2-(4-Methylsulfonylaminophenyl) propanamide TRPV1 antagonists: Structure-activity relationships in the B and C-regions

Article abstract of DOI:10.1016/j.bmc.2011.12.014

On the basis of the previous lead N-4-t-butylbenzyl 2-(3-fluoro-4- methylsulfonylaminophenyl) propanamide (3) as a potent TRPV1 antagonist, structure-activity relationships for the B (propanamide part) and C-region (4-t-butylbenzyl part) have been investi

Full text of DOI:10.1016/j.bmc.2011.12.014

Bioorganic & Medicinal Chemistry 20 (2012) 1310–1318
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Bioorganic & Medicinal Chemistry
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2-(4-Methylsulfonylaminophenyl) propanamide TRPV1 antagonists:
Structure–activity relationships in the B and C-regions
Wei Sun a, Keliang Liu a, HyungChul Ryu b, Dong Wook Kang b, Yong Soo Kim b, Myeong Seop Kim b,
Yongsung Cho b, Rahul S. Bhondwe b, Shivaji A. Thorat b, Ho Shin Kim b, Larry V. Pearce c,
Vladimir A. Pavlyukovets c, Richard Tran c, Matthew A. Morgan c, Jozsef Lazar c, Christopher B. Ryder c,
Attila Toth c, Peter M. Blumberg c, Jeewoo Lee b,
a Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
⇑
b Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea
c Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
On the basis of the previous lead N-4-t-butylbenzyl 2-(3-fluoro-4-methylsulfonylaminophenyl) propan-
amide (3) as a potent TRPV1 antagonist, structure–activity relationships for the B (propanamide part) and
C-region (4-t-butylbenzyl part) have been investigated for rTRPV1 in CHO cells. The B-region was mod-
ified with dimethyl, cyclopropyl and reverse amides and then the C-region was replaced with 4-substi-
tuted phenyl, aryl alkyl and diaryl alkyl derivatives. Among them, compound 50 showed high binding
affinity with Ki = 21.5 nM, which was twofold more potent than 3 and compound 54 exhibited potent
antagonism with Ki(ant) = 8.0 nM comparable to 3.
Received 1 November 2011
Revised 8 December 2011
Accepted 8 December 2011
Available online 23 December 2011
Keywords:
TRPV1 antagonists
Analgesic
Ó 2011 Elsevier Ltd. All rights reserved.
Capsaicin
Resiniferatoxin
1. Introduction
potent antagonism not only for capsaicin stimulation of rTRPV1
but also for stimulation by temperature and pH.14,16 Further opti-
The transient receptor potential V1 (TRPV1) receptor1 is a
molecular integrator of nociceptive stimuli, functioning as a non-
selective cation channel with high Ca2+ permeability. The receptor,
located predominantly in primary sensory neurons, is activated by
protons,2 heat,3 inflammatory mediators such as anandamide4 and
lipoxygenase products,5 and vanilloids such as capsaicin (CAP)6
and resiniferatoxin (RTX).7 Its activation leads to an increase in
intracellular Ca2+, which in turn causes excitation of the primary
sensory neurons and ultimately the central perception of pain.
Since TRPV1 antagonists inhibit the transmission of nociceptive
signaling from the periphery to the CNS as well as block other
pathological states associated with this receptor, they have been
promising drug candidates as novel analgesic and antiinflamma-
tory agents, particularly for chronic pain and inflammatory hyper-
algesia.8 The clinical development and therapeutic potentials of
TRPV1 antagonists has been extensively reviewed.9–13
mization in the B-region (thiourea part) provided the propanamide
antagonist 3, which exhibited higher binding affinity and more
potent antagonism for both rTRPV1 and hTRPV1 in CHO cells com-
pared to 1 (Fig. 1).18 Its stereospecific activity was demonstrated
with marked selectivity for the (S)-configuration (S-3 vs. R-3);
whereas the (S)-isomer was ca. twofold more potent than the race-
mate 3, the (R)-isomer was 30- to 40-fold weaker. A docking study
of S-3 isomer with our hTRPV1 homology model identified crucial
hydrogen bonds between the ligand and the receptor contributing
to its stereospecific potency. A further advantage of the propana-
mide antagonists over the thiourea antagonists, such as 1, is that
the propanamide antagonists avoid the potential toxicity associ-
ated with the thiourea functionality.
As a continuation of our effort to optimize the 4-methylsulfona-
mide TRPV1 antagonists, we reported the structure–activity rela-
tionships for the A-region (4-methylsulfonylaminophenyl part) in
a series of N-4-t-butylbenzyl 2-(4-methylsulfonylaminophenyl)
propanamides as TRPV1 antagonists.18 In this paper, we have
investigated the structure–activity relationships of the B (propan-
amide part) and C-region (4-t-butylbenzyl part) in a series of 2-
(3-fluoro-4-methylsulfonylaminophenyl) propanamide TRPV1
antagonists.
Previously, we have reported a prototype antagonist, N-(4-
t-butylbenzyl)-N0-4-(3-fluoro-4-methylsulfonylaminobenzyl) thio-
urea (1),14–17 in rat TRPV1/CHO (Fig. 1). The thiourea showed
⇑
Corresponding author. Tel.: +82 2 880 7846; fax: +82 2 888 0649.
E-mail address: jeewoo@snu.ac.kr (J. Lee).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.12.014

W. Sun et al. / Bioorg. Med. Chem. 20 (2012) 1310–1318
1311
S
H
N
F
R
N
H
N
H
O
S
O
O
S
O
N
H
A
N
H
O
C
B
B
C
A
1
2 R = H
3 R = F
4 R = OCH3
Figure 1.
Table 1
SAR-1 of B-region
HO
HO
R
H
N
a
a
R
O
S
O
O
O
O
S
O
N
H
H
N
O
X
N
H
R
O
S
O
5 R = H
6 R = F
8 R = H
O
N
H
9
R = F
7 R = OCH3
10 R = OCH3
b
X
R
Kia (nM) binding
EC50 (nM)
agonism
Kia (nM)
antagonism
R
H
N
affinity
R
O
S
O
2
3
4
8
9
>CHCH3
>CHCH3
>CHCH3
>C(CH3)2
>C(CH3)2
H
F
106
46.2
NE
NE
NE
NE
NE
NE
NE
NE
NE
17.5
7.6
232
2550 ( 760)
467 ( 86)
707 ( 81)
1770 ( 140)
WE
O
S
O
N
H
O
N
H
OCH3 540
H
F
14 R = H
11 R = H
12 R = F
13 R = OCH3
430 ( 120)
1070 ( 330)
15 R = F
16 R = OCH3
10 >C(CH3)2 OCH3 414 ( 55)
14 >C(CH2)2
15 >C(CH2)2
16 >C(CH2)2 OCH3 750 ( 130)
H
F
610 ( 130)
NE
Scheme 1. Syntheses of dimethyl and cyclopropyl amide analogues. Reagents and
conditions: (a) R-NH2, EDC, CH2Cl2.
2250 ( 610)
a
Values represent mean SEM from 3 or more experiments.
NE, no effect. WE, weak effect (quantitation of no effect/fractional agonism/
b
O
antagonism is from 1 to 3 experiments).
F
F
H2N
R
N
H
a
b
O
S
O
O
S
O
N
H
N
H
Table 2
SAR-2 of B-region
18-20
22-60
17
21
H
N
HO
F
F
R
O
O
S
O
O
S
O
O
O
F
N
H
N
H
N
H
X
O
S
O
N
H
Scheme 2. Syntheses of reverse amide and propanamide analogues. Reagents and
conditions: (a) R-CO2H, EDC, CH2Cl2; (b) R-NH2, EDC, CH2Cl2.
X
Kia (nM) binding
affinity
EC50 (nM)b
agonism
Kia (nM)
antagonism
3
46.2
2100 ( 500)
380 ( 100)
NE
NE
NE
NE
7.6
18 CH2
19 CH2CH2
20 CH@CH(E) 105 ( 14)
2220 ( 400)
104 ( 24)
23.9 ( 4.6)
2. Result and discussion
2.1. Chemistry
a
Values represent mean SEM from 3 or more experiments.
NE, no effect. WE, weak effect (quantitation of no effect/fractional agonism/
b
The dimethyl and cyclopropyl amide analogues of 2–4 were
synthesized from the corresponding acids, 5–7 and 11–13,19 by
the coupling with 4-t-butylbenzyl amine to provide 8–10 and
14–16, respectively (Scheme 1). The reverse amide analogues were
antagonism is from 1 to 3 experiments).
prepared by the coupling of
a
-methyl benzylamine 1720 with the
itive binding assay with [3H]RTX and by a functional 45Ca2+ uptake
assay using rat TRPV1 heterologously expressed in Chinese ham-
ster ovary (CHO) cells, as previously described.16 The results are
summarized in Tables 1–4, together with the potencies of the pre-
viously reported parent antagonists 2–4.18
corresponding acids to give the final compounds 18–20 (Scheme
2). The syntheses of 2-(3-fluoro-4-methylsulfonylaminophenyl)
propanamide analogues 22–60 were conducted by following the
previous report.18
For the modification of the propanamide B-region, the two
a,
a0-disubstituted analogues, the dimethyl (8–10) and cyclopropyl
2.2. Biological activity
amides (14–16), have been investigated as TRPV1 ligands (Table 1).
The binding affinities and potencies as agonists/antagonists of
the synthesized TRPV1 ligands were assessed in vitro by a compet-
They all showed a dramatic loss in receptor activity compared to
the corresponding
a-methyl amides (propanamide) (2–4)

1312
W. Sun et al. / Bioorg. Med. Chem. 20 (2012) 1310–1318
Table 3
SAR-1 of C-region
Table 3 (continued)
b
R
Kia (nM)
EC50 (nM)
Kia (nM)
H
N
F
binding affinity
agonism
antagonism
R
O
S
O
O
N
H
39
554 ( 64)
NE
43 ( 11)
b
R
Kia (nM)
binding affinity
EC50 (nM)
agonism
Kia (nM)
antagonism
40
41
42
43
413 ( 53)
950 ( 140)
257 ( 47)
277 ( 64)
NE
NE
NE
NE
97 ( 43)
3
46.2
NE
7.6
204 ( 28)
33.7 ( 6.4)
153 ( 20)
22
1060 ( 220)
412 ( 24)
502 ( 84)
200 ( 52)
NE
NE
NE
NE
367 ( 23)
250 ( 70)
107 ( 38)
115 ( 43)
Cl
23
Br
44
45
46
470 ( 140)
897 ( 63)
NE
NE
NE
135 ( 40)
384 ( 78)
(34%)c
Cl
Cl
24
I
Cl
25
Cl
O
9400 ( 1400)
26
660 ( 170)
NE
274 ( 90)
a
Values represent mean SEM from 3 or more experiments.
NE, no effect. WE, weak effect (quantitation of no effect/fractional agonism/
F3C
b
antagonism is from 1 to 3 experiments).
c
27
7800 ( 1100)
3100 ( 570)
NE
NE
5350 ( 810)
930 ( 160)
Only fractional antagonism.
H3CO
28
29
regardless of the 3-substituents, indicating that an a-methyl in the
B-region might constitute a principal pharmacophore by making a
stereospecific interaction with the hydrophobic pocket of the
receptor, as modeled previously.19 As another B-region modifica-
127 ( 23)
411 ( 92)
NE
NE
144 ( 28)
tion, the reversed amides, N-acyl
a-methyl benzylamine (18–20),
30
31
55.5 ( 9.1)
were explored (Table 2). Compound 18, a reverse amide of 3,
exhibited a marked loss of activity compared to 3. However, its
one-carbon elongation analogue (19) improved the receptor
activity and conformational restriction (20) provided further
enhancement in activity, achieving a level only 2–3-fold less
potent than parent 3.
Previously, the structure–activity relations for the A-region in a
series of 2-(4-methylsulfonylaminophenyl) propanamides were
evaluated with the 4-t-butylbenzyl group as a fixed C-region.
These studies identified the 2-(3-fluoro-4-methylsulfonylami-
no)phenyl propanamide moiety as the best A/B-regions with high
binding affinity and potent antagonism. We therefore explored
the extensive structure–activity relationships of the C-region with
the above fixed A/B-region. The aryl alkyl and diaryl alkyl ana-
logues of the C-region were represented in Tables 3 and 4,
respectively.
The SAR of the C-region was started from the modification at
the 4-position of the 4-t-butyl benzyl group. First, halogen groups,
including 4-chloro (22), 4-bromo (23), 4-iodo (24) and 3,4-dichloro
(25), were introduced as electron-withdrawing and lipophilic
groups to replace the 4-t-butyl group of lead compound 3.
Although their receptor activities improved as the size of the halo-
gen increased, the activity of the 4-iodo analogue (24) was still 10-
fold less potent than that of the parent 3. The 4-trifluoromethyl
analogue (26) showed similar potency compared to the 4-chloro
and 4-bromo analogues, reflecting their similar physicochemical
properties. The 4-methoxy analogue (27), which placed an elec-
tron-donating group in the 4-position, exhibited a dramatic reduc-
tion in receptor potency. Next, various alkyl groups were
incorporated into the 4-position. The activity increased with the
size of 4-alkyl group up to the cyclopentyl group (32) but was then
162 ( 31)
93 ( 23)
138 ( 49)
NE
NE
NE
15 ( 1.1)
20.8 ( 2.5)
43 ( 17)
32
33
34
1750 ( 480)
47 ( 11)
NE
NE
261 ( 69)
Br
35
36
12.7 ( 3.4)
CN
44.0 ( 5.5)
NE
40 ( 15)
37
38
960 ( 110)
WE
NE
NE
240 ( 95)
NE

W. Sun et al. / Bioorg. Med. Chem. 20 (2012) 1310–1318
1313
Table 4
SAR-2 of C-region
Table 4 (continued)
a
R
Kia (nM)
EC50 (nM)
Kia (nM)
binding affinityc
agonismc
antagonismc
H
N
F
R
O
S
O
Cl
O
N
H
57
29.6 ( 7.0)
NE
24.5 ( 6.3)
a
R
Kia (nM)
EC50 (nM) Kia (nM)
binding affinityc
agonismc
antagonismc
Cl
47
5900 ( 1300)
NE
(58%)b
58
121 ( 48)
NE
31 ( 11)
F
48
49
50
51
52
1680 ( 640)
130 ( 21)
21.5 ( 5.1)
188 ( 35)
115 ( 25)
NE
NE
NE
NE
NE
2490 ( 880)
36.6 ( 7.2)
14.2 ( 4.0)
148 ( 51)
47 ( 24)
59
60
141 ( 44)
117 ( 31)
NE
NE
122 ( 11)
163 ( 7.6)
a
Values represent mean SEM from 3 or more experiments.
NE, no effect. WE, weak effect (quantitation of no effect/fractional agonism/
antagonism is from 1 to 3 experiments).
b
c
Only fractional antagonism.
reduced in the cyclohexyl analogue (33). Interestingly, the 4-phe-
nyl analogue (34) led to a dramatic loss in activity. The analysis
indicated that the t-butyl group at the 4-position was best for
potency, among the compounds examined, probably due to an
optimal fit to the hydrophobic pocket.19 Incorporation of the 2-bro-
mo (35) and 2-cyano (36) groups into the 4-t-butylbenzyl did not
affect the potency of the parent compound (3), suggesting that the
2-substituent was directed away from the binding pocket. Bicyclic
analogues, naphthalene (37) and tetrahydronaphthalene (38),
were found to be weak antagonists. One-carbon elongation of 3
to give 39 led a modest reduction in potency. The 3,4-dimethylphe-
nylpropyl group, found in the previous clinical candidate DA-5018,
was used as the C-region to provide 40. Although it was found to be
ca. 10-fold less potent than 3, the stereospecific potency of the
N
53
54
96 ( 21)
NE
NE
32.1 ( 3.7)
a
-methyl group could be further confirmed with its two chiral
compounds (41, 42), in which the (S)-isomer (42) proved to be
the active isomer with ca. twofold more potency than the racemate
40. Conformational restriction of 40 to give 43 yielded little
improvement in receptor potency. The 4-chlorophenylpropyl
analogues, 44 and 45, showed similar potencies compared to the
corresponding 3,4-dimethylphenyl analogues, 40 and 43, respec-
tively. The benzyloxy analogue (46) was found to a weak partial
antagonist.
30.9 ( 5.5)
8.0 ( 1.9)
F
55
56
79 ( 34)
NE
NE
24.8 ( 0.99)
Next, a series of diphenylalkyl groups (47–60) as a C-region
were investigated (Table 4).
F
F
The diphenylmethyl analogue (47) showed very weak binding
affinity and partial antagonism. However, activity was enhanced
as the number of carbons in the linker increased. The diphenylpro-
pyl analogue (49) exhibited good binding affinity and antagonism.
The modification of the propyl linker provided the three derivatives
50–52; whereas the diphenylpropenyl analogue (50) showed sev-
eral-fold enhanced potency, the diphenylcyclopropylmethyl (51)
and the diphenylaminoethyl (52) analogues displayed a modest
reduction in potency compared to 49. The analysis indicated that
F
43.3 ( 8.1)
29.2 ( 5.4)

1314
W. Sun et al. / Bioorg. Med. Chem. 20 (2012) 1310–1318
the flat environment rather than a conformational restriction in the
C-region was favorable for binding to the receptor. Compound 50
was found to have high affinity and potent antagonism with
Ki = 21.5 nM and Ki(ant) = 14.2 nM, which was twofold more potent
in binding affinity and twofold less potent in antagonism compared
to lead 3. For further optimization from 49, 4,40-disubstituted
diphenylpropyl (53, 55 and 58) and diphenylpropenyl (54, 56 and
57) analogues were explored, indicating that the substitutions did
not affect the activity. They exhibited similar activities compared
to the corresponding unsubstituted analogues, 49 and 50. In partic-
ular, the (4,40-dimethyl)diphenylpropenyl analogue (54) had potent
antagonism with Ki(ant) = 8.0 nM. The two diphenylcycloheptane
analogues (59, 60), as further conformationally constrained ana-
logues of 50, were prepared. However, they showed a 5–10-fold
reduction in binding affinity and antagonism compared to 50.
4.2.2. N-(4-tert-Butylbenzyl)-2-[3-fluoro-4-(methylsulfonyl-
amino)phenyl]-2-methylpropionamide (9)
Yield 74%, white solid, mp = 48–51 °C, 1H NMR (CDCl3) d 7.53 (t,
1H, J = 8.2 Hz, H-5), 7.33 (d, 2H, Ar), 7.14–7.2 (m, 2H, H-2 and H-6),
7.09 (d, 2H, Ar), 6.45 (br s, 1H, NHSO2), 5.50 (br t, 1H, NH), 4.37 (d,
1H, J = 5.5 Hz, ArCH2NH), 3.03 (s, 3H, SO2CH3), 1.58 (s, 3H, CH3),
1.55 (s, 3H, CH3), 1.30 (s, 9H, C(CH3)3); IR (KBr) 2964, 1648,
1512, 1333, 1272, 1158, 1121 cmꢀ1; MS (FAB) m/z 421 (MH+); Anal.
Calcd for C22H29FN2O3S: C, 62.83; H, 6.95; N, 6.66. Found: C, 62.60;
H, 6.93; N, 6.64.
4.2.3. N-(4-tert-Butylbenzyl)-2-[3-methoxy-4-(methylsulfonyl-
amino)phenyl]-2-methylpropionamide (10)
Yield 93%, white solid, mp = 54–56 °C, 1H NMR (CDCl3) d 7.46 (d,
1H, J = 8.2 Hz, H-5), 7.30 (d, 2H, Ar), 7.09 (d, 2H, Ar), 6.98 (dd, 1H,
J = 1.8, 8.2 Hz, H-6), 6.83 (d, 1H, J = 1.8 Hz, H-2), 6.77 (br s, 1H,
NHSO2), 5.55 (br t, 1H, NH), 4.36 (d, 1H, J = 5.7 Hz, ArCH2NH),
3.80 (s, 3H, OCH3), 2.94 (s, 3H, SO2CH3), 1.59 (s, 6H, 2 ꢁ CH3),
1.29 (s, 9H, C(CH3)3); IR (KBr) 3348, 2964, 1652, 1513, 1461,
1395, 1335, 1267, 1157, 1127, 1032 cmꢀ1; MS (FAB) m/z 433
(MH+); Anal. Calcd for C23H32N2O4S: C, 63.86; H, 7.46; N, 6.48.
Found: C, 63.60; H, 7.43; N, 6.45.
3. Conclusion
In order to further optimize the TRPV1 antagonism from the pre-
vious lead, N-4-t-butylbenzyl 2-(3-fluoro-4-methylsulfonylamin-
ophenyl) propanamide (3), the structure activity relationships for
the B and C-region have been investigated in detail. In the B-region,
the propanamide was modified by dimethyl, cyclopropyl and re-
verse amides and in the C-region the 4-t-butylbenzyl was replaced
with 4-substituted phenyl, aryl alkyl and diaryl alkyl derivatives.
Among the compounds in the series, the diphenylpropenyl analogue
(50) showed high binding affinity with Ki = 21.5 nM, which was
twofold more potent than the lead 3, and the (4,40-dimethyl)diphe-
nylpropenyl (54) analogue exhibited potent antagonism with
Ki(ant) = 8.0 nM comparable to 3 for rTRPV1 in the CHO cells.
4.2.4. N-(4-tert-Butylbenzyl)-1-[4-(methylsulfonylamino)
phenyl]cyclopropanecarboxamide (14)
Yield 90%, white solid, mp = 200–203 °C, 1H NMR (DMSO-d6) d
9.75 (br s, 1H, NH), 4.15 (d, 2H, J = 6 Hz, ArCH2NH), 2.98 (s, 3H,
SO2CH3), 1.32 (dd, 2H, CH2CCH2), 1.25 (s, 9H, C(CH3)3), 0.94
(dd, 2H, CH2CCH2); IR (KBr) 2961, 1644, 1515, 1331, 1224,
1154 cmꢀ1; MS (FAB) m/z 401(MH+); Anal. Calcd for C22H28N2O3S:
C, 65.97; H, 7.05; N, 6.99. Found: C, 66.21; H, 7.08; N, 6.96.
4. Experimental
4.1. General
4.2.5. N-(4-tert-Butylbenzyl)-1-[3-fluoro-4-(methylsulfonyl-
amino)phenyl]cyclopropanecarboxamide (15)
Yield 75%, white solid, mp = 56–58 °C, 1H NMR (CDCl3) d 7.50
(br s, 1H, NHSO2), 7.32 (br d, 2H, Ar), 7.05–7.2 (m, 5H, Ar), 5.84
(br t, 1H, NH), 4.36 (d, 2H, J = 5.7 Hz, ArCH2NH), 3.33 (s, 3H,
SO2CH3), 1.67 (dd, 2H, CH2CCH2), 1.29 (s, 9H, C(CH3)3), 1.15 (dd,
2H, CH2CCH2); IR (KBr) 2961, 1640, 1520, 1469, 1324, 1263,
All chemical reagents were commercially available. Melting
points were determined on a melting point Buchi B-540 apparatus
and are uncorrected. Silica gel column chromatography was per-
formed on Silica Gel 60, 230–400 mesh, Merck. Proton NMR spec-
tra were recorded on a JEOL JNM-LA 300 at 300 MHz and Bruker
Analytik, DE/AVANCE Digital 400 at 400 MHz. Chemical shifts are
reported in ppm units with Me4Si as a reference standard. Mass
spectra were recorded on a VG Trio-2 GC–MS. Combustion analy-
ses were performed on an EA 1110 Automatic Elemental Analyzer,
CE Instruments.
;
1149 cmꢀ1 MS (FAB) m/z 441 ([M+Na]+); Anal. Calcd for
C22H27FN2O3S: C, 63.13; H, 6.50; N, 6.69. Found: C, 62.82; H,
6.47; N, 6.66.
4.2.6. N-(4-tert-Butylbenzyl)-1-[3-methoxy-4-(methylsulfonyl-
amino)phenyl]cyclopropanecarboxamide (16)
Yield 82%, white solid, mp = 78–80 °C, 1H NMR (CDCl3) d 7.48 (d,
1H, J = 8.1 Hz, H-5), 7.31 (br d, 2H, Ar), 7.09 (br d, 2H, Ar), 7.03 (dd,
1H, J = 1.8, 8.1 Hz, H-6), 6.94 (d, 1H, J = 1.8 Hz, H-2), 6.80 (br s, 1H,
NHSO2), 5.67 (br t, 1H, NH), 4.36 (d, 2H, J = 5.85 Hz, ArCH2NH), 3.86
(s, 3H, OCH3), 2.97 (s, 3H, SO2CH3), 1.65 (dd, 2H, CH2CCH2), 1.29 (s,
9H, C(CH3)3), 1.06 (dd, 2H, CH2CCH2); IR (KBr) 2961, 1652, 1513,
1338, 1246, 1157, 1125, 1032 cmꢀ1; MS (FAB) m/z 431(MH+), 453
([M+Na]+); Anal. Calcd for C23H30N2O4S: C, 64.16; H, 7.02; N,
6.51. Found: C, 63.91; H, 7.00; N, 6.48.
4.2. Generel procedure for coupling
A mixture of acid (10 mmol), amine (12 mmol) and 1-(3-
dimethylaminopropyl)-3-ethyl-carbodiimide
(12 mmol) in CH2Cl2 (20 mL) was stirred for 12 h at room temper-
ature. The reaction mixture was filtered off and the filtrate was
concentrated. The residue was purified by flash column chroma-
tography on silica gel using EtOAc–hexanes as eluant.
hydrochloride
4.2.7. N-{1-[3-Fluoro-4-(methylsulfonylamino)phenyl]ethyl}-3-
(4-tert-butylphenyl)acetamide (18)
4.2.1. N-(4-tert-Butylbenzyl)-2-[4-(methylsulfonylamino) phenyl]-
2-methylpropionamide (8)
Yield 36%, white solid, mp = 134–136 °C, 1H NMR (CDCl3) d 7.48
(t, 1H, J = 8.8 Hz, H-5), 7.39 (br d, 2H, J = 8.3 Hz, Ar), 7.18 (br d, 2H,
J = 8.3 Hz, Ar), 6.92–7.02 (m, 2H, Ar), 6.44 (br s, 1H, NHSO2), 5.58 (d,
1H, J = 7.8 Hz, NH), 5.06 (m, 1H, CHCH3), 3.56 (s, 2H, ArCH2CO), 3.00
(s, 3H, SO2CH3), 1.37 (d, 3H, J = 7 Hz, CHCH3), 1.33 (s, 9H, C(CH3)3);
IR (KBr) 3279, 2963, 1648, 1513, 1331, 1156 cmꢀ1; MS (FAB) m/z
407 (MH+); Anal. Calcd for C21H27FN2O3S: C, 62.05; H, 6.69; N,
6.89. Found: C, 61.85; H, 6.67; N, 6.86.
Yield 92%, white solid, mp = 141–143 °C, 1H NMR (CDCl3) d 7.36
(d, 2H, J = 8.5 Hz, Ar), 7.31 (d, 2H, J = 7.9 Hz, Ar), 7.18 (d, 2H,
J = 8.5 Hz, Ar), 7.07 (d, 1H, J = 7.9 Hz, Ar), 6.40 (br s, 1H, NHSO2),
5.46 (br t, 1H, NH), 4.36 (d, 1H, J = 5.7 Hz, ArCH2NH), 3.00 (s, 3H,
SO2CH3), 1.59 (s, 3H, CH3), 1.55 (s, 3H, CH3), 1.30 (s, 9H,
C(CH3)3); IR (KBr) 2964, 1644, 1513, 1333, 1154 cmꢀ1; MS (FAB)
m/z 403 (MH+); Anal. Calcd for C22H30N2O3S: C, 65.64; H, 7.51; N,
6.96. Found: C, 65.84; H, 7.49; N, 6.93.

W. Sun et al. / Bioorg. Med. Chem. 20 (2012) 1310–1318
1315
4.2.8. N-{1-[3-Fluoro-4-(methylsulfonylamino)phenyl]ethyl}-3-
(4-tert-butylphenyl) propanamide (19)
CH3CH); IR (KBr) 3738, 1647, 1512, 1459, 1325, 1153 cmꢀ1; MS
(FAB) m/z 419 (MH+); Anal. Calcd for C17H17Cl2FN2O3S: C, 48.70;
H, 4.09; N, 6.68. Found: C, 48.87; H, 4.11; N, 6.66.
Yield 29%, white solid, mp = 152–154 °C, 1H NMR (CDCl3) d 7.44
(t, 1H, J = 8 Hz, H-5), 7.31 (br d, 2H, J = 8.3 Hz, Ar), 7.11 (br d, 2H,
J = 8.3 Hz, Ar), 6.95–7.02 (m, 2H, Ar), 6.82 (br s, 1H, NHSO2), 5.72
(d, 1H, J = 7.1 Hz, NH), 5.02 (m, 1H, CHCH3), 3.00 (s, 3H, SO2CH3),
2.93 (t, 2H, J = 7.1 Hz, CH2Ar), 2.50 (m, 2H, CH2CO), 1.34 (d, 3H,
J = 7 Hz, CHCH3), 1.30 (s, 9H, C(CH3)3); IR (KBr) 3274, 2963, 1647,
1513, 1452, 1332, 1157 cmꢀ1; MS (FAB) m/z 421 (MH+); Anal. Calcd
for C22H29FN2O3S: C, 62.83; H, 6.95; N, 6.66. Found: C, 62.62; H,
6.93; N, 6.64.
4.2.14. N-(4-Trifluoromethylbenzyl)-2-[3-fluoro-4-(methyl-
sulfonylamino)phenyl]propionamide (26)
Yield 81%, white solid, mp = 150–152 °C, 1H NMR (CDCl3) d 7.5–
7.6 (m, 3H, Ar), 7.26 (d, 2H, Ar), 7.05–7.2 (m, 2H, Ar), 5.86 (br t, 1H,
NHCO), 4.46 (ddd of AB, 2H, ArCH2NH), 3.56 (q, 1H, J = 7.1 Hz,
CH3CH), 3.02 (s, 3H, SO2CH3), 1.52 (d, 3H, J = 7.1 Hz, CH3CH); IR
(KBr) 3291, 1653, 1512, 1421, 1327, 1159, 1119, 1067, 1019 cmꢀ1
;
MS (FAB) m/z 419 (MH+); Anal. Calcd for C18H18F4N2O3S: C,
51.67; H, 4.34; N, 6.70. Found: C, 51.87; H, 4.32; N, 6.68.
4.2.9. N-{1-[3-Fluoro-4-(methylsulfonylamino)phenyl]ethyl}-3-
(4-tert-butylphenyl)-2-propenamide (20)
Yield 67%, white solid, mp = 154–156 °C, 1H NMR (CDCl3) d 7.62
(d, 1H, J = 15.5 Hz, CH@), 7.52 (t, 1H, J = 8 Hz, H-5), 7.41 (dd, 4H,
Ar), 7.12–7.18 (m, 2H, Ar), 6.54 (br s, 1H, NHSO2), 6.37 (d, 1H,
J = 15.5 Hz, @CH), 5.88 (d, 1H, J = 7.1 Hz, NH), 5.21 (m, 1H, CHCH3),
3.02 (s, 3H, SO2CH3), 1.53 (d, 3H, J = 7 Hz, CHCH3), 1.32 (s, 9H,
C(CH3)3); IR (KBr) 3274, 2964, 1657, 1616, 1514, 1331, 1221,
4.2.15. N-(4-Methoxybenzyl)-2-[3-fluoro-4-(methylsulfonyl-
amino)phenyl]propionamide (27)
Yield 96%, white solid, mp = 138 °C, 1H NMR (CDCl3) d 7.48 (t,
1H, J = 8.3 Hz, H-5), 7.05–7.2 (m, 4H, Ar), 6.82 (d, 2H, Ar), 6.69
(br s, 1H, NHSO2), 5.80 (br t, 1H, NHCO), 4.33 (ddd of AB, 2H,
ArCH2NH), 3.78 (s, 3H, OCH3), 3.52 (q, 1H, J = 7.1 Hz, CH3CH),
3.01 (s, 3H, SO2CH3), 1.51 (d, 3H, J = 7.1 Hz, CH3CH); IR (KBr)
3315, 3206, 1642, 1510, 1455, 1322, 1246, 1155, 1033 cmꢀ1; MS
(FAB) m/z 381 (MH+); Anal. Calcd for C18H21FN2O4S: C, 56.83; H,
5.56; N, 7.36. Found: C, 56.61; H, 5.54; N, 7.33.
1156 cmꢀ1
22H27FN2O3S: C, 63.13; H, 6.50; N, 6.69. Found: C, 63.23; H,
6.52; N, 6.67.
;
MS (FAB) m/z 419 (MH+); Anal. Calcd for
C
4.2.10. N-(4-Chlorobenzyl)-2-[3-fluoro-4-(methylsulfonyl-
amino)phenyl]propionamide (22)
4.2.16. N-(4-Methylbenzyl)-2-[3-fluoro-4-(methylsulfonyl-
amino)phenyl]propionamide (28)
Yield 98%, white solid, mp = 129–130 °C, 1H NMR (CDCl3) d 7.53
(t, 1H, J = 8.3 Hz, H-5), 7.25–7.3 (m, 2H), 7.06–7.2 (m, 4H, Ar), 6.44
(br s, 1H, NHSO2), 5.67 (br t, 1H, NHCO), 4.37 (ddd of AB, 2H,
ArCH2NH), 3.53 (q, 1H, J = 7.1 Hz, CH3CH), 3.03 (s, 3H, SO2CH3),
1.52 (d, 3H, J = 7.1 Hz, CH3CH); IR (KBr) 3295, 1652, 1539, 1496,
1330, 1235, 1156, 1092 cmꢀ1; MS (FAB) m/z 385 [MꢀH]+; Anal.
Calcd for C17H18ClFN2O3S: C, 53.05; H, 4.71; N, 7.28. Found: C,
52.87; H, 4.70; N, 7.25.
Yield 96%, white solid, mp = 166 °C, 1H NMR (CDCl3) d 7.51 (t,
1H, J = 8.3 Hz, H-5), 7.05–7.2 (m, 6H, Ar), 6.50 (br s, 1H, NHSO2),
5.66 (br t, 1H, NHCO), 4.36 (ddd of AB, 2H, ArCH2NH), 3.51 (q,
1H, J = 7.1 Hz, CH3CH), 3.02 (s, 3H, SO2CH3), 2.32 (s, 3H, CH3),
1.52 (d, 3H, J = 7.1 Hz, CH3CH); IR (KBr) 3307, 3212, 1637, 1537,
1445, 1326, 1154 cmꢀ1; MS (FAB) m/z 365 (MH+); Anal. Calcd for
C18H21FN2O3S: C, 59.32; H, 5.81; N, 7.69. Found: C, 59.07; H,
5.79; N, 7.67.
4.2.11. N-(4-Bromo-benzyl)-2-(3-fluoro-4-methanesulfonyl-
amino-phenyl)-propionamide (23)
4.2.17. N-(4-Isopropylbenzyl)-2-[3-fluoro-4-(methylsulfonyl-
amino)phenyl]propionamide (29)
Yield 60%, white solid, mp = 172–174 °C, 1H NMR (CD3OD) d
7.38–7.44 (m, 3H, Ar-H), 7.07–7.21 (m, 4H, Ar-H), 4.23 (s, 2H,
ArCH2NH), 3.64 (q, 1H, J = 7.2 Hz, CH3CH), 2.96 (s, 3H, SO2CH3),
1.44 (d, 3H, J = 7.2 Hz, CHCH3); IR (KBr) 3741, 3274, 1650, 1512,
1330, 1155, 973, 757, 616 cmꢀ1; MS (FAB) m/z 431 [M-H]+; Anal.
Calcd for C17H18BrFN2O3S: C, 47.56; H, 4.23; N, 6.53. Found: C,
47.43; H, 4.22; N, 6.51.
Yield 69%, white solid, mp = 137–139 °C, 1H NMR (CDCl3) d 7.49
(t, 1H, J = 8.3 Hz, H-5), 7.05–7.2 (m, 6H, Ar), 6.70 (br s, 1H, NHSO2),
5.80 (br t, 1H, NHCO), 4.36 (ddd of AB, 2H, ArCH2NH), 3.52 (q, 1H,
J = 7.1 Hz, CH3CH), 3.00 (s, 3H, SO2CH3), 2.88 (m, 2H, CH(CH3)2),
1.51 (d, 3H, J = 7.1 Hz, CH3CH), 1.22 (d, 6H, CH(CH3)2); IR (KBr)
3364, 2957, 1664, 1509, 1456, 1333, 1219, 1155 cmꢀ1; MS (FAB)
m/z 393 (MH+); Anal. Calcd for C20H25FN2O3S: C, 61.20; H, 6.42;
N, 7.14. Found: C, 61.43; H, 6.40; N, 7.16.
4.2.12. 2-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-(4-
iodo-benzyl)-propionamide (24)
Yield 60%, white solid, mp = 79–81 °C, 1H NMR (CDCl3) d 7.62 (d,
2H, J = 8.4 Hz, Ar-H), 7.51 (dd,1H, J = 8.1, 1.8 Hz, Ar-H), 7.16 (dd, 1H,
J = 8.1, 1.8 Hz, Ar-H), 7.08 (d, 1H, J = 8.1 Hz, Ar-H), 6.94 (d, 2H,
J = 8.4 Hz, Ar-H), 6.52 (br s, 1H, NHSO2), 5.73 (br t, 1H, NHCO),
4.33 (d, 2H, J = 5.7 Hz, ArCH2NH), 3.52 (q, 1H, J = 7.2 Hz, CH3CH),
3.02 (s, 3H, SOCH3), 1.51 (d, 3H, J = 7.2 Hz, CHCH3); IR (KBr)
3739, 3293, 2922, 1642, 1511, 1332, 1153, 789 cmꢀ1; MS (FAB)
m/z 477 [MꢀH]+; Anal. Calcd for C17H18FIN2O3S: C, 42.87; H,
3.81; N, 5.88. Found: C, 42.66; H, 3.83; N, 5.86.
4.2.18. N-(4-Cyclopropyl-benzyl)-2-(3-fluoro-4-methane-
sulfonylamino-phenyl)-propionamide (30)
Yield 71%, white solid, mp = 115–117 °C, 1H NMR (DMSO-d6) d
9.54 (s, 1H, NHCO), 8.46 (t, 1H, J = 5.7 Hz, Ar-H), 7.12–7.34 (m,
4H, Ar-H), 6.95–7.04 (m, 3H, Ar-H), 4. 17 (d, 2H, J = 5.7 Hz,
ArCH2NH), 3.67 (q, 1H, J = 7.2 Hz, CH3CH), 3.00 (s, 3H, SO2CH3),
1.86 (m, 1H, cyclo-H), 1.33 (d, 3H, J = 7.2 Hz, CHCH3), 0.89 (m,
2H, cyclo-H), 0.60 (m, 2H, cyclo-H); IR (KBr) 3289, 1650, 1600,
1512, 1331, 1156, 973 cmꢀ1; MS (FAB) m/z 391 (MH+); Anal. Calcd
for C20H23FN2O3S: C, 61.52; H, 5.94; N, 7.17. Found: C, 61.78; H,
5.92; N, 7.15.
4.2.13. N-(3,4-Dichlorobenzyl)-2-[3-fluoro-4-(methylsulfonyl-
amino)phenyl]propionamide (25)
Yield 76%, white solid, mp = 130–133 °C, 1H NMR (CDCl3) d 7.53
(t, 1H, J = 8.3 Hz, H-5), 7.36 (d, 1H, Ar), 7.23 (d, 1H, Ar), 7.16 (dd, 1H,
Ar), 7.10 (br d, 1H, Ar), 7.02 (dd, 1H, Ar), 6.51 (br s, 1H, NHSO2),
5.76 (br t, 1H, NHCO), 4.36 (d of AB, 2H, ArCH2NH), 3.54 (q, 1H,
J = 7.1 Hz, CH3CH), 3.03 (s, 3H, SO2CH3), 1.52 (d, 3H, J = 7.1 Hz,
4.2.19. N-(4-Cyclopent-2-enyl-benzyl)-2-(3-fluoro-4-methane-
sulfonylamino-phenyl)-propionamide (31)
Yield 68%, white solid, mp = 125–127 °C, 1H NMR (CDCl3) d 7.51
(t, 1H, J = 8.25 Hz, Ar), 7.12 (m, 6H, Ar), 6.45 (br s, 1H, NH), 5.93 (m,
1H, CH2CH2), 5.73 (m, 1H, CH2CH2), 5.64 (br s, 1H, NH), 4.39 (ddd,

1316
W. Sun et al. / Bioorg. Med. Chem. 20 (2012) 1310–1318
2H, ArCH2NH), 3.86 (m, 1H, cyclopentene), 3.50 (q, 1H, J = 7.14 Hz,
CHCH3), 3.02 (s, 1H, SO2CH3), 2.43 (m, 2H, cyclopentene), 1.68 (m,
2H, cyclopentene), 1.52 (d, 3H, J = 7.14 Hz, CHCH3); IR (KBr) 3740,
3294, 1649, 1512, 1455, 1333, 1157, 973, 757, 616 cmꢀ1; MS
(FAB) m/z 417 (MH+); Anal. Calcd for C22H25FN2O3S: C, 63.44; H,
6.05; N, 6.73. Found: C, 63.24; H, 6.03; N, 6.71.
4.2.25. N-(1-Naphthylmethyl)-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (37)
Yield 79%, white solid, mp = 159–161 °C, 1H NMR (CDCl3) d
7.75–7.9 (m, 3H, Ar-H), 7.3–7.5 (m, 5H, Ar-H), 7.16 (dd, 1H, Ar-
H), 7.04 (br d, 1H, Ar-H), 6.52 (br s, 1H, NHSO2), 5.69 (br t, 1H,
NHCO), 4.86 (ddd, 2H, ArCH2NH), 3.49 (q, 1H, J = 7.1 Hz, CH3CH),
2.96 (s, 3H, SO2CH3), 1.51 (d, 3H, J = 7.1 Hz, CH3CH); IR (KBr)
3292, 1648, 1511, 1453, 1329, 1156 cmꢀ1; MS (FAB) m/z 401
(MH+); Anal. Calcd for C21H21FN2O3S: C, 62.98; H, 5.29; N, 7.00.
Found: C, 62.79; H, 5.27; N, 6.98.
4.2.20. N-(4-Cyclopentyl-benzyl)-2-(3-fluoro-4-methane-
sulfonylamino-phenyl)-propionamide (32)
Yield 74%, white solid, mp = 121–123 °C, 1H NMR (CDCl3) d 7.51
(t, 1H, J = 8.32 Hz, Ar), 7.14 (m, 6H, Ar), 6.50 (br s, 1H, NH), 5.66 (br
t, 1H, NH), 4.38 (ddd, 2H, ArCH2), 3.50 (q, 1H, J = 7.14 Hz, CHCH3),
3.02 (s, 1H, SO2CH3), 2.96 (m, 1H, cyclopentyl), 2.04 (m, 2H, cyclo-
pentyl), 1.79 (m, 4H, cyclopentyl), 1.68 (m, 4H, cyclopentyl), 1.57
(d, 3H, J = 7.14 Hz, CHCH3); IR (KBr) 3438, 3227, 2951, 1640,
1547, 1509, 1332, 1157, 1116, 983, 774 cmꢀ1; MS (FAB) m/z 419
(MH+); Anal. Calcd for C22H27FN2O3S: C, 63.13; H, 6.50; N, 6.69.
Found: C, 63.39; H, 6.52; N, 6.67.
4.2.26. N-(1,2,3,4-Tetrahydro-1-naphthalenyl)-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (38)
Yield 73%, white solid, mp = 116–117 °C, 1H NMR (CDCl3) d 7.51
(m, 1H, Ar-H), 6.8–7.2 (m, 6H, Ar-H), 6.53 (br s, 1H, NHSO2), 5.62
(br d, 1H, NHCO), 5.15 (m, 1H, CHNH), 3.51 (q, 1H, J = 7.14 Hz,
CH3CH), 3.00 (s, 3H, SO2CH3), 2.75 (m, 2H, cyclo-H), 1.7–1.9 (m,
4H, cyclo-H), 1.53 (d, 3H, J = 7.14 Hz, CH3CH); IR (KBr) 3430,
3235, 1657, 1511, 1452, 1325, 1153 cmꢀ1; MS (FAB) m/z 391
(MH+); Anal. Calcd for C20H23FN2O3S: C, 61.52; H, 5.94; N, 7.17.
Found: C, 61.32; H, 5.91; N, 7.15.
4.2.21. N-(4-Cyclohexyl-benzyl)-2-(3-fluoro-4-methane-
sulfonylamino-phenyl)-propionamide (33)
Yield 61%, white solid, mp = 72–74 °C, 1H NMR (CDCl3) d 7.51
(dd, 1H, J = 8.1, 1.8 Hz, Ar-H), 7.08–7.20 (m, 6H, Ar-H), 5.63 (br t,
1H, NHCO), 4.38 (qd, 2H, J = 14.4, 5.4 Hz, ArCH2NH), 3.50 (q, 1H,
J = 7.2 Hz, CH3CH), 3.02 (s, 3H, SO2CH3), 2.47 (m, 1H, cyclo-H),
1.72–1.84 (m, 4H, cyclo-H), 1.52 (d, 3H, J = 7.2 Hz, CHCH3), 1.26–
1.41 (m, 6H, cyclo-H); IR (KBr) 3290, 2925, 2851, 1650, 1511,
1449, 1332, 1157, 973 cmꢀ1; MS (FAB) m/z 433 (MH+); Anal. Calcd
for C23H29FN2O3S: C, 63.86; H, 6.76; N, 6.48. Found: C, 63.63; H,
6.78; N, 6.47.
4.2.27. N-[2-(4-t-Butylphenyl)ethyl]-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (39)
Yield 64%, white solid, mp = 124–126 °C, 1H NMR (CDCl3) d
7.50 (t, 1H, J = 8.3 Hz, H-5), 7.29 (br d, 2H, Ar-H), 6.95–7.15 (m,
4H, Ar-H), 6.52 (br s, 1H, NHSO2), 5.41 (br t, 1H, NHCO), 3.47
(m, 3H, CH2NH and CH3CH), 3.03 (s, 3H, SO2CH3), 2.72 (t, 2H,
J = 6.8 Hz, CH2Ar), 1.47 (d, 3H, J = 7.3 Hz, CH3CH), 1.31 (s, 9H,
C(CH3)3); IR (KBr) 3286, 2961, 1734, 1650, 1512, 1455, 1334,
1265, 1157 cmꢀ1; MS (FAB) m/z 421 (MH+); Anal. Calcd for
C
22H29FN2O3S: C, 62.83; H, 6.95; N, 6.66. Found: C, 62.99; H,
4.2.22. N-(4-Biphenylmethyl)-2-[3-fluoro-4-(methylsulfonyl-
amino)phenyl]propionamide (34)
6.98; N, 6.64.
Yield 78%, white solid, mp = 155–157 °C, 1H NMR (CDCl3) d 7.1–
7.58 (m, 12H, Ar), 6.45 (br s, 1H, NHSO2), 5.71 (br t, 1H, NHCO),
4.45 (ddd, 2H, ArCH2NH), 3.55 (q, 1H, J = 7.1 Hz, CH3CH), 3.01 (s,
3H, SO2CH3), 1.54 (d, 3H, J = 7.1 Hz, CH3CH); IR (KBr) 3430, 1647,
1530, 1405, 1324, 1152 cmꢀ1; MS (FAB) m/z 427 (MH+); Anal. Calcd
for C23H23FN2O3S: C, 64.77; H, 5.44; N, 6.57. Found: C, 64.51; H,
5.43; N, 6.53.
4.2.28. N-[3-(3,4-Dimethylphenyl)propyl]-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (40)
Yield 95%, white solid, mp = 128–130 °C, 1H NMR (CDCl3) d 7.50
(t, 1H, J = 8.3 Hz, H-5), 7.13 (dd, 1H, J = 1.95, 11.2 Hz, H-2), 7.0–7.07
(m, 2H, Ar-H), 6.83–6.92 (m, 2H, Ar-H), 6.57 (br s, 1H, NHSO2), 3.41
(q, 1H, J = 7.1 Hz, CHMe), 3.2–3.3 (m, 2H, CH2NH), 3.01 (s, 3H,
SO2CH3), 2.51 (t, 2H, J = 7.6 Hz, CH2Ar), 2.22 (s, 6H, 2 ꢁ CH3), 1.7–
1.8 (m, 2H, CH2), 1.45 (d, 3H, J = 7.1 Hz, CHCH3); IR (KBr) 3294,
2931, 1648, 1509, 1449, 1331, 1157 cmꢀ1; MS (FAB) m/z 407
(MH+)+); Anal. Calcd for C21H27FN2O3S: C, 62.05; H, 6.69; N, 6.89.
Found: C, 62.25; H, 6.67; N, 6.86.
4.2.23. N-(2-Bromo-4-tert-butyl-benzyl)-2-(3-fluoro-4-
methanesulfonylamino-phenyl)-propionamide (35)
Yield 71%, white solid, mp = 138–140 °C, 1H NMR (CDCl3) d
7.51–7.46 (m, 2H, Ar-H), 7.28–7.06 (m, 4H, Ar-H), 6.71 (br s, 1H,
NHSO2), 6.00 (br s, 1H, NHCO), 4.42 (m, 2H, ArCH2NH), 3.54 (q,
1H, J = 7.14 Hz, CH3CH), 3.02 (s, 3H, SO2CH3), 1.49 (d, 3H,
J = 7.14 Hz, CH3CH), 1.28 (s, 9H, C(CH3)3); IR (KBr) 3315, 2931,
1649, 1510, 1421, 1327, 1159, 1110, 927 cmꢀ1; MS (FAB) m/z 486
(MH+); Anal. Calcd for C21H26BrFN2O3S: C, 51.96; H, 5.40; N, 5.77.
Found: C, 51.76; H, 5.43; N, 5.74.
4.2.29. N-[3-(3,4-Dimethylphenyl)propyl]-(2R)-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (41)
Yield 96%, white solid, mp = 128–130 °C, 1H NMR (CDCl3) d
7.50 (t, 1H, J = 8.3 Hz, H-5), 7.13 (dd, 1H, J = 1.95, 11.2 Hz, H-2),
7.0–7.07 (m, 2H, Ar-H), 6.83–6.92 (m, 2H, Ar-H), 6.57 (br s, 1H,
NHSO2), 3.41 (q, 1H, J = 7.1 Hz, CHMe), 3.2–3.3 (m, 2H, CH2NH),
3.01 (s, 3H, SO2CH3), 2.51 (t, 2H, J = 7.6 Hz, CH2Ar), 2.22 (s, 6H,
2 ꢁ CH3), 1.7–1.8 (m, 2H, CH2), 1.45 (d, 3H, J = 7.1 Hz, CHCH3);
IR (KBr) 3294, 2931, 1648, 1509, 1449, 1331, 1157 cmꢀ1; MS
4.2.24. N-(4-tert-Butyl-2-cyano-benzyl)-2-(3-fluoro-4-
methanesulfonylamino-phenyl)-propionamide (36)
Yield 68%, white solid, mp = 129–131 °C, 1H NMR (CDCl3) d 7.51
(m, 2H, Ar-H), 7.24 (m, 2H, Ar-H), 7.13 (dd, 1H, J = 11.37, 2.01 Hz,
Ar-H), 7.07 (d, 1H, J = 7.43 Hz, Ar-H), 6.50 (br s, 1H, NHSO2), 5.88
(br s, 1H, NHCO), 4.42 (m, 2H, ArCH2NH), 3.52 (q, 1H, J = 7.14 Hz,
CH3CH), 3.02 (s, 3H, SO2CH3), 1.50 (d, 3H, J = 7.14 Hz, CH3CH),
1.29 (s, 9H, C(CH3)3); IR (KBr) 3421, 2951, 2928, 2250, 1650,
1512, 1449, 1333, 1200, 1120, 981 cmꢀ1; MS (FAB) m/z 432
(MH+); Anal. Calcd for C22H26FN3O3S: C, 61.23; H, 6.07; N, 9.74.
Found: C, 61.00; H, 6.05; N, 9.72.
(FAB) m/z 407 (MH+); [
21H27FN2O3S: C, 62.05; H, 6.69; N, 6.89. Found: C, 62.31; H,
6.72; N, 6.90.
a] ꢀ4.23 (c 0.25, CHCl3); Anal. Calcd for
C
4.2.30. N-[3-(3,4-Dimethylphenyl)propyl]-(2S)-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (42)
Yield 95%, white solid, mp = 128–130 °C, 1H NMR (CDCl3) d
7.50 (t, 1H, J = 8.3 Hz, H-5), 7.13 (dd, 1H, J = 1.95, 11.2 Hz, H-2),
7.0–7.07 (m, 2H, Ar-H), 6.83–6.92 (m, 2H, Ar-H), 6.57 (br s, 1H,

W. Sun et al. / Bioorg. Med. Chem. 20 (2012) 1310–1318
1317
NHSO2), 3.41 (q, 1H, J = 7.1 Hz, CHMe), 3.2–3.3 (m, 2H, CH2NH),
4.2.36. N-(2,2-Diphenylethyl)-2-[3-fluoro-4-(methyl-
3.01 (s, 3H, SO2CH3), 2.51 (t, 2H, J = 7.6 Hz, CH2Ar), 2.22 (s, 6H,
2 ꢁ CH3), 1.7–1.8 (m, 2H, CH2), 1.45 (d, 3H, J = 7.1 Hz, CHCH3);
IR (KBr) 3294, 2931, 1648, 1509, 1449, 1331, 1157 cmꢀ1; MS
sulfonylamino)phenyl]propionamide (48)
Yield 64%, white solid, mp = 129 °C, 1H NMR (CDCl3) d 7.42 (t,
1H, J = 8.3 Hz, H-5), 7.1–7.3 (m, 10H, Ar), 6.95 (dd, 1H, H-6), 6.87
(d, 1H, H-2), 6.50 (br s, 1H, NHSO2), 5.28 (br t, 1H, NHCO), 4.12
(t, 1H, Ph2CH), 3.75–3.95 (m, 2H, CH2NH), 3.37 (q, 1H, J = 7.1 Hz,
CHCH3), 3.01 (s, 3H, SO2CH3), 1.40 (d, 3H, J = 7.1 Hz, CHCH3); IR
(KBr) 3374, 3027, 1656, 1508, 1451, 1330, 1158, 1116 cmꢀ1; MS
(FAB) m/z 441 (MH+); Anal. Calcd for C24H25FN2O3S: C, 65.43; H,
5.72; N, 6.36. Found: C, 65.19; H, 5.74; N, 6.38.
(FAB) m/z 407 (MH+); [
a
] +4.34 (c 0.25, CHCl3); Anal. Calcd for
21H27FN2O3S: C, 62.05; H, 6.69; N, 6.89. Found: C, 61.93; H,
6.71; N, 6.86.
C
4.2.31. N-[3-(3,4-Dimethylphenyl)-2-propenyl]-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (43)
Yield 78%, white solid, mp = 144–146 °C, 1H NMR (CDCl3) d 7.52
(t, 1H, J = 8.3 Hz, H-5), 7.0–7.2 (m, 5H, Ar-H), 6.58 (br s, 1H, NHSO2),
6.37 (d, 1H, J = 15.8 Hz, ArCH@CH), 6.06 (dt, 1H, J = 6.2, 15.8 Hz,
ArCH@CH), 5.57 (br t, 1H, NHCO), 3.9–4.02 (m, 2H, CH2NH), 3.53
(q, 1H, J = 7.14 Hz, CHMe), 3.01 (s, 3H, SO2CH3), 2.24 (s, 6H,
2 ꢁ CH3), 1.52 (d, 3H, J = 7.14 Hz, CH3); IR (KBr) 3280, 1642,
1509, 1331, 1157 cmꢀ1; MS (FAB) m/z 405 (MH+); Anal. Calcd for
4.2.37. N-(3,3-Diphenylpropyl)-2-[3-fluoro-4-(methyl-
sulfonylamino)phenyl]propionamide (49)
Yield 76%, white solid, mp = 66–68 °C, 1H NMR (CDCl3) d 7.51 (t,
1H, J = 8.3 Hz, H-5), 7.0–7.3 (m, 12H, Ar-H), 6.45 (br s, 1H, NHSO2),
5.27 (br t, 1H, NHCO), 3.85 (t, 1H, J = 7.8 Hz, Ph2CH), 3.34 (q, 1H,
J = 7.1 Hz, CH3CH), 3.21 (ddd, 2H, CH2NH), 3.01 (s, 3H, SO2CH3),
2.24 (dd, 2H, CHCH2), 1.43 (d, 3H, J = 7.1 Hz, CH3CH); IR (KBr)
3290, 1649, 1510, 1450, 1331, 1156 cmꢀ1; MS (FAB) m/z 455
(MH+); Anal. Calcd for C25H27FN2O3S: C, 66.06; H, 5.99; N, 6.16.
Found: C, 66.29; H, 5.97; N, 6.13.
C21H25FN2O3S: C, 62.35; H, 6.23; N, 6.93. Found: C, 62.57; H,
6.21; N, 6.90.
4.2.32. N-[3-(4-Chloro-phenyl)-propyl]-2-(3-fluoro-4-
methanesulfonylamino-phenyl)-propionamide (44)
Yield 70%, white solid, mp = 141–143 °C, 1H NMR (CDCl3) d 7.51
(t, 1H, J = 8.3 Hz, H-5), 7.02–7.25 (m, 6H, Ar-H), 6.52 (br s, 1H,
NHSO2), 5.38 (br t, 1H, NHCO), 3.44 (q, 1H, J = 7.14 Hz, CH3CH),
3.24 (ddd, 2H, CH2NH), 3.02 (s, 3H, SO2CH3), 2.55 (t, 2H,
J = 7.5 Hz, ArCH2), 1.76 (m, 2H, ArCH2CH2), 1.47 (d, 3H,
J = 7.14 Hz, CH3CH); IR (KBr) 3430, 2934, 1644, 1548, 1509, 1445,
1405, 1325, 1154, 1116 cmꢀ1; MS (FAB) m/z 413 (MH+); Anal. Calcd
for C19H22ClFN2O3S: C, 55.27; H, 5.37; N, 6.78. Found: C, 55.10; H,
5.39; N, 6.80.
4.2.38. N-(3,3-Diphenyl-2-propenyl)-2-[3-fluoro-4-(methyl-
sulfonylamino)phenyl]propionamide (50)
Yield 78%, white solid, mp = 155–157 °C, 1H NMR (CDCl3) d 7.52
(t, 1H, J = 8.3 Hz, H-5), 7.05–7.4 (m, 12H, Ar), 6.50 (br s, 1H, NHSO2),
6.00 (t, 1H, J = 7.0 Hz, >C@CH), 5.44 (br t, 1H, NHCO), 3.85–4.0 (m,
2H, CH2NH), 3.46 (q, 1H, J = 7.1 Hz, CHCH3), 3.01 (s, 3H, SO2CH3),
1.48 (d, 3H, J = 7.1 Hz, CHCH3); IR (KBr) 3736, 1647, 1512, 1333,
1157 cmꢀ1; MS (EI) m/z 452 (M+); Anal. Calcd for C25H25FN2O3S:
C, 55.73; H, 5.23; N, 7.65. Found: C, 55.61; H, 5.22; N, 7.64.
4.2.39. N-(2,2-Diphenyl-cyclopropylmethyl)-2-(3-fluoro-4-
methanesulfonylamino-phenyl)-propionamide (51)
Yield 83%, white solid, mp = 166–168 °C, 1H NMR (CDCl3) d 7.55
(m, 1H, Ar-H), 7.24–7.06 (m, 12H, Ar-H), 6.52 (s, 1H, SO2NH), 5.30
(s, 1H, NHCO), 3.49 (m, 4H, Ar2CH, CH2NH and COCH), 2.95 (s, 3H,
SO2CH3), 1.95 (m, 1H), 1.50 (d, 3H, J = 4.95 Hz), 1.34 (m, 1H, cyclo-
H), 1.16 (m, 1H, cyclo-H); IR (KBr) 3290, 2983, 1649, 1510, 1450,
1331, 1156, 1045, 974 cmꢀ1; MS (FAB) m/z 467 (MH+); Anal. Calcd
for C26H27FN2O3S: C, 66.93; H, 5.83; N, 6.00. Found: C, 66.68; H,
5.81; N, 6.03.
4.2.33. N-[3-(4-Chloro-phenyl)-allyl]-2-(3-fluoro-4-
methanesulfonylamino-phenyl)-propionamide (45)
Yield 72%, white solid, mp = 151–153 °C, 1H NMR (CDCl3) d 7.52
(t, 1H, J = 8.3 Hz, H-5), 7.08–7.3 (m, 6H, Ar), 6.60 (br s, 1H, NHSO2),
6.37 (d, 1H, J = 15.8 Hz, ArCH@CH), 6.10 (dt, 1H, J = 6.2, 15.8 Hz,
ArCH@CH), 5.61 (br t, 1H, NHCO), 3.9–4.1 (m, 2H, CH2NH), 3.54
(q, 1H, J = 7.1 Hz, CHMe), 3.02 (s, 3H, SO2CH3), 1.52 (d, 3H,
J = 7.1 Hz, CH3); IR (KBr) 3430, 3318, 3216, 1644, 1543, 1508,
1407, 1326, 1156, 1092 cmꢀ1; MS (EI) m/z 410 (M+); Anal. Calcd
for C19H20ClFN2O3S: C, 55.54; H, 4.91; N, 6.82. Found: C, 55.77;
H, 4.93; N, 6.80.
4.2.40. N-(2-Diphenylamino-ethyl)-2-(3-fluoro-4-methane-
sulfonylamino-phenyl)-propionamide (52)
Yield 87%, white solid, mp = 156–158 °C, 1H NMR (CDCl3) d 7.47
(t, 1H, J = 8.23 Hz, Ar), 7.25 (m, 4H, Ar), 7.07 (d, 1H, J = 11.16 Hz,
Ar), 6.95 (m, 7H, Ar), 6.49 (s, 1H, Ar), 5.58 (br t, 1H, NH), 3.86 (q,
2H, CH2NH), 3.46 (q, 2H, Ar2NCH2), 3.37 (q, 1H, CHCH3), 2.99 (s,
3H, SO2CH3), 1.44 (d, 3H, J = 7.14 Hz, CHCH3); IR (KBr) 3296,
4.2.34. N-Benzyloxy-2-[3-fluoro-4-(methylsulfonylamino)
phenyl]propionamide (46)
Yield 76%, white solid, mp = 182–183 °C, 1H NMR (CDCl3) d 7.94
(s, 1H, ONH), 7.49 (t, 1H, J = 8.3 Hz, H-5), 7.25–7.35 (m, 5H, Ph),
7.12 (dd, 1H, J = 2, 11.2 Hz, H-2), 7.02 (dd, 1H, J = 2, 8.2 Hz, H-6),
6.52 (br s, 1H, NHSO2), 4.87 (s, 2H, PhCH2O), 3.35 (q, 1H,
J = 7.1 Hz, CHCH3), 3.02 (s, 3H, SO2CH3), 1.46 (d, 3H, J = 7.1 Hz,
CHCH3); IR (KBr) 3235, 1671, 1511, 1455, 1331, 1156 cmꢀ1; MS
(FAB) m/z 367 (MH+); Anal. Calcd for C17H19FN2O4S: C, 55.73; H,
5.23; N, 7.65. Found: C, 55.94; H, 5.21; N, 7.64.
1651, 1589, 1498, 1332, 1157, 1116, 972, 909, 752, 697 cmꢀ1
;
MS (FAB) m/z 455 (MH+); Anal. Calcd for C24H26FN3O3S: C, 63.28;
H, 5.75; N, 9.22. Found: C, 63.57; H, 5.73; N, 9.20.
4.2.41. N-(3,3-Di-p-tolyl-propyl)-2-(3-fluoro-4-
methansulfonylamino-phenyl)-propionamide (53)
Yield 90%, white solid, mp = 150–152 °C, 1H NMR (CDCl3) d 7.51
(t, 1H, J = 8.40 Hz, Ar-H), 7.13–7.01 (m, 10H, Ar), 6.45 (br s, 1H,
NHSO2), 5.25 (br t, 1H, NHCO), 3.33 (q, 1H, J = 7.14 Hz, CHCH3),
3.20 (m, 2H, CH2NH), 3.01 (s, 3H, SO2CH3), 2.28 (s, 6H, (Ar-
CH3)2), 2.18 (q, 2H, J = 7.50 Hz, Ar-CH2), 1.42 (d, 3H, J = 7.14 Hz,
CHCH3); IR (KBr) 3292, 2928, 1649, 1511, 1448, 1332, 1158,
4.2.35. N-Benzhydryl-2-[3-fluoro-4-(methylsulfonyl-
amino)phenyl]propionamide (47)
Yield 79%, white solid, mp = 160–161 °C, 1H NMR (CDCl3) d 7.51
(t, 1H, J = 8.3 Hz, H-5), 7.0–7.4 (m, 10H, Ar), 6.20 (d, 1H, Ph2CH),
6.04 (br t, 1H, NHCO), 3.58 (q, 1H, J = 7.1 Hz, CHCH3), 3.00 (s, 3H,
SO2CH3), 1.52 (d, 3H, J = 7.1 Hz, CHCH3); IR (KBr) 3374, 3089,
1657, 1588, 1513, 1445, 1323, 1156 cmꢀ1; MS (FAB) m/z 427
(MH+); Anal. Calcd for C23H23FN2O3S: C, 64.77; H, 5.44; N, 6.57.
Found: C, 64.95; H, 5.42; N, 6.59.
1118, 972 cmꢀ1
27H31FN2O3S: C, 67.19; H, 6.47; N, 5.80. Found: C, 67.37; H,
6.45; N, 5.81.
;
MS (EI) m/z 483 (M+); Anal. Calcd for
C

1318
W. Sun et al. / Bioorg. Med. Chem. 20 (2012) 1310–1318
4.2.42. N-[3,3-Di(4-methylphenyl)-2-propenyl]-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (54)
5.80 (t, 1H, >C@CH), 5.40 (br t, 1H, NHCO), 4.13 (m, 1H, CH2NH),
3.71 (m, 1H, CH2NH), 3.43 (q, 1H, J = 7.1 Hz, CHCH3), 3.2–3.4 (m,
4H, PhCH2CH2Ph), 3.01 (s, 3H, SO2CH3), 1.46 (d, 3H, J = 7.1 Hz,
Yield 72%, white solid, mp = 163–165 °C, 1H NMR (CDCl3) d 7.49
(t, 1H, J = 8.3 Hz, H-5), 6.95–7.2 (m, 10H, Ar-H), 5.93 (t, 1H,
J = 7.0 Hz, >C@CH), 5.56 (br t, 1H, NHCO), 3.8–4.0 (m, 2H, CH2NH),
3.47 (q, 1H, J = 7.1 Hz, CHCH3), 3.00 (s, 3H, SO2CH3), 2.34 (d, 6H,
2 ꢁ CH3), 1.47 (d, 3H, J = 7.1 Hz, CHCH3); IR (KBr) 3279, 1648,
1511, 1451, 1332, 1158, 1116 cmꢀ1; MS (FAB) m/z 481 (MH+); Anal.
Calcd for C27H29FN2O3S: C, 67.48; H, 6.08; N, 5.83. Found: C, 67.19;
H, 6.05; N, 5.80.
CHCH3); IR (KBr) 3294, 2927, 1649, 1511, 1453, 1332, 1156 cmꢀ1
;
MS (FAB) m/z 479 (MH+); Anal. Calcd for C27H27FN2O3S: C, 67.76;
H, 5.69; N, 5.85. Found: C, 67.54; H, 5.70; N, 5.82.
4.2.48. N-[2-Dibenzo[a,d]cyclohepten-5-ylidene-ethyl]-2-(3-
fluoro-4-methylsulfonylamino-phenyl)-propionamide (60)
Yield 91%, white solid, mp = 70–72 °C, 1H NMR (CDCl3) d 7.48
(m, 1H, Ar-H), 7.33–7.26 (m, 8H, Ar-H), 7.16–7.00 (m, 3H, Ar-H),
6.85 (s, 2H, Ar-H and NHSO2), 5.50 (m, 1H, >C@CH), 5.34 (br t,
1H, NHCO), 4.30 (m, 1H, CH2NH), 3.55 (m, 1H, CH2NH), 3.39 (q,
1H, J = 6.78 Hz, CHCH3), 3.00 (s, 3H, SO2CH3), 1.44 (d, 3H,
J = 7.14 Hz, CHCH3); IR (KBr) 3450, 2951, 2938, 1650, 1511, 1448,
1332, 1160 cmꢀ1; MS (FAB) m/z 477 (MH+); Anal. Calcd for
C27H25FN2O3S: C, 68.05; H, 5.29; N, 5.88. Found: C, 68.31; H,
5.27; N, 5.86.
4.2.43. N-[3,3-Bis-(4-fluoro-phenyl)-propyl]-2-(3-fluoro-4-
methansulfonylamino-phenyl)-propionamide (55)
Yield 93%, white solid, mp = 62–64 °C, 1H NMR (CDCl3) d 7.52 (t,
1H, J = 8.43 Hz, Ar-H), 7.14–6.93 (m, 10H, Ar-H), 6.46 (br s, 1H,
NHSO2), 5.32 (s, 1H, NHCO), 3.82 (t, 1H, J = 7.71 Hz, Ar-CH), 3.40
(q, 1H, J = 7.14 Hz, CHCH3), 3.18 (m, 2H, CH2NH), 3.02 (s, 3H,
SO2CH3), 2.17 (q, 2H, J = 7.50 Hz, CH–CH2), 1.45 (d, 3H,
J = 7.14 Hz, CHCH3); IR (KBr) 3291, 1650, 1508, 1451, 1334, 1223,
1158, 970 cmꢀ1
25H25F3N2O3S: C, 61.21; H, 5.14; N, 5.71. Found: C, 61.48; H,
5.15; N, 5.70.
;
MS (EI) m/z 491 (M+); Anal. Calcd for
Acknowledgments
C
This research was supported by Research Funding from Digital-
biotech, Grants R11-2007-107-02001-0 from the National Re-
search Foundation of Korea (NRF), and the Intramural Research
Program of the National Institutes of Health, Center for Cancer Re-
search, National Cancer Institute (Z1A BC 005270). We thank mul-
tiple additional fellows for technical assistance.
4.2.44. N-[3,3-Di(4-fluorophenyl)-2-propenyl]-2-[3-fluoro-4-
(methylsulfonylamino)phenyl]propionamide (56)
Yield 78%, white solid, mp = 57–60 °C, 1H NMR (CDCl3) d 7.49 (t,
1H, J = 8.3 Hz, H-5), 6.9–7.2 (m, 10H, Ar), 6.72 (br s, 1H, NHSO2),
5.92 (t, 1H, J = 7.0 Hz, >C@CH), 5.58 (br s, 1H, NHCO), 3.8–4.0 (m,
2H, CH2NH), 3.48 (q, 1H, J = 7.1 Hz, CHCH3), 3.02 (s, 3H, SO2CH3),
1.48 (d, 3H, J = 7.1 Hz, CHCH3); IR (KBr) 3280, 1650, 1599, 1509,
1332, 1225, 1157 cmꢀ1; MS (FAB) m/z 489 (MH+); Anal. Calcd for
References and notes
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Julius, D. Nature 1997, 389, 816.
C25H23F3N2O3S: C, 61.46; H, 4.75; N, 5.73. Found: C, 61.66; H,
4.73; N, 5.71.
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Marzo, V.; Julius, D.; Hogestatt, E. D. Nature 1999, 400, 452.
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O.; Kang, S.-U.; Kil, M.-J.; Koo, J.-Y.; Shin, S. S.; Joo, Y.-H.; Kim, J. K.; Jeong, Y.-S.;
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4.2.45. N-[3,3-Bis-(4-chloro-phenyl)-allyl]-2-(3-fluoro-4-
methanesulfonylamino-phenyl)-propionamide (57)
Yield 73%, white solid, mp = 72–74 °C, 1H NMR (CDCl3) d 7.50 (t,
1H, J = 8.23 Hz, Ar), 7.34 (d, 2H, J = 8.61 Hz, Ar), 7.24 (d, 2H,
J = 12.99 Hz, Ar), 7.15 (dd, 1H, J = 11.37 Hz, Ar), 7.10–7.02 (m, 5H,
Ar), 6.60 (br s, 1H, NH), 5.97 (t, 1H, J = 6.87 Hz, CCHCH2), 5.54 (br
t, 1H, NH), 3.89 (m, 2H, CH2NH), 3.47 (q, 1H, J = 7.14 Hz, CHCH3),
3.02 (s, 3H, SO2CH3), 1.48 (d, 3H, J = 7.14 Hz, CHCH3); IR (KBr)
3293, 1649, 1512, 1332, 1157, 1092, 973, 831, 757 cmꢀ1; MS
(FAB) m/z 521 (MH+); Anal. Calcd for C25H23Cl2FN2O3S: C, 57.59;
H, 4.45; N, 5.37. Found: C, 57.32; H, 4.43; N, 5.35.
4.2.46. 2-(3-Fluoro-4-methanesulfonylamino-phenyl)-N-[3-(4-
fluoro-phenyl)-3-p-tolyl-propyl]-propionamide (58)
Yield 72%, white solid, mp = 63–65 °C, 1H NMR (CDCl3) d 7.51 (t,
1H, Ar), 7.15–7.02 (m, 8H, Ar), 6.94 (t, 1H, Ar), 6.46 (br, 1H, NH),
5.28 (br t, 1H, NH), 3.78 (td, 1H, ArCHAr), 3.37 (q, 1H, J = 7.14 Hz,
CHCH3), 3.18 (m, 2H, CH2NH), 3.01 (s, 3H, SO2CH3), 2.29 (s, 3H,
ArCH3), 2.17 (q, 2H, Ar2CHCH2), 1.44 (d, 3H, J = 7.14 Hz, CHCH3);
IR (KBr)
, 1649, 1509, 1454, 1332, 1222, 1157, 972, 819,
758 cmꢀ1; MS (FAB) m/z 487 (M+); Anal. Calcd for C26H28F2N2O3S:
C, 64.18; H, 5.80; N, 5.76. Found: C, 64.39; H, 5.82; N, 5.75.
4.2.47. N-[2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-
yliden)ethyl]-2-[3-fluoro-4-(methylsulfonylamino)
phenyl]propionamide (59)
19. Ryu, H.; Jin, M.-K.; Kang, S.-U.; Kim, S. Y.; Kang, D. W.; Lee, J.; Pearce, L. V.;
Pavlyukovets, V. A.; Morgan, M. A.; Tran, R.; Toth, A.; Lundberg, D. J.; Blumberg,
P. M. J. Med. Chem. 2008, 51, 57.
20. Chung, J.-U.; Kim, S. Y.; Lim, J.-O.; Choi, H.-K.; Kang, S.-U.; Yoon, H.-S.; Ryu, H.;
Kang, D. W.; Lee, J.; Kang, B.; Choi, S.; Toth, A.; Pearce, L. V.; Pavlyukovets, V. A.;
Lundberg, D. J.; Blumberg, P. M. Bioorg. Med. Chem. 2007, 15, 6043.
Yield 76%, white solid, mp = 67–69 °C, 1H NMR (CDCl3) d 7.50 (t,
1H, J = 8.3 Hz, H-5), 7.05–7.25 (m, 10H, Ar), 6.49 (br s, 1H, NHSO2),