Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious γ-secretase inhibitors (Part II)

Article abstract of DOI:10.1016/j.bmcl.2010.04.148

Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.

Full text of DOI:10.1016/j.bmcl.2010.04.148

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3502–3506
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a novel sulfonamide-pyrazolopiperidine series as potent
and efficacious c-secretase inhibitors (Part II)
a
a
a
a
Xiaocong M. Ye a, , Andrei W. Konradi , Jenifer Smith , Danielle L. Aubele , Albert W. Garofalo ,
Jennifer Marugg a, Marty L. Neitzel a, Chris M. Semko a, Hing L. Sham a, Minghua Sun a, Anh P. Truong a,
Jing Wu b, Hongbin Zhang c, Erich Goldbach c, John-Michael Sauer c, Elizabeth F. Brigham d, Michael Bova e,
Guriqbal S. Basi e
*
a Department of Medicinal Chemistry, Élan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States
b Department of Process and Analytical Chemistry, Élan Pharmaceuticals, 1000 Gateway Boulevard, South San Francisco, CA 94080, United States
c Department of Lead, Discovery, and Optimization, Élan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States
d Department of In Vivo Pharmacology, Élan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States
e Department of Biology, Élan Pharmaceuticals, 1000 Gateway Boulevard, South San Francisco, CA 94080, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series
were achieved and this stability improvement translated in an improved in vivo efficacy.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 April 2010
Revised 28 April 2010
Accepted 30 April 2010
Available online 6 May 2010
Keywords:
Alzheimer’s disease
Amyloid precursor protein
c
c
-Secretase
-Secretase inhibitor
Alzheimer’s disease (AD) is a progressive neurodegenerative dis-
been reported in the literature (for recent reviews, see Olson and
Albright5 and Garofalo6). Recently, we have reported on the discov-
ery of novel GSIs as exemplified by 1.7 Herein, we report our pro-
gress to improve metabolic stability of this series while retain its
excellent inhibitory activity (see Fig. 1).
order accompanied by cognitive impairment, memory deficit, and
visual-spatial disorientation. Amyloid plaques and neurofibrillary
tangles within the hippocampus and the cerebral cortex, containing
aggregated amyloid beta peptide (Ab) and hyperphosphorylated tau
protein are the defining diagnostic feature of AD. Aggregation/depo-
sition of Ab42 in the brain of AD patients is thought to contribute to
AD pathology.1 Ab, ranging from 37 to 42 amino acids in length, are
formed by sequential cleavageof amyloid precursorprotein (APP) by
Compound
1 demonstrated good potency and selectivity
(18-fold selectivity over Notch in an enzymatic assay and 71-fold
in a cellular assay) and was efficacious in a wild type FVB mouse
model with 25% Ab40 reduction in the brain at 5 mg/kg PO. This
series, however, also suffers from poor oxidative metabolic
stability, rapid glucuronide formation and glutathione conjugation.
Therefore, we initiated efforts to overcome the above limitations.
two aspartyl proteases, b-secretase (BACE) and c-secretase, respec-
tively. In addition to APP, c-secretase also cleaves a large number of
other type 1 transmembrane proteins including Notch.2 The inhibi-
tion of Notch proteolysis has been shown to result in undesirable
side effects observed in the thymus, spleen, and intestine.3 Accord-
Cl
ingly, while an inhibitor of
for AD, nonselective inhibitors may find limited utility.
The first example of a -Secretase Inhibitor (GSI) that achieved
in vivo inhibition of brain Ab was the dipeptide, DAPT. This work
was jointly reported by researchers from Elan and Eli Lilly.4 Since
then, several classes of nonpeptidic, orally bioavailable GSIs have
c-secretase may serve as a treatment
O
S
N
IC50 (APP) = 0.3 nM
c
O
IC50 (Notch) = 6 nM
ED50 (APP) = 1 nM
ED50 (Notch) = 70 nM
F = 2.5%
t1/2 = 3.8 h (rat)
HN
N
1
* Corresponding author. Tel.: +1 650 616 2683; fax: +1 650 794 2387.
E-mail address: michael.ye@elan.com (X.M. Ye).
Figure 1. Representative N-bicyclic sulfonamide c-secretase inhibitor.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.148

X. M. Ye et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3502–3506
3503
Metabolic identification studies revealed that the poor meta-
CF3
CF3
O
S
N
bolic stability resulted from extensive oxidation on the ethyl
groups and the methylene carbon adjacent to the pyrazole ring.
Also, glutathione conjugation on the phenyl ring of the arylsulfona-
mide was detected. In our previous papers,7,8 we reported that the
cyclopropyl group was an effective replacement for the ethyl group
to achieve better stability while maintaining its potency. To allevi-
ate the glutathione conjugation, we needed to find substituents to
replace the chloride on the phenyl ring, and trifluoromethyl turned
out to be the choice as demonstrated by our previous papers.7,8
Glucuronidation occurred on the pyrazole ring. Since our SAR indi-
cates that the unsubstituted pyrazole was critical to the binding
interaction,9 we hoped we could minimize glucuronidation
through an electronic effect. For the methylene carbon next to
the pyrazole ring, we believed that the best strategy was to convert
it to difluoromethylene, since it has been well established in the
literatures that fluorine can enhance metabolic stability by lower-
ing the susceptibility of nearby moieties to cytochrome P450 enzy-
matic oxidation.10 By doing so, we hoped that this change could
reduce glucuronidation due to the electron-withdrawing effect of
the fluorine atoms adjacent to the pyrazole ring.
O
S
N
R
O
NH2
O
O
O
a, b
c, d
e
R
O
R'
R
O
R'
O
Cl
8
6
7
CF3
CF3
CF3
O
S
N
O
S
N
O
S
N
O
O
O
g
f
R
R'
R
R'
R
F
R'
O
O
F
N2
HN
3
HN
2
N
N
4
Scheme 2. Reagents and conditions: (a) 4-trifluoromethylbenzenesulfonyl chlo-
ride, DCM, TEA; (b) Ph3P, DIAD, THF, corresponding propargyl alcohols; (c) LiOH,
H2O, THF; (d) oxalyl chloride, DCM, DMF (cat.); (e) MNNG, KOH, Et2O; (f) EtOH,
80 °C, 1 h; (g) BAST.
Retrosynthetic analysis illustrated in Scheme 1 led to com-
pound 5 as the key intermediate that could be rapidly prepared
from the readily available amino acid for this synthesis.
A number of compounds were synthesized using this scheme.
The ketone compounds are listed in Table 1 while the fluoro com-
pounds in Table 2. Both the ketones (compound 3) and their di-
fluoro analogs (compound 2) have excellent potencies,12
sometimes slightly higher than that of compound 1 (e.g., 3aa and
2hh).
The synthesis is illustrated in Scheme 2. Starting with the com-
mercially available amino acid 6, sulfonylation followed by Mitsun-
obu reaction with the appropriate propargyl alcohol, either from a
commercially available source or prepared from the corresponding
aldehyde and ethynylmagnesium bromide, gave the intermediate
7. Saponification of the ester, followed by treatment with oxalyl
chloride, yielded acid chloride 8. On treatment with diazomethane,
generated from methylnitronitroso-guanidine (MNNG), acid chlo-
ride 8 was converted to diazoketone 4. The [2+3] cyclization11
was carried out in refluxing ethanol leading to key ketopyrazole
3. After treatment with bis(2-methoxymethyl)aminosulfur trifluor-
ide (BAST), various difluoro analogs (2) were obtained.
Initially we anticipated that we could control the stereochemis-
try outcome in this synthesis by starting a chirally pure amino acid,
because we rationalized that only syn isomer of compound 4 would
be able to cyclize to give the compound 3, as only the syn isomer
could bring the diazoketone and the alkyne groups in a close prox-
imity to react. However, partial racemization was observed in
Mitsunobu step (ꢀ10–15%). For [2+3] cyclization, the fact that both
syn and anti compound 4 gave cyclized products further dampened
hope to control the stereochemistry outcome in this synthesis,
although in many cases the trans products were not stable and
some of them decomposed during separation by flash
chromatograph.
As listed in Table 1, although both 4-trifluoromethy-lbenzene-
sulfonamide and the trifluoromethylpyridiyl-sulfonamide are
slightly less potent than 4-chloro-benzenesulfonamide analog,
metabolic identification studies on these compounds revealed that
both are free of the glutathione conjugation. Furthermore, to our
satisfaction, all ketones and all fluorine compounds give very good
stabilities in the glucuronidation assay, suggesting the electronic
effect of the carbonyl group or fluorine atoms adjacent to the pyr-
azole ring indeed works as anticipated. Oxidative stability was im-
proved over compound 1, especially when cyclopropyl groups
were used for the side chains. However, one noticeable concern
for the ketone compounds was a dramatic loss of the activity in
the cellular assay13 compared with its activity in the enzymatic as-
say. In the series of compounds with compound 1 as the prototype,
we normally observed about 3–5-fold potency loss in the cellular
assay over the enzymatic assay.7 However, for some ketone com-
pounds 3, 50–1000-fold potency decrease was observed. Interest-
ingly, this loss of cellular potency correlated well with the size of
the substituent in C6 position. Indeed, when tert-butyl is used in
C6 position (compounds 3t and 3u), the ratio fell back to the range
of 3–5-fold reduction. Metabolic identification study established
that this potency loss was due to the instability of compound 3 un-
der the conditions of cellular assay, and decomposition occurred
via elimination of the sulfinic acid and subsequent tautermization
leading to a fully aromatic system as the driving force (Scheme 3).
Substitution at C4 position appears to have huge impact in its
potency. Methyl group at this position is far less potent than cyclo-
propyl group (compounds 3f and 3g). Isopropyl and cyclopropyl
group are almost identical (3h and 3i) and ethyl group is slightly
less potent than isopropyl and cyclopropyl groups (compounds
3p and 3q). On the other hand, substitution at C6 position gener-
ally has small effect on potency (compounds 3i and 3n).
CF3
CF3
O
S
N
O
S
N
O
O
R
R'
R
O
R'
F
F
HN
HN
N
N
3
2
CF3
CF3
O
S
NH
O
S
N
O
O
R
O
R
R'
The fluoro compounds, as expected, do not have this elimina-
tion–aromatization problem. As we can see from Table 2, the po-
tency discrepancy between the cellular and enzymatic assays
improved dramatically compared with the ketone compounds.
More importantly, these compounds have very good metabolic sta-
bility almost across the board.
O
O
N2
5
4
Scheme 1.

3504
X. M. Ye et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3502–3506
Table 1
In vitro activities of synthetic analogues of the ketone compounds
X
R3
O
S
N
O
6
R2
O
R1
4
3
2
HN
1
N
Compound
R1
R2
X
R3
Notes
c
APP
c
Notch
SNC
SNC
c
cellular
Glucuron.
Oxidat.
(cell-free)
IC50 (nM)
(cell-free)
IC50 (nM)
Cellular
ED50 (nM)
Notch IC50
Microsom. %
Metabol. %
a(nM)
remain (human)c
remain (human)d
a
a
a
3a
3aa
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
Et
Et
i-Pr
Et
Et
Et
H
H
H
H
Me
Me
i-Pr
c-Pr
MeOCH2
H
Me
Me
Me
3,5-diF-Ph
Et
c-Pr
c-Pr
4-THP
t-Bu
t-Bu
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
N
N
N
N
N
N
N
N
Cl
Cl
Cl
cis, rac.
cis, ent of 3a
cis, rac.
Racemic
cis, rac.
0.3
0.1
3.7
6.5
9.1
2.6
6.8
0.5
0.5
0.4
3.2
5.6
13.2
91
0.6
0.7
0.8
0.3
3
1
0.2
4.8
N/A
6 (1)b
5
546
288
77
65
71
N/A
N/A
6
77
67
82
76
N/A
42
91
N/A
59
N/A
83
75
87
6
5 (2)b
10
12
19
N/A
1
63
62
0
67
14
5
67
62
72
9
91 (1)b
N/A
3999 (1)b
>10,000 (1)b
>10,000 (1)b
>10,000 (1)b
5106
>40,000
>40,000
>40,000
>40,000
>40,000
>40,000
2302
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
c-Pr
CF3
Me
c-Pr
i-Pr
c-Pr
c-Pr
c-Pr
Me
Me
c-Pr
c-Pr
Et
354 (1)b
51 (1)b
89 (1)b
12 (1)b
14 (1)b
21 (2)b
126 (1)b
193 (2)b
144 (1)b
2267 (1)b
21 (1)b
17 (2)b
36 (1)b
10 (1)b
66
Racemic
Enantiomer A
Enantiomer A
cis, ent.
Racemic
cis, rac.
2335 (1)b
33
21 (2)b
2792
>10,000 (1)b
5995 (1)b
1099 (1)b
>10,000 (1)b
>10,000 (2)b
>1000 (1)b
21 (1)b
>40,000
>40,000
18,334
>40,000
>40,000
>4000
2361
6704
25,072
187
Racemic
cis, ent. A
cis, ent. B
cis, ent. A
Racemic
cis, ent.
cis, rac.
trans, rac.
Racemic
Unassigned
Unassigned
57
77
21
57
8
c-Pr
c-Pr
c-Pr
c-Pr
c-Pr
130 (2)b
374 (2)b
1 (2)b
3s
3t
3u
19
64
66
N/A
N
N
6
0.6
71
1636
107 (1)b
16 (2)b
12
a
b
c
Values are means of at least three experiments unless otherwise noted.
Number in bracket indicates the number of experiments.
Percentage of compound (2
l
M) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM UDPGA, 100 mM MgCl2 and 25
lg/mL
alamethacin at 37 °C in phosphate buffer.
d
Percentage of compound (1
lM) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM NADPH at 37 °C in phosphate buffer.
Table 2
In vitro activities of synthetic analogues of the fluoro compounds
X
R3
O
S
N
O
6
R2
F
4 R1
3
F
HN
1
N
2
Compound
R1
R2
X
R3
Notes
c
APP cell-free
c
Notch
SNC Cellular
ED50 (nM)
SNC
c
cellular
Glucuron.
Oxidat.
a
a
IC50 (nM)
cell-free
IC50 (nM)
Notch
Microsom. %
Metabol. %
IC50 (nM)
remain (human)c
remain (human)d
a
a
2a
2b
2c
2d
2e
2f
i-Pr
c-Pr
c-Pr
c-Pr
Et
CF3
c-Pr
c-Pr
c-Pr
c-Pr
H
CH
CH
N
CH
N
CH
N
N
Cl
Racemic
0.7
1
12 (1)b
18
20
11 (2)b
7
574
418
358
771
304
403
304
138
34
42
46
59
64
66
35
67
75
61
41
2
75
79
76
22
84
71
80
53
43
Me
Me
c-Pr
Et
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
cis, ent. A
cis, ent. A
Diaster. Mix
cis, rac.
Racemic
cis, rac.
cis, ent. of 2g
trans, rac.
trans, ent of 2h
1.2
1.5
1.8
0.9
0.8
0.6
0.3
0.1
6
42 (1)b
50 (1)b
10 (2)b
47 (2)b
23
6 (1)b
6 (1)b
4
H
2g
c-Pr
c-Pr
c-Pr
c-Pr
3
2
0.5
0.2
2gg
2h
2hh
N
N
3
3
13
a
b
c
Values are means of at least three experiments unless otherwise noted.
Number in bracket indicates the number of experiments.
Percentage of compound (2
l
M) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM UDPGA, 100 mM MgCl2 and 25
lg/mL
alamethacin at 37 °C in phosphate buffer.
d
Percentage of compound (1
lM) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM NADPH at 37 °C in phosphate buffer.

X. M. Ye et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3502–3506
3505
CF3
As mentioned above, there are huge potency discrepancies of
the ketone compounds between the cellular assay and the enzy-
matic assay, which we assume is a result of decomposition of the
ketone compounds via elimination–aromatization process. We also
pointed out that the substituent at the C6 position does not con-
tribute to compound’s activity much. Based on these observations,
we proposed to introduce gem-dialkyl substitution at the C6 posi-
tion to ameliorate the elimination process, therefore, to solve this
potency discrepancy.
O
N
N
S
N
O
O
HO
H
O
HN
HN
N
N
HN
3
N
9
10
Scheme 3.
Gem-dimethyl was obviously the easy choice. We also decided
to have a spiro-cyclopropyl group at this position, in case we would
observe oxidative liability for the gem-dimethyl compound, be-
cause cyclopropyl group has been proven to fare better in oxidative
assay than methyl group. The synthetic route is illustrated in
Scheme 4 with the same strategy as Scheme 2, except for a few
modifications. One is that TMS protected propargyl alcohol was
used to afford a better yield in the Mitsunobu reaction step. The
other is basic hydrolysis condition failed to hydrolyze the methyl
ester and allene formation was observed when temperature was
raised. Fortunately, this problem was solved by LiI/pyridine condi-
tion via a dealkylation mechanism.
Using this synthesis, we made the gem-dimethyl, spiro-cyclo-
propyl and spiro-cyclobutyl compounds. Since the ketone will
not be able to cause the elimination–aromatization any more, we
just convert one ketone compound to its difluoro analog to check
out its properties. All compounds are listed in Table 3.
F3C
X
F3C
X
O
S
N
O
S
NH
O
O
NH2
OH
c
a, b
O
O
O
X
O
O
OMe
11
12
13 TMS
F3C
F3C
X
O
S
N
O
S
N
O
d, e, f
g
O
O
X
Cl
N2
O
14
15
F3C
F3C
X
O
As expected, the potency discrepancies between the cellular as-
say and enzymatic assay on these ketone compounds fall into the
normal range of 3–5-fold. All compounds are very potent, suggest-
ing that the original assumption of di-substitution tolerance in C6
position is valid. Interestingly, spiro-cyclobutyl group (compound
16d) is significantly more potent than spiro-cyclopropyl group
(compound 16b). This is in contrast to the observed relative insen-
sitivity when varying methyl to ethyl or isopropyl group at C6
position in compound 3. We also observed significant potency in-
crease in this spiro substituted system when converting the ketone
to the difluoro compound (16c to 17a), while a slight loss of
O
O
N
S
N
S
N
i
h
F
O
F
HN
16
HN
17
N
Scheme 4. Reagents and conditions: (a) HCl(g), MeOH; (b) TEA, DCM, the
corresponding sulfonyl chloride (X = N or CH), 0 °C; (c) DIAP, TBP, PhMe, 1-
cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-ol; (d) LiOH, MeOH, rt; (e) LiI, pyridine,
115 °C; (f) oxalyl chloride, DCM, DMF (cat.); (g) CH2N2, Et2O; (h) EtOH, 80 °C; (i)
BAST.
Table 3
In vitro activities of synthetic analogues of the di-substituted compounds
O
S
N
O
S
N
R3
R3
O
O
R2
R2
R1
R1
F
O
F
HN
16
HN
17
N
N
Compound
R1
R2
R3
Notes
c
APP
c
Notch
SNC Cellular
ED50 (nM)
SNC
Notch IC50
(nM)
c
cellular
Glucuron.
Oxidat.
a
a
cell-free
IC50 (nM)
cell-free
IC50 (nM)
Microsom. %
Metabol. %
remain (human)c
remain (human)d
a
a
16a
16b
16c
16d
16e
16f
16g
16h
16i
Me
CH2CH2
CH2CH2
Me
4-CF3-Ph
4-CF3-Ph
6-CF3-3-Py
4-CF3-Ph
6-CF3-3-Py
6-CF3-3-Py
5-CF3-2-Py
5-CF3-2-Py
5-CF3-2-Py
5-Cl-2-Thiophene
6-CF3-3-Py
6-CF3-3-Py
6-CF3-3-Py
Racemic
Racemic
Racemic
Racemic
ent. A of 16c
ent. B of 16c
Racemic
ent. A of 16g
ent. B of 16g
Racemic
Racemic
ent. A of 17a
ent. B of 17a
7.3
1.9
1.8
0.4
1071
1.4
24
897
9.6
2
268 (2)b
69 (2)b
35 (2)b
8 (1)b
N/A
60
2656
995
688
235
>40,000
250
6209
>40,000
2289
576
50
25
67
84
91
N/A
88
94
89
N/A
96
N/A
89
68
85
86
3
83
86
76
80
82
1
11 (2)b
7 (2)b
2
CH2CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
CH2CH2
2681 (1)b
4 (1)b
87 (1)b
1854 (1)b
26 (2)
7 (2)b
0.5
15 (1)b
502 (2)b
8276 (1)b
223
16j
18
2
1
221
17a
17b
17c
0.2
0.2
56
61
85
72
0.3
86
85
100
9277
a
b
c
Values are means of at least three experiments unless otherwise noted.
Number in bracket indicates the number of experiments.
Percentage of compound (2
l
M) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM UDPGA, 100 mM MgCl2 and 25
lg/mL
alamethacin at 37 °C in phosphate buffer.
d
Percentage of compound (1
lM) remaining after 30 min incubation in liver microsomes (0.5 mg protein) supplemented with 1 mM NADPH at 37 °C in phosphate buffer.

3506
X. M. Ye et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3502–3506
N
CF3
N
CF3
Cristian Cabrera, Ferdie Soriano, Bhushan Samant, Rose Lawler, Juri
Fukada for their contributions to this work.
O
O
S
N
S
N
O
O
References and notes
F
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Wolfe, M. S. J. Med. Chem. 2001, 44, 2039.
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O
F
HN
HN
N
N
2gg
16f
Figure 2. Representative in vivo compounds.
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potency was observed from this conversion in the previous system
(compounds 3q to 2g).
The in vivo activity of compounds 2gg and 16f (Fig. 2) were
evaluated in our wild type FVB mouse model. Both compounds
achieved significant Ab40 reduction (20% and 27%, respectively)
in the brain 3 h after a single 1 mg/kg oral dose of 2gg and 16f.
Clearly, the improvement of the in vitro PK properties of these
compounds has translated to improved in vivo activity when com-
paring with the result of compound 1.7
In summary, by applying medicinal chemistry principals, we
have dramatically improved the metabolic stability of the original
series while still maintaining its favorable potency. These im-
proved pharmacokinetic properties have resulted in better efficacy
in an animal model.
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12. IC50s determined as described in note 11 in Ref. 8.
13. Manuscript in preparation by Basi, G.S.; et al.
Acknowledgments
We would like to thank Gary D. Probst, Daniel Ness, Lee Latimer,
Michael Dappen, Jacek Jagodzinski, David Quincy, Pam Keim, Lan
Nguyen, William Wallace, David Nakamura, Karina Wong, Wes
Zmolek, Michael Lee, Kang Hu, Anna Liao, Terence Hui, Tracy Cole,