Design, synthesis, and pharmacological evaluation of N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives as potent glycogen phosphorylase inhibitors

Article abstract of DOI:10.1016/j.bmc.2008.10.021

As a result of the various N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives with a hydroxy moiety synthesized in an effort to discover novel glycogen phosphorylase (GP) inhibitors, 5-chloro-N-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indole-2

Full text of DOI:10.1016/j.bmc.2008.10.021

Bioorganic & Medicinal Chemistry 16 (2008) 10001–10012
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis, and pharmacological evaluation of
N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives
as potent glycogen phosphorylase inhibitors
*
Kenichi Onda , Ryota Shiraki, Takashi Ogiyama, Kazuhiro Yokoyama, Kazuhiro Momose, Naoko Katayama,
Masaya Orita, Tomohiko Yamaguchi, Masako Furutani, Noritaka Hamada, Makoto Takeuchi, Minoru Okada,
Mitsuaki Ohta, Shin-ichi Tsukamoto
Drug Discovery Research, Astellas Pharma Inc., 5-2-3 Toukoudai, Tsukuba, Ibaraki 300-2698, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
As a result of the various N-bicyclo-5-chloro-1H-indole-2-carboxamide derivatives with a hydroxy moi-
ety synthesized in an effort to discover novel glycogen phosphorylase (GP) inhibitors, 5-chloro-N-(5-
hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (5b) was found to have potent
inhibitory activity. The introduction of fluorine atoms both at a position adjacent to the hydroxy group
and in the central benzene moiety lead to the optically active derivative 5-chloro-N-[(5R)-1,3,6,6-tetra-
Received 5 September 2008
Revised 8 October 2008
Accepted 9 October 2008
Available online 12 October 2008
fluoro-5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl]-1H-indole-2-carboxamide (25e
most potent compound in this series (IC50 = 0.020 M). This compound inhibited glucagon-induced glu-
cose output in cultured primary hepatocytes with an IC50 value of 0.69 M, and showed oral hypoglyce-
mic activity in diabetic db/db mice at 10 mg/kg. Compound 25e also had an excellent pharmacokinetic
profile, with high oral bioavailability and a long plasma half-life, in male SD rats. The binding mode of
25e to this molecule and the role of fluorine atoms in that binding were speculated in an enzyme dock-
ing study.
a, which was the
Keywords:
l
Glycogen phosphorylase
Hepatic glucose output
Docking study
l
a
Hypoglycemic activity
a
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
High blood glucose levels in type 2 diabetic patients are caused
in part by an increase in hepatic glucose output (HGO), which con-
sists of gluconeogenesis (de novo synthesis of glucose from 2- and
According to the International Diabetes Federation’s report in
2007, diabetes currently affects 246 million people worldwide
and is expected to affect 380 million by 2025.1 This disease and
its complications result in serious economic consequences for both
individuals and society (the total cost attributable to diabetes in
the US in 2007 was estimated to be $174 billion2).
Over 90% of these cases are type 2 diabetes, which is character-
ized by insulin resistance in target tissues and progressive insulin
secretory dysfunction. This metabolic disease often leads to micro-
vascular and macrovascular complications, such as retinopathy,
neuropathy, nephropathy, atherosclerosis, and heart disease. Cur-
rent approaches for treatment of type 2 diabetes usually consist
of a combination of diet, physical exercise, and drug therapies.
However, gaining tight control of the plasma glucose level is often
difficult with current oral hypoglycemic agents because of weak
effectiveness, increasing tolerance, and side effects, including
hypoglycemia, weight gain, and edema. Therefore, safer and more
effective hypoglycemic agents are urgently needed.
3-carbon precursors), and glycogenolysis (phosphorolysis of
a-
(1,4)-linkages within glycogen molecules).3–6 Several studies have
suggested that glycogenolysis is an important contributor to HGO
in type 2 diabetes patients,3,7 and glycogen phosphorylase (GP) is
known to be its regulatory enzyme. In the liver, glucose-1-phos-
phate produced by GP from glycogen is converted by phosphoglu-
comutase and glucose-6-phosphatase to glucose, which is released
from the liver to other tissues as fuel.8 Thus, inhibition of glycogen-
olysis by GP inhibitors has recently attracted a lot of interest as a
therapeutic target for this disease.
The GP molecule is a homodimeric enzyme that can be regu-
lated by ligand binding at four sites, including an allosteric site, a
catalytic site, a caffeine-binding site, and a dimer interface site;
in fact, the binding of several types of GP inhibitors at these sites
has been reported.9–16 In a prior paper, we reported that a series
of N-aryl-5-chloro-1H-indole-2-carboxamide derivatives with a
side-chain containing hydroxy groups, such as 1, derived from
CP-320626 showed human liver GPa (hLGPa; active form of hLGP)
inhibitory activity. X-ray crystallographic imaging of the complex
of 1 with hLGPa showed that the 5-chloro-1H-indole-2-carboxam-
* Corresponding author. Tel.: +81 29 847 8611; fax: +81 29 847 8313.
E-mail address: kenichi.onda@jp.astellas.com (K. Onda).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.10.021

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K. Onda et al. / Bioorg. Med. Chem. 16 (2008) 10001–10012
ide moiety had appropriate interactions with hLGPa at the dimer
interface site. In addition, two hydroxy groups interacted electro-
statically with the enzyme in which the primary and secondary hy-
droxy groups also made direct electrostatic connections with the
imidazole ring of Tyr185 and the backbone of His57, respectively
(Fig. 1).17
We then attempted to generate new derivatives by introducing
a conformationally restricted structure with hydroxy moiety(ies)
into a 5-chloro-N-phenyl-1H-indole-2-carboxamide template as a
side chain. In our previous study, compound 2 inhibited hLGPa
IC50 value of 0.44 lM, which was about four times more potent
than 2. This result prompted us to investigate further modification
of 3 via ring expansion, introduction of substituents to the central
benzene moiety or to adjacent position to the hydroxy group, and
synthesis of optically active compounds (Fig. 2).
In the present article, we wish to report both the structure–
activity relationships (SARs) of the compounds derived from 3 as
a new class of GP inhibitor, and their modes of binding to the en-
zyme, which were elucidated a docking study.
with an IC50 of 1.6 lM. This molecule also has a hydroxy group
2. Chemistry
in a position appropriate for interacting with GP; therefore, it
seemed to be a suitable lead compound. In hLGPa, the pocket
around the hydroxy moiety of this molecule can afford to be occu-
pied by a hydrophobic moiety, such as a 4-fluorophenyl ring, which
was observed in an X-ray crystallographic study of CP-320626.16,17
Therefore, it seemed possible to obtain inhibitory activity by mod-
ifying 2 into a bicyclic system via fixation of the hydroxy methyl
side chain.
5-Chloro-N-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-1H-indole-
2-carboxamide (3) was prepared via a coupling reaction between
5-aminoindan-1-one (4a) and 5-chloro-1H-indole-2-carboxylic
acid. A carbonyl moiety on this compound was reduced because
that on 4a was not successful. Six- or 7-membered ring derivatives
(5b, c) were obtained by the reduction of a carbonyl moiety and a
successive coupling reaction with 5-chloro-1H-indole-2-carboxylc
acid.19 The naphthol derivative (7) was also obtained via the cou-
pling reaction (Scheme 1).
To that end, we first evaluated the 5-membered ring derivative
(3). This compound exhibited hLGPa inhibitory activity with an
A derivative with a cis 5,6-diol moiety (9a) was obtained by the
dehydration of 5b followed by dihydroxylation using osmium
A
Cl
Cl
tetroxide and N-methylmorpholine-N-oxide.
A trans analogue
(9b) was synthesized from 9a by isomerization under acidic condi-
tions (Scheme 2).20
O
H
A dimethyl analogue (12) was obtained via the series of reac-
tions described in Scheme 3. An amino moiety of 4b was protected
as a 2,5-dimethylpyrrole ring, after which dimethyl groups were
N
H
N
N
N
H
N
O
OH
H
O
OH
introduced at the
a position of a carbonyl moiety. Ozonolysis of
OH
the pyrrole ring and reduction of the carbonyl moiety in 10, fol-
lowed by a coupling reaction with 5-chloro-1H-indole-2-carboxylc
acid led to the desired product.21,22
F
CP-320626
1
The preparation of tetrahydronaphthalene-5-ol derivatives with
difluoro groups (15) are shown in Scheme 4. The protection of an
amino group in 4b with a trifluoroacetyl group, followed by diflu-
orination, afforded intermediate 13. Conversion of 13 to 14 was
B
Cl
a, b (for 3)
b, a (for 5b, 5c)
( )n
H
N
( )n
OH
N
H
O
O
4a: n = 1
4b: n = 2
4c: n = 3
3: n = 1
5b: n = 2
5c: n = 3
Cl
H2N
H
N
a
N
H
O
OH
Figure 1. (A) Structure of CP-320626 and an example of N-aryl-1H-indole-2-
carboxamide derivative (1). (B) Schematic diagram of the interactions made by 1
with hLGPa revealed by crystallographic analysis. Protein residues of the two hLGPa
molecules in the dimer are distinguished with labels (A) and (B), respectively. The
figure was prepared using the Ligand Interactions application in MOE .18
OH
6
7
Scheme 1. Syntheses of compounds 3, 5b, 5c, and 7. Reagents: (a) 5-Chloro-1H-
indole-2-carboxylic acid, WSCꢀHCl, HOBt, DMF; (b) NaBH4, MeOH.
Cl
Cl
Cl
H
X
H
H
N
( )n
R1
R2
N
N
N
N
N
H
H
H
O
O
O
Y
* OH
OH
OH
2
3
Figure 2. Structure of compound 2 and the modification route.

K. Onda et al. / Bioorg. Med. Chem. 16 (2008) 10001–10012
10003
Cl
Cl
b
H
N
H
a
N
N
N
5b
H
H
O
O
OH
OH
8
9a: cis
9b: trans + 9a
c
Scheme 2. Syntheses of compounds 9a, 9b. Reagents and conditions: (a) AcOH, 80 °C; (b) OsO4, NMO, THF-H2O; (c) 1% H2SO4, H2O-1,4-dioxane, 80 °C.
Cl
H2N
d
N
c
a, b
H
4b
N
N
H
O
OH
O
OH
10
11
12
Scheme 3. Synthesis of compound 12. Reagents and conditions: (a) 2,5-hexanedione, AcOH, PhH, reflux; (b) MeI, NaH, DMF; (c) O3, EtOH–CHCl3, ꢁ78 °C then NaBH4, 0 °C,
then 2 M HCl, reflux; (d) 5-Chloro-1H-indole-2-carboxylic acid, SOCl2, then 11, pyridine.
Cl
H
H2N
e
F3C
N
H
c, d
a, b
F
F
N
F
F
4b
N
O
F
F
H
O
OH
14
O
OH
13
15
Scheme 4. Synthesis of compound 15. Reagents and conditions: (a) (CF3CO)2O, CHCl3; (b) (C6H5SO2)2NF, NaHMDS, THF, ꢁ78 °C to rt; (c) K2CO3, MeOH–H2O, 60 °C; (d) NaBH4,
MeOH; (e) 5-Chloro-1H-indole-2-carboxylic acid, SOCl2, then 14, pyridine.
achieved by deprotecting the trifluoroacetyl moiety and reducing a
carbonyl group. Finally, a coupling reaction between 14 and 5-
chloro-1H-indole-2-carbonyl chloride afforded the desired
compound.
ature precipitated only a single diastereomer (27), and then
hydrolysis of 27 afforded 25ea with >99% ee.
3. Results and discussion
The serial preparation of substituted analogues on the tetrahy-
dronaphthalene ring of 15 is shown in Scheme 5. For the methoxy
analogues, intermediates 18a and 18b were obtained from benzoic
acid derivatives (16a, b) via Curtius rearrangement (via bromina-
tion for 16a).23 The fluoro analogue intermediates (18c–e) were
prepared from 17a–c via carboxylation24 followed by Curtius rear-
rangement. Intermediates 18a–e were converted to 1-hydroxybu-
The structures of synthesized compounds and their in vitro
hLGPa inhibitory activities are summarized in Tables 1 and 2.
As for the size of the ring fused to the central benzene moiety,
the 5-membered ring derivative (3) had almost the same level of
inhibitory activity as the 6-membered compound (5b), but the 7-
membered ring derivative (5c) exhibited lower activity
tyl derivatives 20a–e via
a
Pd-catalyzed coupling reaction25
(IC50 = 0.44 lM for 3, 1.2 lM for 5c vs 0.32 lM for 5b). The differ-
followed by catalytic hydrogenation. Jones oxidation of 20a–e
yielded the corresponding carboxylic acid derivatives (21a–e),
which were cyclized under acidic conditions using PPA for 22a–e.
These products were difluorinated after protection of their amino
groups to yield 23a–e. The precursors of the desired products were
obtained by deprotecting the trifluoroacetamide moiety and reduc-
ing the carbonyl group with NaBH4 (24a, b). Compounds 24c–e
were prepared via an improved one-step procedure using the
NaBH4–LiCl system instead of two successive reactions. Finally, a
coupling reaction with 5-chloro-1H-indole-2-carbonyl chloride
afforded the desired products 25a–e.
ence in activity among these compounds seemed to be due to ste-
ric hindrance of the 7-membered ring, which occurs when the
hydroxy group binds to His57 in the enzyme. The reason why
the naphthol ring analogue (7) was less active than 5b was not
clear; however, the character of the phenolic hydroxy group and/
or the sterically restricted structure of 7 may be related.
To investigate the influence of the substituents around the hy-
droxy group in 5b, another hydroxy group, methyl groups, and
fluorine atoms were introduced into the moiety next. When the
second hydroxy group was introduced, the potency of the trans diol
Compound 25e was separated via chiral HPLC (CHIRALPAK ADÒ,
(9b) decreased slightly (IC50 = 0.80
lM), and the cis diol (9a) was
10 times less potent (IC50 = 8.5 M) than the trans analogue. The
l
EtOH) into the corresponding enantiomers, 25e
configuration of the carbon atom that bound to the hydroxy group
of 25e was determined using single-crystal X-ray analysis (Fig. 3A
and B).
Another route for obtaining the optically active isomer of com-
pound 25e is described in Scheme 6. Condensation of 25e with
a and 25eb. The R
difference in potency can be attributed to the intramolecular
hydrogen bonding of the cis diol, which may inhibit the benzylic
hydroxy group from properly binding to the His57 in hLGPa. In
addition, the two methyl moieties at this position in 12 detracted
from its inhibitory activity. It was speculated that the hydroxy
group in this molecule could not approach the binding site on
hLGPa due to the existence of these two methyl groups. Interest-
a
N-(p-toluenesulfonyl)-L-phenylalanyl chloride yielded a diastereo-
metric mixture (26). Stirring the mixture in CHCl3 at room temper-

10004
K. Onda et al. / Bioorg. Med. Chem. 16 (2008) 10001–10012
X
HO2C
Y
Z
a, c or c
16a: X=H, Y=OMe, Z=H
16b: X=OMe, Y=H, Z=Br
OH
X
X
H
N
H
N
d
O
e
O
Br
O
b, c
X
O
Y
Y
Br
19a: X=H, Y=OMe
19b: X=OMe, Y=H
19c: X=H, Y=F
19d: X=F, Y=H
19e: X=Y=F
18a: X=H, Y=OMe
18b: X=OMe, Y=H
18c: X=H, Y=F
18d: X=F, Y=H
18e: X=Y=F
Y
17a: X=H, Y=F
17b: X=F, Y=H
17c: X=Y=F
X
X
X
H
g
H2N
Y
h, i
H
f
O
N
OH
O
N
CO2H
O
O
Y
Y
O
22a: X=H, Y=OMe
22b: X=OMe, Y=H
22c: X=H, Y=F
22d: X=F, Y=H
22e: X=Y=F
20a: X=H, Y=OMe
20b: X=OMe, Y=H
20c: X=H, Y=F
20d: X=F, Y=H
20e: X=Y=F
21a: X=H, Y=OMe
21b: X=OMe, Y=H
21c: X=H, Y=F
21d: X=F, Y=H
21e: X=Y=F
Cl
X
X
H
X
H2N
Y
m
H
N
j, k
or l
F3C
N
F
N
F
F
H
O
F
O
Y
F
Y
F
OH
O
OH
23a: X=H, Y=OMe
23b: X=OMe, Y=H
23c: X=H, Y=F
23d: X=F, Y=H
23e: X=Y=F
24a: X=H, Y=OMe
24b: X=OMe, Y=H
24c: X=H, Y=F
24d: X=F, Y=H
24e: X=Y=F
25a: X=H, Y=OMe
25b: X=OMe, Y=H
25c: X=H, Y=F
25d: X=F, Y=H
25e: X=Y=F
Scheme 5. Syntheses of compounds 25a–e. Reagents and conditions: (a) 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione, aq NaOH (for 18a); (b) LDA, THF, then CO2,
ꢁ78 °C to rt; (c) DPPA, t-BuOH–toluene, reflux; (d) 3-Butyn-1-ol, Pd(PPh3)4, CuI, i-Pr2NH, reflux; (e) H2, 10% Pd–C, MeOH; (f) Jones reagent, acetone, 0 °C; (g) PPA, 110 °C; (h)
(CF3CO)2O, CHCl3; (i) (C6H5SO2)2NF, NaHMDS, THF, ꢁ78 °C to rt; (j) K2CO3, MeOH–H2O, 60 °C; (k) NaBH4, MeOH (two steps for 24a, b); (l) NaBH4, LiCl, MeOH–H2O (for 24c–e);
(m) 5-chloro-1H-indole-2-carboxylic acid, SOCl2, then 24a–e, pyridine.
A
B
Cl
F
H
N
N
F
F
H
O
F
OH
25eα
Figure 3. (A) Structure of compound 25ea. (B) The molecular structure of 25e
a
hemiacetonitrilate with the crystallographic numbering scheme.
Cl
Cl
F
F
H
H
N
c
N
b
N
H
N
H
a
25eα
F
F
O
F
F
O
25e
O
O
F
F
O
O
26
27
NHTs
NHTs
Scheme 6. Synthesis of compound 25ea. Reagents: (a) n-BuLi, N-(p-toluenesulfonyl)-L-phenylalanyl chloride, THF; (b) stirring in CHCl3 then filtration; (c) 2 M KOH, EtOH.

K. Onda et al. / Bioorg. Med. Chem. 16 (2008) 10001–10012
10005
Table 1
SARs of N-aryl-5-chloro-1H-indole-2-carboxamide derivatives
configuration of S, had an IC50 value of 0.16
pound 25e
ity (IC50 = 0.020
Next, the ability of the most potent hLGPa inhibitor, 25e
l
M, whereas com-
a
(R-isomer) exhibited the most potent inhibitory activ-
l
M) in a series of synthesized compounds.
Cl
Cl
a, to in-
hibit glycogenolysis in cultured rat hepatocytes and to have hypo-
glycemic activity in diabetic model mice was investigated (Table
H
N
H
N
( )n
R1
R2
N
N
H
3). Compound 25e
from hepatocytes dose-dependently with an IC50 value of
0.69 M, which was an improvement of more than twofold over
CP-320626. In addition, oral administration of 10 mg/kg 25e to
a inhibited glucagon-induced glucose output
H
O
O
OH
OH
l
3, 5b, 5c, 9a, 9b, 12, 15
7
a
diabetic db/db mice lowered plasma glucose at the 2 h time point.
This hypoglycemic activity was almost equal to that of 30 mg/kg
CP-320626.
Entry
Compound
n
R1
R2
hLGPa IC50 (lM)
1
2
3
4
5
6
7
8
9
3
1
2
3
H
H
H
—
H
H
H
H
—
0.44
0.32
1.2
0.90
8.5
0.80
>10
0.068
0.92
5b
5c
7
9a
9b
12
15
Compound 25ea also exhibited an excellent pharmacokinetic
profile, with high oral bioavailability (F = 100%) and a long plasma
half-life (t1/2 = 12 h), in male SD rats (Table 4).
Compound 25ea had two kinds of fluorine atoms, ‘aliphatic’ and
‘aromatic,’ both of which were thought to be important to high
2
2
2
2
OH (cis)
H
Me
F
OH (trans)
Me
F
inhibitory activity. To understand the role of these fluorine atoms,
CP-320626
a docking study of 25e
a to hLGPa was carried out. The locations of
the indole ring, the amide moiety, and the hydroxy group of 25e
a,
all of which were thought to be key parts of activity, were assigned
to the same dimer interface site as the complex between 1 and
hLGPa, as follows: first, the dimer interface site was occupied by
two inhibitor molecules; second, the 5-chloroindole group was
buried in a hydrophobic pocket composed of lipophilic amino acid
side chains; third, the indole NH, the amide NH, and the carbonyl O
moiety made polar contact with the enzyme; and last, the hydroxy
group interacted electrostatically with the imidazole ring of
His57.17
Table 2
SARs of 5-chloro-N-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-indole-2-car-
boxamide derivatives
Cl
X
H
N
N
The predicted binding model for 25ea is shown in Figure 4.
F
H
O
The hydrophobic residues, such as Phe53, Pro188, and Gly186,
around the two aliphatic fluorine atoms strongly suggested that
the lipophilic contact among them was an important driver of
activity increases. The fact that the hydrophobic residues Leu39
and Lys191 are close to one of the aromatic fluorine atoms (the po-
sition 3 in Figure 4A), suggests that hydrophobic interactions could
be an indicating factor for good potency. The other aromatic fluo-
rine atom (position 1 in Figure 4A) seemed to be in hydrophobic
Y
F
*
OH
Entry
Compound
X
Y
hLGPa IC50 (lM)
1
2
3
4
5
6
7
8
9
15
25a
25b
25c
25d
25e
H
H
H
0.068
0.81
0.59
0.063
0.048
0.036
0.16
0.020
0.92
OMe
OMe
H
F
H
F
F
F
H
F
F
F
F
25eb (S-isomer)
25ea
(R-isomer)
CP-320626
Table 3
Inhibition of glucagon-induced glucose output in cultured primary hepatocytes and
oral hypoglycemic activity in diabetic db/db mice
Entry
Compound
hLGPa IC50
M)
HGO inh. IC50
M)
db/db Mice
ingly, the presence of the two fluorine atoms at this position (15)
enhanced inhibitory activity by fivefold over the parent compound
(IC50 = 0.068 lM for 15 vs 0.32 lM for 5b), which, next to the hy-
droxy moiety, was the best result obtained out of all the
(l
(l
hypoglycemic activitya
Dose
% Glucose
lowering
(mg/kg, po)
1
2
3
25ea
0.020
0.92
0.69
1.7
3
10
30
14
26**
substituents.
24##
Next, the effects of substituents on a central benzene moiety in
15 were examined. Since X-ray crystallographic observation indi-
cated that the steric allowance around the moiety in the enzyme
would be low,17 only small substituents were introduced.
As shown in Table 2, the introduction of a methoxy group at
CP-320626
a
Percent decrease in drug-treated plasma glucose concentration at 2 h post-dose,
relative to the vehicle-treated control in db/db mice.
**
P < 0.01 versus control (Dunnett’s test).
P < 0.01 versus control (Student’s t-test).
##
positions Y or X on the benzene moiety resulted in 0.81
lM and
0.59 M of IC50 values, respectively, which were one-order of mag-
l
nitude lower in inhibitory activity compared to 15. On the other
hand, introduction of a fluorine atom at the same positions re-
Table 4
Pharmacokinetic data for 25e
administration
a in male SD rats following intravenous and oral
sulted in the retention of or
a slight increase in activity
(IC50 = 0.063 M for 25c, 0.048 M for 25d, respectively). Incorpo-
ration of a fluorine atom at 25c and 25d, resulted in an X,Y-difluoro
substituted derivative (25e), which was about twofold more potent
than 15 (IC50 = 0.036 lM for 25 vs 0.068 lM for 15). The discovery
l
l
Route
AUC0?1
(ng h/mL)
CLtot
(mL/h/kg)
Vd
(mL/kg)
t1/2
(h)
Cmax
(ng/mL)
Tmax
(h)
F
(%)
Intravenousa
Oralb
930
2785
1075
18067
12
785
0.5
100
of the potent hLGPa inhibitor 25e inspired us to divide this com-
pound into enantiomers. Compound 25eb, which had an absolute
a
Administered at 1 mg/kg in 5% propylene glycol–5% Tween 80.
Administered at 3 mg/kg in 5% propylene glycol–5% Tween 80.
b

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K. Onda et al. / Bioorg. Med. Chem. 16 (2008) 10001–10012
5. Experimental
Cl
A
F
5.1. Chemistry
8
H
N
1
N
1H NMR spectra were recorded on a JEOL JNM-LA300 or a JEOL
F
F
H
O
F
JNM-EX400 spectrometer, and the chemical shifts are expressed in
d (ppm) values with tetramethylsilane as an internal standard (in
NMR description, s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, and br = broad peak). Mass spectra were recorded
on a JEOL JMS-700T or micromass Q-Tof Ultima API spectrometer.
The elemental analyses were performed with a Yanaco MT-5
microanalyzer (C, H, N) and were within 0.4% of theoretical val-
ues. The drying of organic solutions during work-up was done over
anhydrous MgSO4 or Na2SO4.
3
OH
25eα
Aromatic fluorines
Aliphatic fluorines
B
(Gly186’)
Pro188’
5.1.1. 5-Chloro-N-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-1H-
indole-2-carboxamide (3)
1-Ethyl-3-(30-dimethylaminopropyl)carbodiimide hydrochlo-
ride (1.43 g, 7.46 mmol) and 1-hydroxybenzotriazole hydrate
(1.11 g, 7.25 mmol) were added to a solution of 5-aminoindan-1-
one (1.00 g, 6.79 mmol) and 5-chloro-1H-indole-2-carboxylic acid
(1.30 g, 6.65 mmol) in DMF (10 mL), and then the mixture was stir-
red at room temperature for 40 h. H2O (100 mL) was added to the
reaction mixture and the resulting precipitate was collected and
washed with CHCl3/MeOH (5:1, 90 mL) to yield 5-chloro-N-(1-
Phe53’
Lys191
Leu39’
Lys191’
Leu39
Phe53
Pro188
(Gly186)
oxo-2,3-dihydro-1H-inden-5-yl)-1H-indole-2-carboxamide as
a
colorless solid (1.09 g, 50%). 1H NMR (400 MHz, DMSO-d6) d:
2.60–2.65 (2H, m), 3.08–3.14 (2H, m), 7.25 (1H, dd, J = 1.9,
8.8 Hz), 7.47–7.51 (2H, m), 7.66 (1H, d, J = 8.3 Hz), 7.78–7.84 (2H,
m), 8.12 (1H, br s), 10.59 (1H, s), 12.02 (1H, s). FABMS m/z: 325
(M+1)+. NaBH4 (70 mg, 1.85 mmol) was added to a solution of
the product obtained above (200 mg, 0.62 mmol) in THF/MeOH
(2:1, 15 mL) at 0 °C, and the mixture was stirred at room temper-
ature for 6 h. H2O was added to this reaction mixture and extracted
with AcOEt. The AcOEt layer was washed with satd NaCl, and then
dried and concentrated in vacuo. The obtained solid was washed
with CHCl3–MeOH to yield 3 (120 mg, 59%) as a colorless powder.
1H NMR (400 MHz, DMSO-d6) d: 1.75–1.85 (1H, m), 2.28–2.39 (1H,
m), 2.66-2.78 (1H, m), 2.88-2.98 (1H, m), 5.03 (1H, q, J = 6.4 Hz),
5.16 (1H, d, J = 6.4 Hz), 7.22 (1H, dd, J = 8.8, 2.4 Hz), 7.31 (1H, d,
J = 7.8 Hz), 7.38–7.42 (1H, m), 7.47 (1H, d, J = 8.8 Hz), 7.55–7.60
(1H, m), 7.69 (1H, br s), 7.77 (1H, d, J = 2.0 Hz), 10.22 (1H, s),
11.91 (1H, s). FABMS m/z: 325 (Mꢁ1)ꢁ.
Figure 4. (A) Two kinds of fluorine atoms on compound 25e
model for compound 25e
tetrahydronaphthalene ring of 25e
molecules in the dimer are labeled (’).
a. (B) Predicted binding
a
with hLGPa. Gly186 was situated on the back side of the
a.
The protein residues of the two hLGPa
contact with an aromatic CH moiety in the tetrahydronaphthalene
ring of the other 25e molecule in the enzyme.
A large difference in the activity between optical isomers
(25eb and 25e may be due to the following reasons: assuming
a
a
that the indole ring, the amide moiety, and the hydroxy group
of the less active isomer 25eb occupied the same regions in the
enzyme as the more active isomer 25ea, the fluorine atom at po-
5.1.2. 5-Chloro-N-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-
yl)-1H-indole-2-carboxamide (5b)
NaBH4 (680 mg, 18.0 mmol) was added to a solution of 6-ami-
no-3,4-dihydronaphthalen-1(2H)-one (970 mg, 6.02 mmol) in
MeOH (50 mL) at 0 °C, and the mixture was stirred at room tem-
perature for 4 h. The resulting mixture was concentrated in vacuo,
and the residue was partitioned between AcOEt (200 mL) and H2O
(80 mL), and the AcOEt layer was washed with satd NaCl, and then
dried and concentrated in vacuo to yield 6-amino-1,2,3,4-tetra-
hydronaphthalen-1-ol (985 mg, quant.) as a colorless solid. 1H
NMR (400 MHz, CDCl3) d: 1.61–2.00 (5H, m), 2.50–2.85 (2H, m),
3.61 (2H, br s), 4.67–4.75 (1H, m), 6.42 (1H, d, J = 2.4 Hz), 6.55
(1H, dd, J = 8.1, 2.4 Hz), 7.20 (1H, d, J = 8.3 Hz). FABMS m/z: 146
sition 1 on the tetrahydronaphthalene ring of one molecule of
25eb and the methylene chain in position 8 of the other molecule
would be too close each other at the dimer interface site. This
unfavorable steric hindrance could cause 25eb to have lower
activity than 25ea.
4. Conclusion
In summary, a novel series of N-bicyclo-5-chloro-1H-indole-
2-carboxamide derivatives containing hydroxy moiety was
a
synthesized, and the derivatives were evaluated for their inhibi-
tion of hLGPa. Of the compounds evaluated, the optically active
(MꢁH2O+1)+.
1-Ethyl-3-(30-dimethylaminopropyl)carbodiimide
hydrochloride (1.27 g, 6.62 mmol) and 1-hydroxybenzotriazole hy-
drate (1.01 g, 6.60 mmol) were added to a mixture of the product
obtained above (980 mg, 6.00 mmol) and 5-chloro-1H-indole-2-
carboxylic acid (1.17 g, 5.98 mmol) in DMF (40 mL), and then the
mixture was stirred at room temperature for 12 h. The resulting
mixture was concentrated in vacuo, the residue was partitioned
between AcOEt (200 mL) and H2O (100 mL), and the AcOEt layer
5-hydroxy-5,6,7,8-tetrahydronaphthalene derivative 25e
has four fluorine atoms, proved to be the most potent hLGPa
inhibitor in this series. Compound 25e inhibited glucose out-
put from hepatocytes and hypoglycemic activity in diabetic
mice. In rats, this compound also exhibited an excellent phar-
macokinetic profile, with high oral bioavailability and a long
plasma half-life.
a, which
a

K. Onda et al. / Bioorg. Med. Chem. 16 (2008) 10001–10012
10007
was washed with 1 M NaOH, H2O and satd NaCl, and then dried
and concentrated in vacuo. The residue was purified via column
chromatography on silica gel (CHCl3/MeOH = 20:1) to yield 5b
(610 mg, 30%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6)
d: 1.64–1.73 (2H, m), 1.88–1.92 (2H, m), 2.62–2.77 (2H, m),
4.51–4.58 (1H, m), 5.03 (1H, d, J = 5.8 Hz), 7.22 (1H, dd, J = 8.7,
2.0 Hz), 7.34–7.41 (2H, m), 7.45–7.51 (2H, m), 7.55–7.60 (1H, m),
7.76 (1H, d, J = 1.9 Hz), 10.16 (1H, s), 11.89 (1H, s). FABMS m/z:
339 (Mꢁ1)ꢁ.
orated off, and the residue was purified via column chromatogra-
phy on silica gel (CHCl3/MeO = 10:1) to yield 9b (98 mg, 30%) as
a colorless solid (15% recovery of 9a). 1H NMR (400 MHz, DMSO-
d6) d: 1.65–1.72 (1H, m), 1.85–2.00 (1H, m), 2.68–2.75 (1H, m),
2.80–2.85 (1H, m), 3.66–3.70 (1H, m), 4.26 (1H, t, J = 2.4 Hz), 4.81
(1H, d, J = 8.4 Hz), 5.20 (1H, d, J = 6.0 Hz), 7.22 (1H, dd, J = 9.0,
1.8 Hz), 7.36–7.40 (2H, m), 7.46–7.49 (2H, m), 7.57–7.59 (1H, m),
7.76 (1H, d, J = 1.8 Hz), 10.17 (1H, s), 11.88 (1H, s). FABMS m/z:
355 (Mꢁ1)ꢁ.
5.1.3. 5-Chloro-N-(5-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]-
annulen-2-yl)-1H-indole-2-carboxamide (5c)
5.1.8. 6-(2,5-Dimethyl-1H-pyrrol-1-yl)-2,2-dimethyl-3,4-
dihydronaphthalen-1(2H)-one (10)
The title compound was prepared in the same manner as de-
scribed for 5b using 4c instead of 4b, which resulted in a 9% yield
(for 2 steps). 1H NMR (400 MHz, DMSO-d6) d: 1.25–1.43 (1H, m),
1.44–1.61 (1H, m), 1.64–2.05 (4H, m), 2.62–2.90 (2H, m), 4.73
(1H, d, J = 5.9 Hz), 5.15 (1H, d, J = 3.9 Hz), 7.22 (1H, d, J = 8.3 Hz),
7.34–7.54 (4H, m), 7.78 (1H, d, J = 7.8 Hz), 8.31 (1H, s), 10.15 (1H,
s), 11.89 (1H, s). FABMS m/z: 355 (M+1)+.
Hexane-2,5-dione (1.5 mL, 12.6 mmol) was added to a solution
of 4b (2.00 g, 12.4 mmol) in benzene/AcOH (10:1, 22 mL), and the
mixture was stirred under reflux for 21 h. 1 M HCl (50 mL) was
added to the resulting mixture and extracted with AcOEt (2ꢂ
100 mL). The organic layer was washed with satd NaHCO3
(50 mL) and satd NaCl, and then dried and concentrated in vacuo.
The residue was purified via column chromatography on silica
gel (n-hexane/AcOEt = 10:1) to yield 6-(2,5-dimethyl-1H-pyrrol-
5.1.4. 5-Chloro-N-(5-hydroxy-2-naphthyl)-1H-indole-2-carbox-
amide (7)
1-yl)-3,4-dihydronaphthalen-1(2H)-one as
a
colorless solid
(3.00 g, quant.). 1H NMR (400 MHz, CDCl3) d: 2.06 (6H, s), 2.18–
2.24 (2H, m), 2.71 (2H, t, J = 6.8 Hz), 3.01 (2H, t, J = 6.4 Hz), 5.92
(2H, s), 7.09–7.12 (1H, m), 7.15 (1H, dd, J = 8.4, 2.0 Hz), 8.13 (1H,
d, J = 8.0 Hz). FABMS m/z: 240 (M+1)+. NaH (60% in oil, 1.52 g,
38.0 mmol) was added to a solution of the product obtained above
(3.00 g, 12.5 mmol) in DMF (60 mL), and then the mixture was stir-
red at room temperature for 10 min. MeI (2.4 mL, 38.6 mmol) was
added to the resulting mixture, and then the mixture was stirred at
room temperature for 2.5 h. The reaction was quenched by adding
H2O (150 mL) and extracted with AcOEt (3ꢂ 150 mL). The organic
layer was washed with satd NaCl, and then dried and concentrated
in vacuo. The residue was purified via column chromatography on
silica gel (n-hexane/AcOEt = 10:1) to yield 10 (1.44 g, 43%) as a
light brown solid. 1H NMR (400 MHz, CDCl3) d: 1.26 (6H, s), 2.02
(2H, t, J = 6.4 Hz), 2.06 (6H, s), 3.02 (2H, t, J = 6.4 Hz), 5.91 (2H, s),
7.07 (1H, d, J = 1.2 Hz), 7.14 (1H, dd, J = 8.4, 1.5 Hz), 8.13 (1H, d,
J = 8.4 Hz). FABMS m/z: 268 (M+1)+.
The title compound was prepared via the same coupling reac-
tion as described for 3 using 6-amino-1-naphthol instead of 4a,
which resulted in a 58% yield. 1H NMR (400 MHz, DMSO-d6) d:
6.70–6.85 (1H, m), 7.24 (1H, dd, J = 8.8, 1.9 Hz), 7.29 (2H, d,
J = 4.4 Hz), 7.46–7.52 (2H, m), 7.78–7.83 (2H, m), 8.12 (1H, d,
J = 8.8 Hz), 8.33 (1H, d, J = 1.9 Hz), 10.07 (1H, s), 10.44 (1H, s),
11.96 (1H, s). FABMS m/z: 337 (M+1)+.
5.1.5. 5-Chloro-N-(7,8-dihydronaphthalen-2-yl)-1H-indole-2-
carboxamide (8)
A solution of 5b (570 mg, 1.67 mmol) in AcOH (40 mL) was stir-
red at 80 °C for 21 h. The reaction mixture was concentrated in va-
cuo, and then the residue was purified via column chromatography
on silica gel (n-hexane/AcOEt = 1:1) to yield 8 (370 mg, 69%) as a
colorless solid. 1H NMR (400 MHz, DMSO-d6) d: 2.23–2.33 (2H,
m), 2.75 (2H, t, J = 8.3 Hz), 5.97–6.02 (1H, m), 6.47 (1H, d,
J = 10.1 Hz), 7.05 (1H, d, J = 10.1 Hz), 7.20–7.25 (1H, m), 7.38–7.65
(4H, m), 7.77 (1H, s), 10.21 (1H, s), 11.91 (1H, s). FABMS m/z: 323
(M+1)+.
5.1.9. 6-Amino-2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-
ol (11)
A solution of 10 (1.40 g, 5.24 mmol) in MeOH/CHCl3 (4:1,
150 mL) was stirred under an O3 atmosphere at ꢁ78 °C for
45 min. NaBH4 (0.99 g, 26.2 mmol) was added to the reaction mix-
ture, and then the mixture was stirred at 0 °C for 2 h. The reaction
mixture was concentrated in vacuo, and then 2 M HCl (50 mL) and
MeOH (50 mL) were added. The mixture was stirred under reflux
for 2 h, and then concentrated in vacuo. The residue was treated
with 1 M NaOH to pH 9.0 and extracted with CHCl3 (2ꢂ 100 mL).
The organic layer was washed with satd NaCl, and then dried
and concentrated in vacuo. The residue was purified via column
chromatography on silica gel (n-hexane/AcOEt = 4:1) to yield 11
(167 mg, 17%) as a colorless amorphous compound. 1H NMR
(400 MHz, DMSO-d6) d: 0.85 (6H, s), 1.50–1.60 (1H, m), 1.62–1.73
(1H, m), 2.50–2.65 (2H, m), 3.92 (1H, d, J = 6.4 Hz), 4.57 (1H, d,
J = 6.4 Hz), 4.76 (2H, s), 6.24 (1H, d, J = 2.0 Hz), 6.37 (1H, dd,
J = 8.0, 2.0 Hz), 6.99 (1H, d, J = 8.4 Hz). EIMS m/z: 191 (M)+.
5.1.6. cis-5-Chloro-N-(5,6-dihydroxy-5,6,7,8-tetrahydronaphth-
alen-2-yl)-1H-indole-2-carboxamide (9a)
Osmium tetroxide (0.08 Mt-t-BuOH solution; 1.20 mL,
0.096 mmol)
and
N-methylmorpholine-N-oxide
(220 mg,
1.88 mmol) were added to a solution of 8 (395 mg, 1.22 mmol) in
THF (20 mL), and then the mixture was stirred at room tempera-
ture for 2.5 h. The resulting mixture was concentrated in vacuo,
and the residue was washed with H2O (50 mL) and dried at
50 °C. The crude product was washed with AcOEt–ether to yield
9a (333 mg, 76%) as a colorless solid. 1H NMR (400 MHz, DMSO-
d6) d: 1.71–1.75 (1H, m), 1.90–1.97 (1H, m), 2.65–2.73 (1H, m),
2.83–2.91 (1H, m), 3.78–3.83 (1H, m), 4.43–4.47 (1H, m), 4.52
(1H, d, J = 4.9 Hz), 4.79 (1H, d, J = 5.9 Hz), 7.22 (1H, dd, J = 8.8,
1.9 Hz), 7.33 (1H, d, J = 8.3 Hz), 7.39–7.41 (1H, m), 7.47 (1H, d,
J = 8.3 Hz), 7.47–7.54 (1H, m), 7.57–7.62 (1H, m), 7.75–7.77 (1H,
m), 10.18 (1H, s), 11.89 (1H, s). FABMS m/z: 355 (Mꢁ1)ꢁ.
5.1.10. 5-Chloro-N-(6,6-dimethyl-5-hydroxy-5,6,7,8-
5.1.7. trans-5-Chloro-N-(5,6-dihydroxy-5,6,7,8-tetrahydronaphth-
alen-2-yl)-1H-indole-2-carboxamide (9b)
tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (12)
A mixture of 5-chloro-1H-indole-2-carbonyl chloride (453 mg,
2.12 mmol) and 11 (162 mg, 0.85 mmol) in pyridine (20 mL) was
stirred at room temperature for 12 h. The reaction mixture was
concentrated in vacuo and EtOH (100 mL) and 1 M NaOH (20 mL)
were added to the residue, after which the mixture was stirred at
room temperature for 30 min. The solvent was evaporated in
A solution of 9a (325 mg, 0.91 mmol) in 1% H2SO4 (5 mL) and
1,4-dioxane (15 mL) was stirred at 80 °C for 1 h. The resulting mix-
ture was concentrated in vacuo, and the residue was partitioned
between AcOEt (150 mL) and H2O (70 mL). The AcOEt layer was
washed with satd NaCl and dried, and then the solvent was evap-

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K. Onda et al. / Bioorg. Med. Chem. 16 (2008) 10001–10012
vacuo, and the residue was diluted with H2O (100 mL), and then
extracted with CHCl3/i-PrOH (4:1, 2ꢂ 100mL). The organic layer
was washed with satd NaCl, and then dried and concentrated in va-
cuo. The residue was purified via column chromatography on silica
gel (n-hexane/AcOEt = 4:1) to yield 12 (107 mg, 34%) as a colorless
solid. 1H NMR (400 MHz, DMSO-d6) d: 0.87 (3H, s), 0.93 (3H, s),
1.43–1.52 (1H, m), 1.69–1.78 (1H, m), 2.64–2.82 (2H, m), 4.07
(1H, d, J = 6.3 Hz), 5.00 (1H, d, J = 6.3 Hz), 7.22 (1H, dd, J = 8.8,
1.9 Hz), 7.34–7.40 (2H, m), 7.45–7.52 (2H, m), 7.57 (1H, dd,
J = 8.3, 1.9 Hz), 7.76 (1H, d, J = 1.9 Hz), 10.16 (1H, s), 11.88 (1H, s).
FABMS m/z: 369 (M+1)+.
5.1.13. 5-Chloro-N-(6,6-difluoro-5-hydroxy-5,6,7,8-
tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (15)
The title compound was prepared in the same manner as de-
scribed for 12 using 14 instead of 11, which resulted in a 57% yield.
1H NMR (400 MHz, DMSO-d6) d: 2.15–2.42 (2H, m), 2.89–3.01 (2H,
m), 4.63 (1H, dt, J = 6.9, 11.7 Hz), 6.03 (1H, d, J = 6.9 Hz), 7.23 (1H,
dd, J = 8.8, 2.0 Hz), 7.38 (1H, d, J = 8.8 Hz), 7.41 (1H, s), 7.48 (1H, d,
J = 8.8 Hz), 7.62 (1H, s), 7.67 (1H, dd, J = 8.8, 2.0 Hz), 7.77 (1H, d,
J = 2.0 Hz), 10.26 (1H, s), 11.91 (1H, s). FABMS m/z: 377 (M+1)+.
5.1.14. tert-Butyl (5-bromo-2-methoxyphenyl)carbamate (18a)
1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione
(7.86 g,
5.1.11. N-(6,6-Difluoro-5-oxo-5,6,7,8-tetrahydronaphthalen-2-
yl)-2,2,2-trifluoroacetamide (13)
27.5 mmol) was added to a solution of 16a (7.61 g, 50.0 mmol) in
aq NaOH (2.8%, 80 mL), and then the mixture was stirred at room
temperature for 31 h. H2O (200 mL) was added to the resulting
mixture and washed with AcOEt (200 mL). The water layer was
acidified (pH 3) by adding 1 M HCl, and then extracted with CHCl3
(2ꢂ 200 mL). The AcOEt layer was washed with satd NaCl, and then
dried and concentrated in vacuo to yield 5-bromo-2-methoxyben-
zoic acid as a colorless solid (8.74 g, 76%). 1H NMR (400 MHz,
CDCl3) d: 4.07 (3H, s), 6.96 (1H, d, J = 9.2 Hz), 7.66 (1H, dd, J = 8.8,
2.8 Hz), 8.28 (1H, d, J = 2.4 Hz), 10.66 (1H, s). i-Pr2NEt (7.90 mL,
45.3 mmol) and DPPA (9.80 mL, 45.4 mmol) were added to a solu-
tion of the product obtained above (8.72 g, 37.7 mmol) in t-BuOH/
toluene (1:1, 200 mL), and then the mixture was stirred under re-
flux for 33 h. The resulting mixture was concentrated in vacuo, and
the residue was partitioned between CHCl3 (2ꢂ 200 mL) and 1 M
NaOH (200 mL), and the CHCl3 layer was washed with satd NaCl,
and then dried and concentrated in vacuo. The residue was purified
via column chromatography on silica gel (n-hexane/AcOEt = 9:1) to
yield 18a as an oily product (13.6 g, quant.). 1H NMR (400 MHz,
CDCl3) d: 1.52 (9H, s), 3.83 (3H, s), 6.68 (1H, d, J = 8.8 Hz), 7.03–
7.07 (2H, m), 8.28 (1H, s). FABMS m/z: 300 (Mꢁ1)ꢁ.
A mixture of 4b (3.68 g, 22.8 mmol) and trifluoroacetic anhy-
dride (7.36 g, 35.0 mmol) in CHCl3 (30 mL) was stirred at room
temperature for 1.5 h. The reaction mixture was concentrated
in vacuo, and the residue was purified via column chromatogra-
phy on silica gel (CHCl3). The obtained solid was recrystallized
from MeOH to yield N-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-
yl)-2,2,2-trifluoroacetamide as a brownish solid (3.41 g, 58%).
1H NMR (400 MHz, CDCl3) d: 2.10–2.20 (2H, m), 2.66 (2H, t,
J = 7.0 Hz), 2.99 (2H, t, J = 6.1 Hz), 7.38 (1H, dd, J = 8.4, 2.2 Hz),
7.72 (1H, d, J = 0.9 Hz), 8.05 (1H, d, J = 8.6 Hz), 8.46 (1H, s). FAB-
MS m/z: 258 (M+1)+. NaHMDS-THF solution (1.0 M, 14 mL) was
added to a solution of this material (1.00 g, 3.89 mmol) in THF
(40 mL) at ꢁ78 °C under an argon atmosphere, and then the
mixture was stirred at 0 °C for 30 min. After cooling at ꢁ78 °C,
a solution of N-fluorobenzenesulfonimide (5.0 g, 15.9 mmol) in
THF (20 mL) was added to the mixture and stirred at room tem-
perature for 3.5 h. HCl (1 M, 20 mL) was added to the reaction
mixture and concentrated in vacuo. The residue was diluted with
AcOEt (100 mL), and washed with 1 M HCl (2ꢂ 30 mL) and satd
NaCl, and then the organic layer was dried and concentrated in
vacuo. The residue was purified via column chromatography on
silica gel (n-hexane/AcOEt = 3:1), and the material obtained
was washed with CHCl3 to yield 13 (744 mg, 65%) as a colorless
solid. 1H NMR (400 MHz, DMSO-d6) d: 2.62–2.73 (2H, m), 3.16
(2H, t, J = 6.3 Hz), 7.75 (1H, dd, J = 8.3, 2.2 Hz), 7.81 (1H, d,
J = 1.9 Hz), 8.04 (1H, d, J = 8.3 Hz), 11.65 (1H, s). FABMS m/z:
294 (M+1)+.
5.1.15. tert-Butyl (3-bromo-2-methoxyphenyl)carbamate (18b)
The title compound was prepared in the same manner as de-
scribed for the later part in 18a using 16b which resulted in an
89% yield. 1H NMR (400 MHz, DMSO-d6) d: 1.47 (9H, s), 3.73 (3H,
s), 7.02 (1H, t, J = 7.8 Hz), 7.30 (1H, dd, J = 1.4, 7.8 Hz), 7.50 (1H,
dd, J =1.5, 7.8 Hz), 8.52 (1H, s). EIMS m/z: 302 (M)+.
5.1.16. tert-Butyl (5-bromo-2-fluorophenyl)carbamate (18c)
n-BuLi (1.55 M, 90 mL, 140 mmol) was added to a solution of
N,N-diisopropylamine (21.6 mL, 154 mmol) in THF (100 mL) at
0 °C, and the mixture was stirred under an Ar atmosphere for 30
min. After cooling at ꢁ78 °C a solution of 17a (24.5 g, 140 mmol)
in THF (150 mL) was added to the mixture and stirred at the same
temperature for 1 h. The mixture obtained above was added to a
stirred suspension of CO2 (solid) in THF (250 mL), and the resulting
mixture was warmed to room temperature and quenched by add-
ing 0.5 M HCl (200 mL). This mixture was then concentrated and
0.5 M NaOH was added (pH 8), after which it was washed with
AcOEt. The aqueous layer was acidified by adding 1 M HCl, and
then extracted with CHCl3 (2ꢂ 200 mL). The organic layer was
washed with satd NaCl and dried, and then concentrated in vacuo
to yield 5-bromo-2-fluorobenzoic acid as a colorless solid (29.0 g,
86%). 1H NMR (DMSO-d6) d: 7.30–7.36 (1H, m), 7.80–7.86 (1H,
m), 7.96 (1H, dd, J = 6.0, 2.4 Hz), 13.52 (1H, s). FABMS m/z: 217
(Mꢁ1)ꢁ. i-Pr2NEt (9.54 mL, 54.8 mmol), and DPPA (10.0 mL,
57.1 mmol) were added to a suspension of the product obtained
above (10.0 g, 45.7 mmol) in t-BuOH/toluene (1:1, 120 mL), and
then the mixture was stirred under reflux for 2 d. The resulting
mixture was concentrated in vacuo, the residue was partitioned
between CHCl3 (500 mL) and H2O (500 mL), and the organic layer
was washed with satd NaCl, after which it was dried and concen-
trated in vacuo. The residue was purified via column chromatogra-
5.1.12. 6-Amino-2,2-difluoro-1,2,3,4-tetrahydronaphthalen-1-
ol (14)
A mixture of 13 (335 mg, 1.14 mmol) and K2CO3 (200 mg,
1.45 mmol) in MeOH (3 mL) and H2O (2 mL) was stirred at room
temperature for 19 h. H2O (30 mL) was added to the reaction mix-
ture, and the precipitate was collected, washed with H2O, and
dried at 60 °C to yield N-(6,6-difluoro-5-oxo-5,6,7,8-tetra-
hydronaphthalen-2-yl)-2,2,2-trifluoroacetamide as
a
colorless
powder (179 mg, 80%). 1H NMR (400 MHz, DMSO-d6) d: 2.40–
2.55 (2H, m), 2.92 (2H, t, J = 6.4 Hz), 6.37 (1H, d, J = 2.2 Hz), 6.54–
6.57 (3H, m), 7.68 (1H, d, J = 8.8 Hz). FABMS m/z: 198 (M+1)+.
NaBH4 (100 mg, 2.64 mmol) was added to the product obtained
above (175 mg, 0.887 mmol) dissolved in a solution of MeOH
(5 mL), and then the mixture was stirred at room temperature
for 2 h. The resulting mixture was concentrated in vacuo, and the
residue was partitioned between AcOEt (50 mL) and H2O (20 mL),
and the AcOEt layer was washed with satd NaCl, and then dried
and concentrated in vacuo. The residue was purified via column
chromatography on silica gel (CHCl3/MeOH = 10:1) to yield 14
(165 mg, 93%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6):
1.98–2.12 (1H, m), 2.20–2.37 (1H, m), 2.65–2.84 (2H, m), 4.38–
4.46 (1H, m), 5.03 (2H, s), 5.64 (1H, d, J = 6.6 Hz), 6.29 (1H, d,
J = 2.0 Hz), 6.44 (1H, dd, J = 8.2, 2.2 Hz), 6.99 (1H, d, J = 8.2 Hz).
EIMS m/z: 199 (M)+.

K. Onda et al. / Bioorg. Med. Chem. 16 (2008) 10001–10012
10009
phy on silica gel (n-hexane/AcOEt = 20:1) to yield 18c (4.48 g, 34%)
5.1.24. tert-Butyl [5-(4-hydroxybutyl)-2-methoxyphenyl]-
carbamate (20a)
as a colorless solid. 1H NMR (DMSO-d6) d: 1.46 (9H, s), 7.16–7.29
(2H, m), 7.85–7.92 (1H, m), 9.22 (1H, s). FABMS m/z: 288 (Mꢁ1)ꢁ.
A mixture of 19a (14.0 g, 48.0 mmol) and Pd/C (10 w/w%,
2.80 g) in EtOH/MeOH/THF (10:10:1, 220 mL) was stirred under a
hydrogen atmosphere at room temperature for 12 h. The catalyst
was filtered through celite, and the filtrate was concentrated in va-
cuo to yield 20a (12.3 g, 87%) as a light brown oil. 1H NMR
(400 MHz, CDCl3) d: 1.52 (9H, s), 1.55–1.70 (5H, m), 2.58 (2H, t,
J = 7.6 Hz), 3.62 (2H, t, J = 6.8 Hz), 3.83 (3H, s), 6.74–6.78 (2H, m),
7.07 (1H, s), 7.93 (1H, s). FABMS m/z: 296 (M+1)+.
5.1.17. tert-Butyl (3-bromo-2-fluorophenyl)carbamate (18d)
The title compound was prepared in the same manner as de-
scribed for 18c using 17b instead of 17a, which resulted in a 68%
yield (for two steps). 1H NMR (DMSO-d6) d: 1.46 (9H, s), 7.09
(1H, t, J = 8.0 Hz), 7.35–7.42 (1H, m), 7.55–7.65 (1H, m), 9.16 (1H,
s).
5.1.18. tert-butyl (3-bromo-2,6-difluorophenyl)carbamate (18e)
The title compound was prepared in the same manner as de-
scribed for 18c using 17c instead of 17a, which resulted in an
85% yield (for two steps). NMR (DMSO-d6) d: 1.43 (9H, s), 7.17
(1H, dd, J = 9.3, 2.0 Hz), 7.64 (1H, ddd, J = 9.3, 7.8, 5.9 Hz), 9.03
(1H, s). FABMS m/z: 307 (Mꢁ1)ꢁ.
5.1.25. tert-Butyl [3-(4-hydroxybutyl)-2-methoxyphenyl]-
carbamate (20b)
The title compound was prepared in the same manner as de-
scribed for 20a using 19b instead of 19a, which resulted in a 93%
yield. 1H NMR (400 MHz, CDCl3) d: 1.53 (9H, s), 1.55–1.74 (5H,
m), 2.66 (2H, t, J = 7.4 Hz), 3.67 (2H, t, J = 6.4 Hz), 3.74 (3H, s),
6.84 (1H, dd, J = 1.4, 8.0 Hz), 6.98 (1H, s), 7.02 (1H, t, J = 8.0 Hz),
7.90 (1H, d, J = 8.0 Hz). FABMS m/z: 296 (M+1)+.
5.1.19. tert-Butyl [5-(4-hydroxybut-1-yn-1-yl)-2-methoxyphenyl]-
carbamate (19a)
Pd(PPh3)4 (13.5 g, 11.7 mmol), CuI (4.46 g, 23.4 mmol), and 3-
butyn-1-ol (17.7 mL, 234 mmol) were added to a solution of 18a
(35.4 g, 117 mmol) in i-Pr2NH (260 mL) under an argon atmo-
sphere, and then the mixture was stirred under reflux for 3 h. After
cooling to room temperature, the precipitate was removed via fil-
tration and washed with AcOEt (200 mL), after which the filtrate
was concentrated in vacuo. The residue was purified via column
chromatography on silica gel (n-hexane/AcOEt = 3:1) to yield 19a
(14.0 g, 41%) as a colorless oil. 1H NMR (400 MHz, CDCl3) d: 1.52
(9H, s), 1.90–2.00 (1H, m), 2.65 (2H, t, J = 6.0 Hz), 3.78 (2H, q,
J = 6.0 Hz), 3.86 (3H, s), 6.74 (1H, d, J = 8.0 Hz), 7.00–7.06 (2H, m),
8.18 (1H, s). FABMS m/z: 290 (Mꢁ1)ꢁ.
5.1.26. tert-Butyl [5-(4-hydroxybutyl)-2-fluorophenyl]-
carbamate (20c)
The title compound was prepared in the same manner as de-
scribed for 20a using 19c instead of 19a, in quantitative yield. 1H
NMR (400 MHz, CDCl3) d: 1.53 (9H, s), 1.55–1.70 (4H, m), 2.60
(2H, t, J = 7.2 Hz), 3.64 (2H, t, J = 6.4 Hz), 6.70 (1H, s), 6.74–6.78
(1H, m), 6.91–6.97 (1H, m), 7.91 (1H, d, J = 7.2 Hz). FABMS m/z:
284 (M+1)+.
5.1.27. tert-Butyl [3-(4-hydroxybutyl)-2-fluorophenyl]-
carbamate (20d)
The title compound was prepared in the same manner as de-
scribed for 20a using 19d instead of 19a, in quantitative yield. 1H
NMR (400 MHz, CDCl3) d: 1.40–1.75 (13H, m), 2.67 (2H, t,
J = 7.1 Hz), 3.60–3.73 (2H, m), 6.70 (1H, s), 6.82 (1H, t, J = 7.1 Hz),
7.01 (1H, t, J = 7.9 Hz), 7.85–7.97 (1H, m).
5.1.20. tert-Butyl [3-(4-hydroxybut-1-yn-1-yl)-2-methoxyphenyl]-
carbamate (19b)
The title compound was prepared in the same manner as de-
scribed for 19a using 18b instead of 18a, which resulted in a 91%
yield. 1H NMR (400 MHz, CDCl3) d: 1.53 (9H, s), 2.03 (1H, t,
J = 6.2 Hz), 2.74 (2H, t, J = 6.4 Hz), 3.81–3.86 (2H, m), 3.98 (3H, s),
6.99 (1H, t, J = 8.0 Hz), 7.02 (1H, dd, J = 2.2, 8.0 Hz), 7.10 (1H, s),
8.06 (1H, d, J = 8.0 Hz). FABMS m/z: 292 (M+1)+.
5.1.28. tert-Butyl [2,6-difluoro-3-(4-hydroxybutyl)phenyl]-
carbamate (20e)
The title compound was prepared in the same manner as de-
scribed for 20a using 19e instead of 19a, which resulted in an
86% yield. 1H NMR (300 MHz, CDCl3) d: 1.50 (9H, s), 1.52–1.72
(4H, m), 2.64 (2H, t, J = 7.2 Hz), 3.63–3.70 (2H, m), 5.93 (1H, s),
6.84 (1H, dt, J = 1.7, 8.8 Hz), 6.95–7.04 (1H, m). FABMS m/z: 302
(M+1)+.
5.1.21. tert-Butyl [5-(4-hydroxybut-1-yn-1-yl)-2-fluorophenyl]-
carbamate (19c)
The title compound was prepared in the same manner as de-
scribed for 19a, using 18c instead of 18a, which resulted in a 97%
yield. 1H NMR (400 MHz, CDCl3) d: 1.53 (9H, s), 1.87 (1H, t,
J = 6.0 Hz), 2.65 (2H, t, J = 6.4 Hz), 3.79 (2H, q, J = 6.0 Hz), 6.68
(1H, s), 6.93–7.05 (2H, m), 8.20 (1H, d, J = 7.2 Hz). FABMS m/z: FAB-
MS m/z: 278 (Mꢁ1)ꢁ.
5.1.29. 4-{3-[(tert-Butoxycarbonyl)amino]-4-methoxyphenyl}-
butanoic acid (21a)
2.67 M Jones reagent (27.8 mL) was added to a solution of 20a
(12.2 g, 41.3 mmol) in acetone (300 mL) at 0 °C, and the mixture
was stirred at the same temperature for 1.5 h. i-PrOH (200 mL)
was added to the reaction mixture, and the precipitate was re-
moved via filtration. The filtrate was then concentrated in vacuo.
NaOH (1 M, 500 mL) was added to the residue and washed with
CHCl3 (300 mL), after which the aqueous layer was neutralized
by adding 1 M HCl and extracted with CHCl3 (3ꢂ 500 mL). The or-
ganic layer was washed with satd NaCl, dried, and then concen-
trated in vacuo to yield 21a (10.0 g, 79%) as a brown oil. 1H NMR
(400 MHz, CDCl3) d: 1.52 (9H, s), 1.90–2.00 (2H, m), 2.35 (2H, t,
J = 7.2 Hz), 2.62 (2H, t, J = 8.0 Hz), 3.84 (3H, s), 6.74–6.78 (2H, m),
7.07 (1H, s), 7.92 (1H, s). FABMS m/z: 310 (M+1)+.
5.1.22. tert-Butyl [3-(4-hydroxybut-1-yn-1-yl)-2-
fluorophenyl]carbamate (19d)
The title compound was prepared in the same manner as de-
scribed for 19a using 18d instead of 18a, in quantitative yield. 1H
NMR (400 MHz, CDCl3) d: 1.53 (9H, s), 2.73 (2H, t, J = 6.2 Hz),
3.83 (2H, q, J = 6.2 Hz), 4.12 (1H, q, J = 7.1 Hz), 6.69 (1H, s), 7.00–
7.07 (2H, m), 7.98–8.08 (1H, m). EIMS m/z: 279 (M+).
5.1.23. tert-Butyl [2,6-difluoro-3-(4-hydroxybut-1-yn-1-
yl)phenyl]carbamate (19e)
The title compound was prepared in the same manner as de-
scribed for 19a using 18e instead of 18a, which resulted in an
88% yield. 1H NMR (300 MHz, CDCl3) d: 1.50 (9H, s), 2.71 (2H, t,
J = 6.2 Hz), 3.82 (2H, q, J = 6.3 Hz), 5.97 (1H, s), 7.12 (1H, dt,
J = 1.4, 8.8 Hz), 7.19–7.28 (1H, m). FABMS m/z: 296 (Mꢁ1)ꢁ.
5.1.30. 4-{3-[(tert-Butoxycarbonyl)amino]-2-methoxyphenyl}-
butanoic acid (21b)
The title compound was prepared in the same manner as de-
scribed for 21a using 20b instead of 20a, which resulted in a 91%

10010
K. Onda et al. / Bioorg. Med. Chem. 16 (2008) 10001–10012
yield. 1H NMR (400 MHz, CDCl3) d: 1.53 (9H, s), 1.96 (2H, q,
J = 7.6 Hz), 2.39 (2H, t, J = 7.6 Hz), 2.69 (2H, t, J = 7.6 Hz), 3.74
(3H, s), 6.83 (1H, dd, J = 0.8, 7.6 Hz), 7.01 (1H, s), 7.03 (1H, t,
J = 7.6 Hz), 7.91 (1H, d, J = 7.6 Hz). FABMS m/z: 310 (M+1)+.
2.43 (2H, t, J = 7.1 Hz), 2.81 (2H, t, J = 6.1 Hz), 6.08 (2H, s), 6.66
(1H, t, J = 8.6 Hz), 7.48 (1H, d, J = 8.3 Hz). FABMS m/z: 180 (M+1)+.
5.1.38. 6-Amino-5,7-difluoro-3,4-dihydronaphthalen-1(2H)-
one (22e)
5.1.31. 4-{3-[(tert-Butoxycarbonyl)amino]-4-fluorophenyl}-
butanoic acid (21c)
The title compound was prepared in the same manner as de-
scribed for 22a using 21e instead of 21a, which resulted in a 66%
yield. 1H NMR (400 MHz, DMSO-d6) d: 1.96–2.02 (2H, m), 2.33–
2.47 (2H, m), 2.80 (2H, t, J = 6.1 Hz), 6.21 (2H, br s), 7.33 (1H, dd,
J = 11.5, 1.2 Hz). FABMS m/z: 198 (M+1)+.
The title compound was prepared in the same manner as de-
scribed for 21a using 20c instead of 20a, which resulted in a 91%
yield. 1H NMR (400 MHz, DMSO-d6) d: 1.46 (9H, s), 1.72–1.80
(2H, m), 2.21 (2H, t, J = 7.2 Hz), 2.54 (2H, t, J = 7.2 Hz), 6.85–6.92
(1H, m), 7.04–7.10 (1H, m), 7.43 (1H, d, J = 6.4 Hz), 8.84 (1H, s),
11.99 (1H, s). FABMS m/z: 298 (M+1)+.
5.1.39. N-(6,6-Difluoro-3-methoxy-5-oxo-5,6,7,8-
tetrahydronaphthalen-2-yl)-2,2,2-trifluoroacetamide (23a)
Trifluoroacetic anhydride (3.79 mL, 27.1 mmol) was added to a
solution of 22a (2.59 g, 13.5 mmol) in CHCl3 (100 mL) at 0 °C and
the mixture was stirred at room temperature for 1 h. This reaction
mixture was concentrated in vacuo, and the residue was purified
via column chromatography on silica gel (n-hexane/AcOEt = 4:1)
5.1.32. 4-{3-[(tert-Butoxycarbonyl)amino]-2-fluorophenyl}-
butanoic acid (21d)
The title compound was prepared in the same manner as de-
scribed for 21a using 20d instead of 20a, which resulted in a 64%
yield. 1H NMR (400 MHz, DMSO-d6) d: 1.45 (9H, s), 1.73–1.81
(2H, m), 2.23 (2H, t, J = 7.3 Hz), 2.61 (2H, t, J = 7.8 Hz), 6.94–7.06
(2H, m), 7.43 (1H, t, J = 7.4 Hz), 8.84 (1H, s), 12.07 (1H, s). FABMS
m/z: 296 (Mꢁ1)ꢁ.
to
yield
2,2,2-trifluoro-N-(3-methoxy-5-oxo-5,6,7,8-tetra-
colorless solid (3.56 g,
hydronaphthalen-2-yl)acetamide as
a
92%). 1H NMR (400 MHz, CDCl3) d: 2.10–2.18 (2H, m), 2.64 (2H, t,
J = 7.2 Hz), 2.94 (2H, t, J = 6.0 Hz), 3.97 (3H, s), 7.57 (1H, s), 8.27
(1H, s), 8.71 (1H, s). FABMS m/z: 288 (M+1)+. NaHMDS (43 mL,
1.0 M in THF) was added to a solution of this material in THF
(150 mL) at ꢁ78 °C under an argon atmosphere, and the mixture
was stirred at 0 °C for 1 h, and then N-fluorobenzenesulfonimide
(15.6 g, 49.4 mmol) was added at ꢁ78 °C. After stirring for 1 h at
0 °C, the reaction was quenched by adding 1 M HCl (60 mL), and
then concentrated. The residue was partitioned between CHCl3
(200 mL) and 1 M HCl (100 mL), and the CHCl3 layer was washed
with H2O (100 mL) and satd NaCl, after which it was dried and con-
centrated in vacuo. The residue was purified via column chroma-
tography on silica gel (n-hexane/AcOEt = 5:1) to yield 23a as a
colorless solid, which included inseparable materials; therefore,
further purification was not attempted. 1H NMR (400 MHz, CDCl3)
5.1.33. 4-{3-[(tert-Butoxycarbonyl)amino]-2,4-difluorophenyl}-
butanoic acid (21e)
The title compound was prepared in the same manner as de-
scribed for 21a using 20e instead of 20a, which resulted in a 55%
yield. 1H NMR (400 MHz, DMSO-d6) d: 1.42 (9H, s), 1.71–1.79
(2H, m), 2.22 (2H, t, J = 7.3 Hz), 2.59 (2H, t, J = 7.6 Hz), 7.03 (1H, t,
J = 8.8 Hz), 7.16 (1H, dt, J = 6.4, 8.8 Hz), 8.73 (1H, br s), 12.08 (1H,
br s). FABMS m/z: 314 (Mꢁ1)ꢁ.
5.1.34. 6-Amino-7-methoxy-3,4-dihydronaphthalen-1(2H)-one
(22a)
A mixture of P2O5 (120 g) and phosphoric acid (60 mL) was
heated at 150 °C for 1 h, and then 21a (10.0 g, 32.3 mmol) was added
at 120 °C. The mixture was stirred at the same temperature for 1 h,
and then H2O (500 mL) was added slowly at room temperature
and extracted with CHCl3 (3ꢂ 500 mL). The CHCl3 layer was washed
with 1 M NaOH (500 mL), H2O (500 mL), and satd NaCl, and then
dried and concentrated in vacuo. The residue was purified via col-
umn chromatography on silica gel (n-hexane/AcOEt = 4:1) to yield
22a (2.60 g, 41%) as a yellow solid. 1H NMR (400 MHz, CDCl3) d:
2.03–2.10 (2H, m), 2.56 (2H, t, J = 6.8 Hz), 2.79 (2H, t, J = 6.0 Hz),
3.88 (3H, s), 4.31 (2H, s), 6.85 (1H, s), 7.44 (1H, s). FABMS m/z: 192
(M+1)+.
d: 2.50–2.65 (2H, m), 3.16 (2H, t, J = 6.0 Hz), 4.01 (3H, s), 7.60 (1H,
s), 8.33 (1H, s), 8.76 (1H, s). FABMS m/z: 324 (M+1)+.
5.1.40. N-(6,6-Difluoro-1-methoxy-5-oxo-5,6,7,8-
tetrahydronaphthalen-2-yl)-2,2,2-trifluoroacetamide (23b)
The title compound was prepared in the same manner as de-
scribed for 23a using 22b instead of 22a, which resulted in a 73%
yield (for 2 steps). 1H NMR (300 MHz, CDCl3) d: 2.50–2.65 (2H,
m), 3.21 (2H, t, J = 6.3 Hz), 3.88 (3H, s), 8.01 (1H, d, J = 8.7 Hz),
8.41 (1H, d, J = 8.7 Hz), 8.66 (1H, s). FABMS m/z: 324 (M+1)+.
5.1.41. 2,2,2-Trifluoro-N-(3,6,6-trifluoro-5-oxo-5,6,7,8-
tetrahydronaphthalen-2-yl)acetamide (23c)
5.1.35. 6-Amino-5-methoxy-3,4-dihydronaphthalen-1(2H)-one
(22b)
The title compound was prepared in the same manner as de-
scribed for 23a using 22c instead of 22a, which resulted in a 13%
yield (for two steps). 1H NMR (400 MHz, CDCl3) d: 2.54–2.64 (2H,
m), 3.21 (2H, t, J = 6.0 Hz), 7.88 (1H, d, J = 10.8 Hz), 8.30 (1H, s),
8.37 (1H, d, J = 7.2 Hz). FABMS m/z: 310 (M-1)-.
The title compound was prepared in the same manner as de-
scribed for 22a using 21b instead of 21a, which resulted in a 46%
yield. 1H NMR (400 MHz, CDCl3) d: 2.03–2.10 (2H, m), 2.56 (2H, t,
J = 6.4 Hz), 2.93 (2H, t, J = 6.4 Hz), 3.75 (3H, s), 4.28 (2H, s), 6.64
(1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.6 Hz). FABMS m/z: 192 (M+1)+.
5.1.42. 2,2,2-Trifluoro-N-(1,6,6-trifluoro-5-oxo-5,6,7,8-
tetrahydronaphthalen-2-yl)acetamide (23d)
5.1.36. 6-Amino-7-fluoro-3,4-dihydronaphthalen-1(2H)-one (22c)
The title compound was prepared in the same manner as de-
scribed for 22a using 21c instead of 21a, which resulted in a 37%
yield. 1H NMR (400 MHz, DMSO-d6) d: 1.90–2.00 (2H, m), 2.42
(2H, t, J = 6.0 Hz), 2.73 (2H, t, J = 6.0 Hz), 6.12 (2H, s), 6.55 (1H, d,
J = 8.4 Hz), 7.37 (1H, d, J = 12.4 Hz). EIMS m/z: 179 (M+).
The title compound was prepared in the same manner as de-
scribed for 23a using 22d instead of 22a, which resulted in an
82% yield (for two steps). 1H NMR (400 MHz, DMSO-d6) d: 2.68–
2.81 (2H, m), 3.14 (2H, t, J = 6.3 Hz), 7.70 (1H, t, J = 7.4 Hz), 7.90
(1H, d, J = 8.8 Hz), 11.67 (1H, s). FABMS m/z: 312 (M+1)+.
5.1.37. 6-Amino-5-fluoro-3,4-dihydronaphthalen-1(2H)-one (22d)
The title compound was prepared in the same manner as de-
scribed for 22a using 21d instead of 21a, which resulted in an
89% yield. 1H NMR (400 MHz, DMSO-d6) d: 1.93–2.02 (2H, m),
5.1.43. 2,2,2-Trifluoro-N-(1,3,6,6-tetrafluoro-5-oxo-5,6,7,8-
tetrahydronaphthalen-2-yl)acetamide (23e)
The title compound was prepared in the same manner as de-
scribed for 23a using 22e instead of 22a, which resulted in a 71%

K. Onda et al. / Bioorg. Med. Chem. 16 (2008) 10001–10012
10011
yield (for two steps). 1H NMR (400 MHz, DMSO-d6) d: 2.71–2.83
(2H, m), 3.11 (2H, t, J = 6.2 Hz), 7.82 (1H, dd, J = 9.2, 1.4 Hz),
11.92 (1H, s). FABMS m/z: 328 (Mꢁ1)ꢁ.
5.1.49. 5-Chloro-N-(6,6-difluoro-5-hydroxy-3-methoxy-5,6,7,8-
tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (25a)
The title compound was prepared in the same manner as de-
scribed for 12 using 24a instead of 11, which resulted in a 66%
yield. 1H NMR (400 MHz, DMSO-d6) d: 2.15–2.42 (2H, m), 2.82–
2.98 (2H, m), 3.85 (3H, s), 4.61–4.70 (1H, m), 6.11 (1H, d,
J = 6.8 Hz), 7.08 (1H, s), 7.22 (1H, dd, J = 8.8, 2.0 Hz), 7.34 (1H, s),
7.47 (1H, d, J = 8.8 Hz), 7.57 (1H, s), 7.73 (1H, d, J = 2.0 Hz), 9.52
(1H, s), 11.94 (1H, s). FABMS m/z: 407 (M+1)+.
5.1.44. 6-Amino-2,2-difluoro-7-methoxy-3,4-
dihydronaphthalen-1-ol (24a)
A mixture of crude 23a and K2CO3 (5.10 g, 36.9 mmol) in MeOH/
H2O (5:2, 70 mL) was stirred at 70 °C for 2 h. The mixture was con-
centrated in vacuo and H2O (100 mL) was added, followed by
extraction with AcOEt (2ꢂ 100 mL). The AcOEt layer was washed
with H2O (50 mL) and satd NaCl, and then dried and concentrated
5.1.50. 5-Chloro-N-(6,6-difluoro-5-hydroxy-1-methoxy-5,6,7,8-
tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (25b)
The title compound was prepared in the same manner as de-
scribed for 12 using 24b instead of 11, which resulted in a 73%
yield. 1H NMR (400 MHz, DMSO-d6) d: 2.18–2.40 (2H, m), 2.86–
3.02 (2H, m), 3.70 (3H, s), 4.66 (1H, dt, J = 6.8, 12.2 Hz), 6.14 (1H,
d, J = 6.8 Hz), 7.22 (1H, d, J = 8.3 Hz), 7.23 (1H, dd, J = 8.7, 2.0 Hz),
7.41 (1H, d, J = 1.4 Hz), 7.47 (1H, d, J = 8.7 Hz), 7.60 (1H, d,
J = 8.3 Hz), 7.75 (1H, d, J = 2.0 Hz), 9.82 (1H, s), 11.98 (1H, s). FABMS
m/z: 407 (M+1)+.
in
vacuo
to
yield
6-amino-2,2-difluoro-7-methoxy-3,4-
dihydronaphthalen-1(2H)-one as a colorless solid (1.10 g, 36% for
2 steps). 1H NMR (400 MHz, CDCl3) d: 2.42–2.57 (2H, m), 3.00
(2H, t, J = 6.6 Hz), 3.90 (3H, s), 4.56 (2H, s), 6.43 (1H, s), 7.45 (1H,
s). EIMS m/z: 227 (M)+. NaBH4 (98 mg, 2.59 mmol) was added to
a solution of this material (490 mgl) in MeOH (40 mL), and the
mixture was stirred at room temperature for 12 h. The resulting
mixture was concentrated in vacuo, and the residue was parti-
tioned between CHCl3/i-PrOH (3:1, 80 mL) and satd NaCl (50 mL),
and the organic layer was dried and concentrated in vacuo to yield
24a (480 mg, 16% from 22a) as a yellow solid. 1H NMR (400 MHz,
CDCl3) d: 2.05–2.25 (1H, m), 2.30–2.55 (2H, m), 2.77–2.97 (2H,
m), 3.86 (3H, s), 4.63–4.75 (1H, m), 6.46 (1H, s), 6.84 (1H, s). EIMS
m/z: 229 (M)+.
5.1.51. 5-Chloro-N-(3,6,6-trifluoro-5-hydroxy-5,6,7,8-
tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (25c)
The title compound was prepared in the same manner as de-
scribed for 12 using 24c instead of 11, which resulted in an 85%
yield. 1H NMR (400 MHz, DMSO-d6) d: 2.18–2.40 (2H, m), 2.86–
3.02 (2H, m), 4.65–4.75 (1H, m), 6.25 (1H, d, J = 6.9 Hz), 7.23 (1H,
dd, J = 8.8, 2.4 Hz), 7.28 (1H, d, J = 11.2 Hz), 7.38 (1H, s), 7.40–
7.49 (2H, m), 7.77 (1H, d, J = 2.0 Hz), 10.22 (1H, s), 11.97 (1H, s).
FABMS m/z: 395 (M+1)+.
5.1.45. 6-Amino-2,2-difluoro-5-methoxy-3,4-
dihydronaphthalen-1-ol (24b)
The title compound was prepared in the same manner as de-
scribed for 24a using 23b instead of 23a, which resulted in an
82% yield. 1H NMR (400 MHz, DMSO-d6) d: 2.03–2.15 (1H, m),
2.20–2.36 (1H, m), 2.70–2.79 (1H, m), 2.85–2.93 (1H, m), 3.60
(3H, s), 4.41–4.47 (1H, m), 4.88 (2H, s), 5.70 (1H, d, J = 6.9 Hz),
6.61 (1H, d, J = 8.3 Hz), 6.84 (1H, d, J = 8.3 Hz). FABMS m/z: 230
(M+1)+.
5.1.52. 5-Chloro-N-(1,6,6-trifluoro-5-hydroxy-5,6,7,8-
tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (25d)
The title compound was prepared in the same manner as de-
scribed for 12 using 24d instead of 11, which resulted in a 39%
yield. 1H NMR (400 MHz, DMSO-d6) d: 2.20–2.48 (2H, m), 2.82–
3.03 (2H, m), 4.67–4.77 (1H, m), 6.27 (1H, d, J = 6.8 Hz), 7.26
(1H, dd, J = 8.8, 2.0 Hz), 7.29 (1H, d, J = 8.8 Hz), 7.39 (1H, d,
J = 1.9 Hz), 7.47 (1H, d, J = 8.8 Hz), 7.54 (1H, t, J = 8.3 Hz), 7.77
(1H, d, J = 1.4 Hz), 10.20 (1H, s), 11.97(1H,s). FABMS m/z: 395
(M+1)+.
5.1.46. 6-Amino-2,2,7-trifluoro-3,4-dihydronaphthalen-1-ol
(24c)
NaBH4 (109 mg, 2.89 mmol) and LiCl (123 mg, 2.89 mL) were
added to a solution of 23c (180 mg, 0.578 mmol) in MeOH/H2O
(4:1, 10 mL), and then the mixture was stirred at room tempera-
ture for 1 h. The mixture was concentrated in vacuo and H2O
(50 mL) was added. The resulting precipitate was collected and
washed with H2O, and then dried to yield 24c (80 mg, 64%) as a
colorless solid. 1H NMR (300 MHz, DMSO-d6) d: 2.00–2.40 (2H,
m), 2.70–2.81 (2H, m), 4.42–4.52 (1H, m), 5.13 (2H, s), 5.83 (1H,
d, J = 6.7 Hz), 6.49 (1H, d, J = 9.0 Hz), 6.93 (1H, d, J = 12.2 Hz). FAB-
MS m/z: 216 (M+1)+.
5.1.53. 5-Chloro-N-(1,3,6,6-tetrafluoro-5-hydroxy-5,6,7,8-
tetrahydronaphthalen-2-yl)-1H-indole-2-carboxamide (25e)
The title compound was prepared in the same manner as de-
scribed for 12 using 24e instead of 11, which resulted in a 76%
yield. 1H NMR (400 MHz, DMSO-d6) d: 2.25–2.44 (2H, m), 2.84–
2.94 (2H, m), 4.74–4.81 (1H, m), 6.43 (1H, d, J = 6.9 Hz), 7.24
(2H, d, J = 8.8 Hz), 7.38 (1H, s), 7.47 (1H, d, J = 8.8 Hz), 7.79
(1H, d, J = 1.5 Hz), 10.27 (1H, s), 11.99 (1H, s). FABMS m/z:
413 (M+1)+.
5.1.47. 6-Amino-2,2,5-trifluoro-3,4-dihydronaphthalen-1-ol
(24d)
The title compound was prepared in the same manner as de-
scribed for 24c using 23d instead of 23c, which resulted in a 63%
yield. 1H NMR (400 MHz, DMSO-d6) d: 2.06–2.20 (1H, m), 2.22–
2.40 (1H, m), 2.68–2.78 (1H, m), 2.82–2.91 (1H, m), 4.44–4.53
(1H, m), 5.09 (2H, s), 5.83 (1H, d, J = 6.4 Hz), 6.67 (1H, t,
J = 8.3 Hz), 6.88 (1H, d, J = 8.3 Hz). FABMS m/z: 216 (M+1)+.
5.1.54. (1R)-6-{[(5-Chloro-1H-indol-2-yl)carbonyl]amino}-
2,2,5,7-tetrafluoro-1,2,3,4-tetrahydronaphthalen-1-yl N-[(4-
methylphenyl)sulfonyl]-L-phenylalaninate (27)
n-BuLi (0.35 mL, 0.55 mmol, 1.56 M n-hexane solution) was
added dropwise to a solution of 25e (140 mg, 0.34 mmol) in THF
(6 mL) at 0 °C, and the mixture was stirred at room temperature
5.1.48. 6-Amino-2,2,5,7-tetrafluoro-1,2,3,4-
for 1 h. N-(p-Toluenesulfonyl)-L-phenylalanyl chloride (270 mg,
tetrahydronaphthalen-1-ol (24e)
0.80 mmol) was added to the mixture at 0 °C, and then stirring
was continued at room temperature for 27.5 h. After concentration
of the reaction mixture, H2O (20 mL) was added to the residue and
extracted with AcOEt (50mL). The AcOEt layer was washed with
satd NaCl, and then dried and concentrated in vacuo. The residue
was purified via column chromatography on silica gel (n-hexane/
AcOEt = 2:1) to yield 26 (92 mg, 38%) as a colorless foam. A solu-
The title compound was prepared in the same manner as de-
scribed for 24a using 23e instead of 23a, which resulted in a 65%
yield (for two steps). 1H NMR (400 MHz, DMSO-d6) d: 2.11–2.38
(2H, m), 2.67–2.86 (2H, m), 4.53 (1H, dd, J = 12.0, 7.1 Hz), 5.19
(2H, s), 5.99 (1H, s), 6.89 (1H, d, J = 11.2 Hz). FABMS m/z: 234
(Mꢁ1)ꢁ.

10012
K. Onda et al. / Bioorg. Med. Chem. 16 (2008) 10001–10012
tion of 26 (90 mg, 0.13 mmol) in CHCl3 (5 mL) was stirred at room
temperature, and the resulting precipitate was collected by filtra-
tion to yield 27 (35mg, 39%, 99% de). 1H NMR (400 MHz, DMSO-
d6) d: 2.20–2.50 (5H, m), 2.75–2.95 (4H, m), 4.11 (1H, q,
J = 3.4 Hz), 6.01–6.08 (1H, m), 6.78 (1H, d, J = 3.7 Hz), 7.02–7.06
(2H, m), 7.15–7.20 (3H, m), 7.23–7.29 (3H, m), 7.40 (1H, s), 7.45–
7.53 (3H, m), 7.80 (1H, d, J = 0.8 Hz), 8.61 (1H, d, J = 3.3 Hz), 10.36
(1H, s), 12.03 (1H, s). FABMS m/z: 714 (M+1)+.
References and notes
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Acknowledgments
The authors wish to thank Ms. Akiko Matsuyama-Yokono and
Ms. Fumie Narazaki for helpful support in the preparation of this
manuscript, and the staff of the Division of Analytical Science Lab-
oratories for the elemental analysis and spectral measurements.
The authors also wish to thank Dr. Hitoshi Sakashita, Dr. Hideaki
Nakahara, and Mr. Tatsuya Maruyama, for their support of this
work.
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