Discovery of 3-chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide as a potent glycine transporter 1 inhibitor

Article abstract of DOI:10.1248/cpb.c16-00314

A novel glycine transporter 1 (GlyT1) inhibitor was designed by the superposition of different chemotypes to enhance its inhibitory activity. Starting from 2-chloro-N-{(S)-phenyl[(2S)-piperidin-2-yl]methyl}-3-(trifluoromethyl)benzamide (2, SSR504734), the

Full text of DOI:10.1248/cpb.c16-00314

Vol. 64, No. 9
Chem. Pharm. Bull. 64, 1321–1337 (2016)
1321
Regular Article
Discovery of 3-Chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl][(2S)-
piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide as a
Potent Glycine Transporter 1 Inhibitor
,a
Shuji Yamamoto,* Tsuyoshi Shibata,a Kumi Abe,a Koji Oda,a Takeshi Aoki,b
Yasunori Kawakita,c and Hiroshi Kawamotoa
a Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd.; 1–403 Yoshino-cho, Kita-ku, Saitama 331–9530, Japan:
b Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd.; 1–403 Yoshino-cho, Kita-ku, Saitama 331–9530,
c
Japan: and Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd.; 1–403 Yoshino-cho,
Kita-ku, Saitama 331–9530, Japan.
Received April 4, 2016; accepted June 10, 2016
A novel glycine transporter 1 (GlyT1) inhibitor was designed by the superposition of different chemo-
types to enhance its inhibitory activity. Starting from 2-chloro-N-{(S)-phenyl[(2S)-piperidin-2-yl]methyl}-3-
(trifluoromethyl)benzamide (2, SSR504734), the introduction of heteroaromatic rings enabled an increase
in the GlyT1 inhibitory activity. Subsequent optimization led to the identification of 3-chloro-N-{(S)-[3-(1-
ethyl-1H-pyrazol-4-yl)phenyl][(2S)-piperidine-2-yl]methyl}-4-(trifluoromethyl)pyridine-2-carboxamide (7w),
which showed a powerful GlyT1 inhibitory activity (IC50=1. 8 n M), good plasma exposure and a plasma to
brain penetration in rats that was sufficient to evaluate the compound’s pharmacological properties. Com-
pound 7w showed significant effects in several rodent models for schizophrenia without causing any undesir-
able central nervous system side effects.
Key words glycine transporter 1 inhibitor; ligand based drug design; schizophrenia; structure–activity rela-
tionship
N-Methyl-D-aspartate (NMDA) receptor hypofunction is inhibitor.11) The reported IC50 values of 2 were 18 and 15nM
thought to be involved in the pathophysiology of schizophre- in in vitro human and rat glycine uptake inhibitory assays.
nia.1,2) This NMDA hypofunction hypothesis is based on the Merck’s researchers have reported a sulfone based chemical
observation that NMDA receptor antagonists mimic the posi- class, represented by 3 (DCCCyB),12) as well as sulfonamide
tive, negative, and cognitive symptoms of schizophrenia.3,4) class inhibitors, represented by 4.13–16) At present, many other
Thus enhancing NMDA function may improve the symptoms chemical classes, such as 5 (PF-0346275)17) and 6 (RG1678),18)
of schizophrenia, but excess activation of the glutamate bind- have been reported. Among them, 6 showed a significant im-
ing site is considered to induce neurotoxicity.5) Elevating provement in the negative symptoms of patients with schizo-
the levels of glycine, which is an important coagonist of the phrenia in phase 2 clinical trial.19)
NMDA receptor, is an alternative approach. In fact, the co-
administration of glycine or the glycine site agonist D-serine (TP0439150), which showed a potent in vitro glycine uptake
with atypical antipsychotics helps to improve schizophrenia.6)
inhibitory activity in rats (IC50=1.5 nM) and exhibited sig-
Recently, we reported the pharmacological profiles of 7w
Levels of glycine are controlled by the glycine transporter, nificant effects in a rodent model of negative symptoms and
which consist of two subunits, glycine transporter 1 (GlyT1) cognitive impairment associated with schizophrenia.20) In the
and GlyT2. GlyT1 is widely expressed in forebrain areas such present article, we describe the medicinal chemistry efforts
as cortex and hippocampus, where it might be co-localized that resulted in the potent inhibitor 7w.
with strychnine-insensitive glycine regulatory sites on NMDA
To discover a novel GlyT1 inhibitor with a strong in vitro
receptors. In contrast, the expression of GlyT2 is limited to the potency and in vivo efficacy at low doses, we selected a ligand
brain stem, spinal cord, and cerebellum, and GlyT2 is known based drug design (LBDD) approach using known GlyT1
to be co-localized with strychnine-sensitive glycine receptors. inhibitors. Among the reported chemotypes, we focused on
Thus increasing NMDA receptor activity by inhibiting GlyT1 the N-[phenyl(piperidin-2-yl)methyl]benzamide derivatives
is an attractive drug discovery target for schizophrenia.7,8)
represented by 2 (scaffold A, Fig. 2) and the sulfonamide de-
Most effort has been focused on the development of GlyT1 rivatives represented by 4 (scaffold B, Fig. 2). Both of these
inhibitors.9) Early inhibitors were designed based on sarcosine chemotypes have a secondary benzamide with ortho substitu-
(methylglycine) structure, a weak GlyT1 inhibitor, like 110) ent as a similar substructure, and we supposed that these two
(ALX-5407, Fig. 1). Reported sarcosine-based inhibitors have different chemotypes inhibit GlyT1 by binding at the same site
suffered from poor pharmacokinetics (PK) profiles, including and have similar pharmacophore.
low brain penetration. Thus, recent development has focused
Compound 4 (scaffold B) has been reported to have a po-
on non-sarcosine type inhibitors, and several structurally tent GlyT1 inhibitory activity (IC50=3nM),15) and we thought
diverse inhibitors have been reported from many groups. N- that the structurally characteristic SO2 group likely played a
[Phenyl(piperidin-2-yl)methyl]benzamide derivatives, repre- key role as a hydrogen bond acceptor (HBA) in increasing
sented by 2 (SSR504734), are one type of non-sarcosine type potency. On the other hand, corresponding HBAs are absent
*To whom correspondence should be addressed. e-mail: shu-yamamoto@so.taisho.co.jp
© 2016 The Pharmaceutical Society of Japan

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Vol. 64, No. 9 (2016)
Fig. 1. Structures of GlyT1 Inhibitors
yield an alcohol (10a–c). After the exchange of the protec-
tive group from a tert-butoxycarbonyl (Boc) to an allyl group,
the mesylation of the hydroxyl group and the subsequent
reaction with ammonia provided a benzylamine intermediate
(13a–c). In this amination step, the configuration of the ben-
zylic position was retained, since the aziridine intermediate
was firstly formed by the intramolecular reaction of an allyl
amine moiety with a methansulfonyloxy group. Condensation
with 2-chloro-3-(trifluoromethyl)benzoic acid provided 14a–c,
which was then converted to 7a and b by the removal of an
allyl group.
Intermediate 14c was used for the introduction of hetero-
aromatic rings (Chart 2). The removal of a methyl group by
boran tribromide and the subsequent triflation led to 16. Then,
Fig. 2. Comparison of N-[Phenyl(piperidin-2-yl)]benzamide Derivative
(Scaffold A) and Sulfonamide Derivative (Scaffold B)
in scaffold A; therefore, we presumed that the introduction the introduction of an Ar1 group by Suzuki coupling and the
of suitable HBAs to scaffold A would enhance the inhibitory removal of an allyl group yielded 7f, h, and i.
activity. According to this hypothesis, the superposition of the
An alternative route is shown in Chart 3. Compounds 17a
two chemotypes was performed to explore suitable positions and b, which were prepared in the same way as 9c, were hy-
for introducing HBAs to scaffold A. Firstly, a pharmacophore drogenated, followed by triflation to yield 18a and b, respec-
model for scaffold B was generated from known sulfonamide tively. Compounds 18a and b were reduced by L-Selectride
derivatives described in the literature13–16) by applying the followed by coupling with the desired boronic acid or its pina-
“Common Feature Pharmacophore Generation” protocol in the col ester to yield 20a–g, which were converted to 21a–g using
BIOVIA Discovery Studio21) (Fig. 3(a)). Secondly, compound the same way as that shown in Charts 1(c)–(e). Subsequent
2, which represents a typical compound of scaffold A, was su- condensation with desired carboxylic acid and deprotection
perposed onto the obtained pharmacophore model (Fig. 3(b)). provided 7c–e and k–y, respectively.
The result clearly showed that the characteristic HBAs of scaf-
fold B were missing in scaffold A and were placed over the 4. The coupling reaction of 19b with bis(pinacolato)diboron
outer space of the phenyl or piperidine moiety of 2. provided 22. A subsequent Suzuki-coupling reaction with aryl
Compounds 7g and j were prepared according to Chart
Based on this model, we decided to introduce HBAs around halide provided 23a and b, which were converted to 7g and j
the phenyl moiety of scaffold A in consideration of the syn- using the same method as that shown in Charts 1(c)–(g).
thetic accessibility (Fig. 3(c)). For the HBAs, heteroaromatic An improved synthetic route for 7w is shown in Chart 5.
rings were selected because of their size and the ease at which In this scheme, we aimed to reduce the number of synthetic
the heteroatom positions can be adjusted.
steps. Mono lithiation of 1,3-dibromobenzene and a subse-
quent reaction with Weinreb amide 8 provided ketone 25,
which was converted to hydroxyimine 26 (mixture of cis and
Chemistry
The compounds described in this work were prepared as trans isomers) by reaction with hydroxylamine hydrochloride
shown in Charts 1–5. All the final compounds were formed under reflux condition in ethanol. The Boc group was re-
from a hydrochloric acid salt. Chart 1 describes the synthesis moved in this step; thus, re-protecion was needed. A Suzuki
of the reference biphenyl derivatives 7a, b, and intermediate coupling reaction of N-hydroxyimine 26 using [1,3-bis(2,6-
14c. The reaction of Grignard reagent with Weinreb amide diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)-
8 prepared from (S)-pipecolinic acid provided ketone (9a–c), palladium(II) dichloride (PEPPSI-IPR) as a palladium catalyst
which was reduced diastereoselectively by L-Selectride to yielded 27,22) which was reduced diastereoselectively by cata-

Vol. 64, No. 9 (2016)
Chem. Pharm. Bull.
1323
Fig. 3. (a) A Pharmacophore Model of Sulfonamide Derivatives; (b) Superposition of 2 on the Pharmacophore Model; (c) Schematic Representation
of Compounds of the Scaffold A and B, and the Designed Compounds in This Study
The green arrow and the associated spheres show a hydrogen bond acceptor, the purple ones show a hydrogen bond donor, the blue sphere shows a hydrophobic site, and
the orange arrow and the spheres show an aromatic ring.
Reagents and conditions: (a) 4-Biphenylmagnesium bromide (for 9a) or 3-biphenylmagnesium bromide (for 9b) or 3-methoxyphenylmagnesium bromide (for 9c), THF,
0°C; (b) L-Selectride, THF, −78°C; (c) KOH, MeOH, H2O, reflux; (d) allyl bromide, K2CO3, DMF, 80°C; (e) (1) MsCl, Et3N, CHCl3; (2) ammonia, MeOH; (f) 2-Cl–3-CF3-
benzoic acid, HOBt–H2O, WSC–HCl, DMF; (g) Pd(PPh3)4, 1,3-dimethylbarbituric acid, CHCl3.
Chart 1
lytic hydrogenation in a methanol solvent containing ammonia phenyl group with the same size as the heteroaromatic rings
to yield amine 28. Racemization was not observed in any that we intended to introduce. The biphenyl derivatives 7a
of steps. Subsequent condensation and deprotection yielded and b showed reduced inhibitory activities (7a: IC50=0.42µM,
7w. In this matter, 7w was prepared from Weinreb amide 8 7b: 0.52µM), compared with the literature value for 2, sug-
in seven steps, compared with the eleven steps that were re- gesting that the introduction of bulkiness without HBA at this
quired in Chart 4.
position had a negative effect on the activity. According to
our initial synthetic plan, several heteroaromatic rings were
introduced. The introduction of a 3-pyridine group to the para
Results and Discussion
Introduction of Heteroaromatic Rings to Improve Ac- and meta positions led to increased activities (7c: 0.037µM,
tivity The glycine uptake inhibitory activity was evaluated 7d: 0.014µM), compared with those of the biphenyl derivatives.
according to reported methods utilizing glioma T98G cells For the 5-pyrimidine derivatives, a meta-substituted derivative
expressing human GlyT1.23) The investigation of optimal Ar1 had a higher activity (7f: 0.0063µM) than the correspond-
groups is described in Table 1. As a reference, we introduced ing 3-pyridine derivative 7d and the literature value for 2

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Chem. Pharm. Bull.
Vol. 64, No. 9 (2016)
Reagents and conditions: (a) BBr3, CHCl3; (b) Tf2O, pyridine, CHCl3; (c) (1) Ar1B(OH)2 or pinacolester, Pd(PPh3)4, K2CO3, DMF, EtOH, 80°C; (2) Pd(PPh3)4, 1,3-dimeth-
ylbarbituric acid, CHCl3.
Chart 2
(0.018µM), while the para-substitution led to a reduced activ- crease the potency, we examined 2,6-disubstitution, but both
ity (7e: 0.093µM). We thought that the increased activity of 7f the dichloro derivative 7o and the dimethyl derivative 7p
was obtained through the introduction of a suitable HBA, as showed moderate activities (7o: 0.021µM, 7p: 0.042µM). We
per our initial hypothesis. thought that these reductions in activity were caused by the
A comparison between para-substituted derivatives (7c, removal of the meta-substituent.
e) and meta-substituted derivatives (7d, f) suggested that the
The replacement of the trifluoromethyl group of 7h with
meta-position was suitable for modification. Since the 5-py- chlorine, methyl, or a methoxy group each reduced the activ-
rimidine derivative 7f had a higher activity than the 3-pyri- ity; in particular, the methoxy group had a detrimental effect
dine derivative 7d, we further explored rings that included two on the activity (7s: 0.21µM). We considered that electron-with-
nitrogen atoms. The introduction of pyrazine resulted in an drawing substituents at the meta-position might be important
intermediate activity between that of 3-pyridine 7d and that of for potent inhibitory activity. The 2-chloro-5-(trifluoromethyl)-
5-pyrimidine 7f, while the 1-methylpyrazol-4-yl derivative 7h benzamide derivative 7t also exhibited a reduced activity
had a greater inhibitory activity (7h: 0.0025µM). The intro- (7t: 0.0097µM). A comparison of 7k, o, and q suggested that
duction of the 1-methylpyrazol-5-yl group as a regioisomer of 2,3-disubstitution was the best pattern for higher activity.
the pyrazole derivative 7h proved to decrease the activity by
Pyridinecarboxamide derivatives were also examined in an
more than 10 times (7i: 0.042µM). The 1-methylimidazol-5-yl attempt to reduce the lipophilicity of 7h (7h: ClogP=4.56).24)
derivative 7j, which was a nitrogen atom transferred analog of The 3-chloro-2-(trifluoromethyl)pyridine-4-carboxamide de-
7i, had a better IC50 value (7j: 0.0036µM) than that of 7i and rivative 7u (ClogP=3.52) and the 3-chloro-4-(trifluoromethyl)-
was equal or slightly inferior to that of 7h. Based on these pyridine-2-carboxamide derivative 7v (ClogP=3.87) were
modifications of the Ar1 moiety, the two nitrogen atoms of the synthesized, and both analogs showed favorable inhibi-
1-methylpyrazol-4-yl group were thought to be suitable for tory activities (7u: 0.0049µM, 7v: 0.0015µM). In particular,
interaction with GlyT1.
the 2-pyridine derivative 7v showed an equipotent or slightly
Modification of Substituents on Benzamide and Pyrazole higher activity than 7h.
Moieties The influence of substituents on the benzamide
Regarding drug-likeness properties, the reduction in lipo-
moiety of scaffold A has not been reported until now. The re- philicity provided an opportunity for another derivatization.
sults of modification of the benzamide moiety (Ar2) of 7h are As shown in Table 3, the elongation of the alkyl group on
shown in Table 2. We synthesized the 2,4-dichlorobenzamide the pyrazole moiety was investigated as a final fine tuning.
derivative 7k, the substituents of which were often used in the The ethyl pyrazole derivative 7w showed almost the same
derivatization of scaffold B; however, only weak inhibitory inhibitory activity (7w: 0.0018µM), although isopropyl and
activity was observed (Table 2, 7k: 0.20µM). We thought that normal-propyl substitution showed slightly reduced activities
the suitable substituents might differ depending on the scaf- (7x: 0.0024µM, 7y: 0.0039µM). These results indicated that the
fold, and further structure–activity relationships were studied modification of the alkyl substituent of the pyrazole moiety
to confirm the optimum substituents on Ar2.
was unlikely to increase the activity.
The replacement of a chlorine atom of 7h with a fluorine
Results of Metabolism, Pharmacokinetics, and Phar-
atom led to a decrease in activity (7l: 0.068µM), as did the macological Studies Among the synthetic derivatives, we
removal of 2-chlorine atom (7m: 0.22µM). Replacement with selected the most potent compounds 7v and w for further
a methyl group also produced a 5-fold decrease in activity evaluation. Both compounds had low metabolism rates in
(7n: 0.012µM), compared with the chlorine substituent. These human liver microsomes (7v: 13.8%, 7w: 16.4%),25) and did
results indicated that substituents at the ortho-position had not significantly inhibit the major CYP450 enzymes (3A4,
a considerable effect on the GlyT1 inhibitory activity. To in- 2D6, 2C9, 2C19, 1A2) at a concentration of 10µM. As shown

Vol. 64, No. 9 (2016)
Chem. Pharm. Bull.
1325
Reagents and conditions: (a) 4-Benzyloxyphenylmagnesium bromide or 3-benzyloxyphenylmagnesium bromide, THF, 0°C; (b) (1) H2, Pd–C, EtOH; (2) Tf2O, pyri-
dine, CHCl3, 0°C; (c) L-Selectride, THF, −78°C; (d) Ar1B(OH)2 or pinacol ester, Pd(PPh3)4, K2CO3, DMF, EtOH, 80°C; (e) Ar2–CO2H, HOBt–H2O, WSC–HCl, DMF; (f)
Pd(PPh3)4, 1,3-dimethylbarbituric acid, CHCl3; (g) 3-chloro-4-(trifluoromethyl)pyridine-2-carboxylic acid, HOBt–H2O, WSC–HCl, DMF.
Chart 3
Reagents and conditions: (a) Bis(pinacolato)diboron, Pd(dppf)Cl2, dppf, KOAc, DMSO, 80°C; (b) Ar1–Cl, Pd(PPh3)4, K2CO3, DMF, EtOH, 80°C.
Chart 4

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Chem. Pharm. Bull.
Vol. 64, No. 9 (2016)
Reagents and conditions: (a) 1,3-Dibromobenzene, n-BuLi, THF, −78°C; (b) (1) NH2OH–HCl, EtOH, reflux; (2) Boc2O, CHCl3; (c) 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pyrazole, PEPPSI–IPR, K2CO3, toluene, EtOH, H2O, 110°C; (d) H2, Pd–C, NH3/MeOH; (e) (1) 3-chloro-4-(trifluoromethyl)pyridine-2-carboxylic acid,
WSC–HCl, HOBt–H2O, DMF; (2) HCl, EtOAc.
Chart 5
in Table 4, both compounds showed acceptable plasma ex-
posure and brain/plasma concentration ratios after oral ad-
ministration in rats. Since the pharmacokinetics properties of
Table 1. In Vitro GlyT1 Inhibitory Activity of Compounds 7a–j
7w were more favorable, we selected 7w for further in vivo
evaluation studies. The detailed pharmacological properties of
7w have already been reported.20) Compound 7w significantly
improved MK-801-impaired cognition in social recognition
tests performed in rats at a dose of 0.1mg/kg orally and also
significantly reversed the phencyclidine-induced reduction in
the social interaction of paired mice at a dose of 0.3mg/kg
orally. These studies may reflect the cognitive dysfunction and
negative symptom of schizophrenia, respectively. Moreover,
compound 7w did not affect spontaneous locomotor activity
or rotarod performance when administered 10mg/kg orally.
These results suggest that 7w may be useful for the treatment
of cognitive dysfunction and the negative symptom associated
with schizophrenia without any undesirable side effects in
patients.
Compound
Position
Ar1
—
hGlyT1 IC50 (µM)
2 (SSR504734)
—
4
0.018
0.42
7a
7b
7c
3
4
0.52
0.037
Conclusion
In this article, we have described the identification and ef-
ficient synthetic route of 7w, which showed a potent GlyT1
uptake inhibitory activity. To create a novel GlyT1 inhibitor
with a strong in vitro potency and an in vivo efficacy when
administered at low doses, we selected a ligand based drug
design (LBDD) approach using known GlyT1 inhibitors. We
added HBAs to 2 as a novel interactive structure, which was
designed by superposition with different known chemotype
like sulfonamide-based GlyT1 inhibitors. After reviewing
several heteroaromatic rings as HBA, the introduction of a
1-methylpyrazol-4-yl group led to an increased inhibitory
activity. Through optimization of the benzamide and pyrazole
moieties, we successfully achieved 7w. Compound 7w exhib-
ited an inhibitory activity that was about 10 times higher than
the reference value of 2 and showed good plasma exposure
and a plasma-to-brain penetration sufficient to evaluate its
pharmacological properties. The results of in vivo pharmaco-
logical evaluations showed significant effects in several rodent
models for schizophrenia, suggesting that 7w may be useful
for the treatment of cognitive dysfunction and the negative
symptoms associated with schizophrenia without causing any
7d
7e
3
4
0.014
0.093
7f
3
3
0.0063
0.010
7g
7h
7i
3
3
0.0025
0.042
7j
3
0.0036

Vol. 64, No. 9 (2016)
Chem. Pharm. Bull.
1327
Table 2. In Vitro GlyT1 Inhibitory Activity of Compounds 7h and k–v
Compound
Ar2
hGlyT1IC50 (µM)
Compound
Ar2
hGlyT1IC50 (µM)
7h
0.0025
7q
0.025
7k
0.20
7r
0.036
7l
0.068
0.22
7s
7t
0.21
7m
7n
7o
7p
0.0097
0.0049
0.0015
0.012
0.021
0.042
7u
7v
Table 3. In Vitro GlyT1 Inhibitory Activity of Compounds 7v–y
Table 4. Pharmacokinetics Profiles of 7v and w after Oral Administra-
tion in Rats
Compound
7v
7w
Dose (mg/kg)
Tmax (h)
10
10
3.0 1.73
49.3 12.4
0.69 (4h)
235 53.7
4.0 0.0
117 15.4
0.52 (4h)
661 42.2
Cmax (ng/mL)
B/P ratio
AUC (ng·h/mL)
Compound
Ar1
hGlyT1 IC50 (µM)
ClogP
Each value represents the mean S.D. of three animals.
7v
0.0015
3.87
or Varian GEMINI2000/200, and the chemical shifts were
expressed in δ (ppm) values with trimethylsilane as an in-
ternal reference (s=singlet, d=doublet, t=triplet, q=quartet,
m=multiplet, and br=broad peak). Mass spectra (MS) were
recorded on a micromass Platform LC or Shimadzu LCMS-
2010EV. High resolution (HR) mass spectral data were ac-
quired using a Shimadzu LCMS-IT-TOF equipped with an
electrospray ionization (ESI)/atmospheric pressure chemical
ionization (APCI) dual ion source. The purities of the final
compounds were confirmed using LC-MS on an Agilent
instrument with electrospray ionization. The LC-MS condi-
tions were as follows: Agilent 1290 infinity and Agilent 6150;
column Waters Acquity CSH C18, 1.7µm, 2.1×50mm; eluent
A, water+0.1% formic acid; eluent B, acetonitrile+0.1% for-
mic acid; 20–99% B for 1.2min, 99% B for 0.2min; flow rate
7w
7x
0.0018
0.0024
4.40
4.71
7y
0.0039
4.93
undesirable side effects.
Experimental
1H- and 13C-NMR spectra were recorded on a JEOL JNM- 0.8mL/min; UV detection, λ=254nm. Optical rotations were
ECA600, JEOL JNM-ECA500, Varian UNITYNOVA300, measured on a Rudolph Research Analytical AUTOPOL V.

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Chem. Pharm. Bull.
Vol. 64, No. 9 (2016)
tert-Butyl
(2S)-2-(3-Methoxybenzoyl)piperidine-1-car- was obtained in a manner similar to that described for 10c.
boxylate (9c) Under a nitrogen gas atmosphere, 3-bromo- 1H-NMR (600MHz, CDCl3) δ: 1.30–1.37 (m, 1H), 1.37–1.65
anisole (35mL, 277mmol) was added dropwise to a mixture (m, 4H), 1.52 (s, 9H), 1.65–1.74 (m, 1H), 2.87–3.18 (m, 1H),
of magnesium (7.1g, 292mmol) and a catalytic amount of 3.97–4.54 (m, 2H), 4.95 (d, J=10.1Hz, 1H), 7.31–7.40 (m,
iodine in tetrahydrofuran (THF) (270mL), and the mixture 2H), 7.39–7.49 (m, 3H), 7.50–7.65 (m, 4H); MS (ESI): m/z 368
was stirred for 2h. This reaction solution was added dropwise [M+H]+.
to a solution of tert-butyl (2S)-2-{[methoxy(methyl)amino]-
(S)-{(2S)-1-Allylpiperidin-2-yl}(3-methoxyphenyl)metha-
carbonyl}piperidine-1-carboxylate (8, 50.0g, 184mmol) in nol (12c) KOH (39.2g, 699mmol) in water (350mL) was
THF (300mL) under ice cooling, and the mixture was stirred added to a solution of 10c (28.1g, 87.4mmol) in MeOH
at room temperature for 2h. Ten percent aqueous NH4Cl so- (400mL), and the mixture was stirred under reflux condition
lution was added, followed by extraction with EtOAc. The for 16h. The organic solvent was distilled off, followed by
organic layer was washed with water and brine, dried over extraction with CHCl3. The organic layer was dried over an-
anhydrous Na2SO4, filtered, and concentrated in vacuo. The hydrous Na2SO4, filtered, and concentrated in vacuo. The resi-
residue was purified using silica gel column chromatography due was suspended in 5% EtOAc in hexane, and precipitate
(11% EtOAc in hexane) to yield 9c (32.7g, 56%) as a pale yel- was filtered to yield 11c (19.0g, 98%) as a colorless powder.
1
low oil. H-NMR (600MHz, CDCl3) δ: 1.29–1.53 (m, 11H), 1H-NMR (600MHz, CDCl3) δ: 1.20–1.32 (m, 2H), 1.34–1.44
1.53–1.88 (m, 3H), 1.99–2.22 (m, 1H), 3.07–3.29 (m, 1H), 3.85 (m, 2H), 1.54–1.61 (m, 1H), 1.73–1.79 (m, 1H), 2.56–2.63 (m,
(s, 3H), 3.88–4.05 (m, 1H), 5.41–5.69 (m, 1H), 7.05–7.15 (m, 1H), 2.63–2.68 (m, 1H), 3.06–3.11 (m, 1H), 3.82 (s, 3H), 4.37
1H), 7.30–7.57 (m, 3H); MS (ESI): m/z 342 [M+Na]+.
(d, J=6.9Hz, 1H), 6.79–6.85 (m, 1H), 6.88–6.94 (m, 2H),
tert-Butyl (2S)-2-([1,1′-Biphenyl]-4-carbonyl)piperidine- 7.23–7.28 (m, 1H); MS (ESI): m/z 222 [M+H]+.
1-carboxylate (9a) Compound 9a (55%) was obtained in a K2CO3 (15.9g, 116mmol) and allyl bromide (7.3mL,
1
manner similar to that described for 9c. H-NMR (600MHz, 84.4mmol) were added to a solution of 11c (17.0g, 76.8mmol)
CDCl3) δ: 1.37–1.52 (m, 12H), 1.59–1.74 (m, 1H), 1.77–1.95 (m, in N,N-dimethylformamide (DMF) (200mL), and the mixture
1H), 2.06–2.22 (m, 1H), 3.11–3.29 (m, 1H), 3.88–4.05 (m, 1H), was stirred at 50°C for 2h. The reaction mixture was parti-
5.47–5.78 (m, 1H), 7.35–7.49 (m, 3H), 7.62 (brd, J=7.4Hz, tioned between water and EtOAc, and the organic layer was
2H), 7.64–7.71 (m, 2H), 7.94–8.05 (m, 2H); MS (ESI): m/z 266 washed with brine, dried over anhydrous Na2SO4, filtered, and
[M−Boc+H]+.
concentrated in vacuo. The residue was purified using NH-
tert-Butyl (2S)-2-([1,1′-Biphenyl]-3-carbonyl)piperidine- silica gel column chromatography (5% EtOAc in hexane) to
1
1-carboxylate (9b) Compound 9b (55%) was obtained in a yield 12c (16.8g, 84%) as a colorless oil. H-NMR (200MHz,
manner similar to that described for 9c. H-NMR (600MHz, CDCl3) δ: 1.12–1.77 (m, 6H), 2.56–2.81 (m, 2H), 2.93–3.11
1
CDCl3) δ: 1.33–1.51 (m, 11H), 1.57–1.73 (m, 2H), 1.76–1.89 (m, 1H), 3.27–3.51 (m, 2H), 3.81 (s, 3H), 4.72 (d, J=9.7Hz,
(m, 1H), 2.04–2.22 (m, 1H), 3.08–3.25 (m, 1H), 3.87–4.05 (m, 1H), 5.11–5.26 (m, 2H), 5.76–5.99 (m, 1H), 6.76–6.85 (m, 1H),
1H), 5.49–5.78 (m, 1H), 7.34–7.41 (m, 1H), 7.42–7.56 (m, 3H), 6.89–6.97 (m, 2H), 7.18–7.28 (m, 1H); MS (ESI): m/z 262
7.61 (brd, J=7.4Hz, 2H), 7.78 (brd, J=7.4Hz, 1H), 7.82–7.96 [M+H]+.
(m, 1H), 8.06–8.20 (m, 1H); MS (ESI): m/z 266 [M−Boc+H]+.
(S)-([1,1′-Biphenyl]-4-yl)[(2S)-1-(prop-2-en-1-yl)piper-
tert-Butyl (2S)-{(S)-Hydroxy(3-methoxyphenyl)methyl}- idin-2-yl]methanol (12a) Compound 12a (33% in 2 steps)
piperidine-1-carboxylate (10c) Under a nitrogen gas atmo- was obtained in a manner similar to that described for 12c.
sphere, lithium tri-sec-butylborohydride (L-Selectride, 1mol/L 1H-NMR (600MHz, CDCl3) δ: 1.20–1.31 (m, 1H), 1.32–1.40
solution in THF, 200mL, 200mmol) was added dropwise to a (m, 1H), 1.49–1.66 (m, 3H), 1.68–1.78 (m, 1H), 2.64–2.74 (m,
solution of 9c (32.7g, 103mmol) in THF (300mL) cooled with 1H), 2.74–2.81 (m, 1H), 3.00–3.12 (m, 1H), 3.34–3.41 (m, 1H),
a dryice–acetone bath, and the mixture was stirred for 3h. 3.43–3.51 (m, 1H), 4.80 (brd, J=9.9Hz, 1H), 5.15–5.26 (m,
The reaction was quenched with 15% aqueous H2O2 solution 2H), 5.90 (ddt, J=17.0, 10.4, 6.3, 6.3Hz, 1H), 7.30–7.36 (m,
(200mL) and extracted with EtOAc. The organic layer was 1H), 7.40–7.45 (m, 4H), 7.54–7.61 (m, 4H); MS (ESI): m/z 308
dried over anhydrous MgSO4, filtered, and concentrated in [M+H]+.
vacuo. The residue was suspended in 10% EtOAc in hexane,
(S)-([1,1′-Biphenyl]-3-yl)[(2S)-1-(prop-2-en-1-yl)piper-
and the precipitate was filtered to yield 10c (22.0g, 67%) as a idin-2-yl]methanol (12b) Compound 12b (44% in 2 steps)
1
colorless powder. H-NMR (600MHz, CDCl3) δ: 1.26–1.34 (m, was obtained in a manner similar to that described for 12c.
1H), 1.35–1.75 (m, 5H), 1.51 (s, 9H), 2.84–3.15 (m, 1H), 3.82 1H-NMR (600MHz, CDCl3) δ: 1.21–1.29 (m, 1H), 1.32–1.40
(s, 3H), 3.95–4.46 (m, 2H), 4.83–4.88 (m, 1H), 6.81–6.87 (m, (m, 1H), 1.48–1.66 (m, 3H), 1.68–1.77 (m, 1H), 2.66–2.73
1H), 6.90–7.00 (m, 2H), 7.22–7.31 (m, 1H); MS (ESI): m/z 344 (m, 1H), 2.73–2.80 (m, 1H), 3.01–3.11 (m, 1H), 3.37 (brdd,
[M+Na]+.
J=13.6, 6.6Hz, 1H), 3.43–3.51 (m, 1H), 4.82 (d, J=9.9Hz,
tert-Butyl (2S)-2-[(S)-([1,1′-Biphenyl]-4-yl)(hydroxy)meth- 1H), 5.15–5.25 (m, 2H), 5.84–5.94 (m, 1H), 7.32–7.37 (m, 2H),
yl]piperidine-1-carboxylate (10a) Compound 10a (96%) 7.38–7.47 (m, 3H), 7.47–7.53 (m, 1H), 7.57–7.62 (m, 3H); MS
was obtained in a manner similar to that described for 10c. (ESI): m/z 308 [M+H]+.
1H-NMR (600MHz, CDCl3) δ: 1.32–1.38 (m, 1H), 1.38–1.65
(S)-1-{(2S)-1-Allylpiperidin-2-yl}-1-(3-methoxyphenyl)-
(m, 4H), 1.52 (s, 9H), 1.66–1.74 (m, 1H), 2.89–3.17 (m, 1H), methanamine (13c) Methanesulfonyl chloride (6.9mL,
3.98–4.55 (m, 2H), 4.93 (d, J=10.5Hz, 1H), 7.32–7.37 (m, 89.1mmol) was added to an ice-cooled solution of 12c (16.6g,
1H), 7.40–7.49 (m, 4H), 7.54–7.64 (m, 4H); MS (ESI): m/z 390 63.5mmol) and triethylamine (15mL, 108mmol) in CHCl3
[M+Na]+.
(160mL), and the mixture was stirred under cooling for 1.5h
tert-Butyl (2S)-2-[(S)-([1,1′-Biphenyl]-3-yl)(hydroxy)meth- and at room temperature for an additional 1h. The reaction
yl]piperidine-1-carboxylate (10b) Compound 10b (81%) mixture was concentrated in vacuo and the residue was dis-

Vol. 64, No. 9 (2016)
Chem. Pharm. Bull.
1329
solved in 8mol/L NH3 solution in MeOH (150mL). After stir- (14b) Compound 14b (84%) was obtained in a manner simi-
1
ring at 40°C for 1h, the reaction mixture was concentrated in lar to that described for 14c. H-NMR (600MHz, dimethyl
vacuo. The residue was purified using silica gel column chro- sulfoxide (DMSO)-d6) δ: 1.08–1.14 (m, 1H), 1.27–1.45 (m, 4H),
matography (CHCl3–MeOH–28% NH3 in water=50:1:0.5) to 1.66–1.72 (m, 1H), 1.99 (s, 1H), 2.45–2.49 (m, 1H), 2.73 (s,
1
yield 13c (12.9g, 78%) as a yellow oil. H-NMR (600MHz, 1H), 2.90–2.95 (m, 1H), 2.96–3.01 (m, 1H), 3.34–3.41 (m, 1H),
CDCl3) δ: 1.01–1.07 (m, 1H), 1.29–1.54 (m, 4H), 1.59–1.69 3.46 (brdd, J=14.2, 6.4Hz, 1H), 5.11–5.15 (m, 1H), 5.21–5.26
(m, 1H), 2.62–2.71 (m, 2H), 3.01–3.08 (m, 1H), 3.32–3.42 (m, (m, 1H), 5.43–5.48 (m, 1H), 5.88 (ddt, J=17.0, 10.4, 6.2,
2H), 3.81 (s, 3H), 4.17 (d, J=9.6Hz, 1H), 5.10–5.15 (m, 1H), 6.2Hz, 1H), 7.35–7.40 (m, 1H), 7.42–7.51 (m, 4H), 7.53–7.61
5.18–5.24 (m, 1H), 5.84–5.93 (m, 1H), 6.76–6.80 (m, 1H), (m, 1H), 7.62–7.69 (m, 4H), 7.76–7.79 (m, 1H), 7.93 (dd, J=7.1,
6.91–6.96 (m, 2H), 7.19–7.25 (m, 1H); MS (ESI): m/z 261 2.5Hz, 1H), 9.04–9.10 (m, 1H); MS (ESI): m/z 513 [M+H]+.
[M+H]+.
N-{(S)-([1,1′-Biphenyl]-4-yl)[(2S)-piperidin-2-yl]-
(S)-1-([1,1′-Biphenyl]-4-yl)-1-[(2S)-1-(prop-2-en-1-yl)pi- methyl}-2-chloro-3-(trifluoromethyl)benzamide Hydrochlo-
peridin-2-yl]methanamine (13a) Compound 13a (83% in ride (7a) 1,3-Dimethylbarbituric acid (299mg, 1.9mmol)
2 steps) was obtained in a manner similar to that described and
tetrakis(triphenylphosphine)palladium(0)
(7.4mg,
1
for 13c. H-NMR (600MHz, CDCl3) δ: 1.04–1.16 (m, 1H), 0.0064mmol) were added to a solution of 14a (328mg,
1.28–1.57 (m, 4H), 1.60–1.71 (m, 1H), 2.66–2.73 (m, 2H), 0.64mmol) in CHCl3 (5mL), and the mixture was stirred for
3.07 (ddd, J=13.8, 9.9, 3.4Hz, 1H), 3.35–3.43 (m, 2H), 4.25 2h. The reaction mixture was partitioned between CHCl3 and
(d, J=9.6Hz, 1H), 5.09–5.26 (m, 2H), 5.87–5.96 (m, 1H), saturated NaHCO3 aqueous solution, and the organic layer
7.29–7.35 (m, 1H), 7.39–7.47 (m, 4H), 7.52–7.62 (m, 4 H); MS was dried over anhydrous MgSO4, filtered, and concentrated
(ESI): m/z 307 [M+H]+.
in vacuo. The residue was purified using silica gel column
(S)-1-([1,1′-Biphenyl]-3-yl)-1-[(2S)-1-(prop-2-en-1-yl)pi- chromatography (2% MeOH in CHCl3) to yield the free form
peridin-2-yl]methanamine (13b) Compound 13b (74% in of 7a (212mg). 4mol/L HCl in EtOAc solution (0.2mL) was
2 steps) was obtained in a manner similar to that described added to a solution of the free form of 7a in EtOAc (1mL),
1
for 13c. H-NMR (600MHz, CDCl3) δ: 1.02–1.12 (m, 1H), and the precipitate was filtered to yield 7a (202mg, 62%) as a
1
1.29–1.46 (m, 3H), 1.46–1.56 (m, 1H), 1.60–1.74 (m, 1H), colorless powder. H-NMR (600MHz, DMSO-d6) δ: 1.35–1.51
2.66–2.75 (m, 2H), 3.02–3.10 (m, 1H), 3.33–3.45 (m, 2H), (m, 3H), 1.56–1.67 (m, 1H), 1.68–1.78 (m, 2H), 2.79–2.92
4.27 (d, J=9.6Hz, 1H), 5.09–5.27 (m, 2H), 5.86–5.95 (m, 1H), (m, 1H), 3.27–3.41 (m, 1H), 3.50–3.60 (m, 1H), 5.20–5.26
7.28–7.52 (m, 6H), 7.54–7.66 (m, 3H); MS (ESI): m/z 307 (m, 1H), 7.35–7.41 (m, 1H), 7.45–7.57 (m, 4H), 7.65–7.76 (m,
[M+H]+.
5H), 7.93–8.05 (m, 2H), 8.73–8.85 (m, 1H), 8.99–9.16 (m,
N-[(S)-{(2S)-1-Allylpiperidin-2-yl}(3-methoxyphenyl)- 1H), 9.63 (d, J=8.7Hz, 1H); 13C-NMR (126MHz, DMSO-d6)
methyl]-2-chloro-3-(trifluoromethyl)benzamide (14c) δ: 165.3, 139.8, 139.5, 138.7, 137.0, 133.4, 129.0, 128.7, 128.4,
1-Hydroxybenzotriazole monohydrate (2.18g, 16.1mmol) and 128.0, 127.7, 127.6, 127.2 (q, J=31Hz), 126.9, 126.7, 122.7 (q,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride J=273Hz), 58.2, 55.6, 44.8, 25.8, 21.6, 21.4; HR-MS: Calcd for
(2.54g, 13.2mmol) were added to a solution of 2-chloro-3- C26H24ClF3N2O [M+H]+ 473.1602. Found 473.1590; [α]D=+72
(trifluoromethyl)benzoic acid (2.58g, 11.5mmol) in DMF (c=0.50, MeOH).
(15mL), and the mixture was stirred for 30min. A solution of
N-{(S)-([1,1′-Biphenyl]-3-yl)[(2S)-piperidin-2-yl]-
13c (3.00g, 11.5mmol) was added to the reaction mixture, and methyl}-2-chloro-3-(trifluoromethyl)benzamide (7b) Com-
the mixture was stirred for 3h. The reaction was quenched pound 7b (38%) was obtained from 14b in a manner similar
1
with saturated NaHCO3 aqueous solution and extracted with to that described for 7a. H-NMR (600MHz, DMSO-d6) δ:
EtOAc. The organic layer was washed with water and brine, 1.36–1.45 (m, 1H), 1.45–1.52 (m, 2H), 1.57–1.67 (m, 1H),
dried over anhydrous Na2SO4, filtered, and concentrated 1.68–1.77 (m, 2H), 2.80–2.90 (m, 1H), 3.31–3.38 (m, 1H),
in vacuo. The residue was purified using silica gel column 3.56–3.65 (m, 1H), 5.25–5.32 (m, 1H), 7.36–7.46 (m, 2H),
chromatography (2% MeOH in CHCl3) to yield 14c (3.42g, 7.47–7.54 (m, 3H), 7.63–7.69 (m, 2H), 7.69–7.73 (m, 2H), 7.79
1
64%) as a colorless powder. H-NMR (200MHz, CDCl3) δ: (s, 1H), 7.92–7.97 (m, 1H), 8.01–8.07 (m, 1H), 8.81–8.99 (m,
1.25–1.88 (m, 6H), 2.45–2.64 (m, 1H), 2.75–3.03 (m, 2H), 1H), 9.05–9.19 (m, 1H), 9.69 (d, J=8.3Hz, 1H); 13C-NMR
3.10–3.38 (m, 2H), 3.81 (s, 3H), 4.88–4.98 (m, 1H), 5.02–5.17 (126MHz, DMSO-d6) δ: 165.4, 140.5, 139.7, 138.7, 138.5,
(m, 2H), 5.61–5.83 (m, 1H), 6.75–6.84 (m, 1H), 6.90–7.01 (m, 133.4, 129.3, 128.9, 128.6, 127.7, 127.7, 127.6 (q, J=82Hz),
2H), 7.19–7.32 (m, 1H), 7.36–7.48 (m, 1H), 7.64–7.81 (m, 3H); 127.1, 127.0, 126.8, 126.4, 126.0, 122.7 (q, J=274Hz), 58.2,
MS (ESI): m/z 467 [M+H]+.
55.8, 44.8, 25.7, 21.6, 21.3; HR-MS: Calcd for C26H24ClF3N2O
N-{(S)-([1,1′-Biphenyl]-4-yl)[(2S)-1-(prop-2-en-1-yl)- [M+H]+ 473.1602. Found 473.1596; [α]D=+76 (c=0.52,
piperidin-2-yl]methyl}-2-chloro-3-(trifluoromethyl)benz- MeOH).
amide (14a) Compound 14a (67%) was obtained in a manner
3-{(S)-{[2-Chloro-3-(trifluoromethyl)benzoyl]amino}-
1
similar to that described for 14c. H-NMR (600MHz, CDCl3) [(2S)-piperidin-2-yl]methyl}phenyl Trifluoromethanesulfo-
δ: 1.35–1.62 (m, 5H), 1.77–1.90 (m, 1H), 2.54–2.62 (m, 1H), nate (16) Boran tribromide (2.0mL, 21.2mmol) was added
2.85–2.91 (m, 1H), 2.94–3.01 (m, 1H), 3.21–3.27 (m, 1H), 3.33 to an ice cooled solution of 14c (3.29g, 7.05mmol) in CHCl3
(brdd, J=13.8, 6.4Hz, 1 H), 4.97–5.04 (m, 1H), 5.08–5.18 (30mL), and the mixture was stirred under ice cooling for
(m, 2H), 5.70–5.80 (m, 1H), 7.26 (s, 1H), 7.31–7.36 (m, 1H), 1.5h. The reaction was quenched with saturated NaHCO3
7.41–7.49 (m, 5H), 7.56–7.61 (m, 4H), 7.71–7.79 (m, 2H); MS aqueous solution and extracted with EtOAc. The organic layer
(ESI): m/z 513 [M+H]+.
was dried over anhydrous Na2SO4, filtered, and concentrated
N-{(S)-([1,1′-Biphenyl]-3-yl)[(2S)-1-(prop-2-en-1-yl)piper- in vacuo. The residue was purified using silica gel column
idin-2-yl]methyl}-2-chloro-3-(trifluoromethyl)benzamide chromatography (0–12% MeOH in CHCl3) to yield 15 (3.15g,

1330
Chem. Pharm. Bull.
Vol. 64, No. 9 (2016)
1
98%) as a colorless amorphous. H-NMR (300MHz, CDCl3) [(2S)-piperidin-2-yl]methyl}-3-(trifluoromethyl)benzamide
δ: 1.28–1.63 (m, 5H), 1.70–1.86 (m, 1H), 2.51–2.65 (m, 1H), Hydrochloride (7h) Compound 7h (44% in 2 steps) was
2.74–3.03 (m, 2H), 3.16–3.37 (m, 2H), 4.90 (d, J=9.2Hz, 1H), obtained from 16 in a manner similar to that described for
5.04–5.20 (m, 2H), 5.62–5.82 (m, 1H), 6.59–6.67 (m, 1H), 7f. 1H-NMR (600MHz, DMSO-d6) δ: 1.34–1.49 (m, 3H),
6.78–6.93 (m, 2H), 7.10–7.20 (m, 1H), 7.37–7.45 (m, 1H), 1.56–1.65 (m, 1H), 1.68–1.77 (m, 2H), 2.80–2.90 (m, 1H),
7.65–7.93 (m, 3H); MS (ESI): m/z 453 [M+H]+.
3.33–3.38 (m, 1H), 3.48–3.55 (m, 1H), 3.88 (s, 3H), 5.15–5.19
Trifluoromethanesulfonic anhydride (1.3mL, 7.74mmol) (m, 1H), 7.24–7.27 (m, 1H), 7.39 (t, J=7.8Hz, 1H), 7.52–7.55
was added to an ice cooled solution of 15 (2.97g, 6.56mmol) (m, 1H), 7.63–7.69 (m, 2H), 7.86 (s, 1H), 7.93–7.97 (m, 1H),
and pyridine (2.6mL, 32.2mmol) in CHCl3 (20mL), and the 7.97–8.02 (m, 1H), 8.14 (s, 1H), 8.68–8.81 (m, 1H), 8.90–9.02
mixture was stirred under ice cooling for 30min and at room (m, 1H), 9.51 (d, J=8.7Hz, 1H); 13C-NMR (126MHz, DMSO-
temperature for an additional 1.5h. The reaction was quenched d6) δ: 165.3, 138.7, 138.4, 136.0, 133.5, 132.9, 129.2, 128.6,
with saturated NaHCO3 aqueous solution and extracted with 128.0, 127.9, 127.7, 127.2 (q, J=31Hz), 125.2, 124.6, 124.4,
CHCl3. The organic layer was washed with water and brine, 122.7 (q, J=274Hz), 121.6, 58.2, 55.8, 44.8, 38.7, 25.7, 21.6,
dried over anhydrous MgSO4, filtered, and concentrated in 21.3; HR-MS: Calcd for C24H24ClF3N4O [M+H]+ 477.1664.
vacuo. The residue was purified using silica gel column chro- Found 477.1663; [α]D=+74 (c=1.05, MeOH).
matography (0–3% MeOH in CHCl3) to yield 16 (3.39g, 88%)
2-Chloro-N-{(S)-[3-(1-methyl-1H-pyrazol-5-yl)phenyl]-
1
as a brown oil. H-NMR (200MHz, CDCl3) δ: 1.22–1.91 (m, [(2S)-piperidin-2-yl]methyl}-3-(trifluoromethyl)benzamide
6H), 2.49–2.70 (m, 1H), 2.71–3.03 (m, 2H), 3.12–3.38 (m, 2H), Hydrochloride (7i) Compound 7i (21% in 2 steps) was
4.92–5.03 (m, 1H), 5.05–5.20 (m, 2H), 5.61–5.84 (m, 1H), obtained from 16 in a manner similar to that described for
7.12–7.34 (m, 2H), 7.37–7.50 (m, 3H), 7.65–7.85 (m, 3H); MS 7f. 1H-NMR (600MHz, DMSO-d6) δ: 1.37–1.51 (m, 3H),
(ESI): m/z 585 [M+H]+.
1.54–1.64 (m, 1H), 1.69–1.77 (m, 2H), 2.82–2.90 (m, 1H),
2-Chloro-N-{(S)-(2S)-piperidin-2-yl[3-(pyrimidin-5-yl)- 3.33–3.39 (m, 1H), 3.51–3.60 (m, 1H), 3.88 (s, 3H), 5.22–5.27
phenyl]methyl}-3-(trifluoromethyl)benzamide Hydrochloride (m, 1H), 6.44 (d, J=1.8Hz, 1H), 7.47–7.58 (m, 4H), 7.61
(7f) Pyrimidine-5-boronic acid (212mg, 1.71mmol), potas- (s, 1H), 7.68 (t, J=7.8Hz, 1H), 7.95 (s, 1H), 7.97 (s, 1H),
sium carbonate (236mg, 1.71mmol), and tetrakis(triphenyl- 8.63–8.77 (m, 1H), 8.83–8.99 (m, 1H), 9.54 (d, J=8.7Hz,
phosphine)palladium(0) (40mg, 0.035mmol) were added to a 1H); 13C-NMR (126MHz, DMSO-d6) δ: 165.3, 142.3, 138.6,
solution of 16 (657mg, 1.12mmol) in a mixed solvent of 138.5, 137.9, 133.4, 130.5, 129.2, 128.6, 128.1, 127.9, 127.9,
DMF–EtOH (2:1, 10mL), and the mixture was stirred at 127.7, 127.6, 127.2 (q, J=31Hz), 122.7 (q, J=274Hz), 105.9,
90°C for 4h. The reaction mixture was partitioned be- 58.1, 55.6, 44.8, 37.6, 25.7, 21.6, 21.3; HR-MS: Calcd for
tween saturated NaHCO3 aqueous solution and EtOAc, and C24H24ClF3N4O [M+H]+ 477.1664. Found 477.1662; [α]D=+66
the organic layer was washed with water and brine, dried (c=0.50, MeOH).
over anhydrous MgSO4, filtered, and concentrated in
tert-Butyl (2S)-2-[4-(Benzyloxy)benzoyl]piperidine-1-car-
vacuo. The residue was purified using NH-silica gel column boxylate (17a) Compound 17a (53%) was obtained in a
1
chromatography (20% EtOAc in hexane) to yield a color- manner similar to that described for 9c. H-NMR (600MHz,
less amorphous solid (237mg). 1,3-Dimethylbarbituric acid CDCl3) δ: 1.31–1.72 (m, 13H), 1.74–1.90 (m, 1H), 1.98–2.18
(215mg, 1.38mmol) and tetrakis(triphenylphosphine)palla- (m, 1H), 3.10–3.29 (m, 1H), 3.84–4.02 (m, 1H), 5.12 (s, 2H),
dium(0) (5.3mg, 0.0046mmol) were added to a solution of 5.38–5.69 (m, 1H), 6.96–7.05 (m, 2H), 7.31–7.46 (m, 5H),
the amorphous solid in CHCl3 (4mL), and the mixture was 7.86–7.96 (m, 2H); MS (ESI): m/z 418 [M+Na]+.
stirred for 3h. The reaction mixture was partitioned between
tert-Butyl (2S)-2-[3-(Benzyloxy)benzoyl]piperidine-1-car-
saturated NaHCO3 aqueous solution and CHCl3, and the or- boxylate (17b) Compound 17b (60%) was obtained in a
1
ganic layer was dried over anhydrous MgSO4, filtered, and manner similar to that described for 9c. H-NMR (600MHz,
concentrated in vacuo. The residue was purified using silica CDCl3) δ: 1.30–1.50 (m, 11H), 1.52–1.73 (m, 2H), 1.74–1.85
gel column chromatography (5% MeOH in CHCl3) and NH- (m, 1H), 1.98–2.16 (m, 1H), 3.07–3.28 (m, 1H), 3.86–4.03
silica gel column chromatography (100% EtOAc) to yield the (m, 1H), 5.10 (s, 2H), 5.39–5.70 (m, 1H), 7.13–7.20 (m, 1H),
free form of 7f (70mg). 2mol/L HCl in isopropanol solution 7.30–7.41 (m, 4H), 7.41–7.45 (m, 2H), 7.46–7.58 (m, 2H); MS
(1.0mL) was added to an ice-cooled solution of the free form (ESI): m/z 418 [M+Na]+.
of 7f in EtOH (1.0mL). After concentration in vacuo, the
tert-Butyl (2S)-2-(4-{[(Trifluoromethyl)sulfonyl]oxy}ben-
residue was solidified with EtOAc to yield 7f (59mg, 10% in zoyl)piperidine-1-carboxylate (18a) 5% Pd/C (1.0g) was
1
2 steps from 16) as a colorless powder. H-NMR (600MHz, added to a solution of 17a (9.90g, 25mmol) in MeOH
DMSO-d6) δ: 1.37–1.54 (m, 3H), 1.54–1.66 (m, 1H), 1.66–1.78 (120mL), and the mixture was stirred overnight under a
(m, 2H), 2.81–2.91 (m, 1H), 3.31–3.39 (m, 1H), 3.56–3.64 (m, hydrogen gas atmosphere. After filtration, the filtrate was
1H), 5.26–5.33 (m, 1H), 7.51–7.57 (m, 1H), 7.60 (t, J=7.8Hz, concentrated in vacuo. The residue was solidified with 33%
1H), 7.67 (t, J=7.8Hz, 1H), 7.81–7.86 (m, 1H), 7.92–7.97 (m, EtOAc in hexane to yield a colorless powder (4.94g), which
2H), 7.98–8.02 (m, 1H), 8.73–8.80 (m, 1H), 8.88–8.97 (m, 1H), was converted to 18a (6.82g, 62% in 2 steps from 17a, pale
9.20 (s, 2H), 9.23 (s, 1H), 9.55 (d, J=8.7Hz, 1H); 13C-NMR yellow powder) in a manner similar to that described for 16.
(126MHz, DMSO-d6) δ: 165.4, 157.5, 154.8, 138.9, 138.6, 1H-NMR (600MHz, CDCl3) δ: 1.30–2.16 (m, 15H), 2.96–3.26
134.1, 133.4, 132.8, 129.6, 128.6, 128.5, 128.0, 127.7, 127.2 (q, (m, 1H), 3.83–4.05 (m, 1H), 5.35–5.65 (m, 1H), 7.32–7.43 (m,
J=30Hz), 126.6, 126.2, 122.7 (q, J=274Hz), 58.2, 55.6, 44.8, 2H), 7.99–8.11 (m, 2H); MS (ESI): m/z 438 [M+H]+, m/z 460
25.7, 21.6, 21.3; HR-MS: Calcd for C24H22ClF3N4O [M+H]+ [M+Na]+.
475.1507. Found 475.1493; [α]D=+72 (c=0.48, MeOH).
tert-Butyl (2S)-2-{3-[(Trifluoromethanesulfonyl)oxy]ben-
2-Chloro-N-{(S)-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]- zoyl}piperidine-1-carboxylate (18b) Compound 18b (66%

Vol. 64, No. 9 (2016)
Chem. Pharm. Bull.
1331
in 2 steps) was obtained from 17b in a manner similar to that δ: 1.31–1.75 (m, 6H), 1.52 (s, 9H), 2.85–3.19 (m, 1H), 3.95 (s,
1
described for 18a. H-NMR (600MHz, CDCl3) δ: 1.29–2.16 3H), 3.97–4.50 (m, 2H), 4.90 (d, J=10.1Hz, 1H), 7.21 (brd,
(m, 15H), 2.96–3.25 (m, 1H), 3.80–4.00 (m, 1H), 5.29–5.61 (m, J=7.3Hz, 1H), 7.32–7.36 (m, 1H), 7.39–7.43 (m, 1H), 7.48
1H), 7.40–7.62 (m, 2H), 7.75–8.02 (m, 2H); MS (ESI): m/z 438 (brs, 1H), 7.63 (brs, 1H), 7.76 (s, 1H); MS (ESI): m/z 372
[M+H]+.
[M+H]+.
tert-Butyl (2S)-2-[(S)-Hydroxy(4-{[(trifluoromethyl)sul-
tert-Butyl (2S)-2-[(S)-[3-(1-Ethyl-1H-pyrazol-4-yl)phen-
fonyl]oxy}phenyl)methyl]piperidine-1-carboxylate (19a) yl](hydroxy)methyl]piperidine-1-carboxylate (20e) Com-
Compound 19a (6.3g, 94%) was obtained from 18a (6.70g) pound 20e (80%) was obtained from 19b in a manner similar
in a manner similar to that described for 10c. 1H-NMR to that described for 20a. 1H-NMR (600MHz, CDCl3) δ:
(600MHz, CDCl3) δ: 1.21–1.32 (m, 1H), 1.37–1.76 (m, 14H), 1.29–1.72 (m, 6H), 1.52 (s, 9H), 1.54 (t, J=7.3Hz, 3H),
2.85–3.17 (m, 1H), 3.96–4.50 (m, 2H), 4.87–5.00 (m, 1H), 2.86–3.17 (m, 1H), 3.97–4.47 (m, 2H), 4.21 (q, J=7.3Hz, 2H),
7.26–7.37 (m, 2H), 7.44–7.55 (m, 2H); MS (ESI): m/z 440 4.90 (dd, J=10.5, 5.0Hz, 1H), 7.21 (d, J=7.3Hz, 1H), 7.32–7.36
[M+H]+.
(m, 1H), 7.39–7.44 (m, 1H), 7.50 (brs, 1H), 7.68 (brs, 1H), 7.78
tert-Butyl (2S)-2-[(S)-Hydroxy{3-[(trifluoromethanesulfon- (s, 1H); MS (ESI): m/z 386 [M+H]+.
yl)oxy]phenyl}methyl]piperidine-1-carboxylate (19b) Com- tert-Butyl (2S)-2-[(S)-Hydroxy{3-[1-(propan-2-yl)-1H-
pound 19b (96%) was obtained from 18a in a manner similar pyrazol-4-yl]phenyl}methyl]piperidine-1-carboxylate (20f)
to that described for 10c. 1H-NMR (600MHz, CDCl3) δ: Compound 20f (quant.) was obtained from 19b in a man-
1
1.22–1.29 (m, 1H), 1.38–1.73 (m, 5H), 1.51 (s, 9H), 2.93–3.11 ner similar to that described for 20a. H-NMR (600MHz,
(m, 1H), 3.99–4.36 (m, 2H), 4.92 (brd, J=10.3Hz, 1H), CDCl3) δ: 1.27–1.77 (m, 15H), 1.53 (d, J=6.9Hz, 3H), 1.56
7.20–7.24 (m, 1H), 7.29 (s, 1H), 7.41–7.48 (m, 2H); MS (ESI): (d, J=6.9Hz, 3H), 2.86–3.15 (m, 1H), 3.99–4.47 (m, 2H),
m/z 462 [M+Na]+.
4.48–4.57 (m, 1H), 4.91 (dd, J=10.3, 4.4Hz, 1H), 7.20 (d,
tert-Butyl (2S)-2-{(S)-Hydroxy[4-(pyridin-3-yl)phenyl]- J=7.3Hz, 1H), 7.32–7.36 (m, 1H), 7.40–7.45 (m, 1H), 7.51
methyl}piperidine-1-carboxylate (20a) 3-Pyridineboronic (brs, 1H), 7.71 (brs, 1H), 7.78 (s, 1H); MS (ESI): m/z 400
acid (2.50g, 20.3mmol), potassium carbonate (2.84g, [M+H]+.
20.5mmol), and tetrakis(triphenylphosphine)palladium(0)
tert-Butyl (2S)-2-{(S)-Hydroxy[3-(1-propyl-1H-pyrazol-
(0.47g, 0.41mmol) were added to a solution of 19a (6.00g, 4-yl)phenyl]methyl}piperidine-1-carboxylate (20g) Com-
13.7mmol) in a mixed solvent of DMF–EtOH (2:1, 135mL) pound 20g (78%) was obtained from 19b in a manner similar
were added, and the mixture was stirred at 90°C for 1.5h. The to that described for 20a. 1H-NMR (600MHz, CDCl3) δ:
reaction mixture was partitioned between water and EtOAc, 0.91–0.98 (m, 3H), 1.29–1.73 (m, 6H), 1.52 (s, 9H), 1.87–1.96
and the organic layer was washed with water and brine, dried (m, 2H), 2.90–3.17 (m, 1H), 3.98–4.52 (m, 4H), 4.90 (brdd,
over anhydrous MgSO4, filtered, and concentrated in vacuo. J=10.1, 4.1Hz, 1H), 7.20 (brd, J=7.8Hz, 1H), 7.32–7.36 (m,
The residue was purified using NH-silica gel column chro- 1H), 7.39–7.44 (m, 1H), 7.50 (brs, 1H), 7.66 (brs, 1H), 7.78 (s,
matography (33–50% EtOAc in hexane) to yield 20a (4.40g, 1H); MS (ESI): m/z 400 [M+H]+.
1
87%) as a pale yellow powder. H-NMR (600MHz, CDCl3) δ:
(S)-1-[(2S)-1-(Prop-2-en-1-yl)piperidin-2-yl]-1-[4-
1.31–1.38 (m, 1H), 1.40–1.55 (m, 2H), 1.52 (s, 9H), 1.56–1.84 (pyridin-3-yl)phenyl]methanamine (21a) Compound 21a
(m, 3H), 2.97–3.16 (m, 1H), 3.99–4.50 (m, 2H), 4.89–5.01 (m, (33% in 4 steps) was obtained from 20a in a manner smilar
1
1H), 7.35–7.39 (m, 1H), 7.45–7.62 (m, 4H), 7.85–7.90 (m, 1H), to that described for the synthesis of 13c from 10c. H-NMR
8.56–8.61 (m, 1H), 8.82–8.86 (m, 1H); MS (ESI): m/z 369 (600MHz, CDCl3) δ: 1.04–1.12 (m, 1H), 1.23–1.56 (m, 4H),
[M+H]+.
1.62–1.72 (m, 1H), 2.67–2.74 (m, 2H), 3.03–3.11 (m, 1H),
tert-Butyl (2S)-2-{(S)-Hydroxy[3-(pyridin-3-yl)phenyl]- 3.36–3.42 (m, 2H), 4.28 (d, J=10.1Hz, 1H), 5.12–5.16 (m,
methyl}piperidine-1-carboxylate (20b) Compound 20b 1H), 5.20–5.25 (m, 1H), 5.87–5.95 (m, 1H), 7.33–7.37 (m,
(quant.) was obtained from 19b in a manner similar to that 1H), 7.47–7.50 (m, 2H), 7.52–7.56 (m, 2H), 7.85–7.89 (m, 1H),
1
described for 20a. H-NMR (600MHz, CDCl3) δ: 1.32–1.37 8.57–8.59 (m, 1H), 8.85 (d, J=2.3Hz, 1H); MS (ESI): m/z 308
(m, 1H), 1.39–1.81 (m, 5H), 1.51 (s, 9H), 2.93–3.18 (m, 1H), [M+H]+.
3.98–4.48 (m, 2H), 4.97 (brd, J=9.9Hz, 1H), 7.37 (dd, J=7.6,
(S)-1-[(2S)-1-(Prop-2-en-1-yl)piperidin-2-yl]-1-[3-
4.7Hz, 1H), 7.39–7.54 (m, 3H), 7.59 (brs, 1H), 7.88–7.91 (m, (pyridin-3-yl)phenyl]methanamine (21b) Compound 21b
1H), 8.60 (dd, J=4.7, 1.4Hz, 1H), 8.85 (d, J=2.1Hz, 1H); MS (43% in 4 steps) was obtained from 20b in a manner simi-
(ESI): m/z 369 [M+H]+.
lar to that described for 21a. 1H-NMR (600MHz, CDCl3)
tert-Butyl (2S)-2-{(S)-Hydroxy[4-(pyrimidin-5-yl)phen- δ: 1.03–1.11 (m, 1H), 1.31–1.57 (m, 4H), 1.63–1.71 (m, 1H),
yl]methyl}piperidine-1-carboxylate (20c) Compound 20c 2.66–2.76 (m, 2H), 3.03–3.11 (m, 1H), 3.35–3.44 (m, 2H),
(97%) was obtained from 19a in a manner similar to that de- 4.29 (d, J=10.1Hz, 1H), 5.12–5.17 (m, 1H), 5.20–5.25 (m,
1
scribed for 20a. H-NMR (500MHz, DMSO-d6) δ: 1.20–1.39 1H), 5.86–5.95 (m, 1H), 7.34–7.38 (m, 1H), 7.39–7.52 (m,
(m, 3H), 1.40 (s, 9H), 1.43–1.49 (m, 1H), 1.59–1.82 (m, 2H), 3H), 7.58–7.61 (m, 1H), 7.87–7.91 (m, 1H), 8.57–8.60 (m, 1H),
2.85–3.02 (m, 1H), 3.86–3.96 (m, 1H), 4.07–4.23 (m, 1H), 4.89 8.85–8.86 (m, 1H); MS (ESI): m/z 308 [M+H]+.
(brdd, J=8.9, 4.1Hz, 1H), 5.33 (brs, 1H), 7.51 (d, J=8.2Hz,
(S)-1-[(2S)-1-(Prop-2-en-1-yl)piperidin-2-yl]-1-[4-
2H), 7.80 (d, J=8.3Hz, 2H), 9.15 (s, 2H), 9.18 (s, 1H); MS (pyrimidin-5-yl)phenyl]methanamine (21c) Compound 21c
(ESI): m/z 370 [M+H]+.
(99% in 4 steps) was obtained from 20c in a manner similar
tert-Butyl (2S)-2-{(S)-Hydroxy[3-(1-methyl-1H-pyrazol- to that described for 21a. 1H-NMR (600MHz, CDCl3) δ:
4-yl)phenyl]methyl}piperidine-1-carboxylate (20d) Com- 1.31–4.44 (m, 12H), 5.46 (d, J=11.0Hz, 2H), 6.05–6.19 (m,
pound 20d (quant.) was obtained from 19b in a manner 1H), 7.49–7.72 (m, 4H), 8.89–8.92 (m, 2H), 9.20 (s, 1H); MS
similar to that described for 20a. H-NMR (600MHz, CDCl3) (ESI): m/z 309 [M+H]+.
1

1332
Chem. Pharm. Bull.
Vol. 64, No. 9 (2016)
1
(S)-1-[3-(1-Methyl-1H-pyrazol-4-yl)phenyl]-1-[(2S)-1- 21b in a manner similar to that described for 7c. H-NMR
(prop-2-en-1-yl)piperidin-2-yl]methanamine (21d) Com- (600MHz, DMSO-d6) δ: 1.36–1.46 (m, 1H), 1.46–1.52 (m,
pound 21d (17% in 4 steps) was obtained from 20d in a 2H), 1.58–1.67 (m, 1H), 1.69–1.77 (m, 2H), 2.80–2.90 (m,
1
manner similar to that described for 21a. H-NMR (600MHz, 1H), 3.32–3.39 (m, 1H), 3.59–3.70 (m, 1H), 5.29–5.33 (m, 1H),
CDCl3) δ: 1.01–1.09 (m, 1H), 1.29–1.55 (m, 4H), 1.60–1.89 (m, 7.58–7.64 (m, 2H), 7.66 (t, J=7.8Hz, 1H), 7.84–7.86 (m, 1H),
1H), 2.65–2.72 (m, 2H), 3.02–3.08 (m, 1H), 3.33–3.43 (m, 2H), 7.93–8.00 (m, 3H), 8.05 (dd, J=7.8, 1.4Hz, 1H), 8.65–8.71
3.94 (s, 3H), 4.22 (d, J=10.1Hz, 1H), 5.13 (dd, J=10.1, 1.8Hz, (m, 1H), 8.83 (dd, J=5.5, 1.4Hz, 1H), 8.92–8.98 (m, 1H),
1H), 5.19–5.24 (m, 1H), 5.86–5.94 (m, 1H), 7.18–7.21 (m, 1H), 9.10–9.18 (m, 1H), 9.21 (d, J=2.3Hz, 1H), 9.73 (d, J=8.7Hz,
7.30 (t, J=7.8Hz, 1H), 7.34–7.37 (m, 1H), 7.46–7.50 (m, 1H), 1H); 13C-NMR (126MHz, DMSO-d6) δ: 165.4, 144.1, 143.3,
7.64 (s, 1H), 7.77 (s, 1H); MS (ESI): m/z 311 [M+H]+.
139.3, 139.1, 138.6, 137.0, 135.4, 133.5, 129.7, 128.6, 128.6,
(S)-1-[3-(1-Ethyl-1H-pyrazol-4-yl)phenyl]-1-[(2S)-1- 128.0, 127.7, 127.2 (q, J=30Hz), 126.9, 126.6, 125.8, 122.7 (q,
(prop-2-en-1-yl)piperidin-2-yl]methanamine (21e) Com- J=273Hz), 58.1, 55.7, 44.8, 25.7, 21.6, 21.3; HR-MS: Calcd for
pound 21e (48% in 4 steps) was obtained from 20e in a manner C25H23ClF3N3O [M+H]+ 474.1555. Found 474.1552; [α]D=+76
1
similar to that described for 21a. H-NMR (600MHz, CDCl3) (c=0.60, MeOH).
δ: 1.02–1.10 (m, 1H), 1.30–1.57 (m, 4H), 1.53 (t, J=7.3Hz,
2-Chloro-N-{(S)-(2S)-piperidin-2-yl[4-(pyrimidin-5-
Hydro-
3H), 1.58–1.84 (m, 1H), 2.67–2.73 (m, 2H), 3.03–3.09 (m, yl)phenyl]methyl}-3-(trifluoromethyl)benzamide
lH), 3.34–3.44 (m, 2H), 4.18–4.24 (m, 3H), 5.11–5.16 (m, 1H), chloride (7e) Compound 7e (24% in 2 steps) was obtained
5.18–5.26 (m, 1H), 5.85–5.95 (m, 1H), 7.19 (d, J=7.8Hz, 1H), from 21c in a manner similar to that described for 7c. 1H-NMR
7.30 (t, J=7.8Hz, 1H), 7.35–7.38 (m, 1H), 7.50 (brs, 1H), 7.68 (600MHz, DMSO-d6) δ: 1.34–1.51 (m, 3H), 1.56–1.69 (m,
(s, 1H), 7.78 (s, 1H); MS (ESI): m/z 325 [M+H]+.
1H), 1.69–1.79 (m, 2H), 2.81–2.93 (m, 1H), 3.32–3.43 (m,
(S)-1-{3-[1-(Propan-2-yl)-1H-pyrazol-4-yl]phenyl}-1- 1H), 3.50–3.63 (m, 1H), 5.21–5.33 (m, 1H), 7.63 (d, J=8.3Hz,
[(2S)-1-(prop-2-en-1-yl)piperidin-2-yl]methanamine (21f) 2H), 7.68 (t, J=7.8Hz, 1H), 7.91 (d, J=8.3Hz, 2H), 7.97 (d,
Compound 21f (39% in 4 steps) was obtained from 20f J=7.8Hz, 1H), 8.02 (d, J=7.3Hz, 1H), 8.75–8.82 (m, 1H),
in a manner similar to that described for 21a. 1H-NMR 9.03–9.11 (m, 1H), 9.17–9.24 (m, 3H), 9.67 (d, J=8.7Hz, 1H);
(600MHz, CDCl3) δ: 1.02–1.09 (m, 1H), 1.30–1.59 (m, 4H), 13C-NMR (126MHz, DMSO-d6) δ: 165.3, 157.4, 154.7, 138.7,
1.55 (d, J=6.9Hz, 6H), 1.61–1.85 (m, 1H), 2.67–2.73 (m, 2H), 138.6, 133.5, 133.4, 132.6, 128.7, 128.6, 128.0, 127.7, 127.2,
3.03–3.09 (m, 1H), 3.34–3.43 (m, 2H), 4.23 (d, J=9.6Hz, 1H), 127.2 (q, J=30Hz), 122.7 (q, J=274Hz), 58.1, 55.5, 44.8,
4.50–4.56 (m, 1H), 5.11–5.15 (m, 1H), 5.19–5.25 (m, 1H), 25.7, 21.6, 21.3; HR-MS: Calcd for C24H22ClF3N4O [M+H]+
5.86–5.95 (m, 1H), 7.16–7.19 (m, 1H), 7.29 (t, J=7.6Hz, 1H), 475.1507. Found 475.1498; [α]D=+71 (c=0.53, MeOH).
7.36–7.39 (m, 1H), 7.50–7.52 (m, 1H), 7.71 (s, 1H), 7.79 (s,
2,4-Dichloro-N-{(S)-[3-(1-methyl-1H-pyrazol-4-yl)-
phenyl][(2S)-piperidin-2-yl]methyl}benzamide Hydrochlo-
1H); MS (ESI): m/z 339 [M+H]+.
(S)-1-[(2S)-1-(Prop-2-en-1-yl)piperidin-2-yl]-1-[3-(1- ride (7k) Compound 7k (62% in 2 steps) was obtained from
propyl-1H-pyrazol-4-yl)phenyl]methanamine (21g) Com- 21d in a manner similar to that described for 7c. H-NMR
1
pound 21g (33% in 4 steps) was obtained from 20g in a (600MHz, DMSO-d6) δ: 1.33–1.45 (m, 3H), 1.55–1.64 (m,
1
manner similar to that described for 21a. H-NMR (600MHz, 1H), 1.67–1.76 (m, 2H), 2.79–2.88 (m, 1H), 3.31–3.37 (m, 1H),
CDCl3) δ: 0.95 (t, J=7.3Hz, 3H), 1.03–1.11 (m, 1H), 1.29–1.73 3.48–3.55 (m, 1H), 3.87 (s, 3H), 5.12–5.16 (m, 1H), 7.24 (d,
(m, 5H), 1.89–1.96 (m, 2H), 2.67–2.73 (m, 2H), 3.02–3.10 J=7.8Hz, 1H), 7.38 (t, J=7.6Hz, 1H), 7.52 (d, J=7.8Hz, 1H),
(m, 1H), 3.33–3.44 (m, 2H), 4.11 (t, J=7.1Hz, 2H), 4.22 7.56 (dd, J=8.3, 2.3Hz, 1H), 7.65 (brs, 1H), 7.67 (d, J=2.3Hz,
(d, J=9.6Hz, 1H), 5.10–5.16 (m, 1H), 5.19–5.25 (m, 1H), 1H), 7.74–7.77 (m, 1H), 7.86 (s, 1H), 8.13 (s, 1H), 8.63–8.76
5.85–5.96 (m, 1H), 7.17–7.20 (m, 1H), 7.30 (t, J=7.6Hz, 1H), (m, 1H), 8.94–9.08 (m, 1H), 9.42 (d, J=8.7Hz, 1H); 13C-NMR
7.35–7.39 (m, 1H), 7.49–7.52 (m, 1H), 7.66 (s, 1H), 7.79 (s, (126MHz, DMSO-d6) δ: 165.3, 138.7, 136.0, 134.9, 134.6,
1H); MS (ESI): m/z 339 [M+H]+.
132.9, 131.5, 131.0, 129.2, 129.1, 127.9, 127.1, 125.2, 124.6,
2-Chloro-N-{(S)-(2S)-piperidin-2-yl[4-(pyridin-3-yl)- 124.3, 121.6, 58.2, 55.7, 44.7, 38.7, 25.8, 21.6, 21.3; HR-MS:
phenyl]methyl}-3-(trifluoromethyl)benzamide Dihydrochlo- Calcd for C23H24Cl2N4O [M+H]+ 443.1400. Found 443.1397;
ride (7c) Compound 7c (42% in 2 steps) was obtained from [α]D=+66 (c=0.55, MeOH).
21a in a manner similar to that described for the synthesis
2-Fluoro-N-{(S)-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-
1
of 14c and 7a. H-NMR (600MHz, DMSO-d6) δ: 1.35–1.52 [(2S)-piperidin-2-yl]methyl}-3-(trifluoromethyl)benzamide
(m, 3H), 1.59–1.68 (m, 1H), 1.70–1.77 (m, 2H), 2.80–2.89 (m, Hydrochloride (7l) Compound 7l (55% in 2 steps) was
1H), 3.34–3.40 (m, 1H), 3.54–3.63 (m, 1H), 5.23–5.28 (m, 1H), obtained from 21d in a manner similar to that described for
7.63–7.65 (m, 2H), 7.67 (t, J=8.0Hz, 1H), 7.90–7.97 (m, 4H), 7c. 1H-NMR (600MHz, DMSO-d6) δ: 1.32–1.48 (m, 3H),
8.04 (dd, J=7.8, 1.4Hz, 1H), 8.64–8.69 (m, 1H), 8.81 (dd, 1.57–1.67 (m, 1H), 1.68–1.76 (m, 2H), 2.77–2.86 (m, 1H),
J=5.5, 1.4Hz, 1H), 8.85–8.90 (m, 1H), 9.16–9.23 (m, 2H), 9.76 3.30–3.37 (m, 1H), 3.55–3.63 (m, 1H), 3.88 (s, 3H), 5.15–5.21
(d, J=8.3Hz, 1H); 13C-NMR (126MHz, DMSO- d6) δ: 165.3, (m, 1H), 7.25–7.30 (m, 1H), 7.40 (t, J=7.8Hz, 1H), 7.50–7.56
143.7, 143.0, 139.6, 139.1, 138.6, 136.9, 134.7, 133.5, 128.7, (m, 2H), 7.66–7.70 (m, 1H), 7.88 (s, 1H), 7.91–7.96 (m, 1H),
128.6, 128.0, 127.7, 127.5, 127.2 (q, J=32Hz), 125.9, 122.8 (q, 8.09–8.14 (m, 1H), 8.16 (s, 1H), 8.67–8.81 (m, 1H), 8.98–9.17
J=274Hz), 58.0, 55.6, 44.7, 25.8, 21.6, 21.3; HR-MS: Calcd for (m, 1H), 9.55 (d, J=8.7Hz, 1H); 13C-NMR (126MHz, DMSO-
C25H23ClF3N3O [M+H]+ 474.1555. Found 474.1547; [α]D=+71 d6) δ: 162.5, 156.3 (d, J=258Hz), 139.0, 136.0, 135.2, 133.0,
(c=0.52, MeOH).
129.3, 128.0, 125.4 (q, J=13Hz), 125.1, 124.9, 124.8, 124.7,
2-Chloro-N-{(S)-(2S)-piperidin-2-yl[3-(pyridin-3-yl)- 124.3, 122.5 (q, J=272Hz), 121.6, 116.9–117.4 (m), 58.2, 55.8,
phenyl]methyl}-3-(trifluoromethyl)benzamide Hydrochlo- 44.6, 38.7, 25.9, 21.6, 21.3; HR-MS: Calcd for C24H24F4N4O
ride (7d) Compound 7d (65% in 2 steps) was obtained from [M+H]+ 461.1959. Found 461.1948; [α]D=+56 (c=0.51,

Vol. 64, No. 9 (2016)
Chem. Pharm. Bull.
1333
MeOH).
403.2492. Found 403.2499; [α]D=+82 (c=0.54, MeOH).
2,3-Dichloro-N-{(S)-[3-(1-methyl-1H-pyrazol-4-yl)-
N-{(S)-[3-(1-Methyl-1H-pyrazol-4-yl)phenyl][(2S)-piper-
idin-2-yl]methyl}-3-(trifluoromethyl)benzamide Hydrochlo- phenyl][(2S)-piperidin-2-yl]methyl}benzamide Hydrochlo-
ride (7m) Compound 7m (58% in 2 steps) was obtained from ride (7q) Compound 7q (39% in 2 steps) was obtained from
1
1
21d in a manner similar to that described for 7c. H-NMR 21d in a manner similar to that described for 7c. H-NMR
(600MHz, DMSO-d6) δ: 1.34–1.48 (m, 3H), 1.57–1.68 (m, (600MHz, DMSO-d6) δ: 1.35–1.47 (m, 3H), 1.54–1.64 (m,
1H), 1.68–1.79 (m, 2H), 2.80–2.89 (m, 1H), 3.32–3.38 (m, 1H), 1H), 1.68–1.77 (m, 2H), 2.79–2.89 (m, 1H), 3.30–3.38 (m,
3.67–3.76 (m, 1H), 3.87 (s, 3H), 5.19–5.26 (m, 1H), 7.28–7.32 1H), 3.46–3.53 (m, 1H), 3.88 (s, 3H), 5.11–5.17 (m, 1H),
(m, 1H), 7.36 (t, J=7.6Hz, 1H), 7.48–7.53 (m, 1H), 7.71–7.77 7.23–7.25 (m, 1H), 7.39 (t, J=7.6Hz, 1H), 7.48 (t, J=7.8Hz,
(m, 2H), 7.87 (s, 1H), 7.94 (d, J=7.8Hz, 1H), 8.14 (s, 1H), 8.33 1H), 7.52–7.55 (m, 1H), 7.63–7.67 (m, 2H), 7.72–7.76 (m, 1H),
(s, 1H), 8.38 (d, J=7.8Hz, 1H), 8.63–8.80 (m, 1H), 9.07–9.21 7.85–7.88 (m, 1H), 8.14 (s, 1H), 8.57–8.68 (m, 1H), 8.85–8.96
(m, 1H), 9.71 (d, J=9.2Hz, 1H); 13C-NMR (126MHz, DMSO- (m, 1H), 9.40 (d, J=8.7Hz, 1H); 13C-NMR (126MHz, DMSO-
d6) δ: 165.0, 139.5, 136.1, 134.8, 133.0, 132.0, 129.5, 129.3, d6) δ: 165.5, 138.6, 138.2, 136.0, 132.9, 132.0, 131.4, 129.1,
129.0 (q, J=32Hz), 128.1, 127.9, 125.2, 124.5, 124.4, 124.4, 128.3, 128.0, 127.9, 125.3, 124.6, 124.3, 121.6, 58.2, 55.7,
124.0 (q, J=273Hz), 121.5, 58.0, 56.0, 44.6, 38.7, 26.0, 21.6, 44.8, 38.7, 25.7, 21.6, 21.3; HR-MS: Calcd for C23H24Cl2N4O
21.3; HR-MS: Calcd for C24H25F3N4O [M+H]+ 443.2053. [M+H]+ 443.1400. Found 443.1394; [α]D=+86 (c=0.63,
Found 443.2053; [α]D=+22 (c=0.66, MeOH).
MeOH).
2-Chloro-3-methyl-N-{(S)-[3-(1-methyl-1H-pyrazol-4-
Hydro-
2-Methyl-N-{(S)-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-
[(2S)-piperidin-2-yl]methyl}-3-(trifluoromethyl)benzamide yl)phenyl][(2S)-piperidin-2-yl]methyl}benzamide
Hydrochloride (7n) Compound 7n (59% in 2 steps) was chloride (7r) Compound 7r (44% in 2 steps) was ob-
obtained from 21d in a manner similar to that described for tained from 21d in a manner similar to that described for
7c. 1H-NMR (600MHz, DMSO-d6) δ: 1.34–1.44 (m, 3H), 7c. 1H-NMR (600MHz, DMSO-d6) δ: 1.33–1.49 (m, 3H),
1.55–1.65 (m, 1H), 1.67–1.77 (m, 2H), 2.26 (s, 3H), 2.78–2.90 1.54–1.63 (m, 1H), 1.67–1.76 (m, 2H), 2.34 (s, 3H), 2.79–2.89
(m, 1H), 3.33–3.40 (m, 1H), 3.48–3.55 (m, 1H), 3.88 (s, 3H), (m, 1H), 3.31–3.37 (m, 1H), 3.41–3.63 (m, 1H), 3.88 (s, 3H),
5.13–5.18 (m, 1H), 7.24–7.27 (m, 1H), 7.40 (t, J=7.6Hz, 1H), 5.12–5.17 (m, 1H), 7.24 (d, J=7.3Hz, 1H), 7.33 (t, J=7.6Hz,
7.48–7.55 (m, 2H), 7.64–7.67 (m, 1H), 7.75–7.81 (m, 2H), 7.87 1H), 7.38 (t, J=7.6Hz, 1H), 7.42–7.45 (m, 1H), 7.45–7.49 (m,
(s, 1H), 8.15 (s, 1H), 8.61–8.73 (m, 1H), 8.89–9.08 (m, 1H), 1H), 7.53 (d, J=7.8Hz, 1H), 7.64 (brs, 1H), 7.84–7.87 (m,
9.37 (d, J=8.7Hz, 1H); 13C-NMR (126MHz, DMSO-d6) δ: 1H), 8.13 (s, 1H), 8.46–8.61 (m, 1H), 8.84–8.99 (m, 1H), 9.19
168.1, 139.2, 139.2, 136.0, 133.9, 133.0, 131.5, 129.3, 128.0 (q, (d, J=8.7Hz, 1H); 13C-NMR (126MHz, DMSO-d6) δ: 166.7,
J=28Hz), 127.9, 126.6, 126.1, 125.1, 124.6, 124.3, 124.3 (q, 138.7, 136.5, 136.3, 136.0, 132.9, 131.9, 130.1, 129.1, 127.9,
J=275Hz), 121.6, 58.0, 55.8, 44.7, 38.7, 25.9, 21.6, 21.3, 15.5; 126.9, 126.6, 125.3, 124.6, 124.4, 121.6, 58.3, 55.6, 44.8, 38.7,
HR-MS: Calcd for C25H27F3N4O [M+H]+ 457.2210. Found 25.7, 21.6, 21.3, 19.9; HR-MS: Calcd for C24H27ClN4O [M+H]+
457.2199; [α]D=+53 (c=0.60, MeOH).
2,6-Dichloro-N-{(S)-[3-(1-methyl-1H-pyrazol-4-yl)-
423.1946. Found 423.1934; [α]D=+85 (c=0.50, MeOH).
3-Methoxy-2-methyl-N-{(S)-[3-(1-methyl-1H-pyrazol-4-
phenyl][(2S)-piperidin-2-yl]methyl}benzamide Hydrochlo- yl)phenyl][(2S)-piperidin-2-yl]methyl}benzamide
Hydro-
ride (7o) Compound 7o (30% in 2 steps) was obtained from chloride (7s) Compound 7s (67% in 2 steps) was ob-
1
21d in a manner similar to that described for 7c. H-NMR tained from 21d in a manner similar to that described for
(600MHz, DMSO-d6) δ: 1.38–1.61 (m, 3H), 1.65–1.72 (m, 7c. 1H-NMR (600MHz, DMSO-d6) δ: 1.31–1.46 (m, 3H),
1H), 1.73–1.82 (m, 2H), 2.86–2.95 (m, 1H), 3.23–3.58 (m, 1.53–1.64 (m, 1H), 1.66–1.77 (m, 2H), 2.01 (s, 3H), 2.77–2.86
2H), 3.88 (s, 3H), 5.27–5.33 (m, 1H), 7.27 (d, J=7.3Hz, 1H), (m, 1H), 3.30–3.37 (m, 1H), 3.42–3.60 (m, 1H), 3.78 (s, 3H),
7.39 (t, J=7.8Hz, 1H), 7.45–7.49 (m, 1H), 7.51–7.56 (m, 3H), 3.88 (s, 3H), 5.11–5.16 (m, 1H), 7.04 (d, J=8.3Hz, 1H), 7.10
7.66–7.69 (m, 1H), 7.85 (s, 1H), 8.11 (s, 1H), 8.52–8.80 (m, (d, J=7.8Hz, 1H), 7.22–7.27 (m, 2H), 7.38 (t, J=7.8Hz, 1H),
2H), 9.58 (d, J=8.3Hz, 1H); 13C-NMR (126MHz, DMSO-d6) 7.50–7.53 (m, 1H), 7.65 (brs, 1H), 7.86 (s, 1H), 8.13 (s, 1H),
δ: 163.4, 137.3, 136.0, 135.7, 132.8, 131.3, 131.2, 129.0, 128.2, 8.46–8.58 (m, 1H), 8.92–9.01 (m, 1H), 9.04 (d, J=8.7Hz, 1H);
127.8, 125.6, 124.6, 121.7, 58.6, 55.1, 45.1, 38.7, 25.0, 21.6, 21.4; 13C-NMR (126MHz, DMSO-d6) δ: 168.9, 157.3, 139.4, 137.7,
HR-MS: Calcd for C23H24Cl2N4O [M+H]+ 443.1400. Found 136.0, 132.9, 129.2, 127.9, 126.3, 125.1, 124.5, 124.3, 123.7,
443.1392; [α]D=+79 (c=0.54, MeOH).
121.6, 119.4, 111.6, 58.1, 55.6, 44.7, 38.7, 25.9, 21.6, 21.4, 12.4;
2,6-Dimethyl-N-{(S)-[3-(1-methyl-1H-pyrazol-4-yl)- HR-MS: Calcd for C25H30N4O2 [M+H]+ 419.2442. Found
phenyl][(2S)-piperidin-2-yl]methyl}benzamide Hydrochlo- 419.2429; [α]D=+59 (c=0.51, MeOH).
ride (7p) Compound 7p (33% in 2 steps) was obtained from
2-Chloro-N-{(S)-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-
1
21d in a manner similar to that described for 7c. H-NMR [(2S)-piperidin-2-yl]methyl}-5-(trifluoromethyl)benzamide
(600MHz, DMSO-d6): δ1.32–1.44 (m, 2H), 1.50–1.62 (m, Hydrochloride (7t) Compound 7t (55% in 2 steps) was
2H), 1.68–1.77 (m, 2H), 2.12 (brs, 6H), 2.80–2.90 (m, 1H), obtained from 21d in a manner similar to that described for
3.27–3.54 (m, 2H), 3.88 (s, 3H), 5.16–5.22 (m, 1H), 7.02 (s, 7c. 1H-NMR (600MHz, DMSO-d6) δ: 1.34–1.45 (m, 3H),
1H), 7.03 (s, 1H), 7.17 (t, J=7.6Hz, 1H), 7.24 (d, J=7.3Hz, 1.58–1.68 (m, 1H), 1.68–1.78 (m, 2H), 2.82–2.92 (m, 1H),
1H), 7.38 (t, J=7.6Hz, 1H), 7.53 (d, J=7.8Hz, 1H), 7.67 (brs, 3.35–3.40 (m, 1H), 3.47–3.56 (m, 1H), 3.87 (s, 3H), 5.15–5.20
1H), 7.85 (s, 1H), 8.12 (s, 1H), 8.37–8.56 (m, 1H), 8.67–8.84 (m, 1H), 7.22–7.25 (m, 1H), 7.38 (t, J=7.6Hz, 1H), 7.52–7.55
(m, 1H), 8.95 (d, J=8.3Hz, 1H); 13C-NMR (126MHz, (m, 1H), 7.66 (brs, 1H), 7.74 (d, J=8.3Hz, 1H), 7.82–7.88
DMSO-d6): δ169.2, 138.8, 137.5, 136.0, 133.9, 132.8, 129.0, (m, 2H), 8.10–8.13 (m, 1H), 8.13 (s, 1H), 8.78–8.91 (m,
128.2, 127.8, 127.1, 125.6, 124.5, 121.7, 58.0, 55.5, 44.9, 38.7, 1H), 8.92–9.08 (m, 1H), 9.49 (d, J=8.7Hz, 1H); 13C-NMR
25.6, 21.6, 21.4, 19.0; HR-MS: Calcd for C25H30N4O [M+H]+ (126MHz, DMSO-d6) δ: 165.1, 138.4, 136.8, 136.0, 134.7,

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Vol. 64, No. 9 (2016)
132.9, 130.9, 129.2, 127.9, 127.8, 127.6 (q, J=34Hz), 126.3, 1H), 3.56–3.65 (m, 1H), 4.49–4.56 (m, 1H), 5.15–5.20 (m,
125.3, 124.7, 124.3, 123.6 (q, J=270Hz), 121.6, 58.3, 55.8, 1H), 7.27 (d, J=7.3Hz, 1H), 7.41 (t, J=7.6Hz, 1H), 7.56 (d,
44.7, 38.7, 25.8, 21.6, 21.2; HR-MS: Calcd for C24H24ClF3N4O J=7.8Hz, 1H), 7.67 (brs, 1H), 7.87 (s, 1H), 8.07 (d, J=5.0Hz,
[M+H]+ 477.1664. Found 477.1658; [α]D=+68 (c=0.52, 1H), 8.23 (s, 1H), 8.50–8.58 (m, 1H), 8.83–8.92 (m, 2H), 9.63
MeOH).
(d, J=9.2Hz, 1H); 13C-NMR (126MHz, DMSO-d6) δ: 163.5,
3-Chloro-N-{(S)-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]- 152.5, 148.4, 138.4, 135.8 (q, J=31Hz), 135.6, 133.2, 129.2,
[(2S)-piperidin-2-yl]methyl}-2-(trifluoromethyl)pyridine- 125.7, 125.1, 124.8, 124.7, 124.4, 123.1, 121.7 (q, J=275Hz),
4-carboxamide Hydrochloride (7u) Compound 7u (43% 121.1, 58.1, 55.5, 53.1, 44.6, 25.6, 22.7, 21.6, 21.3; HR-MS:
in 2 steps) was obtained from 21d in a manner similar to Calcd for C25H27ClF3N5O [M+H]+ 506.1929. Found 506.1917;
that described for 7c. 1H-NMR (600MHz, DMSO-d6) δ: [α]D=+70 (c=0.49, MeOH).
1.33–1.49 (m, 3H), 1.55–1.66 (m, 1H), 1.67–1.77 (m, 2H),
3-Chloro-N-{(S)-(2S)-piperidin-2-yl[3-(1-propyl-1H-
2.81–2.91 (m, 1H), 3.34–3.39 (m, 1H), 3.48–3.58 (m, 1H), pyrazol-4-yl)phenyl]methyl}-4-(trifluoromethyl)pyridine-
3.87 (s, 3H), 5.11–5.24 (m, 1H), 7.25 (d, J=7.8Hz, 1H), 7.39 2-carboxamide Hydrochloride (7y) Compound 7y (61% in
(t, J=7.6Hz, 1H), 7.54 (d, J=7.3Hz, 1H), 7.65 (s, 1H), 7.87 2 steps) was obtained from 21g in a manner similar to that
1
(s, 1H), 8.07–8.21 (m, 2H), 8.82 (d, J=4.6Hz, 1H), 8.89–9.10 described for 7c. H-NMR (600MHz, DMSO-d6) δ: 0.85 (t,
(m, 2H), 9.78–9.86 (m, 1H); 13C-NMR (126MHz, DMSO-d6) J=7.3Hz, 3H), 1.34–1.52 (m, 3H), 1.54–1.65 (m, 1H), 1.67–1.76
δ: 163.5, 147.7, 146.2, 143.3 (q, J=34Hz), 138.1, 136.1, 133.0, (m, 2H), 1.82 (tq, J=7.3, 7.2Hz, 2H), 2.77–2.87 (m, 1H),
129.2, 127.9, 127.4, 126.2, 125.2, 124.8, 124.3, 121.6, 120.9 3.25–3.34 (m, 1H), 3.56–3.65 (m, 1H), 4.09 (t, J=6.9Hz, 2H),
(q, J=277Hz), 58.2, 55.8, 44.8, 38.7, 25.7, 21.6, 21.2; HR-MS: 5.16–5.21 (m, 1H), 7.28 (d, J=7.8Hz, 1H), 7.41 (t, J=7.8Hz,
Calcd for C23H23ClF3N5O [M+H]+ 478.1616. Found 478.1605; 1H), 7.53–7.57 (m, 1H), 7.66–7.68 (m, 1H), 7.89 (s, 1H), 8.06
[α]D=+69 (c=0.53, MeOH).
(d, J=5.0Hz, 1H), 8.19 (s, 1H), 8.51–8.62 (m, 1H), 8.83–8.94
3-Chloro-N-{(S)-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]- (m, 2H), 9.65 (d, J=8.7Hz, 1H); 13C-NMR (126MHz, DMSO-
[(2S)-piperidin-2-yl]methyl}-4-(trifluoromethyl)pyridine- d6) δ: 163.5, 152.5, 148.5, 138.4, 136.0, 135.8 (q, J=32Hz),
2-carboxamide Hydrochloride (7v) Compound 7v (43% in 133.1, 129.3, 127.2, 125.7, 125.1, 124.7, 124.4, 123.1, 121.7 (q,
2 steps) was obtained from 21d in a manner similar to that J=275Hz), 121.2, 58.1, 55.5, 53.0, 44.7, 25.6, 23.2, 21.6, 21.3,
1
described for 7c. H-NMR (600MHz, DMSO-d6) δ: 1.33–1.52 10.9; HR-MS: Calcd for C25H27ClF3N5O [M+H]+ 506.1929.
(m, 3H), 1.53–1.63 (m, 1H), 1.66–1.77 (m, 2H), 2.77–2.86 Found 506.1916; [α]D=+84 (c=0.41, MeOH).
(m, 1H), 3.25–3.36 (m, 1H), 3.55–3.64 (m, 1H), 3.88 (s, 3H),
tert-But yl (2S)-2-{(S)-Hydroxy[3-(4,4,5,5-tetramethyl-1,3,2-
5.12–5.21 (m, 1H), 7.25–7.30 (m, 1H), 7.41 (t, J=7.8Hz, 1H), dioxaborolan-2-yl)phenyl]methyl}piperidine-1-car-
7.52–7.57 (m, 1H), 7.65 (s, 1H), 7.87 (s, 1H), 8.07 (d, J=5.0Hz, boxylate (22) Potassium acetate (5.27g, 53.7mmol),
1H), 8.15 (s, 1H), 8.46–8.60 (m, 1H), 8.75–8.86 (m, 1H), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
8.88 (d, J=5.0Hz, 1H), 9.60 (d, J=8.7Hz, 1H); 13C-NMR (1.46g, 1.79mmol), 1,1′-bis(diphenylphosphino)ferrocene (1.19g,
(126MHz, DMSO-d6) δ: 163.6, 152.6, 148.5, 138.4, 136.1, 2.51mmol), and bis(pinacolato)diboron (5.00g, 19.7mmol)
135.8 (q, J=32Hz), 133.0, 129.3, 127.9, 125.7, 125.2, 124.7, were added to a solution of 19b (7.86g, 17.9mmol) in 1,4-di-
124.4, 123.1, 121.8 (q, J=275Hz), 121.6, 58.1, 55.5, 44.7, 38.7, oxane (150mL), and the mixture was stirred at 80°C for 3h.
25.6, 21.6, 21.4; HR-MS: Calcd for C23H23ClF3N5O [M+H]+ The reaction solution was partitioned between water and
478.1616. Found 478.1603; [α]D=+71 (c=0.50, MeOH).
EtOAc, and the organic layer was washed with water and
3-Chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4-yl)phenyl]- brine, dried over anhydrous MgSO4, filtered, and concentrated
[(2S)-piperidin-2-yl]methyl}-4-(trifluoromethyl)pyridine- in vacuo. The residue was purified using silica gel column
2-carboxamide Hydrochloride (7w) Compound 7w (71% chromatography (33–50% EtOAc in hexane) to yield 22
1
in 2 steps) was obtained from 21e in a manner similar to that (6.82g, 91%) as a pale yellow amorphous. H-NMR (600MHz,
1
described for 7c. H-NMR (600MHz, DMSO-d6) δ: 1.35–1.52 CDCl3) δ: 7.83 (brs, 1H), 7.74 (d, J=7.3Hz, 1H), 7.44–7.49 (m,
(m, 3H), 1.41 (t, J=7.3Hz, 3H), 1.54–1.65 (m, 1H), 1.68–1.77 1H), 7.33–7.40 (m, 1H), 4.89 (d, J=10.1Hz, 1H), 3.98–4.50 (m,
(m, 2H), 2.78–2.87 (m, 1H), 3.27–3.34 (m, 1H), 3.57–3.64 2H), 2.87–3.41 (m, 1H), 1.52 (s, 9H), 1.34 (s, 12H), 1.25–1.73
(m, 1H), 4.17 (q, J=7.3Hz, 2H), 5.16–5.21 (m, 1H), 7.26–7.29 (m, 6H); MS (ESI): m/z 418 [M+H]+.
(m, 1H), 7.41 (t, J=7.8Hz, 1H), 7.53–7.57 (m, 1H), 7.66–7.68
(m, 1H), 7.88 (s, 1H), 8.06 (d, J=4.6Hz, 1H), 8.20 (s, 1H), methyl}piperidine-1-carboxylate
tert-Butyl (2S)-2-{(S)-Hydroxy[3-(pyrazin-2-yl)phenyl]-
(23a) 2-Chloropyrazine
8.52–8.65 (m, 1H), 8.81–9.00 (m, 1H), 8.87 (d, J=5.0Hz, (0.64g, 5.56mmol), tetrakis(triphenylphosphine)palladium(0)
1H), 9.65 (d, J=9.2Hz, 1H); 13C-NMR (126MHz, DMSO- (96mg, 0.083mmol), and potassium carbonate (0.77g,
d6) δ: 163.6, 152.7, 148.5, 138.5, 135.9, 135.8 (q, J=37Hz), 5.56mmol) were added to a solution of 22 (1.16g, 2.78mmol)
133.1, 129.3, 126.5, 125.7, 125.1, 124.7, 124.5, 123.0, 121.7 (q, in a mixed solvent of DMF–EtOH (2:1, 18mL), and the mix-
J=275Hz), 121.4, 58.1, 55.5, 46.4, 44.6, 25.5, 21.6, 21.4, 15.5; ture was stirred at 90°C for 2h. The reaction solution was par-
HR-MS: Calcd for C24H25ClF3N5O [M+H]+ 492.1772. Found titioned between water and EtOAc, and the organic layer was
492.1763; [α]D=+68 (c=0.52, MeOH).
washed with water and brine, dried over anhydrous MgSO4,
3-Chloro-N-[(S)-[(2S)-piperidin-2-yl]{3-[1-(propan-2- filtered, and concentrated in vacuo. The residue was purified
yl)-1H-pyrazol-4-yl]phenyl}methyl]-4-(trifluoromethyl)- using silica gel column chromatography (33–67% EtOAc in
pyridine-2-carboxamide Hydrochloride (7x) Compound hexane) to yield 23a (0.79g, 77%) as a colorless amorphous.
7x (58% in 2 steps) was obtained from 21f in a manner simi- 1H-NMR (200MHz, CDCl3) δ: 1.32–1.86 (m, 6H), 1.52 (s,
1
lar to that described for 7c. H-NMR (600MHz, DMSO-d6) 9H), 2.91–3.18 (m, 1H), 3.99–4.25 (m, 1H), 4.35–4.54 (m, 1H),
δ: 1.32–1.52 (m, 3H), 1.46 (d, J=6.9Hz, 6H), 1.52–1.65 (m, 5.00 (d, J=10.5Hz, 1H), 7.48–7.57 (m, 2H), 7.92–7.99 (m, 1H),
1H), 1.67–1.78 (m, 2H), 2.77–2.87 (m, 1H), 3.27–3.35 (m, 8.03–8.08 (m, 1H), 8.52 (d, J=2.6Hz, 1H), 8.62–8.66 (m, 1H),

Vol. 64, No. 9 (2016)
Chem. Pharm. Bull.
1335
9.04 (d, J=1.3Hz, 1H); MS (ESI): m/z 370 [M+H]+.
late (25) Under
a
nitrogen gas atmosphere, n-BuLi
tert-Butyl (2S)-2-{(S)-Hydroxy[3-(1-methyl-1H-imidazol- (2.64mol/L hexane solution, 175mL) was added dropwise to
5-yl)phenyl]methyl}piperidine-1-carboxylate (23b) Com- a solution of 1,3-dibromobenzene (148g, 629mmol) in THF
pound 23b (74%) was prepared from 22 in a manner similar (680mL) cooled with a dry ice-acetone bath, and the mixture
to that described for 23a. 1H-NMR (600MHz, CDCl3) δ: was stirred at a temperature below −70°C for 30min. A solu-
1.30–1.74 (m, 6H), 1.51 (s, 9H), 2.89–4.47 (m, 3H), 3.67 (s, tion of 8 (114g, 419mmol) in THF (230mL) was added in a
3H), 4.93 (brd, J=9.1Hz, 1H), 7.11 (s, 1H), 7.31–7.35 (m, 1H), dropwise manner, and the reaction mixture was stirred for 2h.
7.36–7.47 (m, 3H), 7.52 (s, 1H); MS (ESI): m/z 372 [M+H]+.
The reaction was quenched with saturated NH4Cl aqueous so-
(S)-1-[(2S)-1-(Prop-2-en-1-yl)piperidin-2-yl]-1-[3- lution and extracted with EtOAc. The organic layer was dried
(pyrazin-2-yl)phenyl]methanamine (24a) Compound 24a over anhydrous MgSO4, filtered, and concentrated in vacuo.
(49% in 4 steps) was prepared from 23a in a manner similar The residue was purified using silica gel column chromatog-
1
to that described for the synthesis of 13c from 10c. H-NMR raphy (11% EtOAc in hexane) to yield 25 (71.2g, 46%) as a
1
(600MHz, CDCl3) δ: 1.04–1.11 (m, 1H), 1.31–1.77 (m, 5H), pale yellow powder. H-NMR (600MHz, CDCl3) δ: 1.28–1.88
2.67–2.77 (m, 2H), 3.04–3.11 (m, 1H), 3.34–3.46 (m, 2H), (m, 14H), 1.96–2.20 (m, 1H), 2.98–3.17 (m, 1H), 3.82–4.06
4.32 (d, J=10.1Hz, 1H), 5.13–5.16 (m, 1H), 5.20–5.25 (m, (m, 1H), 5.33–5.64 (m, 1H), 7.29–7.37 (m, 1H), 7.63–7.72 (m,
1H), 5.87–5.96 (m, 1H), 7.45–7.52 (m, 2H), 7.88–7.91 (m, 1H), 1H), 7.76–7.89 (m, 1H), 8.00–8.09 (m, 1H); MS (ESI): m/z 368
8.02–8.04 (m, 1H), 8.50–8.52 (m, 1H), 8.63–8.65 (m, 1H), [M+H]+.
9.04–9.06 (m, 1H); MS (ESI): m/z 309 [M+H]+.
tert-Butyl (2S)-2-[(3-Bromophenyl)(hydroxyimino)meth-
(S)-1-[3-(1-Methyl-1H-imidazol-5-yl)phenyl]-1-[(2S)-1- yl]piperidine-1-carboxylate (26) Hydroxylamine hydrochlo-
(prop-2-en-1-yl)piperidin-2-yl]methanamine (24b) Com- ride (1.92g, 27.6mol) was added to a solution of 26 (5.10g,
pound 24b (20% in 4 steps) was prepared from 23b in a man- 13.8mmol) in EtOH (50mL), and the mixture was stirred for
ner similar to that described for the synthesis of 13c from 10c. 5h under reflux condition. After cooling with an ice bath,
1H-NMR (600MHz, CDCl3) δ: 1.02–1.09 (m, 1H), 1.31–1.68 4mol/L HCl solution in EtOAc was added to the reaction
(m, 5H), 2.65–2.72 (m, 2H), 3.02–3.09 (m, 1H), 3.36–3.41 mixture and the mixture was stirred overnight at room tem-
(m, 2H), 3.67 (s, 3H), 4.25 (d, J=10.1Hz, 1H), 5.11–5.16 (m, perature. A mixed solvent of hexane–EtOAc (1:1, 50mL) was
1H), 5.19–5.26 (m, 1H), 5.85–5.95 (m, 1H), 7.10–7.11 (m, 1H), added to the solution, and the precipitate was filtered to yield
7.27–7.29 (m, 1H), 7.36–7.41 (m, 3H), 7.51 (s, 1H); MS (ESI): colorless solid (4.97g). This solid was suspended in MeOH
m/z 311 [M+H]+.
(50mL), and triethylamine (5.8mL, 41.6mmol) and di-t-butyl
2-Chloro-N-{(S)-(2S)-piperidin-2-yl[3-(pyrazin-2-yl)- dicarbonate (9.5mL, 41.4mmol) were added under ice cooling.
phenyl]methyl}-3-(trifluoromethyl)benzamide Hydrochlo- The mixture was stirred for 3h at rom temperature and then
ride (7g) Compound 7g (37% in 2 steps) was prepared from concentrated in vacuo. The residue was partitioned between
1
24a in a manner similar to that described for 7c. H-NMR EtOAc and 5% aqueous potassium bisulfate solution, and the
(600MHz, DMSO-d6) δ: 1.34–1.49 (m, 3H), 1.55–1.66 (m, organic layer was washed with saturated NaHCO3 aqueous
1H), 1.68–1.77 (m, 2H), 2.82–2.91 (m, 1H), 3.33–3.39 (m, solution, dried over anhydrous MgSO4, filtered, and concen-
1H), 3.54–3.63 (m, 1H), 5.25–5.31 (m, 1H), 7.57–7.62 (m, 2H), trated in vacuo. The residue was purified using silica gel col-
7.68 (t, J=7.8Hz, 1H), 7.94–7.97 (m, 1H), 7.98–8.02 (m, 1H), umn chromatography (10–33% EtOAc in hexane) to yield 26
1
8.13–8.15 (m, 1H), 8.24–8.27 (m, 1H), 8.66 (d, J=2.8Hz, 1H), (4.18g, 79%) as a pale yellow oil. H-NMR (600MHz, CDCl3)
8.72–8.87 (m, 2H), 8.95–9.10 (m, 1H), 9.29–9.35 (m, 1H), 9.62 δ: 1.37–1.96 (m, 14H), 2.15–2.24 (m, 1H), 2.28–2.94 (m, 1H),
(d, J=8.7Hz, 1H); 13C-NMR (126MHz, DMSO-d6) δ: 165.4, 3.66–3.75 (m, 1H), 5.49–5.54 (m, 1H), 7.18–7.52 (m, 4H), 8.27
151.1, 144.3, 143.7, 142.2, 138.8, 138.6, 136.2, 133.4, 129.4, (s, 1H); MS (ESI): m/z 383 [M+H]+.
128.7, 128.0, 127.7, 127.2 (q, J=31Hz), 126.4, 126.1, 126.0,
122.7 (q, J=273Hz), 58.1, 55.8, 44.8, 25.7, 21.6, 21.3; HR-MS: (hydroxyimino)methyl}piperidine-1-carboxylate
Calcd for C24H22ClF3N4O [M+H]+ 475.1507. Found 475.1498; solution of potassium carbonate (117g, 850mmol) in water
[α]D=+77 (c=0.55, MeOH). (1L) and a solution of 1-ethyl-1H-pyrazole-4-boronic acid
tert-Butyl (2S)-2-{[3-(1-Ethyl-1H-pyrazol-4-yl)phenyl]-
(27)
A
2-Chloro-N-{(S)-[3-(1-methyl-1H-imidazol-5-yl)phenyl]- pinacol ester (163g, 736mmol) in EtOH (1L) and [1,3-bis(2,6-
[(2S)-piperidin-2-yl]methyl}-3-(trifluoromethyl)benzamide diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)-
Hydrochloride (7j) Compound 7j (40% in 2 steps) was palladium(II) dichloride (7.70g, 11.4mmol) were added to
prepared from 24b in a manner similar to that described a solution of 26 (217g, 566mmol) in toluene (1L), and the
for 7c. 1H-NMR (600MHz, DMSO-d6) δ: 1.34–1.51 (m, mixture was stirred for 2h at 72°C. After the reaction mixture
3H), 1.56–1.65 (m, 1H), 1.69–1.77 (m, 2H), 2.79–2.88 (m, was cooled to room temperature, brine (400mL) was added,
1H), 3.29–3.43 (m, 1H), 3.57–3.66 (m, 1H), 3.88 (s, 3H), followed by extraction with EtOAc (400mL×2). The organic
5.24–5.29 (m, 1H), 7.57–7.64 (m, 3H), 7.66 (t, J=7.8Hz, 1H), layer was dried over anhydrous MgSO4, filtered, and concen-
7.72 (s, 1H), 7.88 (s, 1H), 7.93–7.97 (m, 1H), 7.98–8.04 (m, trated in vacuo. The residue was purified using silica gel col-
1H), 8.77–8.92 (m, 1H), 9.07–9.22 (m, 2H), 9.72–9.77 (m, umn chromatography (20–60% EtOAc in hexane) to yield 27
1
1H); 13C-NMR (126MHz, DMSO-d6) δ: 165.3, 139.1, 138.6, (174g, 77%) as a pale yellow amorphous. H-NMR (600MHz,
136.8, 133.8, 133.5, 129.5, 129.1, 128.8, 128.6, 128.3, 128.0, CDCl3) δ: 1.23–1.39 (m, 9H), 1.40–2.26 (m, 9H), 2.28–3.03 (m,
127.7, 127.2 (q, J=30Hz), 126.3, 122.8 (q, J=274Hz), 118.2, 1H), 3.67–3.77 (m, 1H), 4.16–4.24 (m, 2H), 5.59–5.65 (m, 1H),
57.9, 55.5, 44.7, 34.5, 25.7, 21.5, 21.4; HR-MS: Calcd for 7.12–7.19 (m, 1H), 7.30–7.48 (m, 3H), 7.65 (s, 1H), 7.74–7.76
C24H24ClF3N4O [M+H]+ 477.1664. Found 477.1662; [α]D=+54 (m, 1H), 8.01–8.53 (m, 1H); MS (ESI): m/z 399 [M+H]+.
(c=0.59, MeOH).
tert-Butyl (2S)-2-{(S)-Amino[3-(1-ethyl-1H-pyrazol-4-yl)-
(28) Compound
tert-Butyl (2S)-2-(3-Bromobenzoyl)piperidine-1-carboxy- phenyl]methyl}piperidine-1-carboxylate

1336
Chem. Pharm. Bull.
Vol. 64, No. 9 (2016)
27 (50.1g, 126mmol) and 10% Pd/C (5.0g) were added to an the labeled glycine solution was aspirated with a manifold.
8mol/L NH3 solution in MeOH (300mL), and the mixture The cells were then lysed with 0.5mol/L sodium hydroxide
was stirred under a hydrogen gas atmosphere for 20h at room solution. The amount of intracellular glycine was determined
temperature. 8mol/L NH3 solution in MeOH (140mL) and by measuring the radio activity in the cell lysate using a liquid
10% Pd/C (5.0g) were added, and the mixture was stirred for scintillation counter. The quantity of glycine uptake in the
an additional 7.5h at 45°C. After filtration, the solvent was presence of 10µM ALX5407 was defined as nonspecific up-
removed in vacuo. The residue was purified using silica gel take, and the specific uptake amount was determined by sub-
column chromatography (5% MeOH in CHCl3) to yield 28 tracting the nonspecific uptake amount from the total uptake
1
(37.7g, 78%) as a colorless syrup. H-NMR (600MHz, CDCl3) amount in the absence of 10µM ALX5407. The glycine uptake
δ: 1.28–1.32 (m, 1H), 1.34–1.73 (m, 14H), 1.54 (t, J=7.3Hz, inhibitory activity (IC50 value) was calculated from an inhibi-
3H), 2.80–3.04 (m, 1H), 4.01–4.51 (m, 3H), 4.21 (q, J=7.3Hz, tion curve for test compound concentrations of 10−10 to 10−6.
2H), 7.14–7.21 (m, 1H), 7.28–7.35 (m, 1H), 7.37–7.41 (m, 1H),
7.42–7.50 (m, 1H), 7.62–7.71 (m, 1H), 7.77 (s, 1H); MS (ESI):
Acknowledgments The authors would like to thank Drs.
Shigeyuki Chaki, Yoshinori Sekiguchi, Akito Yasuhara and
m/z 385 [M+H]+.
Synthesis of 3-Chloro-N-{(S)-[3-(1-ethyl-1H-pyrazol-4- Taketoshi Okubo for helpful discussions and Dr. Atsushi
yl)phenyl][(2S)-piperidin-2-yl]methyl}-4-(trifluorometh- Okada and Mr. Akira Higuchi for the analytical and spectrum
yl)pyridine-2-carboxamide (7w) from 28 1-Hydroxyben- studies.
zotriazole monohydrate (63.8g, 417mmol) and 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide hydrochloride (68.5g,
Conflict of Interest All authors are employees of Taisho
357mmol) were added to an ice-cooled solution of 3-chloro-4- Pharmaceutical Co., Ltd.
(trifluoromethyl)pyridine-2-carboxylic acid (67.2g, 298mmol)
in DMF (500mL), and the mixture was stirred under ice
cooling for 10min. A solution of 28 (114.5g, 298mmol) in
DMF (400mL) was added dropwise to the reaction mixture,
and the mixture was stirred at room temperature for 4h. The
reaction was quenched with saturated NaHCO3 aqueous solu-
tion and extracted with a mixed solvent of hexane–EtOAc
(1:1). The organic layer was dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was purified
using silica gel column chromatography (40–60% EtOAc in
hexane) to yield a colorless amorphous. The amorphous solid
was dissolved in EtOAc (1100mL), and 4mol/L HCl in EtOAc
(280mL) was then added under ice cooling. The mixture was
stirred at room temperature for 3h, and the reaction solution
was concentrated in vacuo. The residue was suspended in
CHCl3, and 2mol/L aqueous sodium hydroxide solution was
added under ice cooling. The mixture was partitioned, and
the organic layer was dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. The residue was purified using
silica gel column chromatography (3–7% MeOH in CHCl3) to
yield free form of 7w (96.2g, 66% in 2 steps) as a colorless
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GlyT1 were used. The T98G cells were seeded at a den-
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