Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmc.2015.10.001

A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K_i(CAP) = 0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region.

Full text of DOI:10.1016/j.bmc.2015.10.001

Accepted Manuscript
Structure Activity Relationships of Benzyl C-region Analogues of 2-(3-Fluo-
ro-4-methylsulfonamidophenyl) propanamides as Potent TRPV1 Antagonists
Jihyae Ann, Aeran Jung, Mi-Yeon Kim, Hyuk-Min Kim, HyungChul Ryu,
Sunjoo Kim, Dong Wook Kang, Sunhye Hong, Minghua Cui, Sun Choi, Peter
M. Blumberg, Robert Frank-Foltyn, Gregor Bahrenberg, Hannelore
Stockhausen, Thomas Christoph, Jeewoo Lee
PII:
S0968-0896(15)30079-1
DOI:
http://dx.doi.org/10.1016/j.bmc.2015.10.001
BMC 12601
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
5 September 2015
30 September 2015
1 October 2015
Please cite this article as: Ann, J., Jung, A., Kim, M-Y., Kim, H-M., Ryu, H., Kim, S., Kang, D.W., Hong, S., Cui,
M., Choi, S., Blumberg, P.M., Frank-Foltyn, R., Bahrenberg, G., Stockhausen, H., Christoph, T., Lee, J., Structure
Activity Relationships of Benzyl C-region Analogues of 2-(3-Fluoro-4-methylsulfonamidophenyl) propanamides
as Potent TRPV1 Antagonists, Bioorganic & Medicinal Chemistry (2015), doi: http://dx.doi.org/10.1016/j.bmc.
2
015.10.001
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Structure Activity Relationships of Benzyl C-region An-
alogues of 2-(3-Fluoro-4-methylsulfonamidophenyl)
propanamides as Potent TRPV1 Antagonists
a
a
a
a
b
b
Jihyae Ann , Aeran Jung , Mi-Yeon Kim , Hyuk-Min Kim , HyungChul Ryu , Sunjoo Kim ,
c
d
d
d
e
Dong Wook Kang , Sunhye Hong , Minghua Cui , Sun Choi , Peter M. Blumberg , Robert
f
f
f
f
a,
Frank-Foltyn , Gregor Bahrenberg , Hannelore Stockhausen , Thomas Christoph , Jeewoo Lee *
a
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of
Pharmacy, Seoul National University, Seoul 151-742, Korea
b
J2H Biotech, Ansan-si, Gyeonggi-do, Korea
c
Department of Pharmaceutical Science and Technology, College of Health and Medical Science,
Catholic University of Deagu, Gyeongsan-si, Gyeongsangbuk-do 712-702, Korea
d
National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Phar-
macy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha
Womans University, Seoul 120-750, Korea
e
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Insti-
tute, NIH, Bethesda, MD 20892, USA
f
Grünenthal Innovation, Grünenthal GmbH, D-52078 Aachen, Germany
*
To whom correspondence should be addressed.
Phone: 82-2-880-7846
Fax: 82-2-888-0649
E-mail: jeewoo@snu.ac.kr
1

Key Words: Vanilloid Receptor 1, TRPV1 antagonists, analgesic
Abstract
A
series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogues of
2
-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism.
The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those
of the corresponding pyridine surrogates for most of the series examined. Among the phenyl
C-region derivatives, the two best compounds 43 and 44S antagonized capsaicin selectively relative
to their antagonism of other activators and showed excellent potencies with Ki(CAP) = 0.3 nM. These
two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of ac-
tion, and they demonstrated promising analgesic activities in a neuropathic pain model without hy-
perthermia. The docking study of 44S in our hTRPV1 homology model indicated that its binding
mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped
configuration in the C-region.
2

1
. Introduction
Despite its great medical importance, therapeutic approaches for treatment of pain remain
1
-3
limited. Recently, TRPV1 has emerged as a promising new target. TRPV1 is a key nociceptor in-
tegrating direct inputs including low pH, elevated temperature, or chemicals such as capsaicin,
along with indirect inputs routed through signaling pathways such as that of protein kinase C.
4
5
Starting with structures of lead agonists such as capsaicin and resiniferatoxin, intense medicinal
chemistry efforts are yielding potent antagonists along with better understanding of TRPV1 phar-
6
macology. A key finding is that compounds may have different antagonistic activities, both in
7
-8
terms of their efficacy and potency, for different TRPV1 activators. An obstacle to the clinical
development of TRPV1 antagonists that emerged with the first generation of antagonists was their
induction of hyperthermia in vivo. Compounds with selective antagonism, blocking activation by
8
capsaicin but not low pH, show initial promise of circumventing this problem. Here, we describe
our on-going exploration of the structure activity relations for hTRPV1 antagonists and the detailed
characterization of lead compounds for selective antagonism against various activators and for in
vivo activity.
Recently, we demonstrated that a series of N-{(6-trifluoromethyl-pyridin-3-yl)methyl}
2
-(3-fluoro-4-methylsulfonamidophenyl)propanamides were potent hTRPV1 antagonists for multi-
9
-13
ple activators.
The antagonistic template can be divided into three pharmacophoric parts, desig-
nated as the A, B and C-regions, and was initially designed by the pharmacophoric combination of
the A and C-regions of previous leads (Figure 1). The analysis of the structure activity relationship
of the template initially focused on the pyridine C-region in which the 2-substituent was extensively
9
10
11
12
explored by incorporating a variety of functional groups, including amino, oxy, thio, alkyl and
1
3
aryl groups. In addition, the 6-trifluoromethyl was replaced with its isosteres and the pyridine was
1
4
replaced with its isomers. In these series, multiple compounds displayed highly potent and
(
(
S)-stereospecific antagonism of hTRPV1 activators including capsaicin, N-arachidonoyl dopamine
o
NADA), low pH, heat (45 C). In addition, our in vivo analysis of promising candidates from the
3

above series confirmed that they all blocked capsaicin-induced hypothermia, consistent with their in
vitro mechanism of action, and, most importantly, they displayed potent antiallodynic activities in
neuropathic pain models. Molecular modeling using our established hTRPV1 homology model in-
dicated that the 6-trifluoromethyl group and the 2-substituents in the C-region made hydrophobic
interactions with the hydrophobic pockets composed of Leu547/Thr550 and Met514/Leu515, re-
spectively, and were critical for the potent activity of the antagonists.
Figure 1. 4-(Trifluoromethyl)benzyl C-region TRPV1 antagonists
In continuation of our effort to further optimize the C-region as we seek to develop clinical
candidates for neuropathic pain, we have investigated the phenyl surrogates of the selected pyridine
9
-13
C-region derivatives previously reported as potent antagonists (Figure 1).
As reported here, we
synthesized a series of 2-substituted 4-(trifluoromethyl)benzyl C-region derivatives, we evaluated
them for antagonism of hTRPV1 activation by multiple activators, and we compared their activities
with those of the corresponding pyridine surrogates. With selected potent antagonists in the series,
we further characterized their inhibition of capsaicin-induced hypothermia and their analgesic activ-
ity in animal models. Finally, we carried out a docking study with our hTRPV1 homology model to
identify their binding mode to the receptor.
4

2
2
. Result and discussion
.1. Chemistry
A library of 4-(trifluoromethyl)benzonitriles (4) with various 2-substituents was synthesized
starting from commercially available 2-chloro-4-(trifluoromethyl)benzonitrile (2) employing 6 dif-
ferent methods as appropriate. The benzonitriles (4) were reduced to the corresponding C-region
amines by catalytic hydrogenation or with borane. The synthesized C-region amines were then cou-
9
pled with propionic acid as previously reported to afford the final compounds 7-62 (Scheme 1).
Scheme 1. General synthesis of 2-(3-fluoro-4-(methylsulfonamido)phenyl) propanamide analogues
Reagents and conditions: (a) [Method A] NR
neat NR , DMF, 120 ºC, 6 h for 27; [Method C] ROH, KO Bu, Toluene/DMBU, 70 ºC, 5 h for
8-35; [Method D] neat ROH, DBU, 80 ºC, 3 h for 36, 37; [Method E] RSH, K CO , 18-Crown-6,
CH CN, reflux, 12 h for 38-49; [Method F] R-B(OH) , Pd(PPh , dppf, toluene/1,4-dioxane/2N
Na CO , reflux, 12 h for 53-62; (b) [Method G] H , 10% Pd-C, c-HCl, MeOH, 40 ºC, 8 h for 17, 27,
4; [Method H] 2M BH ·SMe in THF, reflux, 12 h for 7-16, 18-26, 28-53, 55-62; (c) EDC, HOBt,
DMF, room temperature, 12 h.
2
, DBU, 1,4-dioxane, 50 ºC, 12 h for 7-26; [Method B]
t
2
2
2
3
3
2
)
3 4
2
3
2
5
3
2
2
.2. In vitro Activity
The synthesized compounds were evaluated in vitro for TRPV1 antagonism as measured
by inhibition of activation by capsaicin (100 nM). The assays were conducted using a fluorometric
imaging plate reader (FLIPR) with human TRPV1 heterologously expressed in Chinese hamster
9
ovary (CHO) cells. The results are summarized in Tables 1-4. Comparison with the corresponding
9
-13
previously reported pyridine surrogates is presented in Table 5.
First, we investigated the SAR for 2-amino derivatives (Table 1). Since the secondary
9
amine derivatives of the pyridine C-region were found previously to be weak antagonists, only ter-
5

tiary amine derivatives were investigated in this study. Among acyclic amine derivatives, the
dipropylamine derivative (8) showed excellent antagonism with K = 0.3 nM. Among cyclic amine
derivatives, 5 to 8-membered ring derivatives (9-12) exhibited similar antagonism around K = 2 nM.
i
i
Since 4-substituted piperidinyl derivatives provided good antagonism in the pyridine C-region, their
phenyl surrogates (13-20) were examined. As anticipated, they all displayed very potent antagonism
with a range of K
i
= 0.4-1.4 nM. In particular, the 4-trifluoromethyl (16) and the
-(fluorobenzyl)piperidinyl (19-20) derivatives exhibited excellent antagonism with K = 0.4 nM.
-Substituted piperazinyl derivatives were also examined. Most derivatives showed good antago-
4
4
i
nism except for the 4-cyclohexyl piperazinyl analog (21). The morpholine derivative (27) was
found to be ca. 4-fold less potent than the corresponding piperidine surrogate (10).
Table 1. In vitro hTRPV1 antagonistic activities for 2-amino derivatives
R
K
i
[CAP]
R
i
K [CAP]
(nM)
(nM)
7
8
1.2
0.3
18
19
1.4
0.4
9
1
2.3
1.7
1.6
2.8
0.9
20
21
22
23
24
0.4
13.8
2.0
0.7
1.8
0
11
1
1
2
3
6

1
1
1
1
4
5
6
7
0.7
1.3
0.4
0.9
25
26
27
3.9
1.6
7.2
Next, to investigate the SAR for 2-oxy derivatives of the phenyl C-region we began with
the straight 2-alkyloxy derivatives (Table 2). Starting from the 2-propoxy derivative (28), the an-
tagonistic activity was enhanced gradually as the number of carbons in the chain increased up to 5-6
carbons. The derivatives with 5-6 carbon chains (30, 31) showed similar and potent antagonism
with a range of K = 0.7-0.8 nM. The SAR of branched 2-alkyloxy and 2-cyclooxy derivatives was
i
also investigated. The comparison of activity between straight and branched alkyl derivatives indi-
cated that the branched alkyl derivatives generally showed slightly better antagonism than did the
corresponding straight ones (e.g. 29 vs. 32, 30 vs. 33). A similar SAR pattern was examined in the
comparison between straight and cyclic alkyl derivatives (e.g. 30 vs. 34, 31 vs. 35). The
2
-benzyloxy derivatives were also investigated and were found to be potent antagonists. In particu-
lar, the 4-fluorobenzyloxy derivative (37) showed excellent antagonism with K
i
= 0.5 nM.
Table 2. In vitro hTRPV1 antagonistic activities for 2-oxy derivatives
K
i
[CAP]
K [CAP]
(nM)
i
R
R
(nM)
28
2.0
33
0.5
7

2
3
3
3
9
0
1
2
1.0
0.7
0.8
0.8
34
35
36
37
0.6
0.7
0.9
0.5
Next, we investigated the SAR for 2-thio derivatives of the phenyl C-region (Table 3). The
SAR pattern was similar to that of the 2-oxy derivatives. The straight 2-alkylthio derivatives with 4
to 6 carbons in the chain showed potent, similar antagonism with a range of K = 1.8-2.3 nM. The
i
comparison of activity between straight and branched/cyclic alkylthio derivatives indicated that the
branched/cyclic alkylthio derivatives generally showed better antagonism than did the correspond-
ing straight ones (e.g. 39 vs. 41, 39 vs. 43 and 40 vs. 44). In particular, the cyclopentylthio (43) and
the cyclohexylthio (44) derivatives exhibited excellent antagonism with K = 0.3 and 0.5 nM, re-
i
spectively. However, the incorporation of a polar group at the terminus of the 2-alkylthio group led
to loss of activity as shown in 42. The two stereoisomers of 44 were also examined and its S-isomer
(
44S) showed marked stereospecific activity as previously reported and excellent antagonism with
3
K
i
= 0.3 nM. In addition, we sought to evaluate the SAR of 2-benzylthio type derivatives since a
series of the corresponding pyridine derivatives displayed potent antagonism. The 2-benzylthio de-
rivative (45) exhibited outstanding antagonism with K = 0.5 nM, while its substituted derivatives
46-48) were found to be slightly less potent. The 2-(furan-2-yl)methylthio derivative (49) showed
moderate antagonism.
i
(
8

Table 3. In vitro hTRPV1 antagonistic activities for 2-thio derivatives
K
i
[CAP]
K [CAP]
(nM)
i
R
R
(nM)
3
3
4
4
8
9
0
1
1.9
2.3
1.8
1.4
WE
44S
44R
45
0.3
S
13.9
0.5
1.1
0.9
2.3
3.2
R
46
4
4
2
3
47
0
.3
48
4
4
0.5
49
Finally, we investigated the SAR for 2-halo, nitro, alkyl and aryl derivatives of the phenyl
C-region (Table 4). Although the 2-chloro derivative (51) showed good antagonism, the 2-fluoro
50) and 2-nitro (52) derivatives were found to be weak antagonists probably due to insufficient hy-
drophobic interactions with the receptor. Two representative 2-alkyl derivatives (53, 54), selected
from the 2-alkyl library of the pyridine C-region, exhibited excellent antagonism with K = 0.4 and
.6 nM as expected. Substituted phenyl derivatives were also examined. Most phenyl derivatives
(
i
0
showed outstanding antagonism with K ≈ 1 nM except for the dimethoxy substituted phenyl de-
i
rivatives (60, 61). The 2-pyridine derivative (62) was found to be a weak antagonist.
9

Table 4. In vitro hTRPV1 antagonistic activities for 2-halo, alkyl and aryl derivatives
K
i
[CAP]
K [CAP]
(nM)
i
R
R
(nM)
5
5
5
5
5
5
5
0
1
2
3
4
5
6
68.7
4.0
NE
0.4
0.6
0.8
1.1
57
58
59
60
61
62
1.9
1.0
0.6
8.6
5.8
59.4
In order to compare the potencies between corresponding phenyl and pyridine C-region
derivatives, representative 2-substituted compounds were listed in Table 5. The SAR analysis indi-
cated that whereas the pyridine derivatives showed better potency in the 2-amino series, the phenyl
derivatives exhibited better potency in the 2-oxy and 2-thio series. The 2-alkyl and aryl series
yielded mixed results.
Table 5. Comparison of in vitro hTRPV1 antagonistic activities for representative, corresponding
antagonists from the pyridine and phenyl C-region series
R
8
0.2
0.3
10

1
1
1
3
3
3
4
4
4
4
5
5
5
3
6
8
3
4
7
3
4
4S
7
3
4
9
0.3
0.4
0.2
0.8
0.9
2.5
1.2
0.9
0.4
4.9
1
0.9
0.6
1.4
0.5
0.6
0.5
0.3
0.5
0.3
0.9
0.4
0.6
0.6
0.6
0.2
For detailed analysis of in vitro activities, the two most potent antagonists in this study, 43
o
and 44S, were investigated for other TRPV1 activators including low pH, heat (45 C) and
N-arachidonoyl dopamine (NADA) (Table 6). Whereas both antagonists showed excellent antago-
nism with subnanomolar potency toward capsaicin and NADA, they exhibited relatively lower po-
11

tency toward pH and heat. This selective pharmacological profile is thought to be promising for
drug candidates.
Table 6. In vitro hTRPV1 antagonistic activities of 43 and 44S for multiple activators.
Activators, parameter
CAP (f)K (nM)
NADA (f)K (nM)
43
0.3
44S
0.3
i
i
0.03
32
0.03
20.4
7.3
pH, IC50 (nM)
o
heat 45 C, IC50 (nM)
37.2
2
4
.3. In vivo Activity
Consistent with its in vitro mechanism of action as an hTRPV1 antagonist, in vivo 43 and
4S likewise blocked response to capsaicin (Table 7). Compounds were administered orally at a
dose of 3 mg/kg 15 min before intraperitoneal injection of 3 mg/kg capsaicin following the proce-
1
dure described previously. This dose of 43 and 44S inhibited the hypothermic response to capsaicin,
assayed 30 min after capsaicin injection, by 80% and 57%, respectively. Compound 43 showed
dose-dependent inhibition in capsaicin-induced hypothermia by 38% at a dose of 0.3 mg/kg. Im-
portantly, both compounds by themselves did not show any hyperthermia at the given doses (data
not shown).
Table 7. Inhibition of capsaicin-induced hypothermia after oral administration in the mouse. Data, n
=
10, mean ± SEM, * p<0.05 vs vehicle.
Dose (mg/kg) /Inhibition %
CAP-induced Hypothermia
0.3
3
4
4
3
38
80
57
4S
NT
12

We evaluated the in vivo analgesic activities of the above antagonists, 43 and 44S, upon
oral administration in the Bennett mouse model of neuropathic pain (Figure 2). Both 43 and 44S
demonstrated dose-dependent antiallodynic efficacy in cold allodynia with max 48% and 57%
MPE at 10 mg/kg, respectively. In addition both compounds were found to be thermoneutral in
body temperature study.
Figure 2. Analgesic activity of compounds 43, 44S on CCI-induced cold allodynia (Bennett model)
after oral administration in the mouse. Data, n = 10, mean ± SEM, * p<0.05 vs vehicle. MPE,
maximal possible effect.
4
3
44S
100
100
75
75
*
%
MPE
%
MPE
*
5
0
5
0
5
0
5
0
*
2
2
0.0001 0.00
0.01
0.1
1
10
100
0.0001 0.001 0.01
0.1
1
10
100
Dose (mg/kg)
Dose (mg/kg)
2
.4. Molecular Modeling
To investigate the binding interactions of compound 44S, we performed a flexible docking
9
study with our human TRPV1 (hTRPV1) model generated based on our rat TRPV1 (rTRPV1)
7
11
model. Compared to the previously reported 24S, the pyridine surrogate of 44S, only the pyridine
11
ring is replaced by the phenyl ring in this compound. The binding modes of 44S and 24S appeared
to be similar in the A- and B-regions. As shown in Figure 3, the methylsulfonamidophenyl group in
the A-region fitted in the deep bottom hole and showed hydrophobic interactions with Tyr511,
Ile564, and Ile569. Moreover, the sulfonamide NH formed a hydrogen bond with Ile564. The amide
group in the B-region participated in hydrogen bonding with Tyr511, contributing to the proper po-
13

sitioning of the C-region for the hydrophobic interactions. In the C-region, the 2-cyclohexylthio
group was expected to extend toward the hydrophobic region composed of Leu547 and Thr550 as
11
did this group in 24S. However, instead of the cyclohexyl ring, the 4-trifluoromethyl group was
oriented toward the upper hydrophobic area and involved in the hydrophobic interaction with
Leu515, Leu518, Leu547 and Thr550, along with Phe587 from the adjacent monomer. The absence
of the pyridine nitrogen made this aromatic ring unable to form a hydrogen bond with Tyr511,
which might have caused the flipped orientation of the two rings in the C-region compared with
11
2
4S.
Figure 3. Docking result of 44S in the hTRPV1 model.
(
A) Binding interactions of 44S at the binding site of hTRPV1. The important interacting residues
are labeled and shown as capped-stick with their carbon atoms in white color. The secondary struc-
ture of hTRPV1 is in gray color and the neighboring monomer helices are depicted in line ribbon.
4
4S is displayed in ball-and-stick with the carbon atoms colored by magenta. The van der Waals
surface of 44S is shown by the lipophilic potential property. Hydrogen bonds are depicted as black
dashed lines, and non-polar hydrogens are undisplayed for clarity. (B) The Fast Connolly surface of
hTRPV1 and the van der Waals surface of the docked 44S. MOLCAD was used to generate the
molecular surface of hTRPV1 and the surface is shown with the lipophilic potential property. For
clarity, the surface of hTRPV1 is Z-clipped and that of the ligand is colored magenta. (C) 2-D rep-
resentation of the interactions between 44S and hTRPV1. Hydrophobic interactions are marked in
light brown. Red and green arrows show the hydrogen bonding interactions with their directionality.
14

3
. Conclusion
The structure activity relationship of 2-substituted 4-(trifluoromethyl)benzyl C-region an-
alogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides was investigated for hTRPV1
antagonism and compared with that of the corresponding pyridine C-region surrogates previously
reported. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism
than did the corresponding pyridine surrogates for most of the series. Among the com
pounds, the two best compounds, 43 and 44S, showed excellent antagonism toward capsaicin with
Ki(CAP) = 0.3 nM and marked selectivity for antagonism of capsaicin and NADA compared to that
for low pH and heat. They blocked capsaicin-induced hypothermia, consistent with their actions in
vitro being through TRPV1 and they demonstrated promising analgesic activities with 48% and 57%
MPE, respectively, at 10 mpk in the neuropathic pain model. The docking study of 44S in our
hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine sur-
rogate in the A- and B-regions but displayed a flipped orientation of two hydrophobic groups in the
C-region compared to its pyridine surrogate due to the absence of the pyridine nitrogen.
4
4
4
. Experimental
.1. Chemistry
.1.1. General
All chemical reagents were commercially available. Melting points were determined on a Büchi
Melting Point B-540 apparatus and are uncorrected. Silica gel column chromatography was per-
1
formed on silica gel 60, 230-400 mesh, Merck. Nuclear magnetic resonance ( H-NMR and
1
3
1
13
C-NMR) spectra were recorded on JEOL JNM-LA 300 [300 MHz ( H), 75 MHz ( C)] and
1
13
Bruker Avance 400 MHz FT-NMR [400 MHz ( H), 100 MHz( C)] spectrometers. Chemical shifts
are reported in ppm units with Me Si as a reference standard. Infrared (IR) spectra were recorded on
4
a JASCO FT/IR-4200 spectrometer. Mass spectra were recorded on a VG Trio-2 GC-MS and 6460
Triple Quad LC/MS. All final compounds were purified to >95% purity, as determined by
15

high-performance liquid chromatography (HPLC). HPLC was performed on an Agilent 1120 Com-
pact LC (G4288A) instrument using an Agilent Eclipse Plus C18 column (4.6 x 250 mm, 5 μm) and
a Daicel Chiralcel OD-H column (4.6 x 250 mm, 5 μm).
4
4
.1.2. General Procedure for Amidation
.1.2.1. Method A
A mixture of 2-chloro-4-(trifluoromethyl)-benzonitrile (1.00 mmol), appropriate amine (NR , 2.00
2
mmol), and DBU (2.5 mmol) were dissolved in 1,4-dioxane (8 ml). The mixture was stirred for 12 h
at 50 °C. The reaction was quenched with water and extracted with EtOAc twice. The combined
organic extracts were dried over MgSO
fied by flash column chromatography on silica gel using EtOAc:hexane (1:7-1:10) eluant condition.
NR = 4-(4-fluorophenyl)-1 2 3 6-tetrahydropyridine hydrochloride for 17)
4
, filtered, and concentrated in vacuo. The residue was puri-
(
2
4
.1.2.2. Method B
A mixture of 2-chloro-4-(trifluoromethyl)-benzonitrile (1.00 mmol), appropriate amine (NR
2
, 2.00
mmol) were dissolved in DMF (8 ml). The mixture was stirred for 6 h at 120 °C. The reaction was
quenched with water and extracted with EtOAc twice. The combined organic extracts were dried
over MgSO
4
, filtered, and concentrated in vacuo. The residue was purified by flash column chro-
matography on silica gel using EtOAc : hexane (1:7) eluant condition.
4
.1.2.3. Method C
Appropriate ROH (3.00 mmol) was added to potassium tert-butoxide (3.00 mmol) solution in tolu-
ene (7 ml). 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 3 ml) was added to the
mixture and stirred for 30 min at 80 °C. After cooled down to ambient temperature of the reaction
mixture, 2-chloro-4-(trifluoromethyl)-benzonitrile (1.00 mmol) in toluene was dropwised and
sttired for 3 h at 80°C. The reaction was quenched by adding water and extracted with with EtOAc
16

twice. The combined organic extracts were dried over MgSO , filtered, and concentrated in vacuo.
4
The residue was purified by flash column chromatography on silica gel using EtOAc:hexane (1:7)
eluant condition.
4
.1.2.4. Method D
2
-chloro-4-(trifluoromethyl)-benzonitrile (1.00 mmol) was dissolved in appropriate alcohol, and
DBU (2.00 mmol) was added. The mixture was stirred for 3 h at 80 °C. The reaction was quenched
with water and extracted with EtOAc twice. The combined organic extracts were dried over MgSO
4
,
filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on
silica gel using EtOAc : hexane (1:4) eluant condition.
4
.1.2.5. Method E
A mixture of 2-chloro-4-(trifluoromethyl)-benzonitrile (1.00 mmol) and appropriate thiol (RSH,
.00 mmol), 18-crown-6-ether (cat.) and potassium carbonate (2.00 mmol) were dissolved in ace-
3
tonitrile (3 ml). The mixture was refluxed for 12 h and then cooled to ambient temperature. The
mixture was quenched by adding water and extracted with EtOAc. Extracted organic compound
was dried over MgSO
umn chromatography on silica gel using EtOAc:hexane (1:4) eluant conditon. (RSH =
CH CO (CH SH for 42)
4
, filtered, and concentrated in vacuo. The residue was purified by flash col-
3
2
)
2 2
4
.1.2.6. Method F
A mixture of 2-chloro-4-(trifluoromethyl)-benzonitrile (1.00 mmol), appropriate boronic acid (1.20
mmol) were dissolved in toluene:dioxane:2N Na CO (2:1:1) solution (6 ml).
Tetrakis(triphenyl-phosphine)palladium(0) (0.10 mmol) and
,1′-Ferrocenediyl-bis(diphenylphosphine) (0.20 mmol) was added to the mixture and it was re-
fluxed for 12 h. After cooled down to ambient temperature, the reaction was filtered over celite and
2
3
1
17

extracted with EtOAc twice. The combined organic extracts were dried over MgSO
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel us-
ing EtOAc : hexanes (1:10) eluant condition. (R-B(OH) = 1-pentenyl boronic acid for 53,
4
, filtered, and
2
1
-cyclohexenylboronicacid for 54)
4
4
.1.3. General Procedure for Nitrile Reduction
.1.3.1. Method G
A suspension of nitrile compounds (1.00 mmol) and 10% Pd-C (20 mg/ mmol) and c-HCl (1 drop)
in MeOH (3 ml) was charged with hydrogen gas for 6 h at room temperature and filtered through
celite. The filtrate was concentrated in vacuo. The residue was purified by flash column chroma-
tography on silica gel using MeOH:DCM (1:10) eluant condition.
4
.1.3.2. Method H
To a stirred solution of nitrile (1.00 mmol) in anhydrous THF (10 ml) was added 2M BH
3
∙SMe in
2
THF (1.1 mmol) at room temperature. After being refluxed for 8 h, the mixture was cooled to am-
bient temperature, 2 N HCl was dropwised, and the solution then refluxed for 30 min. After cooling
to ambient temperature, the mixture was neutralized with 2 N NaOH and extracted with EtOAc
several times. The combined organic layers were washed with brine, dried over MgSO , and con-
4
centrated in vacuo. The residue was purified by flash column chromatography on silica gel using
MeOH:DCM (1:10) eluant condition.
4
.1.4. General Procedure for Amide Coupling
mixture of acid (1.00
-(3-dimethylaminopropyl)-3-ethyl-carbodiimide
A
mmol),
amine
(1.10
(1.10 mmol)
mmol),
and
1
1
hydrochloride
-Hydroxybenzotriazole hydrate (1.50 mmol) in DMF (5 ml) was stirred for 12 h at room
18

temperature. The reaction mixture was extracted with EtOAc (10 ml). The aqueous phase was
saturated with aq. NaCl and extracted again with EtOAc (15 ml). The combined organic ex-
tracts were washed with 1 N HCl (5 ml) and brine (5 ml), dried over MgSO , filtered, and
4
concentrated in vacuo. The residue was purified by flash column chromatography on silica gel
using EtOAc:hexanes (1:2) eluant condition.
4
2
.1.4.1.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(butyl(methyl)amino)-4-(trifluorome-thyl)be
nzyl)propanamide (7).
Yield 55%, white solid, mp = 65-75 °C; H NMR (300 MHz, CDCl
.30 (s, 1H), 7.12 (m, 2H), 6.47 (m, 2H), 4.52 (m, 2H), 3.52 (d, J = 7.10 Hz, 1H), 3.01 (s, 3H), 2.08
m, 2H), 2.60 (s, 3H), 1.52 (d, J = 7.14 Hz, 3H), 1.41 (m, 2H), 1.29 (m, 2H), 0.90 (t, J = 7.20 Hz,
1
3
)  7.52 (t, J = 8.25 Hz, 1H),
7
(
3
H); MS (FAB) m/z 504 (M+H).
4
2
.1.4.2.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(dipropylamino)-4-(trifluoromethyl)-benzyl)p
ropanamide (8).
Yield 60%, white solid, mp = 67 °C; H NMR (300 MHz, CDCl
1
3
)  7.52 (dd, J = 8.4, 8.4 Hz, 1H),
7
1
1
.32 (s, 1H), 7.23-7.28 (m, 2H), 7.17 (dd, J = 11.2, 2.0 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.49 (bs,
H), 6.36 (bt, 1H), 4.47-4.61 (m, 2H), 3.52 (q, J = 7.1 Hz, 1H), 3.03 (s, 3H), 2.79-2.90 (m, 4H),
.52 (d, J = 7.1 Hz, 3H), 1.29-1.45 (m, 4H), 0.77-0.89 (m, 6H); MS (FAB) m/z 518 (M+H).
4
2
.1.4.3.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-(2-pyrrolidin-1-yl-4-trifluoromethyl-benzyl)-
propionamide (9).
Yield 70%, white solid, mp = 134 °C; H NMR (300MHz, CDCl
1
3
)7.49 (t, J = 8.1 Hz, 1H),
19

7
3
.05-7.19 (m, 5H), 6.79 (bs, 1H), 6.26 (bt, 1H), 4.49 (d, J = 4.8 Hz, 2H), 3.54 (q, J = 7.2 Hz, 1H),
.08-3.12 (m, 4H), 3.01 (s, 3H), 1.86-1.90 (m, 4H), 1.50 (d, J = 7.2 Hz, 3H); MS (FAB) m/z 488
(
M+H).
4
2
.1.4.4.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-(2-piperidin-1-yl-4-trifluoromethyl-benzyl)-p
ropionamide (10).
Yield 80%, pale yellow solid, mp = 68 °C; H NMR (300MHz, CDCl
1
3
) 7.48 (t, J = 8.3 Hz, 1H),
.32 (bd, 2H), 7.05-7.15 (m, 4H), 6.81 (bs, 1H), 6.66 (bt, 1H), 4.52 (d, J = 5.1 Hz, 2H), 3.55 (q, J =
.9 Hz, 1H), 3.00 (s, 3H), 2.79 (bs, 4H), 1.49-1.64 (m, 6H), 1.25 (m, 3H); MS (FAB) m/z 502
7
6
(
M+H).
4
2
.1.4.5.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-(2-azepan-1-yl-4-trifluoromethyl-benzyl)-pro
pionamide (11).
Yield 58%, white solid, mp = 76-80 °C; H NMR (300 MHz, CDCl
1
3
) 7.51 (dd, J = 8.2, 8.2 Hz,
1
1
1
H), 7.32 (s, 1H), 7.23 (s, 2H), 7.14 (dd, J = 11.3, 1.9 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.52 (bs,
H), 6.43 (bt, 1H), 4.53 (m, 2H), 3.54 (q, J =7.0 Hz, 1H), 3.04-3.00 (m, 7H), 1.72-1.64 (m, 8H),
.52 (d, J = 7.0 Hz, 3H); MS (FAB) m/z 516 (M+H).
4
2
.1.4.6.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-(2-azocan-1-yl-4-trifluoromethyl-benzyl)-pro
pion-amide (12).
Yield 48%, white solid, mp = 73 °C; H NMR (300 MHz, CDCl
1
3
)  (dd, J = 8.3, 8.3 Hz, 1H),
.38 (s, 1H), 7.22-7.25 (m, 2H), 7.15 (dd, J = 11.2, 2.0 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.51 (bs,
H), 6.01 (bt, 1H), 4.55 (d, J = 5.7 Hz), 3.55 (q, J = 7.5 Hz, 1H), 3.00-3.05 (m, 7H), 1.62-1.72 (m,
7
1
20

1
0H), 1.53 (d, J = 7.1 Hz, 3H); MS (FAB) m/z 530 (M+H).
4
2
.1.4.7.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-(4-(trifluoromethyl)-2-(4-methylpiperidin-1-y
l)phenyl)methyl)-propionamide (13).
Yield 58%, white solid, mp = 156-159 °C; H NMR (300 MHz, CDCl
H), 7.25-7.28 (m, 3H), 7.14 (dd, J = 8.1, 1.8 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.52 (bt, 1H), 4.51
d, J = 5.1 Hz, 2H), 3.54 (q, J = 6.9 Hz, 1H), 3.01 (s, 3H), 2.96 (m, 2 H), 2.65 (m, 2H), 1.74 (m, 2H),
1
3
)  7.48 (dd, J = 8.1, 8.1 Hz,
1
(
1
.51(d, J = 6.9 Hz, 3H), 1.25 (m, 2H), 0.98 (d, J = 5.7 Hz, 3H); MS (FAB) m/z 516 (M+H).
4
2
.1.4.8.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-(2-(4-ethyl-piperidin-1-yl)-4-trifluoro-methyl
-
benzyl)-propionamide (14).
Yield 59%, white solid, mp = 136 °C; H NMR (300 MHz, CDCl
1
3
)  7.51 (dd, J = 8.3, 8.3 Hz, 1H),
7
4
2
.29 (s, 1H), 7.21-7.27 (m, 2H), 7.14 (m, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.48-6.59 (m, 2H),
.46-4.60 (m, 2H), 3.53 (q, J = 6.9 Hz, 1H), 2.91-3.07 (m, 5H), 2.58-2.61 (m, 2H), 1.75-1.86 (m,
H), 1.52 (d, J = 7.1 Hz, 3H), 1.10-1.37 (m, 5H), 0.93 (t, J = 7.0 Hz, 3H); MS (FAB) m/z 530
(
M+H).
4
2
.1.4.9.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-(2-(4,4-dimethyl-piperidin-1-yl)-4-trifluorom
ethyl-benzyl)-propionamide (15)
Yield 57%, white solid, mp = 85 °C; H NMR (300 MHz, CDCl
1
3
)  7.51 (dd, J = 8.3, 8.3 Hz, 1H),
.32 (s, 1H), 7.21-7.30 (m, 2H), 7.14 (dd, J = 11.2,1.8 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.52 (bs,
H), 4.45-4.60 (m, 2H), 3.54 (q, J = 7.1 Hz, 1H), 3.02 (s, 3H), 2.75-2.85 (m, 4H), 1.52 (d, J = 7.1
7
2
Hz, 3H), 1.42-1.50 (m, 4H), 1.00 (s, 6H); MS (FAB) m/z 530 (M+H).
21

4
2
.1.4.10.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-[4-trifluoromethyl-2-(4-trifluoromethyl-piper
idin-1-yl)-benzyl]-propionamide (16)
1
Yield 51%, white solid, mp = 85 °C; H NMR (300 MHz, CDCl
.22-7.32 (m, 3H), 7.12-7.19 (m, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.52 (bs, 1H), 6.12 (bt, 1H), 4.52 (d,
J = 5.9 Hz, 2H), 3.56 (q, J = 7.1 Hz, 1H), 3.05-3.15 (m, 2H), 3.03 (bs, 3H), 2.62-2.77 (m, 2H),
3
)   (dd, J = 8.2, 8.2 Hz, 1H),
7
2
5
.08-2.24 (m, 1H), 1.93-2.02 (m, 2H), 1.61-1.74 (m, 2H), 1.54 (d, J = 7.1 Hz, 3H); MS (FAB) m/z
70 (M+H).
4
2
.1.4.11.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-{2-[4-(4-fluoro-phenyl)-piperidin-1-yl]-4-trifl
uoromethyl-benzyl}-propionamide (17).
1
Yield 67%, white solid, mp = 165 °C; H NMR (300 MHz, CDCl
3
)  7.50 (dd, J = 8.3 Hz, 1H),
7
.30-7.26 (m, 3H), 7.23-7.18 (m, 2H), 7.15 (dd, J = 11.8, 2.0 Hz, 1H), 7.08 (d, J = 10.0Hz, 1H, 7.03
m, 2H), 6.46 (bs, 1H), 6.24 (bt, 1H), 4.56 (d, J = 5.7 Hz, 2H), 3.56 (q, J = 7.1 Hz, 1H), 3.09 (m,
H), 3.00 (s, 3H), 2.83 (m, 2H), 2.64 (m, 1H), 1.94 (m, 2H), 1.78 (m, 2H), 1.54 (d, J = 6.9 Hz, 3H);
MS (FAB) m/z 596 (M+H).
(
2
4
2
.1.4.12.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-{2-(4-benzyl-piperidin-1-yl)-4-triflu-orometh
yl-benzyl}-propionamide (18).
Yield 59%, white solid, mp = 93 °C; H NMR (300 MHz, CDCl
1
3
)  7.52 (dd, J = 8.2, 8.2 Hz, 1H),
7
2
1
.27-7.35 (m, 3H), 7.20-7.26 (m, 2H), 7.11-7.19 (m, 4H), 7.08 (d, J = 8.2 Hz, 1H), 6.38-6.46 (m,
H), 4.51 (d, J = 5.7 Hz, 2H), 3.52 (q, J = 7.1 Hz, 1H), 2.85-3.05 (m, 5H), 2.55-2.70 (m, 4H),
.60-1.80 (m, 3H), 1.52 (d, J = 7.1 Hz, 3H), 1.21-1.38 (m, 2H); MS (FAB) m/z 592 (M+H).
22

4
2
.1.4.13.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(4-(4-fluorobenzyl)piperidin-1-yl)-4-(trifluoro
methyl)benzyl)propanamide (19).
Yield 65%, white solid, mp = 93 °C; H NMR (300 MHz, CDCl
1
3
)  7.52 (dd, J = 8.2, 8.2 Hz, 1H),
7
2
1
.27-7.35 (m, 2H), 7.20-7.26 (m, 2H), 7.11-7.19 (m, 4H), 7.08 (d, J = 8.2 Hz, 1H), 6.38-6.46 (m,
H), 4.51 (d, J = 5.7 Hz, 2H), 3.52 (q, J = 7.1 Hz, 1H), 2.85-3.05 (m, 5H), 2.55-2.70 (m, 4H),
.60-1.80 (m, 3H), 1.52 (d, J = 7.1 Hz, 3H), 1.21-1.38 (m, 2H); MS (FAB) m/z 610 (M+H).
4
2
.1.4.14.
-(2-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(4-(4-fluorobenzyl)piperidin-1-yl)-4-(trifluoro
methyl)benzyl)propanamide (20).
Yield 65%, white solid, mp = 93 °C; H NMR (300 MHz, CDCl
1
3
)  7.52 (dd, J = 8.2, 8.2 Hz, 1H),
7
2
1
.27-7.35 (m, 2H), 7.20-7.26 (m, 2H), 7.11-7.19 (m, 4H), 7.08 (d, J = 8.2 Hz, 1H), 6.38-6.46 (m,
H), 4.51 (d, J = 5.7 Hz, 2H), 3.52 (q, J = 7.1 Hz, 1H), 2.85-3.05 (m, 5H), 2.55-2.70 (m, 4H),
.60-1.80 (m, 3H), 1.52 (d, J = 7.1 Hz, 3H), 1.21-1.38 (m, 2H); MS (FAB) m/z 610 (M+H).
4
2
.1.4.15.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-[2-(4-cyclohexyl-piperazin-1-yl)-4-trifluorom
ethyl-benzyl]-propionamide (21).
Yield 54%, white solid, mp = 84.4 °C; H NMR (300 MHz, CDCl
1
3
)  7.52 (t, J = 8.2 Hz, 1H), 7.31
(
s, 1H), 7.26-7.28 (m, 2H), 7.08-7.16 (m, 2H), 6.42 (bs, 1H), 4.52 (d, J = 5.9 Hz, 2H), 3.54 (q, J =
7
.1 Hz, 1H), 3.0 (s, 3H), 2.88-2.95 (m, 4H), 2.67 (s, 3H), 1.81-1.90 (m, 3H), 1.64 (m, 2H), 1.52 (d,
J = 7.0 Hz, 3H), 1.20-1.30 (m, 5H), 0.89-0.92 (m, 2H); MS (FAB) m/z 585 (M+H).
4
.1.4.16.
23

2
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-[2-(4-phenyl-piperazin-1-yl)-4-triflu-orometh
yl-benzyl]-propionamide (22).
Yield 75%, white solid, mp = 100 °C; H NMR (300MHz, CDCl
1
3
)  (dd, J = 8.4, 8.4 Hz, 1H),
7
4
1
.28-7.35 (m, 5H), 7.13 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.89-6.99 (m, 3H), 6.32 (bt, 1H),
.53-4.67 (m, 2H), 3.55 (q, J = 7.1 Hz, 1H), 3.20-3.28 (m, 4H), 3.00-3.08 (m, 4H), 2.98 (s, 3H),
.51 (d, J = 6.9 Hz, 3H); MS (FAB) m/z 579 (M+H).
4
.1.4.17. 2-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-[2-(4-p-tolyl-piperazin-1-yl)-4-tri리
-
uoromethyl-benzyl]-propionamide (23).
1
Yield 76%, white solid, mp = 165 °C; H NMR (300 MHz, CDCl
3
) 7.46 (dd, J = 8.2, 8.2 Hz, 1H),
7
.34 (s, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 7.0 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 7.14 (dd, J
=
11.2, 2.0 Hz, 1H), 7.08 (d, J = 10.0 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.35 (bt, 1H), 6.22 (bs, 1H),
4
3
.57 (m, 2H), 3.54 (q, J = 7.0 Hz, 1H), 3.18-3.12 (m, 4H), 3.05-3.01 (m, 4H), 2.97 (s, 3H), 2.31 (s,
H), 1.51 (d, J = 7.1 Hz, 3H); MS (FAB) m/z 593 (M+H).
4
2
.1.4.18.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-[2-(4-m-tolyl-piperazin-1-yl)-4-trifl-uorometh
yl-benzyl]-propionamide (24).
Yield 68%, white solid, mp = 82-86 °C; H NMR (300 MHz, CDCl
1
3
) 7.46 (dd, J = 8.2 Hz, 1H),
7
6
4
.36-7.26 (m, 3H), 7.21 (m, 1H), 7.13 (dd, J = 11.2, 2.0 Hz, 1H), 7.07 (d, J = 8.1, 8.1 Hz, 1H),
.79-6.74 (m, 3H), 6.33 (bt, 1H), 6.25 (bs, 1H), 4.57 (m, 2H), 3.54 (q, J = 7.1 Hz, 1H), 3.24-3.18 (m,
H), 3.08-3.01 (m, 4H), 2.97 (s, 3H), 2.36 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H); MS (FAB) m/z 593
(
M+H).
4
2
.1.4.19.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-{4-trifluoromethyl-2-[4-(4-trifluoro-methyl-p
24

henyl)-piperazin-1-yl]-benzyl}-propionamide (25).
1
Yield 56%, white solid, mp = 210-213 °C; H NMR (300 MHz, CDCl
3
) 7.53 (d, J = 8.6 Hz, 2H),
7
.50 (dd, J = 8.3, 8.3 Hz, 1H), 7.33 (s, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.14 (dd, J = 11.2, 2.0 Hz, 1H),
.08 (d, J = 10.0 Hz, 1H), 6.97 (d, J = 8.9Hz, 2H), 6.23 (bt, 1H), 4.58 (d, J = 6.4 Hz, 2H), 3.54 (q, J
7.1 Hz, 1H), 3.39-3.31 (m, 4H), 3.04-2.98 (m, 4H), 3.01 (s, 3H), 1.53 (d, J = 7.1 Hz, 3H); MS
FAB) m/z 647 (M+H).
7
=
(
4
2
.1.4.20.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-{2-[4-(4-methoxy-phenyl)-piperazin-1-yl]-4-tr
ifluoromethyl-benzyl}-propionamide (26).
1
Yield 71%, white solid, mp = 114 °C; H NMR (300 MHz, CDCl
3
) 7.47 (dd, J = 8.2, 8.2 Hz, 1H),
7
6
3
.33 (d, J = 10.1 Hz, 2H), 7.29 (s, 1H), 7.13 (dd, J = 11.2, 2.0 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H),
.98-6.85 (m, 4H), 6.35 (bs, 1H), 6.33 (bt, 1H), 4.59 (m, 2H), 3.80 (s, 3H), 3.54 (q, J = 7.1 Hz, 1H),
.15-3.08 (m, 4H), 3.05-2.98 (m, 4H), 2.98 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H); MS (FAB) m/z 609
(
M+H).
4
2
.1.4.21.
-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-(2-morpholin-4-yl-4-trifluoromethyl-benzyl)-
propionamide (27).
Yield 80%, pale yellow solid, mp = 71-75 °C; H NMR (300MHz, CDCl
1
3
) 7.43 (t, J = 8.3 Hz,
H), 7.16-7.24 (m, 3H), 7.09 (dd, J = 11.1, 2.0 Hz, 1H), 7.01 (dd, J = 7.8, 1.8 Hz, 1H), 6.70 (bs,
H), 6.15 (bt, 1H), 4.47 (d, J = 5.4 Hz, 2H), 3.70 (t, J = 4.2 Hz, 4H), 3.50 (q, J = 7.2 Hz, 1H), 2.95
1
1
(
s, 3H), 2.78 (t, J = 4.2 Hz, 4H), 1.45 (d, J = 7.2 Hz, 3H); MS (FAB) m/z 504 (M+H).
4
2
.1.4.22.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(propyloxy)-4-(trifluoromethyl)ben-zyl)prop
25

anamide (28).
Yield 68%, white solid, mp = 98-105 °C; H NMR (300 MHz, CDCl
1
3
)  7.50 (t, J = 8.04 Hz, 1H),
7
.26 (m, 1H), 7.16-7.02 (m, 4H), 6.43 (s, 1H), 5.90 (bs, 1H), 4.43 (m, 2H), 3.94 (m, 2H), 3.51 (q, J
=
6.39 Hz, 1H), 3.00 (s, 3H), 1.78 (sext, J = 6.24 Hz, 2H), 1.50 (d, J = 7.14 Hz, 3H), 1.02 (t, J =
7
.50 Hz, 3H); MS (FAB) m/z 477 (M+H).
4
2
.1.4.23.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(butoxy)-4-(trifluoromethyl)benzyl)-propana
mide (29).
Yield 47%, white solid, mp = 101 °C; H NMR (300 MHz, CDCl
1
3
)  7.50 (dd, J = 8.2, 8.2 Hz, 1H),
7
1
1
.28 (m, 1H), 7.08-7.17 (m, 2H), 7.06 (d, J = 9.0 Hz, 1H), 7.02 (bs, 1H), 6.46 (bs, 1H), 5.93 (bt ,
H), 4.35-4.51 (m, 2H), 3.91-4.02 (m, 2H), 3.50 (q, J = 7.3 Hz, 1H), 3.02 (s, 3H), 1.67-1.80 (m, 2H),
.39-1.53 (m, 5H), 0.98 (t , J = 7.3 Hz, 3H); MS (FAB ) m/z 491 (M+H).
4
2
.1.4.24.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(pentyloxy)-4(trifluoromethyl)benz-yl)propa
namide (30).
Yield 57%, white solid, mp = 108 °C; H NMR (300 MHz, CDCl
1
3
)  7.49 (t, J = 8.43 Hz, 1H),
7
1
3
.26 (m, 2H), 7.15-7.01 (m, 4H), 5.98 (bt, 1H), 4.43 (m, 2H), 3.97 (m, 2H), 3.50 (q, J = 6.96 Hz,
H), 3.01 (s, 3H), 1.75 (m, 2H), 1.48 (t, J = 7.14 Hz, 3H), 1.42-1.39 (m, 4H), 0.94 (t, J = 6.96 Hz,
H); MS (FAB) m/z 504 (M+H).
4
2
.1.4.25.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(hexyloxy)-4(trifluoromethyl)benz-yl)propan
amide (31).
Yield 50%, white solid, mp = 99-105 °C; H NMR (300 MHz, CDCl
1
3
)  7.48 (t, J = 8.79 Hz, 1H),
26

7
1
.26 (m, 1H), 7.14-7.01 (m, 4H), 5.99 (bt, 1H), 4.43 (m, 2H), 3.98 (m, 2H), 3.50 (q, J = 7.14 Hz,
H), 3.01 (s, 3H), 1.79-1.70 (m, 2H), 1.48 (t, J = 7.14 Hz, 3H), 1.44-1.28 (m, 6H), 0.94 (t, J = 6.78
Hz, 3H); MS (FAB) m/z 519 (M+H).
4
2
.1.4.26.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(isobutyloxy)-4-(trifluoromethyl)be-nzyl)pro
panamide (32).
Yield 57%, white solid, mp = 105 °C; H NMR (300 MHz, CDCl
1
3
)  7.5 (t, J = 8.25 Hz, 1H), 7.26
(
m, 1H), 7.16-7.01 (m, 4H), 6.42 (s, 1H), 5.88 (bs, 1H), 4.43 (m, 2H), 3.76 (dd, J = 2.4, 4.02 Hz,
2
1
H), 3.50 (q, J = 6.96 Hz, 1H), 3.00 (s, 3H), 2.04 (pent, J = 6.78 Hz, 1H), 1.50 (d, J = 7.14 Hz, 3H),
.02 (t, J = 6.78 Hz, 6H); MS (FAB) m/z 491 (M+H).
4
2
.1.4.27.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(isopentyloxy)-4-(trifluoromethyl)-benzyl)pro
panamide (33).
Yield 60%, white solid, mp = 95-103 °C; H NMR (300 MHz, CDCl
1
3
)  7.50 (t, J = 8.07 Hz, 1H),
7
.29 (m, 1H), 7.16-7.03 (m, 4H), 6.43 (bs, 1H), 5.90 (bt, 1H), 4.42 (m, 2H), 4.00 (m, 2H), 3.50 (q, J
=
7.32 Hz, 1H), 3.02 (s, 3H), 1.79 (nonet, J = 6.78 Hz, 1H), 1.65 (q, J = 6.57 Hz, 2H), 1.50 (d, J =
7
.14 Hz, 3H), 0.98 (t, J = 6.6 Hz, 6H); MS (FAB) m/z 505 (M+H).
4
2
.1.4.28.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-cyclopentyloxy)-4-(trifluoromethyl)-benzyl)p
ropanamide (34).
Yield 41%, white solid, mp = 62 °C; H NMR (300 MHz, CDCl
1
3
)  7.51 (dd, J = 8.2, 8.2 Hz, 1H),
.90-7.17 (m, 5H), 6.45 (bs, 1H), 5.90 (m, 1H), 4.80 (m, 1H), 4.31-4.47 (m, 2H), 3.49 (q, J = 7.1 Hz,
H) 3.03 (s, 3H), 1.83-2.00 (m, 2H), 1.62-1.82 (m, 6H), 1.49 (d, J = 7.1 Hz, 3H); MS (FAB) m/z
6
1
27

5
03 (M+H).
4
2
.1.4.29.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-cyclohexyloxy)-4-(trifluoromethyl)-benzyl)pr
opanamide (35).
Yield 63%, white solid, mp = 103 °C; H NMR (300 MHz, CDCl
1
3
)  7.51 (dd, J = 8.4, 8.4 Hz, 1H),
7
1
1
.30 (m, 1H), 7.09-7.10 (m, 2H), 7.06 (d, J = 8.3 Hz, 1H), 7.02 (bs, 1H), 6.47 (bs, 1H), 5.53 (m,
H), 4.27-4.50 (m, 2H), 3.50 (q, J = 7.0 Hz, 1H), 3.02 (s, 3H), 1.84-1.96 (m, 2H), 1.64-1.78 (m, 2H),
.25-1.63 (m, 9H); MS (FAB) m/z 517 (M+H).
4
2
.1.4.30.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-benzyloxy)-4-(trifluoromethyl)ben-zyl)propa
namide (36).
Yield 59%, white solid, mp = 89-91 °C; H NMR (300 MHz, CDCl
1
3
)  7.44 (dd, J = 8.4, 8.4 Hz,
1
H), 7.41-7.34 (m, 5H), 7.33 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 7.14 (s, 1H), 7.05 (dd, J
=
11.3, 2.0 Hz, 1H), 6.95 (d, J = 6.4 Hz, 1H), 6.41 (bs, 1H), 5.94 (bt, 1H), 5.08 (s, 2H), 4.46 (m,
2
H), 3.41 (q, J = 7.0 Hz, 1H), 2.99 (s, 3H), 1.43 (d, J = 7.1 Hz, 3H); MS (FAB) m/z 525 (M+H).
4
2
.1.4.31.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-((4-fluorobenzyl)oxy)-4-(trifluorom-ethyl)ben
zyl)propanamide (37).
Yield 71%, white solid, mp = 86-90 °C; H NMR (300 MHz, CDCl
.36-7.21 (m, 4H), 7.12-7.03 (m, 4H), 6.98 (m, 1H), 6.43 (s, 1H), 4.45 (bs, 1H), 3.44 (q, J = 7.14
Hz, 1H), 3.00 (s, 3H), 1.45 (d, J = 7.14 Hz, 3H); MS (FAB) m/z 543 (M+H).
1
3
)  7.48 (t, J = 8.07 Hz, 1H),
7
4
.1.4.32.
28

2
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(butylthio)-4(trifluoromethyl)benz-yl)propan
amide (38).
Yield 65%, white solid, mp = 95 °C; H NMR (300 MHz, CDCl
1
3
)  7.53-7.37 (m, 2H), 7.34-7.31
(
m, 2H), 7.15-7.06 (m, 2H), 6.59 (bs, 1H), 5.99 (bt, 1H), 4.49 (m, 2H), 3.50 (q, J = 7.32 Hz, 1H),
3
3
.02 (s, 3H), 2.93 (t, J = 7.32 Hz, 2H), 1.67-1.58(m, 2H), 1.50-1.39 (m, 5H), 0.94 (t, J = 7.14 Hz,
H); MS (FAB) m/z 507 (M+H).
4
2
.1.4.33.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(pentylthio)-4-(trifluoromethyl)ben-zyl)prop
anamide (39).
Yield 72%, white solid, mp = 95 °C; H NMR (300 MHz, CDCl
m, 2H), 7.13 (dd, J = 11.3 Hz, 2.9 Hz, 1H), 7.07 (d, J = 8.61 Hz, 1H), 6.66 (bs, 1H), 6.04 (t, J = 5.7
Hz, 1H), 4.48 (m, 2H), 3.55 (q, J = 6.96 Hz, 1H), 3.01 (s, 3H), 2.92 (t, J = 7.32 Hz, 2H), 1.69-1.60
m, 2H), 1.49 (d, J = 7.14 Hz, 3H), 1.44-1.30 (m, 4H), 0.90 (d, J = 6.96 Hz, 3H); MS (FAB) m/z
1
3
)  7.53-7.47 (m, 2H), 7.73-7.31
(
(
5
21 (M+H).
4
2
.1.4.34.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(hexylthio)-4(trifluoromethyl)benz-yl)propan
amide (40).
Yield 81%, white solid, mp = 92 °C; H NMR (300 MHz, CDCl
1
3
)  7.51 (t, J = 8.25 Hz, 1H), 7.47
(
s, 1H), 7.37-7.31 (m, 2H), 7.15-7.06 (m, 2H), 6.42 (bs, 1H), 5.92 (bt, 1H), 4.49 (t, J = 5.49 Hz, 2H),
3
3
.51 (q, J = 7.32 Hz, 1H), 3.02 (s, 3H), 2.92 (t, J = 7.32 Hz, 2H), 1.64(m, 2H), 1.51(d, J = 7.14 Hz,
H), 1.45-1.25(m, 6H), 0.89 (t, J = 6.78 Hz, 3H); MS (FAB) m/z 535 (M+H).
4
2
.1.4.35.
-(3-Fluoro-4-(methylsulfonamido)phenyl)-N-(2-(isopentylthio)-4-(trifluoromethyl)-benzyl)pr
29