3-dihydro-H-1,4-benzodiazepin-4-ium (0.2 g, 0.63 mmol) and
methyl magnesium bromide (1 mL in diethyl ether, 3 M, 3 mmol)
in anhydrous diethyl ether (20 mL) was heated at reflux under
nitrogen for 3 h. The reaction mixture was treated with a satu-
rated aqueous ammonium chloride solution (30 mL). The organic
layer was separated and aqueous layer was extracted with ethyl
acetate (3 ꢂ 30 mL). The organic extracts were combined, dried
(MgSO4), concentrated, and residue purified on a silica gel col-
umn (hexane–ethyl acetate 3:1) to give the title compound as
a white solid (11 mg, 5.2%). 1H NMR (DMSO-d6): d 10.06 (s,
1H), 7.92 (dd, J = 7.1, 2.2 Hz, 1H), 7.68 (m, 1H), 7.45–7.53 (m,
3H), 7.26 (d, J = 8.2 Hz, 1H), 3.78 (s, 2H), 2.18 (s, 3H), 1.52 (s,
6H). MS (ESI) m/z 333/335 ([M+H]+).
4.1.59. 7-(3-Chloro-4-fluorophenyl)-5-(2-furyl)-5-(pentafluoro-
ethyl)-1,5-dihydro-4,1-benzoxazepin-2(H)-one (20a)
Prepared from 7-bromo-5-(2-furyl)-5-(pentafluoroethyl)-1,5-
dihydro-4,1-benzoxazepin- 2(H)-one and 3-chloro-4-fluorophenyl
boronic acid according to the coupling procedure described in
example 10a. 1H NMR (DMSO-d6): d 10.36 (s, 1H), 7.93 (d,
J = 1.3 Hz, 1H), 7.82 (dd, J = 8.5, 2.1 Hz, 1H), 7.72 (dd, J = 7.8,
1.8 Hz, 1H), 7.45–7.58 (m, 3H), 7.36 (d, J = 8.6 Hz, 1H), 6.78 (d,
J = 3.4 Hz, 1H), 6.63 (dd, J = 3.5, 1.8 Hz, 1H), 4.49 (d, J = 14.8 Hz,
1H), 4.12 (d, J = 14.8 Hz, 1H); MS (ESI) m/z 474/476 ([MꢀH]ꢀ).
4.1.60. 7-(3-Chloro-4-fluorophenyl)-5-(2-furyl)-5-(pentafluoro-
ethyl)-1,5-dihydro-4,1-benzoxazepin-2(H)-one (20b)
Prepared from 7-bromo-5-(2-furyl)-5-(pentafluoroethyl)-1,5-
dihydro-4,1-benzoxazepin- 2(H)-one and 3-cyano-5-fluorophenyl
boronic acid according to the coupling procedure described in
example 1. 1H NMR (DMSO-d6): d 10.41 (s, 1H), 7.84–7.94 (m,
4H), 7.76 (td, J = 10.1, 2.1 Hz, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.36
(d, J= 8.6 Hz, 1H), 6.84 (d, J = 3.4 Hz, 1H), 6.64 (dd, J = 3.4,
1.8 Hz, 1H), 4.45 (d, J = 14.9 Hz, 1H), 4.14 (d, J= 14.8 Hz, 1H);
MS (ESI) m/z 467 ([M+H]+); MS (ESI) m/z 465 ([MꢀH]ꢀ); Anal.
Calcd for C22H12F6N2O3: C, 56.66; H, 2.59; N, 6.01. Found: C,
56.64; H, 2.85; N, 5.61.
4.2. Steroid receptor (GAL-4) cross reactivity assays
Plasmids and cells: The ligand binding domains (LBD) of the
GR (aa 485–777), MR (aa 669–984), ERa (aa 303–595), and AR
(aa 644–920) were cloned into the pM GAL4-DBD vector (Clon-
tech). For the AR two-hybrid assay, SRC-2 (aa 620–1121) was
cloned into the pVP16 vector (Clontech). For the GAL4UAS-lucifer-
ase reporter, 5 copies of the 17bp GALUAS sequence along with
the E1b minimal TATA promoter were cloned into the pG5basic
luciferase vector (Promega). Experiments were performed in
COS-7 African green monkey kidney fibroblast-like cells (ATCC
#CRL-1651) grown in phenol red-free Dulbecco’s Modified Mini-
mum Essential Medium (Gibco) supplemented with 10% char-
coal/dextran-treated fetal bovine serum (Hyclone). GAL4 fusion
assays.20 The GAL4-steroid receptor LBD fusion plamid and GA-
L4UAS-luciferase reporter plasmid (50 ng/well each) were trans-
fected for 16 h into COS-7 cells using Fugene6 (0.5 lL/well)
according to the manufacturer’s protocol (Roche). In the AR as-
say the addition of VP16-SRC-2 was necessary for optimal re-
sponse. Cells were treated with compounds for 20 h and
luciferase activity was measured using Cell Culture Lysis Buffer
and Luciferase Reagent (Promega) on a Victor2 luminometer
(Perkin-Elmer).
4.1.61. 7-Bromo-5-methyl-1,3-dihydro-benzo[e][1,4]diazepin-
2-one (22)
A
mixture of 1-(2-amino-5-bromo-phenyl)-ethanone (8.0 g,
37 mmol) and glycine ethyl ester hydrogen chloride (6.7 g,
48 mmol) in pyridine was heated at reflux for 24 h under nitro-
gen. The reaction mixture was cooled, solvent removed, and res-
idue was treated with a saturated aqueous ammonium chloride
solution (200 mL). Ethyl acetate (300 mL) was added and organic
layer was separated, dried (MgSO4), concentrated, and the resi-
due purified on silica gel column (hexane–ethyl acetate, 1:1) to
give 7-bromo-5-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one
as a brown solid (1.5 g, 16%). 1H NMR (DMSO-d6): d 10.49 (s,
1H), 7.92 (d, J = 2.0 Hz, 1 H), 7.66 (dd, J = 8.7, 2.1 Hz, 1 H), 7.08
(d, J = 8.7 Hz, 1H), 3.91 (s, 2H), 2.39 (s, 3H). MS (ESI) m/z 253/
255 ([M+H]+).
Acknowledgements
4.1.62. 7-(3-Chloro-4-fluorophenyl)-5-methyl-1,3-dihydro-H-
1,4-benzodiazepin-2-one (23)
We thank Drs. Len Freedman, Ron Magolda, and Magid Abou-
Gharbia for their support, Department of Analytical Chemistry,
Wyeth Research, for analytical data.
Prepared from 7-bromo-5-methyl-1,3-dihydro-benzo[e][1,4]-
diazepin-2-one and 3-chloro-4-fluorophenyl boronic acid using
the coupling procedure described in example 10a. 1H NMR
(DMSO-d6): d 10.52 (s, 1H), 8.02 (d, J = 2.2 Hz, 1H), 7.99 (d,
J = 2.1 Hz, 1H), 7.83 (dd, J = 8.5, 2.2 Hz, 1H), 7.76 (m, 1H), 7.52 (t,
J = 8.76 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 3.91 (s, 2H), 2.48 (s, 3H);
MS (ESI) m/z 303/305 ([M+H]+); MS (ESI) m/z 301/303 ([MꢀH]ꢀ);
Anal. Calcd for C16H12ClFN2O: C, 63.48; H, 4.00; N, 9.25. Found:
C, 63.16; H, 4.02; N, 8.85.
References and notes
1. Mangelsdorf, D. J.; Thummel, C.; Beato, M.; Herrlich, P.; Schuetz, G.; Umesono,
K.; Blumberg, B.; Kastner, P.; Mark, M. Cell (Cambridge, MA) 1995, 83, 835–839.
2. Brown, A.; Cheng, L.; Lin, S.; Baird, D. T. J. Clin. Endocrinol. Metabol. 2002, 87, 63–
70.
3. Murphy, A. A.; Kettel, L. M.; Morales, A. J.; Roberts, V. J.; Yen, S. S. J. Clin.
Endocrinol. Metabol. 1993, 76, 513–517.
4. Kettel, L. M.; Murphy, A. A.; Morales, A. J.; Ulmann, A.; Baulieu, E. E.; Yen, S. S.
Fertil. Steril. 1996, 65, 23–28.
5. Murphy, A. A.; Castellano, P. Z. Curr. Opin. Obstet. Gynecol. 1994, 6, 269–278.
6. Brogden, R. N.; Goa, K. L.; Faulds, D. Drugs 1993, 45, 384–409.
7. Combs, D. W.; Reese, K.; Cornelius, L. A. M.; Gunnet, J. W.; Cryan, E. V.; Granger,
K. S.; Jordan, J. J.; Demarest, K. T. J. Med. Chem. 1995, 38, 4880–4884.
4.1.63. 7-(3-Chloro-4-fluorophenyl)-4,5,5-trimethyl-1,3,4,5-
tetrahydro-H-1,4-benzodiazepin-2-one (24)
A mixture of 7-(3-chloro-4-fluorophenyl)-5-methyl-1,3-dihy-
dro-H-1,4-benzodiazepin-2-one (0.4 g, 1.32 mmol) and iodometh-

6600
P. Zhang et al. / Bioorg. Med. Chem. 16 (2008) 6589–6600
8. Hamann, L. G.; Winn, D. T.; Pooley, C. L. F.; Tegley, C. M.; West, S. J.; Farmer, L. J.;
Zhi, L.; Edwards, J. P.; Marschke, K. B.; Mais, D. E.; Goldman, M. E.; Jones, T. K.
Bioorg. Med. Chem. Lett. 1998, 8, 2731–2736.
14. Fensome, A.; Koko, M.; Wrobel, J.; Zhang, P.; Zhang, Z.; Cohen, J.; Lundeen,
S.; Rudnick, K.; Zhu, Y.; Winneker, R. Bioorg. Med. Chem. Lett. 2003, 13,
1317–1320.
9. Kurihara, K.; Tanabe, K.; Yamamoto, Y.; Shinei, R.; Ajito, K.; Okonogi, T. Bioorg.
Med. Chem. Lett. 1999, 9, 1837–1842.
10. Zhi, L.; Tegley, C. M.; Pio, B.; West, S. J.; Marschke, K. B.; Mais, D. E.; Jones, T. K.
Bioorg. Med. Chem. Lett. 2000, 10, 415–418.
15. Terefenko, E. A.; Kern, J.; Fensome, A.; Wrobel, J.; Zhu, Y.; Cohen, J.; Winneker,
R.; Zhang, Z.; Zhang, P. Bioorg. Med. Chem. Lett. 2005, 15, 3600–3603.
16. Zhang, P.; Terefenko, E. A.; Fensome, A.; Wrobel, J.; Winneker, R.; Zhang, Z.
Bioorg. Med. Chem. Lett. 2003, 13, 1313–1316.
11. Fensome, A.; Bender, R.; Cohen, J.; Collins, M. A.; Mackner, V. A.; Miller, L. L.;
Ullrich, J. W.; Winneker, R.; Wrobel, J.; Zhang, P.; Zhang, Z.; Zhu, Y. Bioorg. Med.
Chem. Lett. 2002, 12, 3487–3490.
12. Zhang, P.; Terefenko, E. A.; Fensome, A.; Wrobel, J.; Winneker, R.; Lundeen, S.;
Marschke, K. B.; Zhang, Z. J. Med. Chem. 2002, 45, 4379–4382.
13. Zhang, P.; Terefenko, E. A.; Wrobel, J.; Zhang, Z.; Zhu, Y.; Cohen, J.; Marschke, K.
B.; Mais, D. Bioorg. Med. Chem. Lett. 2001, 11, 2747–2750.
17. Beck, C. A.; Weigel, N. L.; Moyer, M. L.; Nordeen, S. K.; Edwards, D. P. Proc. Natl.
Acad. Sci. U.S.A. 1993, 90, 4441–4445.
18. Zhang, Z.; Lundeen, S. G.; Zhu, Y.; Carver, J. M.; Winneker, R. C. Steroids 2000,
65, 637–643.
19. Sadowski, I.; Bell, B.; Broad, P.; Hollis, M. Gene 1992, 1181, 137–141.
20. Zhang, Z.; Funk, C.; Roy, D.; Glasser, S.; Mulholland, J. Endocrinology 1994, 134,
1089–1094.