Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide, a potent and orally active neuropeptide Y Y5 receptor antagonist

Article abstract of DOI:10.1016/j.bmc.2009.08.019

A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.

Full text of DOI:10.1016/j.bmc.2009.08.019

Bioorganic & Medicinal Chemistry 17 (2009) 6971–6982
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Discovery of trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro-
[6-azaisobenzofuran-1(3H),10-cyclohexane]-40-carboxamide, a potent
and orally active neuropeptide Y Y5 receptor antagonist
Yuji Haga, Toshihiro Sakamoto, Takunobu Shibata, Katsumasa Nonoshita, Makoto Ishikawa, Takuya Suga,
Hirobumi Takahashi, Toshiyuki Takahashi, Hidekazu Takahashi, Makoto Ando, Takashi Murai, Akira Gomori,
Zenjun Oda, Hidefumi Kitazawa, Yuko Mitobe, Maki Kanesaka, Tomoyuki Ohe, Hisashi Iwaasa,
*
Yasuyuki Ishii, Akane Ishihara, Akio Kanatani, Takehiro Fukami
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba 300-2611, Japan
a r t i c l e i n f o
a b s t r a c t
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),10-cyclohexane]-40-carboxamide derivatives were
synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 bind-
ing affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility
to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced
food intake in rats with a minimum effective dose of 1 mg/kg. This compound was selected for proof-of-
concept studies in human clinical trials.
Article history:
Received 25 June 2009
Revised 5 August 2009
Accepted 5 August 2009
Available online 14 August 2009
Keywords:
Neuropeptide Y
NPY
Ó 2009 Elsevier Ltd. All rights reserved.
Y5 receptor
Antagonist
1. Introduction
brain-penetrant in rats and mice. Thus, this compound was a pri-
mary candidate for clinical trials. While 1 reduced the body weight
Neuropeptide Y (NPY) is a highly conserved C-terminus amidat-
ed peptide consisting of 36 amino acid residues and has been
shown to have potent, centrally-mediated orexigenic effects.1–4
At least 6 receptor subtypes of the NPY family have been character-
ized based on cloning and/or their pharmacological properties.5–19
Various pharmacological studies, employing receptor deficient
mice and/or subtype-selective agonists and antagonists, have sug-
gested that the Y1 and Y5 receptors are involved in body weight
regulation.14,16,20–33 Thus, antagonism of the Y1 and/or Y5 recep-
tors may have considerable therapeutic benefits for the treatment
of obesity. In diet-induced obese (DIO) mice, treatment with Y5
antagonists reduces body weight in a fat mass-selective manner,
implying that Y5 receptor antagonists are useful for the treatment
of obesity.33,34 We developed various potent and orally
bioavailable Y5 receptor antagonists.35–39 Of the Y5 antagonists, a
of DIO mice in a fat-selective manner, a relatively high dosage of
10 mg/kg was required to show significant efficacy.34 More potent
compounds could be required to produce clearer results in clinical
proof-of-concept studies, and we tried to derivatize 1 to obtain
more potent compounds in in vivo.
In vivo more potent compounds may exhibit stronger Y5 antag-
onistic activities as well as better pharmacokinetic profiles and bet-
ter penetration to the brain and cerebrospinal fluid (CSF). In the
spiro[3-oxoisobenzofurane-1(3H),40-piperidine]-urea
derivative
O
NH
N
N
1
spiro[3-oxoisobenzofurane-1(3H),40-piperidine]-urea
derivative
hY5 IC50: 2.4 nM
N
(1, Fig. 1) was potent at the Y5 receptor, orally bioavailable in
laboratory animals including rats, dogs and rhesus monkeys, and
O
O
* Corresponding author. Tel.: +81 29 877 2361; fax: +81 29 877 2029.
E-mail addresses: takehiro_fukami@merck.com, fukamith@riken.jp (T. Fukami).
Figure 1. Structure of compound 1.
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.08.019

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Y. Haga et al. / Bioorg. Med. Chem. 17 (2009) 6971–6982
Y5 antagonists, CSF levels were a better indicator to predict in vivo
efficacy;39 hence, CSF levels may be a more important parameter
than brain levels. In the course of our structure–activity studies of
spiropiperidine-urea NPY Y5 antagonists, we noticed that replace-
ment of the urea linkage with amide produced increased Y5 antag-
onistic activities. In addition, amide analogs tended to exhibit
better brain penetrability compared with the corresponding urea
analogs.38 In contrast, the urea to amide transformation increased
the lipophilicity of the compounds. Since higher lipophilic com-
pounds could show less CSF/brain ratios, too lipophilic compounds
could not produce very high CSF levels. If amide derivatives of
spiro[3-oxoisobenzofurane-1(3H),40-piperidine] can be appropri-
ately designed while maintaining appropriate lipophilicity, such
compounds may be highly potent at the Y5 receptor, orally avail-
able and well brain- and CSF-penetrant. This working hypothesis
prompted us to design and synthesize various 3-oxospiro[(aza)iso-
benzofuran-1(3H),10-cyclohexane]-40-carboxamide derivatives.
This effort resulted in the discovery of a series of highly potent Y5
antagonists exemplified by 21j, which was tested in clinical
proof-of-concept studies. An oral 1 mg/man dosing of 21j produced
almost complete Y5 receptor occupancy over 24 h and showed sta-
tistically significant reduction in body weight although the magni-
tude of induced weight loss was not clinically meaningful.40 In this
paper, we report discovery of trans-N-[1-(2-fluorophenyl)-3-pyraz-
2. Chemistry
The synthesis of 3-oxospiro[(aza)isobenzofuran-1(3H),10-cyclo-
hexane]-40-carboxamide derivatives comprises the synthesis
of trans-3-oxospiro[(aza)isobenzofuran-1(3H),10-cyclohexane]-40-
carboxylic acid portions (13–17) and subsequent coupling with
aromatic amine partners. 2-Bromobenzoic acid (2) and N-methyl-
2-pyridinecarboxamide (3) were reacted with n-BuLi (2.1 equiv) to
generate dianions, which were subsequently reacted with 1,4-cyclo-
hexanedione mono-ethyleneketal followed by acid-mediate hydro-
lysis to afford spiro[benzofurane-1(3H),10-cyclohexane]-3,40-dione
(10a) and spiro[4-azabenzofurane-1(3H),10-cyclohexane]-3,40-
dione (10b) in 38% and 62% yields, respectively. 2-Bromo-3-cyano-
pyridine (6) was reacted with 1.1 equiv of n-BuLi, and the resulting
anion was treated similarly to yield spiro[7-azabenzofurane-
1(3H),10-cyclohexane]-3,40-dione (10b, 39%). Pyridine-3-carboxylic
acid(4) and pyridine-4-carboxylic acid (5) were treated with lithium
2,2,6,6-tetramethylpiperidide (2.1 equiv), and the resulting anions
were treated similarly to yield spiro[5-azabenzofurane-1(3H),10-
cyclohexane]-3,40-dione (10c, 30%) and spiro[6-azabenzofurane-
1(3H),10-cyclohexane]-3,40-dione (10d, <27%). In the synthesis of
10d, the yield was generally low and was not reproducible presum-
ably due to poor solubility of the intermediate dianion, and we
developed an alternative method. 2-Chloropyridine-4-carboxylic
acid (7) was reacted with lithium 2,2,6,6-tetramethylpiperidide
(2.1 equiv) followed by 1,4-cyclohexanedione mono-ethyleneketal
to afford a spirolactone 8 (49%). Hydrogenolysis of 8 (100%) followed
olyl]-3-oxospiro[6-azaisoben
carboxamide (21j), a potent and orally active NPY Y5 receptor
antagonist.
zofuran-1(3H),10-cyclohexane]-40-
Br
OH
a
O
OH
CN
O
O
2
f or g
Z
Z
Z
h, i
Y
Y
Y
X
a
H
X
X
N
O
O
O
N
W
W
W
3
10a-e O
11a-e O
12a-e O
b
N
N
OH
j
b
e
O
4
O
O
O
a
COOH
OH
NH
Ar
O
5
N
k
Z
Y
O
Z
Y
X
X
N
Br
O
O
O
W
9
W
13-17 O
O
18, 19a-d, 20a-c, 21a-l, 22a-d
CN
d
6
O
O
Cl
Cl
c
10a 11a 12a 13
18
and : W, X, Y and Z = CH
,
,
,
N
10b, 11b, 12b, 14 and 19a-d: W = N, X, Y and Z = CH
N
OH
O
10c, 11c 12c, 15
20a-c
: X = N, W, Y and Z = CH
,
and
10d, 11d, 12d, 16 and 21a-l: Y = N, W, X and Z = CH
10e, 11e, 12e, 17 and 22a-d: Z = N, W, X and Y = CH
O
7
O
8
Scheme 1. Synthesis of 3-oxospiro[(aza)isobenzofuran-1(3H),10-cyclohexane]-40-carboxamide derivatives. Reagents and conditions: (a) n-BuLi, 1,4-cyclohexanedione mono-
ethyleneketal, THF, ꢀ70 °C; then concd HCl, H2O, acetone, 80 °C, 38–62%; (b) n-BuLi, 2,2,6,6-tetramethylpiperidine, 1,4-cyclohexanedione mono-ethylene ketal, THF, ꢀ40 °C;
then 6 N HCl, 80 °C, 30% for the step from 4, 10–27% for the step form 5; (c) n-BuLi, 2,2,6,6-tetramethylpiperidine,4-cyclohexanedione mono-ethyleneketal, THF, ꢀ50 °C, 49%;
(d) H2, Pd/C, Et3N, THF, quant.; (e) TsOH, H2O, acetone, 80 °C, 91%; (f) NaBH4, THF, H2O, 0 °C, 76–77% for the step from 10a and 10d; (g) LiAl(OtBu)3H, THF, 0 °C, 87–98% for the
step from 10b, 10c and 10e; (h) MsCl, Et3N, 0 °C; (i) Et4NCN, DMF, 100 °C, 31–70% over all yield for the steps (h) and (i); (j) 30% H2SO4, 100 °C, 90–92%; (k) Ar-NH2, 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, pyridine.

Y. Haga et al. / Bioorg. Med. Chem. 17 (2009) 6971–6982
6973
by acid-mediate hydrolysis (91%) produced 10d. Although the total
yield was low, this method was practical enough for the medicinal
chemistry purpose. The ketones 10a and 10d were stereoselectively
reduced by NaBH4 to produce cis alcohols 11a and 11d in 76% and
77% yields, respectively. Stereoselective reduction of the ketones
10b, 10c and 10e was accomplished by using LiAl(OtBu)3H to afford
Table 1
Human Y5 receptor binding affinities, bioavailability, and plasma, brain and CSF exposure data in rats
O
O
O
O
O
NH
NH
NH
NH
NH
Ar
Ar
Ar
Ar
Ar
N
N
N
O
O
O
O
O
18
19a-d
20a-c
21a-l
22a-d
N
O
O
O
O
O
Compounds Ar
hY5 binding IC50a (nM) Metabolic stability in Log D7.4
rat hepatocytes,
Brain, plasma and CSF levels at 2 h after 10 mpk po in ratsb
Plasma level (
lM) Brain level (nmol/g tissue) CSF level (lM)
CLh (mL/min/kg)
N
N
18
1.5
4.2
2.1
2.8
5.4
4.4
1.3
2.4
2.0
2.9
2.2
1.8
2.1
35
18
49
6
>4
NT
NT
NT
N
19a
19b
19c
19d
19e
19f
20a
20b
20c
21a
21b
21c
3.10
2.32
3.30
NT
3.75
NT
2.50
NT
0.174
NT
N
N
N
O
N
N
0.83
NT
0.23
NT
0.016
NT
NH
2
N
4
2.80
2.90
NT
6.46
6.68
NT
2.79
0.50
NT
0.416
0.091
NT
N
N
1
N
N
42
42
9
N
N
N
NT
NT
NT
NT
NH
N
NT
NT
NT
NT
N
36
39
6
3.39
2.65
NT
NT
NT
NT
N
N
N
NT
NT
NT
O
N
(0.29)c
NT
NT
(continued on next page)

6974
Y. Haga et al. / Bioorg. Med. Chem. 17 (2009) 6971–6982
Table 1 (continued)
Compounds Ar
hY5 binding IC50a (nM) Metabolic stability in Log D7.4
rat hepatocytes,
Brain, plasma and CSF levels at 2 h after 10 mpk po in ratsb
Plasma level (lM) Brain level (nmol/g tissue) CSF level (lM)
CLh (mL/min/kg)
NH
N
21d
21e
21f
21g
21h
21i
2.7
2.1
1.2
2.3
2.2
0.89
1.3
2.0
0.92
3.9
2.9
2.4
3
3.16
NT
6.10
0.50
NT
0.059
NT
N
14
12
20
<1
21
9
(0.02)c
(0.19)c
2.94
1.52
0.68
1.59
1.09
0.89
NT
S
NT
NT
NT
N
N
3.10
NT
3.13
0.39
1.33
2.15
1.36
1.24
NT
0.276
0.045
0.042
0.152
0.077
0.081
NT
N
N
N
N
3.40
3.20
3.40
3.20
NT
N
N
F
21j
N
N
F
21k
21l
10
7
N
N
N
N
F
N
22a
22b
22c
22d
39
49
36
NT
N
N
N
2.71
3.70
NT
NT
NT
NT
O
N
N
NT
NT
NT
NH
26
NT
NT
NT
NT, not tested. ND, not detected.
a
In vitro data in nM are the average of at least two experiments.
n = 3.
Plasma exposure screening data using 2 animals.
b
c
the cis alcohols 11b, 11c and 11e in 87%, 94% and 98% yields,
respectively. The alcohols 11a–e were reacted with MsCl in the pres-
ence of Et3N, and the resulting mesylates were reacted with Et4NCN
followed by hydrolysis to produce the desired trans-3-oxospi-
ro[(aza)isobenzofuran-1(3H),10-cyclohexane]-40-carboxylic acids
(13–17) in 31–70% yields. The carboxylic acids were reacted with
aromaticaminepartners in thepresenceof 1-(3-dimethylaminopro-
pyl)-3-ethylcarbodiimide hydrochloride in pyridine to give the
desired 3-oxospiro[(aza)isobenzofuran-1(3H),10-cyclohexane]-40-
carboxamide derivatives (Scheme 1).41
3. Results and discussion
The synthesized compounds were first evaluated for their hu-
man Y5 binding affinities,42,43 and potent compounds were evalu-
ated for their metabolic stability in rat hepatocytes.44 Selected
compounds were further evaluated for their brain and CSF penetra-
tion in rats, and the results are listed in Table 1. Replacement of the
urea linkage in 1 with amide produced trans-N-[5-phenyl-2-pyraz-
inyl]-3-oxospiro[isobenzofuran-1(3H),10-cyclohexane]-40-carbox-
amide (18), which showed potent human Y5 binding affinity.

Y. Haga et al. / Bioorg. Med. Chem. 17 (2009) 6971–6982
6975
Table 2
isobenzofuranone analogs 22a–d were generally less stable in rat
hepa- tocytes compared with the other 4-, 5- or 6-aza analogs hav-
ing the same amine-part structures, so the 7-aza analogs were no
longer priorities. Of the remaining 4-aza and 6-aza analogs (19a–
d vs 21a–d), the 6-aza analogs tended to show better brain pene-
tration, and further exploration at the amine-part structure was
made using the 6-azaisobenzofuranone scaffolds. The 5-phenyl-
2-pyridyl and the 2-phenyl-4-thiazolyl analogs (21e and 21f) were
potent at the Y5 receptor and stable in rat hepatocytes; however,
these compounds exhibited unexpectedly low plasma exposure
in rats after 10 mg/kg oral administration. The 1-phenyl-3-pyrazol-
yl analog 21g was a potent Y5 binding inhibitor and fairly stable in
rat hepatocytes, and this compound was well penetrable to the
brain and CSF (brain/plasma ratio = 1.06, CSF/brain ratio = 0.088).
A structurally very close isomer, 1-phenyl-4-pyrazolyl analog
21h was potent at Y5 and metabolically stable; however, 21h
was less brain-penetrant. The 2-phenyl-4-triazolyl analog 21i
was also potent at Y5 and metabolically stable. Although this com-
pound was well penetrant to the brain, its CSF penetration was less
than that of 21g and 21h (CSF/brain ratio = 0.032 for 21i, 0.088 for
21g, 0.115 for 21h). Finally, we focused on the 1-phenyl-3-pyrazol-
yl structure for its high binding affinity, good metabolic stability,
and good brain and CSF penetration profiles. Introduction of F on
the phenyl group in 21g effectively improved the metabolic stabil-
ity, and the analogs 21j, 21k and 21l were potent at Y5 and well
penetrant to the brain and CSF. The 1-phenyl-3-pyrazolyl and 1-
phenyl-4-pyrazolyl structures were combined with the 4-aza-
isobenzofuranone structure, and 19e and 19f were potent at Y5
and metabolically stable. Compounds 19e and 19f were very CSF-
penetrant (CSF/brain ratio = 0.15 and 0.18, respectively) although
their brain/plasma ratios were less than those of the corresponding
6-azaisobenzofuranone analogs.
Inhibitory effects on D-Trp34NPY-induced food intake, rat Y5 receptor binding
affinities and plasma, brain and CSF exposure data in rats and susceptibility to P-gp
transporters
Compounds Minimum effective
dosea (mg/kg po)
rY5 binding
IC50 (nM)
Susceptibility to P-gp
transporters, B-to-A/
A-to-B ratioc
b
Human L- Mouse L-
MDR1d
mdr1ae
1
3
1.7
4.7
2.2
2.1
2.1
2.5
0.99
1.97
6.13
1.05
1.29
1.28
1.36
6.05
21.1
1.74
1.57
2.41
19e
19f
21g
21j
21l
10
>10
3
1
>10
a
b
c
Inhibitory effect on D-Trp34NPY-induced food intake.
In vitro data in nM are the average of at least two experiments.
Transcellular transport across the monolayers of L-MDR1 or L-mdr1a. Values
represent the ratio of basal-to-apical (B-to-A) versus apical-to-basal (A-to-B) at 3 h.
d
Human MDR1 transfectants.
Mouse mdr1a transfectants.
e
However, this compound was unstable in rat hepatocytes. We con-
jectured the poor metabolic stability was due to its high lipophilic-
ity (Log D7.4 >4), and less lipophilic analogs of 18 may be
metabolically more stable. In order to decrease the lipophilicity,
a nitrogen atom was incorporated into the benzene ring of the 3-
oxoisobenzofurane moiety to produce 4-, 5-, 6- and 7-aza analogs,
19a, 20a, 21a and 22a, and these compounds showed Y5 binding
affinities in the low nM range. As demonstrated by 19a and 21a,
the incorporation of a nitrogen atom effectively decreased lipophil-
icity (Log D7.4 = 3.10 and 3.39, respectively), and 19a showed im-
proved metabolic stability as expected. Compound 19a showed
good brain and CSF penetration in rats, and the data encouraged
us to further explore this lead. As for the amine partners so far
examined, heteroaromatic amines, such as 5-phenyl-2-pyrazin-
amine, 5-phenyl-2-pyrimidinamine, 5-phenyl-3-isoxazolamine
and 5-phenyl-3-pyrazolamine, produced potent Y5 binding inhibi-
tors as shown in Table 1. As for the azaisobenzofuranone part, all
isomers produced similar Y5 binding activities if they had the same
aromatic amine partners. However, it should be noted that 5-aza-
isobenzofuranone analogs 20a–c exhibited unacceptable CYP3A
Compounds 19e, 19f, 21g, 21j and 21l were evaluated for their
inhibitory effects on the Y5-agonist [D-Trp34]NPY-induced food in-
take in rats as well as susceptibility to human and mouse P-glyco-
protein (P-gp) transporters,47,48 and the results are listed together
with the data of 1 in Table 2. These compounds exhibited equally
potent binding affinities to the rat Y5 receptor as well as the hu-
man Y5 receptor. A 1-phenyl-4-pyrazolyl analog 19f was weak in
the food intake assay, and its B-to-A/A-to-B ratio in the mouse
P-gp transporter assay of 21.1 indicated this compound is a good
substrate for the mouse P-gp transporter. Compound 19e was the
corresponding 3-pyrazolyl analog of 19f, and its susceptibility to
inhibitory activities (>50% at 10
lM), which decreased the
usefulness of this scaffold for drug candidates.45,46 The 7-aza-
Figure 2. [D-Trp34]NPY-induced food intake of compound 21j in SD rats. Compound 21j was orally administered 2 h before the 3rdV-injection of the agonists. **p <0.01 versus
vehicle-treated group (Dunnett). n = 8–18.

6976
Y. Haga et al. / Bioorg. Med. Chem. 17 (2009) 6971–6982
poor substrate for human and mouse P-gp transporters, and
100
80
60
40
20
0
10–20 ng/mL plasma levels of 21j produced almost perfect brain Y5
receptor occupancy in mice. Compound 21j was selected as a
better Y5 antagonist than compound 1 for clinical proof-of-concept
studies.
5. Experimental
compound 1
compound 21j
All reagents were obtained from commercial suppliers and
used without further purification or drying. TLC was performed
with Merck Silica Gel 60 F254 pre-coated plates. Silica gel
column chromatography was carried out on Wakogel C-300
(mesh 45–75 l
m). 1H NMR spectra were recorded on a JEOL
0.1
1
10
100
1000
JNM-AL 400 spectrometer at 400 MHz, a Varian Gemini 300
spectrometer at 300 MHz or a Varian Gemini 200 spectrometer
at 200 MHz, and are referenced to residual solvent peaks
(DMSO-d6, d 2.49 ppm) or to an internal standard of tetrameth-
ylsilane (TMS, d 0.00 ppm). Mass spectra were recorded with
electronspray ionization (ESI) or atmospheric pressure chemical
ionization (APCI) on a Waters micromass ZQ, micromass Quattro
II or micromass Q-Tof-2 instrument.
Plasma Conc. (ng/mL)
Figure 3. Receptor occupancy and plasma level data of compounds 1 and 21j.
human and mouse P-gp transporters were very different from
those of 19f. In addition, 21g was the corresponding 6-aza analog
of 19f, and a large difference in susceptibility to P-gp transporters
was observed between 21g and 19f. It was interesting that such
small structural alterations largely changed the susceptibility to
P-gp transporters nevertheless these changes did not largely
change their lipophilicity (Log D7.4 = 2.80, 2.90 and 3.10 for 19e,
19f and 21g, respectively). Compounds 19e, 21g, 21j and 21l were
not good substrates for the human P-gp transporter. Of the com-
pounds, 21j most strongly inhibited [D-Trp34]NPY-induced food in-
take with a minimum effective dose of 1 mg/kg po. In contrast, 21j
was very weak in inhibiting NPY-induced food intake, indicating
that the inhibitory effect in [D-Trp34]NPY-induced food intake
was brought about by Y5 receptor-selective antagonism (Fig. 2).
In the in vitro P-gp transporter assay, 21j exhibited B-to-A/A-to-B
ratios of 1.29 and 1.57 in human and mouse, respectively, indicat-
ing that this compound is a very poor substrate for the human and
mouse P-gp transporters. Compound 21j as well as 1 showed a
strong inhibitory effect in the [D-Trp34]NPY-induced food intake
assay, and these compounds were poor substrates for both human
and mouse P-gp transporters. Then, 21j was compared with 1 in
brain Y5 receptor occupancy studies in mice.33 As shown in Figure
3, 1 and 21j showed plasma level-dependent brain Y5 receptor
occupancy. In order to produce almost complete receptor occu-
pancy, 100–200 ng/mL plasma levels were required for 1 while
10–20 ng/mL plasma levels were required for 21j. Assuming the
plasma levels reflect systemic exposure, and a part of the adverse
events, such as liver injury, would result from systemic exposure,
21j is particularly attractive in that relatively lower plasma levels
of 10–20 ng/mL produce almost complete receptor occupancy.
Thus, 21j was selected as a better Y5 antagonist for clinical
proof-of-concept studies.
5.1. 3H,40H-Spiro[4-aza-2-benzofuran-1,10-cyclohexane]-3,40-
dione (10b)
n-Butyllithium (1.5 M in hexane, 500 mL, 750 mmol) was added
dropwise to a solution of N-methylpyridine-2-carboxamide (3,
48.6 g, 357 mmol) in anhydrous tetrahydrofuran (1.5 L) below
ꢀ50 °C under a nitrogen atmosphere. A solution of 1,4-cyclohexane-
dione mono-ethylene ketal (55.7 g, 357 mmol) in anhydrous tetra-
hydrofuran (0.25 L) was added to the solution at ꢀ50 to ꢀ10 °C.
The mixture was poured into water (1 L), which was washed with
hexane (1 L) and ether (0.5 L). The aqueous layer was adjusted to
pH3withconcdHCl, andthemixturewas stirredfor1 h. Themixture
was adjusted to pH 7 with K2CO3, and the produced solid was col-
lected by filtration. The solid was taken into a mixture of 2 N HCl
and acetone, and the mixture was refluxed for 15 h. After being
cooled to room temperature, the mixture was extracted with CHCl3.
The organic layer was washed with brine, dried over Na2SO4, and
concentrated. The residue was crystallized (EtOAc/hexane) to yield
28.3 g (62%) of the desired compound. 1H NMR (300 MHz, CDCl3)
d: 2.11–2.22 (m, 2H), 2.37–2.58 (m, 4H), 2.93–3.08 (m, 2H), 7.60
(dd, J = 7.9, 4.7 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 8.97 (d, J = 4.7 Hz,
1H); MS (ESI) m/z = 218 [M+H]+.
5.2. 3H,40H-Spiro[2-benzofuran-1,10-cyclohexane]-3,40-dione
(10a)
Compound 10a was prepared from the corresponding starting
material 2 in a manner similar to that described for 10b as a yellow
solid in 38% yield. 1H NMR (300 MHz, CDCl3) d: 2.08–2.21 (m, 2H),
2.34–2.58 (m, 4H), 2.92–3.07 (m, 2H), 7.40 (d, J = 7.1 Hz, 1H), 7.59
(t, J = 7.1 Hz, 1H), 7.72 (t, J = 7.1 Hz, 1H), 7.96 (d, J = 7.1 Hz, 1H); MS
(ESI) m/z = 217 [M+H]+.
4. Conclusion
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),10-cyclo-
hexane]-40-carboxamide derivatives were synthesized. Of the
compounds, trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro-
[6-azaisobenzofuran-1(3H),10-cyclohexane]-40-carboxamide (21j)
was very potent at the Y5 receptor, metabolically stable, and well
brain- and CSF-penetrant, and oral administration of the compound
significantly inhibited the Y5 agonist [D-Trp34]NPY-induced food in-
take with a minimum effective dose of 1 mg/kg. Compound 21j was
very weak in inhibiting NPY-induced food intake in rats, indicating
that the inhibitory effect in [D-Trp34]NPY-induced food intake was
attributable to the Y5-selective antagonism. Compound 21j was a
5.3. 3H,40H-Spiro[7-aza-2-benzofuran-1,10-cyclohexane]-3,40-
dione (10e)
Compound 10e was prepared from the nitrile 6 in a manner
similar to that described for 10b as a yellow solid in 39% yield.
1H NMR (300 MHz, CDCl3) d: 2.09–2.11 (m, 2H), 2.52–2.70 (m,
4H), 2.82–2.98 (m, 2H), 7.53 (dd, J = 7.9, 4.7 Hz, 1H), 8.32 (d,
J = 7.9 Hz, 1H), 8.88 (d, J = 4.7 Hz, 1H); MS (ESI) m/z = 218 [M+H]+.

Y. Haga et al. / Bioorg. Med. Chem. 17 (2009) 6971–6982
6977
5.4. 3H,40H-Spiro[5-aza-2-benzofuran-1,10-cyclohexane]-3,40-
dione (10c)
5.6. 3H -Dispiro[6-aza-2-benzofuran-1,10-cyclohexane-40,200-
[1,3]dioxolane]-3-one (9)
n-Butyllithium (1.6 M in hexane, 500 mL, 800 mmol) was added
To a solution of 7-Chloro-3H-dispiro[6-aza-2-benzofuran-1,10-
cyclohexane-40,200-[1,3]dioxolane]-3-one (8, 72.4 g, 245 mmol)
and triethylamine (51 mL, 367 mmol) in tetrahydrfuran (0.5 L)
was added 10% palladium on activated carbon (7.2 g, type M, water
ꢂ50%, Pd 10%, dry weight basis) under a nitrogen atmosphere. The
reaction mixture was stirred for 5.5 h under a hydrogen atmo-
sphere at room temperature, diluted with ethyl acetate (0.5 L)
and filtered through a Celite pad to remove the catalyst and trieth-
ylammonium chloride. The filtrate was concentrated in vacuo to
afford 64.0 g (100%) of the title compound as a pale yellow solid.
1H NMR (300 MHz, CDCl3) d: 1.80–1.89 (m, 4H), 2.14 (dt, J = 14.0,
4.0 Hz, 2H), 2.34 (dt, J = 14.0, 4.0 Hz, 2H), 4.00–4.06 (m, 4H), 7.76
(dd, J = 4.9, 1.3 Hz, 1H), 8.85 (d, J = 4.9 Hz, 1H), 8.89 (d, J = 1.3 Hz,
1H); MS (ESI) m/z = 262 [M+H]+.
to a solution of 2,2,6,6-tetramethylpiperidine (81 mL, 480 mmol)
in anhydrous tetrahydrofuran (1.6 L) at ꢀ40 °C under a nitrogen
atmosphere, and nicotinic acid (4, 39.4 g, 320 mmol) was added
to the solution after 5 min. The mixture was stirred at the same
temperature for 1 h. To the mixture was added dropwise a solution
of 1,4-cyclohexanedione mono-ethylene ketal (50 g, 320 mmol) in
anhydrous tetrahydrofuran (370 mL) at ꢀ40 °C. After being stirred
at ꢀ40 °C for 30 min, the mixture was allowed to warm to room
temperature and poured into water, which was extracted with
diethyl ether. The aqueous layer was acidified (about pH 3) with
6 N hydrochloric acid. The mixture was stirred at room
temperature for 15 h to produce precipitate. The precipitate was
collected by filtration, taken into satd sodium hydrogencarbonate,
which was extracted with chloroform. The organic layer was dried
over magnesium sulfate and concentrated in vacuo. The residual
solid was washed with ethyl acetate/hexane = 1/1 to afford
28.45 g of crude 3H-dispiro[5-aza-2-benzofuran-1,10-cyclohex-
ane-40,200-[1,3]dioxolan]-3-one as a pale brown solid. 1H NMR
(300 MHz, CDCl3) d: 1.77–1.89 (m, 4H), 2.09–2.31 (m, 4H), 3.98–
4.08 (m, 4H), 7.42 (d, J = 5.1 Hz, 1H), 8.84 (d, J = 5.1 Hz, 1H), 9.15
(S, 1H); MS (ESI) m/z = 296 [M+H]+.
2 N Hydrochloric acid (109 mL, 218 mmol) was added to a mix-
ture of the ketal (28.45 g, 109 mmol) in acetone (31 mL). The mix-
ture was stirred under reflux for 2 days, cooled to room
temperature, neutralized with potassium carbonate, and extracted
with chloroform. The organic layer was dried over magnesium sul-
fate and concentrated in vacuo. The residual solid was washed with
ethyl acetate/hexane = 1/1 to afford 21.17 g of the title compound
as pale brown solid in 30% yield. 1H NMR (200 MHz, CDCl3) d: 2.09–
2.23 (m, 2H), 2.31–2.62 (m, 4H), 2.89–3.08 (m, 2H), 7.40 (d,
J = 5.1 Hz, 1H), 8.90 (d, J = 5.1 Hz, 1H), 9.21 (s, 1H); MS (ESI) m/
z = 218 [M+H]+.
5.7. 3H,40H-Spiro[6-aza-2-benzofuran-1,10-cyclohexane]-3,40-
dione (10d)
A solution of 3H-dispiro[6-aza-2-benzofuran-1,10-cyclohexane-
40,200-[1,3]dioxolane]-3-one (9, 64.0 g, 245 mmol) and p-toluene-
sulfonic acid monohydrate (9.3 g, 49.0 mmol) in acetone (0.70 L)
and water (0.70 L) was heated overnight at 70 °C, and then acetone
was removed in vacuo. The residual aqueous solution was neutral-
ized by addition of NaHCO3 (4.2 g, 50 mmol) and extracted with
ethyl acetate (0.60 L + 0.30 L ꢁ 2). The combined organic layers
were washed with brine (0.30 L), dried over magnesium sulfate, fil-
tered and concentrated in vacuo to afford 48.3 g (91%) of the title
compound as a white solid. 1H NMR (300 MHz, CDCl3) d: 2.14–
2.24 (m, 2H), 2.49 (dt, J = 14.0, 5.0 Hz, 2H), 2.51–2.60 (m, 2H),
2.95 (dt, J = 14.0, 5.0 Hz, 2H), 7.82 (d, J = 5.0 Hz, 1H), 8.88 (s, 1H),
8.91 (d, J = 5.0 Hz, 1H); MS (ESI) m/z = 218 [M+H]+.
5.8. cis-40-Hydroxy-3H-spiro[6-aza-2-benzofuran-1,10-
cyclohexan]-3-one (11d)
5.5. 7-Chloro-3H-dispiro[6-aza-2-benzofuran-1,10-cyclohexane-
40,200-[1,3]dioxolane]-3-one (8)
Sodium borohydride (6.73 g, 178 mmol) was added slowly to a
suspension of 3H,40H-spiro[6-aza-2-benzofuran-1,10-cyclohex-
ane]-3,40-dione (10d, 48.3 g, 222 mmol) in anhydrous ethanol
(0.4 L) below ꢀ10 °C. The reaction mixture was stirred for 1 h at
0 °C, and then saturated aqueous ammonium chloride (400 mL)
was added slowly to the mixture at 0 °C. The mixture was diluted
with water and extracted with chloroform (0.80 L + 0.40 L ꢁ 2).
The combined organic layer was dried over magnesium sulfate, fil-
tered and concentrated in vacuo. The residual solid was stirred in
ethanol/hexane = 1/2 (0.30 L) overnight at room temperature. The
solid was collected by filtration and washed with ethanol/hex-
ane = 1/2 (0.3 L) to afford 37.5 g (77%) of the title compound as a
white solid. 1H NMR (300 MHz, DMSO-d6) d: 1.56 (dq, J = 13.5,
3.6 Hz, 2H), 1.70–1.82 (m, 2H), 1.84–1.94 (m, 2H), 2.15 (dt,
J = 13.5, 4.0 Hz, 2H), 3.66 (tt, J = 10.7, 4.3 Hz, 1H), 7.81 (dd, J = 5.0,
1.3 Hz, 1H), 8.84 (d, J = 5.0 Hz, 1H), 9.10 (d, J = 1.3 Hz, 1H); MS
(ESI) m/z = 220 [M+H]+.
n-Butyllithium (2.46 M in hexane, 427 mL, 1.05 mol) was
added to a solution of 2,2,6,6-tetramethylpiperidine (177 mL,
1.05 mol) in anhydrous tetrahydrofuran (1.25 L) at ꢀ50 to
ꢀ45 °C under a nitrogen atmosphere, and 2-chloroisonicotinic
acid (7, 78.8 g, 0.500 mol) was added to the mixture after
20 min. The mixture was stirred at the same temperature for
3.5 h. To the mixture was added dropwise a solution of 1,4-
cyclohexanedione mono-ethylene ketal (78.1 g, 0.500 mol) in
anhydrous tetrahydrofuran (0.25 L) at ꢀ55 to ꢀ50 °C. After being
stirred at ꢀ50 °C for 10 min, the mixture was allowed to warm
to ꢀ30 °C, and 2 N hydrochloric acid (525 mL, 1.05 mol) was
added dropwise. The mixture was stirred for additional 30 min
at 15 °C, poured into water (0.50 L), which was extracted with
ethyl acetate (0.75 L ꢁ 2). The combined organic layers were
washed with 1 N hydrochloric acid (1.2 L), saturated aqueous
NaHCO3 (1.0 L) and brine (0.50 L) successively, dried over mag-
nesium sulfate, filtered and concentrated in vacuo. The residual
solid was stirred in ethanol/hexane = 1/3 (0.4 L) at room
temperature overnight. The solid was collected by filtration
and washed with ethanol/hexane = 1/3 (0.4 L) to afford 72.4 g
5.9. cis-40-Hydroxy-3H-spiro[2-benzofuran-1,10-cyclohexan]-3-
one (11a)
Compound 11a was prepared from 10a in a manner similar to
that described for 11d as a white solid in 76% yield. 1H NMR
(300 MHz, DMSO-d6) d: 1.59 (d, J = 6.1 Hz, 1H), 1.78–2.11 (m,
8H), 3.77–3.89 (m, 1H), 7337 (d, J = 7.1 Hz, 1H), 7.52 (t, J = 7.1 Hz,
1H), 7.67 (t, J = 7.1 Hz, 1H), 7.89 (d, J = 7.1 Hz, 1H); MS (ESI) m/
z = 219 [M+H]+.
(49%) of the title compound as
a
white solid. 1H NMR
(300 MHz, CDCl3) d: 1.64–1.72 (m, 2H), 1.81–1.89 (m, 2H), 2.14
(dt, J = 13.5, 4.5 Hz, 2H), 2.86 (dt, J = 13.5, 4.5 Hz, 2H), 4.03 (s,
4H), 7.73 (d, J = 4.9 Hz, 1H), 8.62 (d, J = 4.9 Hz, 1H); MS (ESI)
m/z = 296 [M+H]+.

6978
Y. Haga et al. / Bioorg. Med. Chem. 17 (2009) 6971–6982
5.10. cis-40-Hydroxy-3H-spiro[5-aza-2-benzofuran-1,10-
cyclohexan]-3-one (11c)
solid was stirred in methanol (80 mL) overnight at room tempera-
ture. The solid was collected by filtration and washed with metha-
nol (80 mL) to afford 18.6 g (59%) of the title compound as a pale
yellow solid. 1H NMR (300 MHz, CDCl3) d: 1.80–1.88 (m, 2H),
2.08–2.19 (m, 2H), 2.20 (tt, J = 13.5, 3.5 Hz, 2H), 2.37 (dt, J = 13.5,
4.5 Hz, 2H), 3.15–3.21 (m, 1H), 7.78 (dd, J = 5.0, 1.2 Hz, 1H), 8.90
(d, J = 5.0 Hz, 1H), 8.95 (d, J = 1.2 Hz, 1H); MS (ESI) m/z = 229
[M+H]+.
Lithium tri-tert-butoxyaluminohydride (1.0 M in tetrahydrofu-
ran, 117 mL, 117 mmol) was added dropwise to a suspension of
3H,40H-spiro[5-aza-2-benzofuran-1,10-cyclohexane]-3,40-dione
(10c, 21.17 g, 97.4 mmol) in anhydrous tetrahydrofuran (500 mL)
at 0 °C under a nitrogen atmosphere. The mixture was stirred at
0 °C for 30 min and quenched with 2 N hydrochloric acid. Tetrahy-
drofuran was evaporated in vacuo. The residue was adjusted to pH
3 with potassium carbonate and extracted with chloroform. The
organic layer was dried over magnesium sulfate. The solvent was
evaporated to give 20.20 g (94%) of the title compound as a pale
brown solid. 1H NMR (300 MHz, CDCl3) d: 1.80–2.15 (m, 8H),
3.80–3.90 (m, 1H), 7.38 (d, J = 5.1 Hz, 1H), 8.86 (d, J = 5.1 Hz, 1H),
9.15 (s, 1H); MS (ESI) m/z = 220 [M+H]+.
5.14. trans-3-Oxo-3H-spiro[2-benzofuran-1,10-cyclohexane]-40-
carbonitrile (12a)
Compound 12a was prepared from the corresponding alcohol
11a in a manner similar to that described for 12d as a white solid
in 79% yield.
5.15. trans-3-Oxo-3H-spiro[4-aza-2–2-benzofuran-1,10-
5.11. cis-40-Hydroxy-3H-spiro[4-aza-2-benzofuran-1,10-
cyclohexan]-3-one (11b)
cyclohexane]-40-carbonitrile (12b)
Compound 12b was prepared from the corresponding alcohol
11b in a manner similar to that described for 12d as a white solid
in 45% yield.
Compound 11b was prepared from ketone 10b in a manner
similar to that described for 11c as a yellow solid in 87% yield.
1H NMR (300 MHz, CDCl3) d: 1.81–2.11 (m, 8H), 3.78–3.90 (m,
1H), 7.55 (dd, J = 7.8, 4.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 8.90 (d,
J = 4.8 Hz, 1H); MS (ESI) m/z = 220 [M+H]+.
5.16. trans-3-Oxo-3H-spiro[5-aza-2–2-benzofuran-1,10-
cyclohexane]-40-carbonitrile (12c)
5.12. cis-40-Hydroxy-3H-spiro[7-aza-2-benzofuran-1,10-
cyclohexan]-3-one (11e)
Compound 12c was prepared from the corresponding alcohol
11c in a manner similar to that described for 12d as a white solid
in 58% yield. 1H NMR (300 MHz, CDCl3) d: 1.78–1.86 (m, 2H), 2.06–
2.36 (m, 6H), 3.15–3.21 (m, 1H), 7.49 (d, J = 5.1 Hz, 1H), 8.91 (d,
J = 5.1 Hz, 1H), 9.185 (s, 1H); MS (ESI) m/z = 229 [M+H]+.
Compound 11e was prepared from ketone 10e in a manner sim-
ilar to that described for 11c as a yellow solid in 98% yield. 1H NMR
(300 MHz, CDCl3) d: 1.55–1.62 (m, 2H), 1.80–1.98 (m, 3H), 2.09–
2.31 (m, 3H), 3.81–3.96 (m, 1H), 7.49 (dd, J = 7.9, 4.7 Hz, 1H),
8.30 (d, J = 7.9 Hz, 1H), 8.90 (d, J = 4.7 Hz, 1H); MS (ESI) m/z = 220
[M+H]+.
5.17. trans-3-Oxo-3H-spiro[7-aza-2–2-benzofuran-1,10-
cyclohexane]-40-carbonitrile (12e)
5.13. trans-3-Oxo-3H-spiro[6-aza-2–2-benzofuran-1,10-
Compound 12e was prepared from the corresponding alcohol
11e in a manner similar to that described for 12d as a white solid
in 33% yield.
cyclohexane]-40-carbonitrile (12d)
Methanesulfonyl chloride (16.1 mL, 207 mmol) was added
dropwise to a solution of cis-40-hydroxy-3H-spiro[6-aza-2-benzo-
furan-1,10-cyclohexan]-3-one (11d, 37.5 g, 171 mmol) and triethyl-
amine (34.1 mL, 244 mmol) in anhydrous dimethylformamide
(0.40 L) below 4 °C. The mixture was stirred at 0 °C for 10 min,
diluted with ethyl acetate (0.80 L) and washed with water
(0.80 L). The aqueous layer was extracted with ethyl acetate
(0.40 L + 0.40 L). The combined organic layers were washed with
water (0.40 L), saturated aqueous NaHCO3 (0.40 L) and brine
(0.30 L) successively, dried over magnesium sulfate and silica gel
(40 g, Wakogel C-300, WAKO), filtered and concentrated in vacuo
to afford 41.3 g (81%) of cis-3-oxo-3H-spiro[6-aza-2-benzofuran-
1,10-cyclohexan]-40-yl methanesulfonate as a pale brown solid.
1H NMR (300 MHz, CDCl3) d: 1.92–2.00 (m, 2H), 2.11 (dt, J = 12.0,
4.3 Hz, 2H), 2.15–2.32 (m, 4H), 3.07 (s, 3H), 4.89 (tt, J = 10.0,
5.0 Hz, 1H), 7.77 (dd, J = 5.0, 1.0 Hz, 1H), 8.84 (d, J = 1.0 Hz, 1H),
8.87 (d, J = 5.0 Hz, 1H); MS (ESI) m/z = 298 [M+H]+.
5.18. trans-3-Oxo-3H-spiro[6-aza-2-benzofuran-1,10-
cyclohexane]-40-carboxylic acid (16)
A solution of trans-3-oxo-3H-spiro[2-benzofuran-1,10-cyclohex-
ane]-40-carbonitrile (12d, 18.5 g, 81.1 mmol) in 47% sulfuric acid
(90 mL, 548 mmol) and water (30 mL) was heated at 100 °C for
48 h. After cooling to room temperature, the mixture was adjusted
to pH 4 with 5 N sodium hydroxide to produce precipitate. The pre-
cipitate was collected by filtration and washed with water to afford
18.4 g (92%) of the title compound as an off-white solid. 1H NMR
(300 MHz, DMSO-d6) d: 1.76–1.85 (m, 2H), 1.90–2.11 (m, 6H),
2.68–2.74 (m, 1H), 7.84 (dd, J = 5.0, 1.0 Hz, 1H), 8.87 (d, J = 5.0 Hz,
1H), 9.06 (d, J = 1.0 Hz, 1H), 12.35 (br s, 1 H); MS (ESI) m/z = 248
[M+H]+.
Tetraethylammmonium cyanide (28.2 g, 180 mmol) was added
to a solution of the methanesulfonate (41.3 g, 139 mmol) in anhy-
drous dioxane (0.30 L). The mixture was heated at 100 °C for 3 h,
and then ca. 150 mL of dioxane was removed in vacuo. The mixture
was diluted with ethyl acetate (0.60 L) and washed with water
(0.60 mL). The aqueous layer was extracted with ethyl acetate
(0.30 L ꢁ 2). The combined organic layers were washed with water
(0.50 L) and brine (0.30 L) successively, dried over magnesium sul-
fate, filtered through a short pad of silica gel column (40 g,
Wakogel C-300, WAKO) and concentrated in vacuo. The residual
5.19. trans-3-Oxo-3H-spiro[2-benzofuran-1,10-cyclohexane]-40-
carboxylic acid (13)
Compound 13 was prepared from the corresponding carboni-
trile 12a in a manner similar to that described for 16 as a white so-
lid in 92% yield. 1H NMR (300 MHz, CDCl3) d: 1.68–1.87 (m, 2H),
2.03–2.37 (m, 6H), 3.13–3.20 (m, 1H), 7.49 (d, J = 7.1 Hz, 1H),
7.56 (t, J = 7.1 Hz, 1H), 7.73 (t, J = 7.1 Hz, 1H), 7.91 (d, J = 7.1 Hz,
1H); MS (ESI) m/z = 247 [M+H]+.

Y. Haga et al. / Bioorg. Med. Chem. 17 (2009) 6971–6982
6979
5.20. trans-3-Oxo-3H-spiro[4-aza-2-benzofuran-1,10-
5.25. trans-3-Oxo-N-(5-phenylpyrazin-2-yl)-3H-spiro[4-aza-2-
cyclohexane]-40-carboxylic acid (14)
benzofuran-1,10-cyclohexane]-40-carboxamide (19a)
Compound 14 was prepared from the corresponding carboni-
trile 12b in a manner similar to that described for 16 as a white so-
lid in 90% yield. 1H NMR (300 MHz, DMSO-d6) d: 1.64–1.82 (m, 2H),
1.90–2.06 (m, 6H), 2.64–2.74 (m, 1H), 7.72 (dd, J = 7.9, 4.7 Hz, 1H),
8.20 (d, J = 7.9 Hz, 1H), 8.85 (d, J = 4.7 Hz, 1H); MS (ESI) m/z = 248
[M+H]+.
Compound 19a was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 58% yield. Mp: 237–239 °C; 1H NMR (300 MHz, DMSO-d6) d:
1.84–1.92 (m, 2H), 2.12–2.20 (m, 6H), 2.93–2.97 (m, 1H), 7.45–
7.55 (m, 3H), 7.76 (dd, J = 7.9, 4.7 Hz, 1H), 8.09 (dd, J = 8.0, 1.3 Hz,
2H), 8.25 (dd, J = 8.0, 1.3 Hz, 1H), 8.89 (dd, J = 4.6, 1.3 Hz, 1H),
9.01(d, J = 1.5 Hz, 1H), 9.46 (d, J = 1.5 Hz, 1H), 10.94 (s, 1H); HRMS
(ESI) m/z = 401.1607 [M+H]+ (C23H20N4O3 requires: 401.1614).
5.21. trans-3-Oxo-3H-spiro[5-aza-2-benzofuran-1,10-
cyclohexane]-40-carboxylic acid (15)
5.26. trans-3-Oxo-N-(5-phenylpyrimidin-2-yl)-3H-spiro[4-aza-
Compound 15 was prepared from the corresponding carboni-
trile 12c in a manner similar to that described for 16 as a white so-
lid in 92% yield. 1H NMR (300 MHz, DMSO-d6) d: 1.67–1.81 (m, 2H),
1.86–2.10 (m, 6H), 2.68–2.75 (m, 1H), 7.77 (d, J = 5.1 Hz, 1H), 8.86
(d, J = 5.1 Hz, 1H), 9.06 (s, 1H); MS (ESI) m/z = 248 [M+H]+.
2-benzofuran-1,10-cyclohexane]-40-carboxamide (19b)
Compound 19b was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 35% yield. Mp: 237–239 °C; 1H NMR (300 MHz, DMSO-d6) d:
1.82–1.89 (m, 2H), 1.97–2.06 (m, 4H), 2.12–2.19 (m, 2H), 2.99–
3.04 (m, 1H), 7.43–7.54 (m, 3H), 7.73–7.80 (m, 3H), 8.21 (dd,
J = 7.9, 1.2 Hz, 1H), 8.88 (dd, J = 4.7, 1.2 Hz, 1H), 9.00 (s, 2H),
10.77 (s, 1H); HRMS (ESI) m/z = 401.1610 [M+H]+ (C23H20N4O3 re-
quires: 401.1614).
5.22. trans-3-Oxo-3H-spiro[7-aza-2-benzofuran-1,10-
cyclohexane]-40-carboxylic acid (17)
Compound 17 was prepared from the corresponding carboni-
trile 12e in a manner similar to that described for 16 as a white so-
lid in 90% yield. 1H NMR (300 MHz, DMSO-d6) d: 1.73–1.85 (m, 2H),
1.85–1.99 (m, 2H), 1.99–2.13 (m, 2H), 2.14–2.27 (m, 2H), 2.64–2.73
(m, 1H), 7.65 (dd, J = 7.8, 4.8 Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.90
(d, J = 4.8 Hz, 1H); MS (ESI) m/z = 248 [M+H]+.
5.27. trans-3-Oxo-N-(5-phenylisoxazol-3-yl)-3H-spiro[4-aza-2-
benzofuran-1,10-cyclohexane]-40-carboxamide (19c)
Compound 19c was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 84% yield. Mp: 260–262 °C; 1H NMR (300 MHz, CDCl3) d: 1.87–
2.00 (m, 2H), 2.19–2.50 (m, 6H), 2.96–3.08 (m, 1H), 7.37 (s, 1H),
7.48–7.64 (m, 4H), 7.78–7.88 (m, 2H), 8.01 (d, J = 7.2 Hz, 1H),
8.91 (dd, J = 4.8, 1.5 Hz, 1H), 10.00 (br s, 1H); HRMS (ESI) m/
z = 390.1460 [M+H]+ (C22H19N3O4 requires: 390.1454).
5.23. trans-N-[1-(2-Fluorophenyl)-1H-pyrazol-3-yl]-3-oxo-3H-
spiro[6-aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide
(21j)
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochlo-
ride (14.0 g, 0.073 mol) was added to a mixture of trans-3-oxo-
3H-spiro[6-aza-2-benzofuran-1,10-cyclohexane]-40-carboxylic acid
(16) (15.9 g, 0.064 mol) and 3-amine-1-(2-fluorophenyl)-1H-pyra-
zole (12.0 g, 0.068 mol) in pyridine (100 mL), and the mixture was
stirred overnight. The reaction mixture was poured into a mixture
of H2O (1 L) and EtOAc (250 mL), and the mixture was stirred for
30 min. Precipitate was collected by filtration to yield 17.45 g
(67%) of the title compound as a white solid. The filtrate was
separated, and the organic layer was washed with 10% citric acid
(300 mL + 200 mL), satd NaHCO3 (200 mL) and brine (200 mL),
dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (EtOAc/hexane),
and crystallized from EtOAc to yield 4.34 g (17%) of the title
compound as a white solid. Mp: 238–239 °C (EtOAc); 1H NMR
(300 MHz, DMSO-d6) d: 1.8–2.2 (m, 8H), 2.7–2.9 (m, 1H), 6.91 (d,
J = 2.6 Hz, 1H), 7.3–7.5 (m, 3H), 7.7–7.8 (m, 1H), 7.87 (dd, J = 4.9,
1.1 Hz, 1H), 8.11 (t, J = 2.6 Hz, 1 H), 8.89 (d, J = 4.9 Hz, 1H),
9.13 (d, J = 1.1 Hz, 1H), 10.82 (br s, 1H); HRMS (ESI) m/
z = 407.1517 [M+H]+ (C22H19FN4O3 requires: 407.1519). Elemental
Anal. Calcd: C, 65.02; H, 4.71; N, 13.79. Found: C, 64.88; H, 4.59; N,
13.70.
5.28. trans-3-Oxo-N-(3-phenyl-1H-pyrazol-5-yl)-3H-spiro[4-
aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide (19d)
Compound 19d was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white
amorphous solid in 24% yield. 1H NMR (300 MHz, DMSO-d6) d:
1.83–1.90 (m, 2H), 1.97–2.02 (m, 4H), 2.10–2.17 (m, 2H), 2.78–
2.79 (m, 1H), 6.97 (d, J = 1.7 Hz, 1H), 7.33–7.37 (m, 1H), 7.42–
7.48 (m, 2H), 8.22 (d, J = 7.3 Hz, 1H), 8.87–8.90 (m, 1H), 10.50 (s,
1H); HRMS (ESI) m/z = 401.1610 [M+H]+ (C23H20N4O3 requires:
401.1614).
5.29. trans-3-Oxo-N-(1-phenyl-1H-pyrazol-3-yl)-3H-spiro[4-
aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide (19e)
Compound 19e was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 71% yield. Mp: 204–206 °C; 1H NMR (300 MHz, DMSO-d6) d:
1.8–2.2 (m, 8H), 2.75–2.85 (m, 1H), 6.86 (d, J = 2.4 Hz, 1H), 7.2–
7.3 (m, 1H), 7.4–7.55 (m, 2H), 7.7–7.8 (m, 3H), 8.23 (d, J = 8.0 Hz,
1H), 8.41 (d, J = 2.4 Hz, 1H), 8.85–8.9 (m, 1H), 10.78 (br s, 1H);
HRMS (ESI) m/z = 389.1609 [M+H]+ (C22H20N4O3 requires:
389.1614).
5.24. trans-3-Oxo-N-(5-phenylpyrazin-2-yl)-3H-spiro[2-
benzofuran-1,10-cyclohexane]-40-carboxamide (18)
Compound 18 was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 73% yield. Mp: 223–225 °C; 1H NMR (300 MHz, DMSO-d6) d:
1.75–2.30 (m, 8H), 2.93–2.95 (m, 1H), 7.30–7.90 (m, 9H), 8.20–
8.60 (m, 3H), 9.05 (d, J = 1.2 Hz, 1H), 9.46 (d, J = 1.2, 1H), 10.93 (s,
1H); HRMS (ESI) m/z = 400.1655 [M+H]+ (C24H21N3O3 requires:
400.1661).
5.30. trans-3-Oxo-N-(1-phenyl-1H-pyrazol-4-yl)-3H-spiro[4-
aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide (19f)
Compound 19f was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 63% yield. Mp: 225–227 °C; 1H NMR (300 MHz, DMSO-d6) d:
1.8–2.2 (m, 8H), 2.7–2.8 (m, 1H), 7.25–7.3 (m, 1H), 7.4–7.55

6980
Y. Haga et al. / Bioorg. Med. Chem. 17 (2009) 6971–6982
(m, 2H), 7.7–7.8 (m, 3H), 8.21 (d, J = 7.2 Hz, 1H), 8.56 (s, 1H), 8.88
(d, J = 4.6 Hz, 1H), 10.22 (br s, 1H); HRMS (ESI) m/z = 389.1611
[M+H]+ (C22H20N4O3 requires: 389.1614).
5.36. trans-3-Oxo-N-(5-phenylisoxazol-3-yl)-3H-spiro[6-aza-2-
benzofuran-1,10-cyclohexane]-40-carboxamide (21c)
Compound 21c was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 76% yield. Mp: 262–264 °C; 1H NMR (300 MHz, CDCl3) d: 1.89–
1.99 (m, 2H), 2.23–2.49 (m, 6H), 2.95–3.03 (m, 1H), 7.40 (s, 1H),
7.50–7.58 (m, 3H), 7.78–7.88 (m, 3H), 8.88 (d, J = 5.1 Hz, 1H),
9.04 (d, J = 0.9 Hz, 1H), 9.86 (br s, 1H); HRMS (ESI) m/
z = 390.1456 [M+H]+ (C22H19N3O4 requires: 390.1454).
5.31. trans-3-Oxo-N-(5-phenylpyrazin-2-yl)-3H-spiro[5-aza-2-
benzofuran-1,10-cyclohexane]-40-carboxamide (20a)
Compound 20a was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a pale yellow
solid in 43% yield. Mp: 269–271 °C; 1H NMR (300 MHz, DMSO-d6)
d: 1.80–1.96 (m, 2H), 1.98–2.22 (m, 6H), 2.95 (m, 1H), 7.40–7.56
(m, 3H), 7.82 (dd, J = 5.2, 1.0 Hz, 1H), 8.06–8.13 (m, 2H), 8.91 (d,
J = 5.2 Hz, 1H), 9.00 (d, J = 1.5 Hz, 1H), 9.09 (d, J = 1.0 Hz, 1H),
9.46 (d, J = 1.5 Hz, 1H), 10.93 (s, 1H); HRMS (ESI) m/z = 401.1609
[M+H]+ (C23H20N4O3 requires: 401.1614).
5.37. trans-3-Oxo-N-(3-phenyl-1H-pyrazol-5-yl)-3H-spiro[6-
aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide (21d)
Compound 21d was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 33% yield. Mp: 196–198 °C; 1H NMR (300 MHz, DMSO-d6) d:
1.87–2.26 (m, 8H), 2.72–2.79 (m, 1H), 6.98 (s, 1H), 7.34–7.36 (m,
1H), 7.42–7.48 (m, 2H), 7.71–7.73 (m, 2H), 7.87 (dd, J = 5.0,
1.1 Hz, 1H), 8.89 (d, J = 5.0 Hz, 1H), 9.12 (s, 1H), 10.50 (br s, 1H),
12.82 (br s, 1H); HRMS (ESI) m/z = 401.1609 [M+H]+ (C23H20N4O3
requires: 401.1614).
5.32. trans-3-Oxo-N-(5-phenylpyrimidin-2-yl)-3H-spiro[5-aza-
2-benzofuran-1,10-cyclohexane]-40-carboxamide (20b)
Compound 20b was prepared from the corresponding
acid and amine in a manner similar to that described for 21j
as
a
white solid in 20% yield. Mp: 219–221 °C; 1H NMR
(300 MHz, DMSO-d6) d: 1.80–1.92 (m, 2H), 1.93–2.22 (m, 6H),
3.02 (m, 1H), 7.40–7.56 (m, 3H), 7.72–7.81 (m, 3H), 8.90 (d,
J = 5.2 Hz, 1H), 9.00 (s, 2H), 9.08 (d, J = 1.0 Hz, 1H), 10.77 (s,
1H); HRMS (ESI) m/z = 401.1607 [M+H]+ (C23H20N4O3 requires:
401.1614).
5.38. trans-3-Oxo-N-(5-phenylpyridin-2-yl)-3H-spiro[6-aza-2-
benzofuran-1,10-cyclohexane]-40-carboxamide (21e)
Compound 21e was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 54% yield. Mp: 238–239 °C; 1H NMR (300 MHz, CDCl3) d: 1.80–
1.98 (m, 2H), 2.14–2.51 (m, 6H), 2.73–2.88 (m, 1H), 7.41 (d,
J = 6.9 Hz, 1H), 7.48 (dd, J = 7.5, 6.9 Hz, 1H), 7.58 (d, J = 7.5 Hz,
1H), 7.77 (dd, J = 5.1, 0.9 Hz, 1H), 7.97 (dd, J = 8.8, 2.4 Hz, 1H),
8.15 (br s, 1H), 8.33 (d, J = 8.7 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H),
8.88 (d, J = 5.1 Hz, 1H), 9.04 (d, J = 0.9 Hz, 1H); HRMS (ESI) m/
z = 400.1664 [M+H]+ (C24H21N3O3 requires: 400.1661).
5.33. trans-3-Oxo-N-(3-phenyl-1H-pyrazol-5-yl)-3H-spiro[5-
aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide (20c)
Compound 20c was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white
amorphous solid in 24% yield. 1H NMR (300 MHz, DMSO-d6) d:
1.80–2.20 (m, 8H), 2.79 (m, 1H), 6.97 (br s, 1H), 7.34 (m, 1H),
7.40–7.50 (m, 2H), 7.72 (d, J = 7.3 Hz, 2H), 7.78 (dd, J = 5.2, 1.0 Hz,
1H), 8.91 (d, J = 5.2 Hz, 1H), 9.09 (d, J = 1.0 Hz, 1H), 10.49 (br s,
1H), 12.82 (br s, 1H); HRMS (ESI) m/z = 401.1608 [M+H]+
(C23H20N4O3 requires: 401.1614).
5.39. trans-3-Oxo-N-(2-phenyl-1,3-thiazol-4-yl)-3H-spiro[6-
aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide (21f)
Compound 21f was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a pale yellow
solid in 65% yield. Mp: 288–289 °C; 1H NMR (300 MHz, DMSO-d6)
d: 1.82–2.23 (m, 8H), 2.80–2.91 (m, 1H), 7.44–7.56 (m, 3H), 7.71 (s,
1H), 7.83–7.97 (m, 3H), 8.88 (d, J = 5.0 Hz, 1H), 9,12 (s, 1H), 11.2 (s,
1H); HRMS (ESI) m/z = 406.1232 [M+H]+ (C22H19N3O3S requires:
406.1225).
5.34. trans-3-Oxo-N-(5-phenylpyrazin-2-yl)-3H-spiro[6-aza-2-
benzofuran-1,10-cyclohexane]-40-carboxamide (21a)
Compound 21a was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 44% yield. Mp: 239–241 °C; 1H NMR (300 MHz, CDCl3) d: 1.88–
1.94 (m, 2H), 2.25–2.45 (m, 6H), 2.84–2.88 (m, 1H), 7.46–7.54
(m, 3H), 7.78 (dd, J = 5.0, 1.1 Hz, 1H), 7.99–8.01 (m, 3H), 8.70 (d,
J = 1.5 Hz, 1H), 8.89 (d, J = 4.9 Hz, 1H), 9.05 (d, J = 0.8 Hz, 1H),
9.63 (s, 1H); HRMS (ESI) m/z = 401.1621 [M+H]+ (C23H20N4O3 re-
quires: 401.1614).
5.40. trans-3-Oxo-N-(1-phenyl-1H-pyrazol-3-yl)-3H-spiro[6-
aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide (21g)
Compound 21g was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 86% yield. Mp: 249–250 °C; 1H NMR (300 MHz, DMSO-d6) d:
1.85–2.2 (m, 8H), 2.75–2.85 (m, 1H), 6.86 (d, J = 2.5 Hz, 1H), 7.2–
7.3 (m, 1H), 7.4–7.55 (m, 2H), 7.7–7.8 (m, 2H), 7.87 (dd, J = 4.9,
1.0 Hz, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.89 (d, J = 4.9 Hz, 1H), 9.13
(s, 1H), 10.79 (br s, 1H); HRMS (ESI) m/z = 389.1612 [M+H]+
(C22H20N4O3 requires: 389.1614).
5.35. trans-3-Oxo-N-(5-phenylpyrimidin-2-yl)-3H-spiro[6-aza-
2-benzofuran-1,10-cyclohexane]-40-carboxamide (21b)
Compound 21b was prepared from the corresponding acid
and amine in a manner similar to that described for 21j as a
white solid in 13% yield. Mp: 193–195 °C; 1H NMR (300 MHz,
CDCl3) d: 1.81–1.90 (m, 2H), 2.04–2.30 (m, 4H), 2.47–2.58 (m,
2H), 3.22 (m, 1H), 7.45–7.58 (m, 5H), 7.77 (dd, J = 5.0, 1.3 Hz,
1H), 8.18 (br s, 1H), 8.85 (s, 2H), 8.87 (d, J = 5.0 Hz, 1H), 9.03
(d, J = 1.3 Hz, 1H); HRMS (ESI) m/z = 401.1615 [M+H]+
(C23H20N4O3 requires: 401.1614).
5.41. trans-3-Oxo-N-(1-phenyl-1H-pyrazol-4-yl)-3H-spiro[6-
aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide (21h)
Compound 21h was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white
amorphous solid in 98% yield. 1H NMR (300 MHz, DMSO-d6) d:
1.85–2.2 (m, 8H), 2.8–2.9 (m, 1H), 7.28 (t, J = 7.3 Hz, 1H),

Y. Haga et al. / Bioorg. Med. Chem. 17 (2009) 6971–6982
6981
7.45–7.50 (m, 2H), 7.75–7.85 (m, 3H), 7.87 (d, J = 5.1 Hz, 1H), 8.59
(s, 1H), 8.89 (d, J = 5.1 Hz, 1H), 9.11 (s, 1H), 10.23 (s, 1H); HRMS
(ESI) m/z = 389.1606 [M+H]+ (C22H20N4O3 requires: 389.1614).
5.47. trans-3-Oxo-N-(5-phenylisoxazol-3-yl)-3H-spiro[7-aza-2-
benzofuran-1,10-cyclohexane]-40-carboxamide (22c)
Compound 22c was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 86% yield. Mp: 253–255 °C; 1H NMR (300 MHz, CDCl3) d: 1.90–
2.02 (m, 2H), 2.20–2.44 (m, 4H), 2.46–2.60 (m, 2H), 2.86–2.96
(m, 1H), 7.40–7.59 (m, 5H), 7.78–7.83 (m, 2H), 8.19 (dd, J = 7.5,
1.5 Hz, 1H), 8.87 (dd, J = 4.8, 1.5 Hz, 1H), 9.60–9.70 (m, 1H); HRMS
(ESI) m/z = 390.1458 [M+H]+ (C22H19N3O4 requires: 390.1454).
5.42. trans-3-Oxo-N-(2-phenyl-2H-1,2,3-triazol-4-yl)-3H-
spiro[6-aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide
(21i)
Compound 21i was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 89% yield. Mp: 231–232 °C; 1H NMR (300 MHz, CDCl3) d: 1.80–
1.90 (m, 2H), 2.15–2.50 (m, 6H), 2.80–2.90 (m, 1H), 7.30–7.40
(m, 1H), 7.45–7.55 (m, 2H), 7.78 (dd, J = 1.2 Hz, 4.9 Hz, 1H), 7.95–
8.00 (m, 2H), 8.07 (br s, 1H), 8.30 (s, 1H), 8.88 (d, J = 4.9 Hz, 1H),
9.03 (d, J = 1.0 Hz, 1H); HRMS (ESI) m/z = 390.1554 [M+H]+
(C21H19N5O3 requires: 390.1566).
5.48. trans-3-Oxo-N-(3-phenyl-1H-pyrazol-5-yl)-3H-spiro[7-
aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide (22d)
Compound 22d was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a pale white
solid in 2.7% yield. Mp: 245–247 °C; 1H NMR (300 MHz, DMSO-d6)
d: 1.18–1.96 (m, 4H), 2.15–2.34 (m, 4H), 2.71–2.75 (m, 1H), 6.89 (s,
1H), 7.30–7.35 (m, 1H), 7.41–7.46 (m, 2H), 7.64 (dd, J = 7.8, 4.9 Hz,
1H), 7.72–7.74 (m, 2H), 8.29 (dd, J = 7.8, 1.5 Hz, 1H), 8.91 (dd,
J = 4.9, 1.5 Hz, 1H); HRMS (ESI) m/z = 401.1609 [M+H]+
(C23H20N4O3 requires: 401.1614).
5.43. trans-N-[1-(4-Fluorophenyl)-1H-pyrazol-3-yl]-3-oxo-3H-
spiro[6-aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide
(21k)
Compound 21k was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 60% yield. Mp: 257–259 °C; 1H NMR (300 MHz, DMSO-d6) d:
1.80–2.25 (m, 8H), 2.70–2.90 (m, 1H), 6.86 (d, J = 2.5 Hz, 1H),
7.33 (t, J = 8.8 Hz, 2H), 7.71–7.83 (m, 2H), 7.88 (dd, J = 10.5,
4.9 Hz, 1H), 8.38 (d, J = 2.5 Hz, 1H), 8.88 (d, J = 4.9 Hz, 1H), 9.13
(s, 1H), 10.8 (s, 1H); HRMS (ESI) m/z = 407.1516 [M+H]+
(C22H19FN4O3 requires: 407.1519).
Acknowledgements
We thank Dr. Lex H. T. Van der Ploeg and Dr. Douglas J. MacNeil
for their suggestions and discussion on the NPY Y5 receptor antag-
onist program.
5.44. trans-N-[1-(3-Fluorophenyl)-1H-pyrazol-3-yl]-3-oxo-3H-
spiro[6-aza-2-benzofuran-1,10-cyclohexane]-40-carboxamide
(21l)
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2009.08.019.
Compound 21l was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a white solid
in 75% yield. Mp: 247–249 °C; 1H NMR (300 MHz, DMSO-d6) d:
1.78–2.25 (m, 8H), 2.70–2.90 (m, 1H), 6.90 (d, J = 2.6 Hz, 1H),
7.03–7.18 (m, 1H), 7.43–7.59 (m, 1H), 7.59–7.70 (m, 2H), 7.87
(dd, J = 5.0, 1.1 Hz, 1H), 8.49 (d, J = 2.6 Hz, 1H), 8.83 (d, J = 5.0 Hz,
1H), 9.13 (d, J = 1.1 Hz, 1H), 10.81 (s, 1H); HRMS (ESI) m/
z = 407.1514 [M+H]+ (C22H19FN4O3 requires: 407.1519).
References and notes
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5.45. trans-3-Oxo-N-(5-phenylpyrazin-2-yl)-3H-spiro[7-aza-2-
benzofuran-1,10-cyclohexane]-40-carboxamide (22a)
Compound 22a was prepared from the corresponding acid and
amine in a manner similar to that described for 21j as a pale yellow
solid in 7% yield. Mp: 246–248 °C; 1H NMR (300 MHz, CDCl3) d:
1.93–2.01 (m, 2H), 2.20–2.37 (m, 4H), 2.47–2.58 (m, 2H), 2.76–
2.80 (m, 1H), 7.45–7.54 (m, 4H), 7.98–8.05 (m, 3H), 8.19 (dd,
J = 7.8, 1.6 Hz, 1H), 8.68 (d, J = 1.6 Hz, 1H), 8.88 (dd, J = 4.9,
1.6 Hz, 1H), 9.66 (d, J = 1.5 Hz, 1H); HRMS (ESI) m/z = 401.1614
[M+H]+ (C23H20N4O3 requires: 401.1614).
14. Gerald, C.; Walker, M. W.; Criscione, L.; Gustafson, E. L.; BatzlHartmann, C.;
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