Identification of 3-sulfonylindazole derivatives as potent and selective 5-HT6 antagonists

Article abstract of DOI:10.1016/j.bmc.2010.10.033

As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT₆ receptor in order to identify potent and selective ligands for this purpose. Herein we report the identification of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and selective 5-HT₆ antagonists. The synthesis and detailed SAR of this class of compounds are reported.

Full text of DOI:10.1016/j.bmc.2010.10.033

Bioorganic & Medicinal Chemistry 19 (2011) 650–662
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Identification of 3-sulfonylindazole derivatives as potent and selective
5-HT6 antagonists
Kevin G. Liu a, , Albert J. Robichaud a, , Alexander A. Greenfield a, Jennifer R. Lo a, Cristina Grosanu a,
James F. Mattes a, Yanxuan Cai a, Guo Ming Zhang b, Jean Y. Zhang b, Dianne M. Kowal b, Deborah L. Smith b,
Li Di a, Edward H. Kerns a, Lee E. Schechter b, Thomas A. Comery b
⇑
⇑
a Chemical Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA
b Discovery Neurosciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT6
receptor in order to identify potent and selective ligands for this purpose. Herein we report the identifi-
cation of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and
selective 5-HT6 antagonists. The synthesis and detailed SAR of this class of compounds are reported.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 15 September 2010
Revised 9 October 2010
Accepted 13 October 2010
Available online 20 October 2010
Keywords:
5-HT
Serotonin
5-Hydroxytryptamine
5-HT6
5-Hydroxytryptamine-6
Alzheimer’s disease
Schizophrenia
Cognition
Cognitive impairment
Cognitive dysfunction
1. Introduction
of the 5-HT6 receptor in great detail and selected 5-HT6 ligands
are depicted in Figure 1 (1–7) showing the diversity of structural
The 5-HT6 receptor was identified by molecular biology in early
1990s1–4 and was the most recent addition to a group receptors
called the 5-HT receptors. This G-protein-coupled receptor (GPCR)
is positively coupled to adenylate cyclase and is localized primarily
in the central nervous system.5 Extensive investigation has shown
that the 5-HT6 receptor is expressed in brain regions known to be
associated with learning and memory.6 In addition, studies have
shown that blockade of 5-HT6 receptor function increases neuro-
transmission, specifically cholinergic and glutamatergic,7,8 and this
leads to improvement in cognition in a number of rodent behav-
ioral models.9,10
types in this area. Currently a number of compounds from these
classes are active in Phase I and II clinical trials for cognitive
impairment in AD and schizophrenia.14,15
We have previously reported the identification of 1-sulfonylin-
dazole derivatives 9 as potent and selective 5-HT6 antagonists
(Fig. 2).22 Herein we report the identification of a series of 3-sulfony-
lindazoles 10 by migrating the arylsulfonyl group from the 1-posi-
tion to the 3-position of the indazole core of 9. This C/N flip
strategy has been successfully used by us for identification of other
series of novel 5-HT6 ligands in the past and has allowed for exten-
sive modification of the drug-like properties of this class of
molecules.16
In the last decade, a great number of 5-HT6 ligands of both ago-
nists and antagonists have been reported.11–13 These compounds
have served as excellent tools to investigate the functional roles
2. Results and discussion
The general synthesis of 3-sulfonylindazole derivatives 17 with
a primary amine side chain is depicted in Scheme 1. Commercially
available 4-, 5-, 6-, or 7-NO2 indazoles 11 were treated with I2/KOH
in DMF to provide 3-iodo-indazoles 12 cleanly in excellent yields.
Coupling of 12 with a thiol using a procedure reported by
⇑
Corresponding authors. Present address: Lundbeck Research USA, 215 College
Road, Paramus, NJ 07652, USA. Tel.: +1 201 350 0129 (K.G.L.); +1 201 350 0357;
fax: +1 201 261 0623 (A.J.R.).
E-mail addresses: liuk@lundbeck.com (K.G. Liu), ajr@lundbeck.com (A.J. Robi-
chaud).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.10.033

K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
651
Cl
N
H2N
H
N
H
N
N
O
NH
S
H
O
O
N
N
O
N
S
S
N
S
O
1
O
O
2
3
HN
O
Ro 04-6790
Ki = 55 nM
antagonists
MS-245
Ki = 2.3 nM
antagonist
H
N
SB-271046
Ki = 1.3 nM
NH2
antagonist
N
F
N
H
N
F
O
F
S
N
N
F
F
S
4
S
N
O
O
O
6
5
N
H
Lu AE58054
Ki = 0.83 nM
antagonist
O
SB-742457
Cl
Ki < 10 nM
SAX-187
Ki = 2.0 nM
agonist
antagonist
O
S
N
O
Cl
H
N
F
S
7
O
O
N
N
N
H
WAY-208466
Ki = 4.8 nM
Agonist
8
E-6837
Ki = 0.7 nM
Agonist
N
Figure 1. Selected 5-HT6 ligands.
O
S
with the expectation that the reaction would be better catalyzed
by acid. To our satisfaction the reaction went smoothly with the
HCl salt of 15 to provide product 17 in good yield and with minor
side-products.
Scheme 2 outlines the synthesis of other target compounds
(18–24) through common intermediates 15. These final compounds
were synthesized by derivatization on 15 either through reductive
amination with an aldehyde bearing a cyclic amino group (18–20)
or amide bond formation with a b-amino acid (21–24).
3
O
Ar
R
R
N
N 1
S
N
N
N
R'
N
H
R'
O
Ar
O
9
10
1-sulfonylindazoles
3-sulfonylindazoles
Figure 2. Identification of 3-sulfonylindazoles as 5-HT6 ligands.
Synthesis of the reverse amide derivatives 31 is depicted in
Scheme 3. Vicarious nucleophilic substitution18 of methyl 4-nitro-
benzoate 25, which was easily synthesized from 4-nitrobenzoic
acid, with a chloromethyl arylsulfone provided 26 in good yield with
excellent regioselectivity. A variety of chloromethyl arylsulfones,
needed to build in the diversity we desired, were conveniently syn-
thesized from commercially available arylsulfonyl chlorides.19 Nitro
group reduction of 26 by catalytic hydrogenation followed by diaz-
otization of 27 and subsequent cyclization under basic conditions
provided 3-sulfonylindazole intermediates 28 in excellent yield
without necessity of purification. The indazole 1-position of 28
was temporarily protected with 3-Cl-Bn group to provide 29 for
direct amidation in order to generate intermediates 30. The
Buchwald17 gave sulfides 13 which were subsequently oxidized
with m-CPBA to afford sulfones 14. Nitro group reduction with
Sn/HCl or with catalytic hydrogenation provided common aniline
intermediates 15 for rapid synthesis of a wide range of final target
compounds with different amino side chains. Among these final
compounds, amines 17 were synthesized by coupling of 15 with
N-Boc amino acids followed by Boc deprotection and BH3
reduction. Alternatively, 17 (R = H) could be more efficiently syn-
thesized through a single-step chemical transformation between
15 and 2-oxazolidinone. Our initial attempts for the ring opening
of 2-oxazolidinone with the free base of 15 only provided mixtures
of products. We solved this by first converting 15 into its HCl salt
O
S
Ar
Ar
I
S
O
4
5
b
c
d
a
N
N
N
N
O2N
O2N
O2N
O2N
6
N
H
N
H
N
N
7 11
12
13
14
H
H
O
O
S
O
R
Ar
S
R
Ar
Ar
O S
O
H
N
O
H
N
Boc
f, g
H2N
e
N
N
N
N
H
H2N
O
N
H
N
H
N
16
h (R = H)
17
H
15
Scheme 1. Reagents and conditions: (a) I2, KOH, DMF, 90–98%; (b) ArSH, CuI, K2CO3, ethylene glycol, iPrOH, 45–85%; (c) m-CPBA, CH2Cl2, 65–90%; (d) Sn, HCl, 70–80%; (e) N-
Boc amino acid, EDC, CH3CN, 48–90%; (f) TFA, CH2Cl2, 90–100%; (g) BH3ꢀEt2O, THF, 38–70%; (h) (i) HCl, (ii) 2-oxazolidinone, diethylene glycol monomethyl ether, 20–70%.

652
K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
O
O
S
R
N
Ar
S
HN
Ar
O
O
H
N
H
N
R
N
N
O
O
N
H
N
22
23
H
f
g, b
O
S
O
O
Ar
O
Ar
S
Ar
S
O
H
N
O
H
N
HN
h, b
H2N
HN
e, b
N
H2N
N
N
N
H
O
O
N
24
N
H
21
15
H
d, b
a, b
c, b
O
S
O
O
Ar
Ar
O S
Ar
S
O
H
N
O
H
N
H
N
N
N
N
HN
N
H
N
H
N
N
H
18
H
19
20
Scheme 2. Reagents and conditions: (a) 1-N-Boc-4-piperidone, NaBH(OAc)3, 1,2-dichloroethane, 60–80%; (b) TFA, CH2Cl2, 90–100%; (c) 1-N-Boc-3-piperidone, NaBH(OAc)3,
1,2-dichloroethane, 60–80%; (d) 1-N-Boc-4-piperidinecarboxaldehyde, NaBH(OAc)3, 1,2-dichloroethane, 60–80%; (e) N-Boc-glycine, EDC, CH3CN, 60–90%; (f) N,N-dialkyl
glycine, EDC, CH3CN, 60–90%; (g) 1-N-Boc-piperidine-4-carboxylic acid, 60–95%; (h) 1-N-Boc-piperidine-3-carboxylic acid, 60–90%.
O
S
O
O
O
Ar
O
O
Ar
Ar
a
b
c
O
d
O
S
O
S
O
N
O
O
O
O
N
NO2
NO2
26
NH2
H
25
27
Ar
28
O
S
O
O
Ar
Ar
O S
O
R
N
O
R
N
O
O
O
S
f
e
O
R
N
R
N
H
N
N
N
H
N
N
N
Cl
Cl
H
29
30
31
Scheme 3. Reagents and conditions: (a) ArSO2CH2Cl, KOtBu, THF, 87%; (b) H2, Pd/C, MeOH, 64%; (c) (i) NaNO2, HCl, (ii) NaHCO3, 90%; (d) 3-Cl-BnBr, Cs2CO3, DMF, 92%;
(e) 1,2-diamines, LDA, THF, 20–50%; (f) air, KOtBu, t-BuOH, DMSO.
3-Cl-Bn protecting group was then successfully removed through air
oxidation of in situ generated carbanions20 to provide the reverse
amide final compounds 31.
similar and uneventful synthetic sequence to that depicted in
Scheme 3 was then followed to provide versatile intermediates
36 for further derivatization through reductive aminations.
Scheme 5 depicts an alternative synthesis of 18 or other 3-sulf-
onylindazole target molecules. This alternative synthesis allows
rapid exploration of the SAR of the arylsulfonyl moiety and
enhances the diversity of the derivatives. Nitro group reduction
of 3-iodoindazole 12 with SnCl2 provided aniline 39. The aniline
Synthesis of derivatives with a carbon spacer between the basic
amine and the indazole core (37 and 38) is depicted in Scheme 4. In
this synthesis, the formyl group was protected as a 1,3-dioxolane
(32 and 33) initially in the synthetic sequence in order to achieve
a clean and regioselective vicarious nucleophilic substitution.18
A
O
O
O
O
Ar
Ar
Ar
O
b
c
O
a
S
H
S
H
S
O
O
O
O
O
O
NO2
33
NO2
NO2
NH2
34
35
32
O
S
O
Ar
O
Ar
S
R
N
O
O
d
e
H
R
N
R'
N
N
N
H
N
H
37
36
f
O
Ar
O
S
N
N
HN
N
H
38
Scheme 4. Reagents and conditions: (a) ArSO2CH2Cl, KOtBu, THF, 80%; (b) HCl, THF, 95%; (c) H2, Pd/C, MeOH, 95%; (d) (i) NaNO2, HCl, (ii) NaHCO3, 80%; (e) 1,2-diamines,
NaBH(OAc)3, 1,2-dichloroethane; (f) (i) 1-Boc-piperazine, NaBH(OAc)3, 1,2-dichloroethane, (ii) TFA, CH2Cl2.

K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
653
I
I
I
H
N
O2N
H2N
c
a
b
N
N
N
N
N
N
N
Boc
H
H
H
40
12
39
O
Ar
S
Ar
Ar
O
S
H
N
S
H
H
N
N
e, f
d
N
N
N
HN
HN
N
N
H
N
N
Boc
H
H
42
41
18 (5-position)
Scheme 5. Reagents and conditions: (a) SnCl2, EtOH; (b) 1-N-Boc-4-piperidone, NaBH(OAc)3, 1,2-dichloroethane; (c) ArSH, CuI, K2CO3, ethylene glycol, iPrOH, 70–90%; (d)
TFA, CH2Cl2, 90%; (e) HCl, MeOH; (f) oxone, MeOH/H2O.
amino group allows installation of the amino side chains such as
4-piperidinylamino side chain as exemplified in Scheme 5 through
reductive amination or other straightforward chemical transfor-
mations. A variety of thiols were then coupled with 40 to provide
the needed sulfides 41. Our initial attempts to oxidize sulfides 41
to their corresponding sulfones with a number of oxidants such
as mCPBA and H2O2 under a variety of reaction conditions were
not fruitful as the reactions gave complex mixtures with over-oxi-
dized products. To reduce the electron-rich nature of the sulfides
41 in order to potentially prevent undesired oxidations, the Boc
protecting group was removed and the resulting piperidines 42
were converted to their HCl salts. Oxidation of HCl salts of 42 with
oxone went smoothly to provide clean sulfone products 18 (5-po-
sition, Scheme 5).
The 3-sulfonylindazole target compounds 17–24, 31, 37, 38
were evaluated for their binding affinity to human 5-HT6 receptor
in a standard competition binding assay.21 The results are summa-
rized in Tables 1–3.
To allow for the full exploration of the SAR of the amine side
chains (Tables 1 and 2), we initially chose derivatives bearing the
1-naphthalenesulfonyl group. The basis of this was founded in our
earlier determination that this particular sulfonyl group has been
shown to be one of the optimal sulfonyl groups for a number of clas-
ses of 5-HT6 ligands with related cores.22–24 Compounds with a vari-
ety of amino groups at the 4–7 positions of the indazole core were
synthesized in order to identify the optimal amine side chain loca-
tion for 5-HT6 activity. Data obtained for 4-piperidinylamino
indazoles (18a–d), 3-piperidinylamino indazoles (19a–d), and 4-
piperidinylmethylamino indazoles (20a–d) (Table 1) provided a
consistent and clear SAR trend for the amine side chain position in
the indazole. For all three amine side chains in 18–20, the 5-position
provided the most potent compounds (i.e., Ki = 0.7, 1.7, and 3.5 nM
for 18b, 19b, and 20b, respectively), as compared to other positions.
While the 4-position (Ki = 2.8, 4.2, and 9.5 nM for 18a, 19a, and 20a,
respectively) was only slightly less potent than the 5-position, the 6-
and 7-positions were significantly less potent with up to 70-fold
reduction in affinity (Ki = 53 and 30 nM for 18c and 18d, respec-
tively). The preference for certain positions of the amino side chain
on the heterocyclic template further underscores our hypothesis
that the relative positions of the basic amine and the arylsulfonyl
pharmacophores, but not the chemical nature of the template, are
important for effective interaction with the 5-HT6 receptor.11,13
Although it varies slightly among a number of heterocyclic tem-
plates, in general it appears that the optimal angle for basic amine/
template/sulfonyl group interaction with the 5-HT6 receptor is
around 120°.11 Further support that derivatives substituted at the
5-position are optimal in this class is seen from the data for the
amide derivatives 21a–c and 23a–c depicted in Table 2. In this case,
while the 5-position provided compounds 21a and 23a with a
potency of 1.5 and 1.1 nM, respectively, the corresponding 6- and
7-position analogs afforded compounds with significant loss of
potency (i.e., Ki = 24 and 31 nM for 21b and 23b, respectively).
Now with the amine position optimization complete, a number
of different amino side chains were explored in order to identify
Table 1
SAR of the amino side chains of 3-sulfonylindazoles 17–20 and 37–38
b
Compound
Position
R
R0
Ar
Kia (nM)
IC50 (nM)
Imax (%)
18a
19a
20a
17a
17b
17c
18b
19b
20b
17d
18c
19c
20c
17e
18d
19d
20d
37a
37b
38a
4
4
4
5
5
5
5
5
5
6
6
6
6
7
7
7
7
5
5
5
—
—
—
H
Me
(R)-iPr
—
—
—
H
—
—
—
H
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
H
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
2.8
4.2
9.5
6.7
1.4
4.3
0.7
1.7
3.5
17
53
57
44
17
30
66
17
12
56
88
21
13
30
103
15
95
174
87
—
—
—
93
—
—
92
98
95
100
100
99
100
99
98
97
—
—
—
100
—
—
87
156
91
19
96
100
94
100
H
CH3
—
CH3
—
14
0.24
a
Displacement of [3H]-LSD binding to cloned human 5-HT6 receptors stably expressed in HeLa cells.21 All compounds tested were HCl salts.
Ki values were determined in triplicate.
b
Imax is defined as the percentage of maximal antagonism as compared to that obtained with SB-271047.

654
K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
Table 2
SAR of the amino side chains of 3-sulfonylindazoles 21–24 and 31
b
Compound
Position
R
Ar
Kia (nM)
IC50 (nM)
Imax (%)
21a
23a
21b
22a
22b
22c
23b
21c
22d
22e
22f
5
5
6
6
6
6
6
7
7
7
7
7
7
5
5
—
—
—
CH3
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1.5
1.1
24
44
65
12
31
3.4
4.8
27
24
28
9.8
2.9
107
3.8
8.2
456
—
—
90
—
23
137
—
—
—
100
100
96
—
—
100
—
100
99
—
—
—
CH3CH2
–CH2CH2CH2CH2CH2–
—
—
CH3
CH3CH2
–CH2CH2CH2CH2CH2–
—
23c
24a
31a
31b
—
CH3
48
103
—
99
98
—
–CH2CH2CH2CH2CH2–
a
Displacement of [3H]-LSD binding to cloned human 5-HT6 receptors stably expressed in HeLa cells.21 All compounds tested were HCl salts.
Ki values were determined in triplicate.
b
Imax is defined as the percentage of maximal antagonism as compared to that obtained with SB-271047.
Table 3
slightly increased potency (Table 1), and a reduced aniline charac-
ter, something that caused us some pause. The comparable potency
among 18b, 23a, and 38a indicates that the linkage between the
basic terminal amine and the indazole template has little effect
on 5-HT6 affinity. Indeed, reverse amide 31a also displayed great
potency (Ki = 2.9 nM, Table 2) and this further underscores the lack
of importance of the linkage for receptor affinity. The effect of
N-substitution on the terminal amine was also briefly investigated.
To that end, we quickly discovered that for the 5-position analogs
small groups (i.e., 31a) are tolerated, but larger groups (i.e., 31b)
significantly reduce potency. Not surprisingly we found that in
general this trend holds for the other positional isomers, such as
6- and 7-positions, but it is somewhat less pronounced (all data
not shown).
SAR of the sulfonyl groups of 3-sulfonylindazoles 18
a
b
Compound
Position
Ar
Ki (nM)
IC50 (nM)
Imax (%)
18b
18e
18f
18g
18h
18i
18j
18k
18l
5
5
5
5
5
5
5
5
5
5
5
1-Naph
Ph
3-F-Ph
0.7
3.1
6.7
1.0
0.8
6.3
2.3
1.0
1.5
9.8
0.6
15
125
94
12
19
118
44
14
27
126
16
100
100
100
100
100
99
99
99
86
96
3-Cl-Ph
3-Me-Ph
4-F-Ph
4-Cl-Ph
4-iPr-Ph
4-CF3-Ph
4-MeO-Ph
2-Naph
18m
18n
97
a
Displacement of [3H]-LSD binding to cloned human 5-HT6 receptors stably
expressed in HeLa cells.21 All compounds tested were HCl salts. Ki values were
As per our optimization strategy, select compounds from Tables
1 and 2 were further evaluated for their functional activity in a
5-HT6 receptor cyclase assay.21 The functional antagonism was
determined against natural 5-HT6 agonist 5-HT and the efficacy
was expressed as Imax in percentage of maximal antagonism as
obtained with SB-271047. All of the 3-sulfonylindazole derivatives
evaluated showed full antagonism as determined by blockage of
5-HT induced cyclic AMP (cAMP) formation. The data is summa-
rized in Tables 1 and 2.
Based on the binding and functional data, the 4-piperidinylami-
no substituted analog 18b (Table 1) was identified as one of the
optimal amine side chain derivatives and was used to further ex-
plore the SAR of the sulfonyl group at 3-position of the indazole
core. A number of arylsulfonyl groups were explored for this pur-
pose and the data is summarized in Table 3. While the benzenesul-
fonyl group (18e) resulted in a 4–5-fold reduction in potency as
compared to its 1-naphthalenesulfonyl analog 18b, certain substi-
tution on the phenyl ring such as 3-Cl (18g), 3-Me (18h), or 4-iPr
(18k) provided compounds with comparable potency to that of
18b in both binding and cyclase functional assays. Note also that
the 2-naphthalenesulfonyl derivative 18n also displayed similar
potency to that of 18b.
determined in triplicate.
Imax is defined as the percentage of maximal antagonism as compared to that
obtained with SB-271047.
b
the optimal substitution at the 5-position. These include acyclic
amines 17a–c and 37, cyclic amines 18–20 and 38, amides 21a
and 23a, and reverse amides 31a–b (Tables 1 and 2). In general,
these compounds displayed high 5-HT6 affinity, with many exam-
ples possessing Ki values below 10 nM. Among these compounds,
unsubstituted ethylenediamine 17a was noted as a milestone
derivative with potency of 6.7 nM (Table 1). Substitution with a
methyl group at the
a-position of the this basic amine sidechain
(17b) further improved the potency by fivefold. Substitution with
a bulkier iPr group (17c) failed to improve the potency compared
to its methyl analog 17b. Attempts to explore the scope by inser-
tion of a methylene group between the aniline nitrogen and the
indazole template of 17a generated compound 37a with twofold
reduction in potency. Dimethylation of the terminal nitrogen of
37a resulted in 37b with comparable potency (Table 1), although
one might predict inferior metabolic stability. After further inves-
tigation of the diversity of sidechains and substitution patterns, it
became apparent to us that compounds with a cyclic amine at
5-position were more potent than their acyclic analogs. One of
the most potent compounds identified in this 3-sulfonylindazole
series was the 4-piperidinyl derivative 18b which displayed a po-
tency of 0.7 nM (Table 1). Furthermore, we soon discovered that
insertion of a carbonyl group between the piperidine and aniline
nitrogen of 18b, affording 23a (Table 2), gives an amide analog
with comparable 5-HT6 affinity. Moving the aniline nitrogen into
the cyclic amine ring afforded piperazine derivative 38a with
In line with our compound advancement strategy, a number of
compounds which displayed excellent potency in both binding and
cyclase functional assays were further profiled for their binding
selectivity against a panel of receptors including several other
5-HT receptor subtypes, adrenergic
a2A and dopamine D2 recep-
tors and the data is summarized in Table 4. In general, all three
compounds highlighted showed >400-fold selectivity over all the
receptors with the exception of 5-HT2B in the cases of 18g, 21a,
and 23a. This was initially some concern to us as 5-HT2B agonism

K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
655
Table 4
Selectivity of selected 3-sulonfylindazole derivativesa
Compound
5-HT6 (nM)
5-HT1A (nM)
5-HT1B (nM)
5-HT1D (nM)
5-HT2B (nM)
5-HT2C (nM)
5-HT7 (nM)
a
2a (nM)
D2 (nM)
18b
18g
18k
18n
21a
23a
0.5
1.0
1.0
0.6
1.5
1.1
>5000
455
859
4347
>5000
3011
>5000
1659
2726
>5000
>5000
>5000
>5000
410
1496
>5000
>5000
1340
675
155
1760
675
344
33
>5000
2427
1767
>5000
573
>5000
3970
3216
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
>5000
a
Ki values were determined in triplicate.
activity has been indicated by several studies to possibly be
responsible for adverse cardiovascular effects associated with
some serotonin ligands.25 To rule out the adverse potential of these
analogs, they were then screened for their potential functional
agonist activity in a 5-HT2B FLIPR assay.25 To our satisfaction, no
agonist activity was observed for all compounds at concentrations
(104 ml) solution of 5-nitroindazole (8.50 g, 52.13 mmol) at room
temperature and stirred for 4 days. The reaction mixture was then
poured into NaHSO3 solution (11.06 g in 200 ml water). The brown
color faded away, and the formed yellow precipitate was filtered
and washed with water and dried in vacuo to provide the title
compound as
a
yellow solid (14.74 g, 98% yield). 1H NMR
of 0.1 nM–10
(18b, 18g, 18k, 18n, 21a, and 23a) have excellent water solubility
(>100 g/ml) and microsomal stability (t1/2 >30 min both rat and
l
M in this functional assay. All the six compounds
(400 MHz, CDCl3) d 7.73 (d, J = 9.2 Hz, 1H) 8.22 (dd, J = 9.2 and
2.2 Hz, 1H) 8.30 (d, J = 2.0, 1H). MS (ES+) m/e 290 (MH+).
l
human). None of them was shown to be P-gp substrates. Though
in general this class of compounds displayed poor brain penetra-
tion (brain/plasma <0.2), the free drug levels at multiple folds of
the 5-HT6 receptor potency was easily achieved in the brain due
to the low protein binding (<80%) of the compounds. In deed,
compounds 18b and 23a demonstrated in vivo efficacy to signifi-
cantly block scopolamine-induced memory deficit following
administration at 10 mg/kg orally in rats in a novel object recogni-
tion assay (NOR) (data not shown).26
4.3. 3-(Naphthalen-1-ylsulfanyl)-5-nitro-1H-indazole (13b)
A mixture of 3-iodo-5-nitro-1H-indazole (10.00 g, 34.60 mmol),
1-naphtylenethiol (5.54 g, 34.60 mmol), CuI (0.659 g, 3.46 mmol),
ethylene glycol (4.30 g, 69.20 mmol) in isopropanol (49.40 ml)
was heated at 90 °C under nitrogen overnight, cooled, diluted with
30% MeOH in CH2Cl2, and passed through a pad of silica gel. The
solution was concentrated in vacuo and purified by chromatogra-
phy with 1% MeOH in CH2Cl2 to provide the title compound
(5.5 g, 49%). MS (ES+) m/e 322 (MH+).
3. Summary
4.4. 3-(Naphthalen-1-sulfonyl)-1H-indazol-5-ylamine (15b)
In summary, we have identified a novel series of 3-sulfonylin-
dazole derivatives as potent and selective 5-HT6 ligands. Synthesis
and detailed SAR of this class of compounds has been reported. The
compounds were shown to be full antagonists in a cyclic AMP
functional assay. Further profiling of this class of compounds,
including efficacy in a number of in vivo behavioral assays, will
be detailed in subsequent reports.
A mixture of 3-(naphthalen-1-ylsulfanyl)-5-nitro-1H-indazole
(5.50 g, 17.11 mmol) and 3-chloroperoxybenzoic acid (17.91 g,
103.80 mmol) in CHCl3 (115 ml) was stirred at room temperature
for 4 h, diluted with EtOAc, washed with Na2SO3 solution, water,
brine, dried over Na2SO4, and concentrated in vacuo to afford the
crude intermediate which was carried out directly for the next step
reaction without further purification.
The mixture of the crude nitro intermediate, tin mossy (15.79 g,
133.01 mmol) in MeOH and conc. hydrochloric acid was heated at
60 °C, diluted with CH2Cl2, and neutralized to basic with NaOH or
Na2CO3 solution. The aqueous layer was extracted with CH2Cl2.
Combined organic layers were dried over Na2SO4 and concentrated
in vacuo followed by chromatography purification to provide the
title compound (2.50 g, 45% overall yield). 1H NMR (400 MHz,
CDCl3) d 7.28 (dd, J = 8.9 and 1.6 Hz, 1H) 7.56–7.78 (m, 5H) 8.04
(d, J = 1.7 Hz, 1H) 8.28 (d, J = 8.2 Hz, 1H) 8.47 (dd, J = 7.4 and
1.1 Hz, 1H) 8.73 (d, J = 8.5 Hz, 1H) 14.4 (s, 1H). MS (ES+) m/e 324
(MH+).
4. Experimental section
4.1. General
All solvents and reagents were obtained commercially and used
as received. 1H and 13C NMR spectra were recorded on a Varian
instrument in the cited deuterated solvents. Chemical shifts are gi-
ven in ppm, and coupling constants are in hertz. All final compounds
were purified by flash chromatography using 220–400 mesh silica
gel or reverse-phase HPLC with CH3CN/water as the solvents.
Thin-layer chromatography was done on silica gel 60 F-254 (0.25-
nm thickness) plates. Visualization was accomplished with UV light
and/or 10% phosphomolybdic acid in ethanol. Nominal (low resolu-
tion) mass spectra were acquired on either a Waters LCT or an Ap-
plied Biosystems API 3000 mass spectrometer. High resolution
mass spectra (HRMS) were acquired on either a Waters LCT or an
Agilent TOF mass spectrometer. All other LC–MS experiments were
done on an Agilent 1100 HPLC coupled with an Agilent single quad-
rupole mass spectrometer. Compound purity was determined by a
LC–MS with 230 nM and 254 nM wavelengths. All final compounds
reported here have purity P95%.
4.5. N1-3-(Napthalene-1-sulfonyl-1H-indazol-5-yl)-ethane-1,2-
diamine HCl (17a)
A mixture of 3-(naphthalen-1-sulfonyl)-1H-indazol-5-ylamine
hydrochloride (334 mg, 0.93 mmol), 2-oxazolidone (81 mg, 0.93
mmol), and diethylene glycol monomethyl ether (0.16 ml) was
heated at 170 °C overnight, diluted with MeOH, and purified by re-
verse phase HPLC followed by conversion to HCl salt by treatment
with HCl solution to provide the title compound as a white
solid (86 mg, 21% yield): 1H NMR (400 MHz, DMSO-d6) d 3.02
(q, J = 6.1 Hz, 2H) 3.32 (t, J = 6.1 Hz, 2H) 6.82 (d, J = 1.7 Hz, 1H)
6.86–6.99 (m, 1H) 7.42 (d, J = 9.0 Hz, 1H) 7.55–7.70 (m, 2H) 7.70–
7.82 (m, 1H) 7.93–8.15 (m, 4H) 8.28 (d, J = 8.0 Hz, 1H) 8.53 (dd,
J = 7.4, 1.1 Hz, 1H) 8.78 (d, J = 8.5 Hz, 1H) 13.93 (br s, 1H); MS (ES+)
4.2. 3-Iodo-5-nitro-1H-indazole (12b)
Iodine (26.46 g, 104.27 mmol) and potassium hydroxide pellets
(11.70 g, 208.5 mmol) were successively added into
a DMF

656
K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
4.10. 3-(Naphthalen-1-ylsulfonyl)-N-(piperidin-4-yl)-1H-indazol-
4-amine HCl (18a)
m/e 367 (M+H)+; HRMS Calcd for (M+H)+: C19H19N4O2S+: 367.1222,
Found: 367.1223.
The title compound was prepared following the procedure for the
synthesis of 18b. 1H NMR (400 MHz, DMSO-d6) d ppm 1.61–1.86 (m,
2H) 2.24 (d, J = 10.7 Hz, 2H) 2.96–3.20 (m, 2H) 3.34 (d, J = 12.9 Hz,
2H) 3.69–3.95 (m, 1H) 6.40 (d, J = 7.8 Hz, 1H) 6.72 (br s, 1H) 6.78
(m, J = 8.0 Hz, 1H) 7.24 (t, J = 7.9 Hz, 1H) 7.54–7.75 (m, 2H) 7.86 (t,
J = 7.8 Hz, 1H) 8.04–8.16 (m, 1H) 8.36 (d, J = 8.0 Hz, 1H) 8.39–8.48
(m, 1H) 8.61–8.73 (m, 1H) 8.74–8.88 (m, 1H) 8.83–8.89 (m, 1H)
14.02 (s, 1H); MS (ES+) m/e 407 (M+H)+; HRMS Calcd for (M+H)+:
4.6. N1-(3-(Naphthalen-1-ylsulfonyl)-1H-indazol-6-yl)propane-
1,2-diamine HCl (17b)
A mixture of 3-(naphthalen-1-sulfonyl)-1H-indazol-5-ylamine
(500 mg, 1.55 mmol), N-t-Boc-alanine (381 mg, 2.01 mmol), 1-[3-
(dimethylamino)propyl)]-3-ethylcarbodimide hydrochloride (386
mg, 2.01 mmol) in CH3CN was stirred at room temperature over-
night, concentrated, and purified by chromatography with 3%
MeOH in CH2Cl2 to provide the title compound (110 mg, 48%),
characterized by NMR and mass spectral analyses.
C
22H23N4O2S+: 407.1535, Found: 407.1539.
4.11. [3-(Naphthalen-1-sulfonyl)-1H-indazol-5-yl]-piperidin-4-
{1-[3-(Naphthalene-1-sulfonyl)-1H-indazol-5-ylcarbamoyl]-
ethyl}-carbamic acid tert-butyl ester (120 mg, 0.37 mmol) was
subjected to TFA at room temperature for 2 h and concentrated
to dryness. The resulting residue was heated with BH3 in THF
(1 M, 4.5 ml) at reflux overnight. To the mixture was slowly added
HCl (6 M, 1 ml). The resulting solution was heated at 80 °C for
20 min, concentrated, and purified by reverse phase HPLC followed
by treatment with HCl solution to provide the title compound
(35 mg, 38%). 1H NMR (400 MHz, DMSO-d6) d ppm 1.28 (d,
J = 6.3 Hz, 3H) 3.12–3.23 (m, 1H) 3.24–3.32 (m, 1H) 3.32–3.41
(m, 1H) 6.82 (d, J = 1.7 Hz, 1H) 6.95 (dd, J = 9.1, 2.1 Hz, 1H) 7.41
(d, J = 9.0 Hz, 1H) 7.53–7.71 (m, 2H) 7.71–7.83 (m, 1H) 7.93–8.18
(m, 4H) 8.28 (d, J = 8.3 Hz, 1H) 8.53 (dd, J = 7.4, 1.1 Hz, 1H) 8.78
(d, J = 8.1 Hz, 1H) 13.91 (br s, 1H); MS (ES+) m/e 381 (M+H)+; HRMS
Calcd for (M+H)+: C20H21N4O2S+: 381.1379, Found: 381.1374.
yl-amine HCl (18b)
A mixture of 3-(naphthalen-1-sulfonyl)-1H-indazol-5-ylamine
(400 mg, 1.24 mmol), 1-Boc-4-piperidone (493 mg, 2.47 mmol),
sodium triacetoxyborohydride (524 mg, 2.47 mmol), and acetic
acid (149 mg, 2.47 mmol) in 1,2-dichloroethane was stirred at
room temperature overnight, diluted with CH2Cl2, washed with
water, dried over Na2SO4, concentrated, and purified by chroma-
tography with 1% MeOH in CH2Cl2 to provide the title compound
(390 mg, 62% yield). MS (ES+) m/e 506 (M+H)+.
4-[3-(Naphthalen-1-sulfonyl)-1H-indazol-5-ylamino]-piperi-
dine-1-carboxylic acid tert-butyl ester (390 mg, 0.77 mmol) was
subjected to 1:1 TFA/CH2Cl2 (v/v) at room temperature for 2 h.
The reaction mixture was concentrated to dryness and treated with
HCl to provide the title compound (359 mg, 98%), characterized by
NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6) d
ppm 1.52–1.77 (m, 2H) 2.01 (d, J = 11.2 Hz, 2H) 2.94–3.14 (m,
2H) 3.32 (d, J = 12.9 Hz, 2H) 3.61 (t, J = 9.4 Hz, 1H) 6.90–7.16 (m,
2H) 7.46 (d, J = 8.3 Hz, 1H) 7.55–7.68 (m, 2H) 7.74 (t, J = 7.9 Hz,
1H) 8.01–8.11 (m, 1H) 8.29 (d, J = 8.1 Hz, 1H) 8.54 (dd, J = 7.4,
1.1 Hz, 1H) 8.75 (d, J = 8.3 Hz, 1H) 8.77–8.87 (m, 1H) 8.86–9.03
(m, 1H) 14.02 (br s, 1H); MS (ES+) m/e 407 (M+H)+; HRMS Calcd
for (M+H)+: C22H23N4O2S+: 407.1541, Found: 407.1534.
4.7. (S)-3-Methyl-N1-[3-(naphthalen-1-sulfonyl)-1H-indazol-5-
yl]-butane-1,2-diamine HCl (17c)
The title compound was prepared following the procedure for
the synthesis of 17b and employing (S)-t-Boc-Valine as the starting
material. 1H NMR (300 MHz, DMSO-d6) d ppm 1.04 (d, J = 6.9 Hz,
6H) 1.89–2.16 (m, 1H) 3.02–3.25 (m, 2H) 3.25–3.41 (m, 1H) 6.83
(d, J = 1.7 Hz, 1H) 6.96 (dd, J = 9.1, 2.0 Hz, 1H) 7.43 (d, J = 9.1 Hz,
1H) 7.52–7.70 (m, 2H) 7.70–7.82 (m, 1H) 7.85–8.17 (m, 4H) 8.29
(d, J = 8.2 Hz, 1H) 8.51 (dd, J = 7.3, 1.1 Hz, 1H) 8.66–8.88 (m, 1H)
13.92 (br s, 1H); MS (ES+) m/e 409 (M+H)+; HRMS Calcd for
(M+H)+: C22H25N4O2S+: 409.1692, Found: 409.1693.
4.12. 3-(Naphthalen-1-ylsulfonyl)-N-(piperidin-4-yl)-1H-indazol-
6-amine HCl (18c)
The title compound was prepared following the procedure for the
synthesis of 18b. 1H NMR (400 MHz, DMSO-d6) d ppm 1.44–1.71 (m,
2H) 2.02 (d, J = 13.7 Hz, 2H) 2.85–3.07 (m, 2H) 3.25 (d, J = 9.5 Hz, 2H)
3.48–3.67 (m, 1H) 6.48 (s, 1H) 6.77 (dd, J = 8.9, 1.6 Hz, 1H) 7.49–7.69
(m, 3H) 7.74 (t, J = 8.1 Hz, 1H) 7.97–8.16 (m, 1H) 8.29 (d, J = 8.3 Hz,
1H) 8.50 (dd, J = 7.3, 1.2 Hz, 1H) 8.64–9.03 (m, 3H) 13.52 (s, 1H);
MS (ES+) m/e 407 (M+H)+; HRMS Calcd for (M+H)+: C22H23N4O2S+:
407.1535, Found: 407.1535.
4.8. N1-(3-(Naphthalen-1-ylsulfonyl)-1H-indazol-6-yl)ethane-
1,2-diamine HCl (17d)
The title compound was prepared following the procedure for
the synthesis of 17a. 1H NMR (400 MHz, DMSO-d6) d ppm 2.93–
3.01 (m, 2H) 3.29 (t, J = 6.2 Hz, 2H) 6.44 (d, J = 1.5 Hz, 1H) 6.75
(dd, J = 8.9, 1.8 Hz, 1H) 7.52–7.69 (m, 3H) 7.75 (t, J = 8.1 Hz, 1H)
7.86–8.16 (m, 4H) 8.29 (d, J = 8.3 Hz, 1H) 8.50 (dd, J = 7.4, 1.1 Hz,
1H) 8.77 (d, J = 8.3 Hz, 1H) 13.58 (s, 1H); MS (ES+) m/e 367
(M+H)+; HRMS Calcd for (M+H)+: C19H19N4O2S+: 367.1222, Found:
367.1224.
4.13. 3-(Naphthalen-1-ylsulfonyl)-N-(piperidin-4-yl)-1H-indazol-
7-amine HCl (18d)
The title compound was prepared following the procedure for the
synthesis of 18b. 1H NMR (400 MHz, DMSO-d6) d ppm 1.57–1.80 (m,
2H) 1.98–2.17 (m, 2H) 2.89–3.11 (m, 2H) 3.23–3.45 (m, 2H) 3.58–
3.83 (m, 1H) 6.48 (dd, J = 6.2, 2.3 Hz, 1H) 6.95–7.16 (m, 2H) 7.52–
7.71 (m, 2H) 7.70–7.81 (m, 1H) 8.05 (d, J = 7.6 Hz, 1H) 8.28 (d,
J = 8.3 Hz, 1H) 8.53 (dd, J = 7.4, 1.1 Hz, 1H) 8.61–8.73 (m, 2H) 8.76
(d, J = 8.8 Hz, 1H) 14.51 (br s, 1H); MS (ES+) m/e 407 (M+H)+; HRMS
Calcd for (M+H)+: C22H23N4O2S+: 407.1535, Found: 407.1535.
4.9. N1-(3-(Naphthalene-1-ylsulfonyl)-1H-indazol-7-yl)ethane-
1,2-diamine HCl (17e)
The title compound was prepared following the procedure for the
synthesis of 17a. 1H NMR (400 MHz, DMSO-d6) d ppm 2.98–3.08 (m,
2H) 3.45 (t, J = 6.1 Hz, 2H) 6.47 (d, J = 6.8 Hz, 1H) 7.01–7.19 (m, 2H)
7.52–7.70 (m, 2H) 7.76 (t, J = 7.8 Hz, 1H) 7.94 (br s, 3H) 8.05 (d,
J = 8.0 Hz, 1H) 8.53 (d, J = 7.3 Hz, 1H) 8.76 (d, J = 8.5 Hz, 1H) 14.26
(s, 1H); MS (ES+) m/e 367 (M+H)+; HRMS Calcd for (M+H)+:
4.14. 3-(Naphthalen-1-ylsulfonyl)-N-(piperidin-3-yl)-1H-indazol-
4-amine HCl (19a)
The title compound was prepared following the procedure for the
19H19N4O2S+: 367.1222, Found: 367.1221.
synthesis of 18b. 1H NMR (400 MHz, DMSO-d6) d ppm 1.63–1.79 (m,
C

K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
657
1H) 1.78–1.94 (m, 1H) 1.92–2.03 (m, 1H) 2.18 (d, J = 9.5 Hz, 1H)
2.69–2.85 (m, 1H) 2.87–3.08 (m, 1H) 3.29 (d, J = 12.0 Hz, 1H) 3.49
(d, J = 12.7 Hz, 1H) 3.79–4.02 (m, 1H) 6.45 (d, J = 7.8 Hz, 1H) 6.70
(d, J = 7.1 Hz, 1H) 6.83 (d, J = 8.0 Hz, 1H) 7.26 (t, J = 8.0 Hz, 1H)
7.56–7.72 (m, 2H) 7.75–7.85 (m, 1H) 8.03–8.16 (m, 1H) 8.35 (d,
J = 8.3 Hz, 1H) 8.44 (dd, J = 7.4, 1.1 Hz, 1H) 8.62–8.74 (m, 1H) 9.04
(br s, 2H) 14.06 (s, 1H); MS (ES+) m/e 407 (M+H)+; HRMS Calcd for
(M+H)+: C22H23N4O2S+: 407.1535, Found: 407.1539.
2H) 1.71–1.86 (m, 1H) 1.92 (d, J = 13.5 Hz, 2H) 2.74–2.91 (m, 2H)
2.96 (d, J = 6.4 Hz, 2H) 3.16–3.45 (m, 2H) 6.78 (br s, 1H) 6.95 (d,
J = 9.3 Hz, 1H) 7.38 (d, J = 9.2 Hz, 1H) 7.54–7.70 (m, 2H) 7.76 (t,
J = 7.7 Hz, 1H) 7.96–8.15 (m, 1H) 8.29 (d, J = 8.2 Hz, 1H) 8.37–8.63
(m, 2H) 8.64–8.93 (m, 2H) 13.89 (br s, 1H); MS (ES+) m/e 421
(M+H)+; HRMS Calcd for (M+H)+: C23H25N4O2S+: 421.1692, Found:
421.1696.
4.20. 3-(Naphthalen-1-ylsulfonyl)-N-(piperidin-4-ylmethyl)-1H-
indazol-6-amine HCl (20c)
4.15. 3-(Naphthalen-1-ylsulfonyl)-N-(piperidin-5-yl)-1H-indazol-
4-amine HCl (19b)
The title compound was prepared following the procedure for the
synthesis of 18b. 1H NMR (400 MHz, DMSO-d6) d ppm 1.18–1.46 (m,
2H) 1.75–1.94 (m, 3H) 2.70–2.86 (m, 2H) 2.93 (d, J = 6.1 Hz, 2H) 3.22
(d, J = 11.7 Hz, 2H) 6.37 (d, J = 1.2 Hz, 1H) 6.74 (dd, J = 8.9, 1.8 Hz, 1H)
7.56 (d, J = 9.0 Hz, 1H) 7.58–7.68 (m, 2H) 7.74 (t, J = 8.1 Hz, 1H) 8.00–
8.14 (m, 1H) 8.28 (d, J = 8.3 Hz, 1H) 8.42–8.64 (m, 2H) 8.66–8.95 (m,
2H) 13.47 (s, 1H); MS (ES+) m/e 421 (M+H)+; HRMS Calcd for (M+H)+:
C23H25N4O2S+: 421.1692, Found: 421.1694.
The title compound was prepared following the procedure for the
synthesis of 18b. 1H NMR (400 MHz, DMSO-d6) d ppm 1.38–1.58 (m,
1H) 1.72–1.86 (m, 1H) 1.87–2.03 (m, 2H) 2.56–2.72 (m, 1H) 2.78–
2.97 (m, 1H) 3.14–3.35 (m, 2H) 3.64–3.80 (m, 1H) 6.84 (s, 1H) 6.92
(dd, J = 9.1, 1.6 Hz, 1H) 7.40 (d, J = 9.0 Hz, 1H) 7.52–7.72 (m, 2H)
7.79 (t, J = 7.8 Hz, 1H) 8.05 (d, J = 7.6 Hz, 1H) 8.27 (d, J = 8.1 Hz, 1H)
8.61 (d, J = 6.8 Hz, 1H) 8.78 (d, J = 8.5 Hz, 1H) 9.14 (br s, 2H) 13.93
(br s, 1H); MS (ES+) m/e 407 (M+H)+; HRMS Calcd for (M+H)+:
C
22H23N4O2S+: 407.1535, Found: 407.1540.
4.21. 3-(Naphthalen-1-ylsulfonyl)-N-(piperidin-4-ylmethyl)-1H-
indazol-7-amine HCl (20d)
4.16. 3-(Naphthalen-1-ylsulfonyl)-N-(piperidin-6-yl)-1H-indazol-
6-amine HCl (19c)
The title compound was prepared following the procedure for the
synthesis of 18b. 1H NMR (400 MHz, DMSO-d6) d ppm 1.22–1.33 (m,
2H) 1.71–1.87 (m, 3H) 2.74–2.84 (m, 2H) 3.07 (d, J = 6.2 Hz, 2H) 3.22
(d, J = 12.3 Hz, 2H) 6.42 (d, J = 2.6 Hz, 1H) 7.05 (s, 1H) 7.54–7.62 (2,
2H) 7.70–7.75 (m, 2H) 8.01–8.15 (m, 2H) 8.26 (d, J = 8.3 Hz, 1H)
8.43–8.51 (m, 2H) 8.72 (dd, J = 8.4 and 1.0 Hz, 1H). MS (ES+) m/e
421 (M+H)+; HRMS Calcd for (M+H)+: C23H25N4O2S+: 421.1692,
Found: 421.1690.
The title compound was prepared following the procedure for the
synthesis of 18b. 1H NMR (400 MHz, DMSO-d6) d ppm 1.36–1.59 (m,
1H) 1.59–1.81 (m, 1H) 1.79–2.05 (m, 2H) 2.56–2.72 (m, 1H) 2.72–
2.96 (m, 1H) 3.07–3.22 (m, 1H) 3.28 (d, J = 12.4 Hz, 1H) 3.50–3.84
(m, 1H) 6.48 (d, J = 1.5 Hz, 1H) 6.76 (dd, J = 9.0, 1.9 Hz, 1H) 7.50–
7.70 (m, 3H) 7.70–7.83 (m, 1H) 7.97–8.16 (m, 1H) 8.29 (d,
J = 8.3 Hz, 1H) 8.50 (dd, J = 7.3, 1.2 Hz, 1H) 8.78 (d, J = 8.5 Hz, 1H)
8.96 (br s, 2H) 13.58 (s, 1H); MS (ES+) m/e 407 (M+H)+; HRMS Calcd
for (M+H)+: C22H23N4O2S+: 407.1535, Found: 407.1536.
4.22. 2-(4-Nitrophenyl)-1,3-dioxolane (32)
p-Nitrobenzaldehyde (1.5 g, 10 mmol) and ethyleneglycol
(20 mmol) in benzene (100 ml) was refluxed for 6 h in the presence
of p-toluenesulfonic acid (0.38 g, 2 mmoles) with the Dean–Stark
adapter. After completion, the reaction mixture was cooled down
and benzene was removed in vacuo. The crude mixture was
quenched with saturated sodium bicarbonate solution and ex-
tracted with ethyl acetate. The organic layer was separated, washed
with water and dried over sodium sulfate. Evaporation of the solvent
afforded the target material as pale crystalline solid (1.85 g, 95%). MS
(ES+) m/e 196 (MH+).
4.17. 3-(Naphthalen-1-ylsulfonyl)-N-(piperidin-7-yl)-1H-indazol-
7-amine HCl (19d)
The title compound was prepared following the procedure for the
synthesis of 18b. 1H NMR (400 MHz, DMSO-d6) d ppm 1.46–1.64 (m,
1H) 1.63–1.83 (m, 1H) 1.86–1.99 (m, 1H) 1.99–2.11 (m, 1H) 2.61–
2.82 (m, 1H) 2.82–3.00 (m, 1H) 3.14–3.26 (m, 1H) 3.28–3.49 (m,
1H) 3.76–3.76 (m, 1H) 5.73 (d, J = 6.8 Hz, 1H) 6.53 (d, J = 7.1 Hz,
1H) 7.00–7.22 (m, 2H) 7.51–7.69 (m, 2H) 7.76 (t, J = 8.1 Hz, 1H)
7.96–8.12 (m, 1H) 8.29 (d, J = 8.3 Hz, 1H) 8.33–8.50 (m, 1H) 8.54
(dd, J = 7.4, 1.1 Hz, 1H) 8.57–8.71 (m, 1H) 8.75 (d, J = 8.3 Hz, 1H)
13.86 (s, 1H); MS (ES+) m/e 407 (M+H)+; HRMS Calcd for (M+H)+:
4.23. 2-[3-(Naphthalene-1-sulfonylmethyl)-4-nitro-phenyl]-[1,3]
dioxolane (33)
C
22H23N4O2S+: 407.1535, Found: 407.1536.
4.18. 3-(Naphthalen-1-ylsulfonyl)-N-(piperidin-4-ylmethyl)-1H-
A
mixture of 2-(4-nitro-phenyl)-[1,3]dioxolane (1.85 g,
indazol-4-amine HCl (20a)
9.5 mmol) and 1-chloromethane-sulfonyl-naphthalene (2.74 g,
11.4 mmol) was stirred in THF (50 ml) at ꢁ78 °C, in a round bottom
flask under nitrogen. A solution of 1 M potassium t-butoxide was
added dropwise (19 ml, 19 mmol) over a half an hour period. Tem-
perature was allowed to rise to ꢁ40 °C, and the reaction mixture
was stirred at this temperature for 5 h. The reaction mixture was
poured into cold 2 N HCl, extracted with EtOAc, dried over Na2SO4,
and concentrated under vacuum. Compound was purified by normal
phase HPLC using as eluent 40% EtOAc/hexane to afford the title
compound as an off-white solid (3.03 g, 80%). MS (ES+) m/e 400
(MH+).
The title compound was prepared following the procedure for the
synthesis of 18b. 1H NMR (400 MHz, DMSO-d6) d ppm 1.34–1.59 (m,
2H) 1.93 (d, J = 14.4 Hz, 2H) 1.97–2.11 (m, 1H) 2.77–3.01 (m, 2H)
3.19 (d, J = 6.8 Hz, 2H) 3.29 (d, J = 12.2 Hz, 2H) 6.33 (d, J = 7.8 Hz,
1H) 6.62 (br s, 1H) 6.76 (d, J = 8.0 Hz, 1H) 7.24 (t, J = 8.0 Hz, 1H)
7.54–7.71 (m, 2H) 7.71–7.86 (m, 1H) 8.01–8.21 (m, 1H) 8.35 (d,
J = 8.3 Hz, 1H) 8.43 (dd, J = 7.4, 1.1 Hz, 1H) 8.54–8.79 (m, 2H) 8.94
(d, J = 8.3 Hz, 1H) 14.02 (s, 1H); MS (ES+) m/e 421 (M+H)+; HRMS
Calcd for (M+H)+: C23H25N4O2S+: 421.1692, Found: 421.1696.
4.19. 3-(Naphthalen-1-ylsulfonyl)-N-(piperidin-4-ylmethyl)-1H-
indazol-5-amine HCl (20b)
4.24. 3-(Naphthalen-1-sulfonylmethyl)-4-nitro-benzaldehyde
(34)
The title compound was prepared following the procedure for the
A
mixture of 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-
synthesis of 18b. 1H NMR (300 MHz, DMSO-d6) d ppm 1.25–1.51 (m,
phenyl]-[1, 3] dioxolane (3.03 g, 7.6 mmol), and 2 N HCl (4 ml,

658
K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
8 mmol) in THF (30 ml) was stirred at 40 °C for 4 h. The reaction
mixture was cooled to room temperature, diluted with water, ex-
tracted with EtOAc, dried over Na2SO4, and concentrated under
vacuum to yield the title compound (2.56 g, 95%). MS (ES+) m/e
356 (MH+).
4.30. 3-Amino-N-[3-(naphthalen-1-sulfonyl)-1H-indazol-5-yl]-
propionamide HCl (21a)
A mixture of 3-(naphthalene-1-sulfonyl)-1H-indazol-5-ylamine
(500 mg, 1.55 mmol), N-Boc-b-alanine (381 mg, 2.01 mmol), 1-[3-
(dimethylamino)propyl)]-3-ethylcarbodimide hydrochloride (EDC,
386 mg, 2.01 mmol) in CH3CN was stirred at room temperature
overnight and concentrated to dryness. The resulting residue was
subjected to TFA cleavage of the Boc protecting group, concentrated,
and purified by reverse phase HPLC followed by treatment with HCl
solution to provide the title compound as a white solid (180 mg, 24%
yield). 1H NMR (400 MHz, DMSO-d6) d ppm 2.77 (t, J = 6.3 Hz, 2H)
3.11 (q, J = 6.3 Hz, 2H) 7.46–7.71 (m, 4H) 7.77 (t, J = 7.6 Hz, 1H)
7.93 (br s, 3H) 8.02–8.13 (m, 1H) 8.30 (d, J = 8.3 Hz, 1H) 8.47 (dd,
J = 7.4, 1.1 Hz, 1H) 8.50 (s, 1H) 8.78 (d, J = 8.3 Hz, 1H) 10.46 (s, 1H)
14.24 (s, 1H); MS (ES+) m/e 395 (MH+).
4.25. 4-Amino-3-(naphthalen-1-sulfonylmethyl)-benzaldehyde
(35)
A mixture of 3-(naphthalen-1-sulfonylmethyl)-4-nitro-benzal-
dehyde (2.5 g, 7.22 mmol) and 10% Pd/C in THF (10 ml) and metha-
nol (20 ml) was hydrogenated in a Parr hydrogenation bottle
(250 ml) at 52 psi overnight. The mixturewas filtered throughCelite,
and the filtrate was concentrated under vacuum to afford the title
compound as an off-white solid (2.4 g, 95%). MS (ES+) m/e 326 (MH+).
4.26. 3-(Naphthalen-1-sulfonyl)-1H-indazole-5-carbaldehyde
(36)
4.31. 3-Amino-N-(3-(naphthalen-1-ylsulfonyl)-1H-indazol-6-
yl)propanamide HCl (21b)
A mixture of 4-amino-3-(naphthalene-1-sulfonylmethyl)-benz-
aldehyde (2.4 g, 6.85 mmol) in THF (10 ml) and 4 M HCl (20 ml)
was stirred in a round bottom flask at 3 °C. A solution of sodium ni-
trite (0.49 g, 7.19 mmol) in H2O (2 ml) was added. The reaction
mixture was poured into a cold solution of saturated sodium bicar-
bonate (100 ml) and extracted with EtOAc. The extracts were dried
over Na2SO4 and concentrated under vacuum to afford the title
compound as an off white solid (1.84 g, 80%). MS (ES+) m/e 337
(MH+).
The title compound was synthesized using the same procedure
as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm 2.75 (t,
J = 6.6 Hz, 2H) 3.08 (q, J = 5.9 Hz, 2H) 7.33 (dd, J = 8.91, 1.3 Hz, 1H)
7.56–7.70 (m, 2H) 7.76 (m, J = 7.8, 7.8 Hz, 1H) 7.79 (br s, 3H) 7.89
(d, J = 8.8 Hz, 1H) 8.07 (d, J = 8.1 Hz, 1H) 8.22 (s, 1H) 8.31 (d,
J = 8.3 Hz, 1H) 8.55 (d, J = 7.3 Hz, 1H) 8.78 (d, J = 8.5 Hz, 1H) 10.53
(s, 1H) 14.10 (s, 1H); MS (ES+) m/e 395 (M+H)+; HRMS Calcd for
(M+H)+: C20H19N4O3S+: 395.1172, Found: 395.1172.
4.32. 3-Amino-N-(3-(naphthalen-1-ylsulfonyl)-1H-indazol-7-
4.27. N,N,N0-Trimethyl-N0-{[3-(1-naphthylsulfonyl)-1H-indazol-
yl)propanamide HCl (21c)
5-yl]methyl}ethane-1,2-diamine HCl (37b)
The title compound was synthesized using the same procedure
as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm 2.81 (t,
J = 6.6 Hz, 2H) 3.10 (q, J = 6.5 Hz, 2H) 7.29 (t, J = 7.8 Hz, 1H) 7.54 (d,
J = 7.6 Hz, 1H) 7.57–7.70 (m, 2H) 7.70–7.90 (m, 5H) 8.07 (d,
J = 7.8 Hz, 1H) 8.31 (d, J = 8.3 Hz, 1H) 8.58 (dd, J = 7.3, 1.0 Hz, 1H)
8.80 (d, J = 8.5 Hz, 1H) 10.63 (s, 1H) 14.05 (s, 1H); MS (ES+) m/e
395 (M+H)+; HRMS Calcd for (M+H)+: C20H19N4O3S+: 395.1172,
Found: 395.1172.
3-(Naphthalen-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.17 g,
0.5 mmol), trimethyl ethylene diamine (0.6 mmol) and sodium
triacetoxyborohydride (0.7 mmol) in dichloroethane (5 ml) was
stirred at room temperature for 24 h. After completion, the solvent
was removed in vacuo, crude material dispersed in water and pH
brought to 3.4. Solid material was filtered off and washed with cold
water to afford, after drying, the target material as a free base. The
latter was converted into the hydrochloride salt by dissolution in
methanol, followed by treatment with excess 2 N HCl, and the
evacuation of the volatiles in vacuo to afford the title compound
hydrochloride salt. Mp >200 °C. 1H NMR (400 MHz, DMSO-d6) d
ppm 2.15 (br s, 3H) 2.59–2.80 (m, 8H) 3.14–3.24 (m, 2H) 3.71 (br
s, 2H) 7.49 (d, J = 8.3 Hz, 1H) 7.55–7.71 (m, 3H) 7.77 (t, J = 7.8 Hz,
1H) 7.90 (br s, 1H) 8.02–8.15 (m, 1H) 8.31 (d, J = 8.3 Hz, 1H) 8.56
(d, J = 7.3 Hz, 1H) 8.78 (d, J = 7.3 Hz, 1H) 14.25 (br s, 1H); MS
(ES+) m/e 423 (MH+).
4.33. 3-(Dimethylamino)-N-(3-(naphthalen-1-ylsulfonyl)-1H-
indazol-6-yl)propanamide HCl (22a)
The title compound was synthesized following a similar proce-
dure as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm
2.76 (d, J = 4.9 Hz, 6H) 2.90 (t, J = 7.2 Hz, 2H) 3.35 (q, 2H) 7.34
(dd, J = 9.0, 1.7 Hz, 1H) 7.54–7.71 (m, 2H) 7.71–7.81 (m, 1H)
7.85–7.94 (m, 1H) 8.03–8.12 (m, 1H) 8.21 (s, 1H) 8.31 (d, J =
8.3 Hz, 1H) 8.55 (dd, J = 7.4, 1.1 Hz, 1H) 8.78 (d, J = 8.5 Hz, 1H)
9.94 (br s, 1H) 10.64 (s, 1H) 14.11 (s, 1H); MS (ES+) m/e 423
(M+H)+; HRMS Calcd for (M+H)+: C22H23N4O3S+: 423.1485, Found:
423.1488.
4.28. N-{[3-(1-Naphthylsulfonyl)-1H-indazol-5yl]methyl}ethane-
1.2-diamine HCl (37a)
The title compound was synthesized using the same procedure
as described for 37b. Mp >200 °C. 1H NMR (400 MHz, DMSO-d6) d
ppm 3.11–3.27 (m, 4H) 4.37 (br s, 2H) 7.52–7.86 (m, 5H) 8.07 (s,
1H) 8.19 (br s, 3H) 8.27–8.36 (m, 2H) 8.59 (d, J = 6.8 Hz, 1H) 8.78
(d, J = 8.3 Hz, 1H) 9.58 (br s, 2H) 14.40 (br s, 1H); MS (ES+) m/e
379 (MH+).
4.34. 3-(Diethylamino)-N-(3-(naphthalen-1-ylsulfonyl)-1H-
indazol-6-yl)propanamide HCl (22b)
The title compound was synthesized following a similar proce-
dure as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm
1.21 (t, J = 7.3 Hz, 6H) 2.88 (t, J = 7.2 Hz, 2H) 3.06–3.19 (m, 4H)
3.35 (q, J = 7.2 Hz, 2H) 7.33 (dd, J = 8.9, 1.6 Hz, 1H) 7.50–7.71 (m,
2H) 7.76 (t, J = 7.8 Hz, 1H) 7.90 (d, J = 8.8 Hz, 1H) 7.99–8.14 (m,
1H) 8.22 (d, J = 1.0 Hz, 1H) 8.31 (d, J = 8.3 Hz, 1H) 8.55 (dd, J = 7.4,
1.1 Hz, 1H) 8.78 (d, J = 8.5 Hz, 1H) 9.69 (br s, 1H) 10.61 (s, 1H)
14.09 (s, 1H); MS (ES+) m/e 451 (M+H)+; HRMS Calcd for (M+H)+:
4.29. 3-(Naphthalen-1-ylsulfonyl)-5-(piperazin-1-ylmethyl)-1H-
indazole HCl (38a)
The title compound was synthesized using the same procedure
as described for 37b. MS (ES+) m/e 407 (MH+).
C
24H27N4O3S+: 451.1798, Found: 451.1802.

K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
659
4.35. N-(3-(Naphthalen-1-ylsulfonyl)-1H-indazol-6-yl)-3-
(piperidin-1-yl)propanamide HCl (22c)
1.72–1.88 (m, 2H) 1.95 (d, J = 11.7 Hz, 2H) 2.59–2.74 (m, 1H)
2.81–3.00 (m, 2H) 3.31 (d, J = 12.4 Hz, 2H) 7.34 (dd, J = 9.0,
1.2 Hz, 1H) 7.56–7.69 (m, 2H) 7.76 (t, J = 7.8 Hz, 1H) 7.89 (d,
J = 8.8 Hz, 1H) 8.07 (d, J = 7.6 Hz, 1H) 8.22 (s, 1H) 8.30 (d,
J = 8.3 Hz, 1H) 8.47–8.61 (m, 2H) 8.76 (d, J = 8.5 Hz, 1H) 8.80–
8.91 (m, 1H) 10.42 (s, 1H) 14.07 (s, 1H); MS (ES+) m/e 435
(M+H)+; HRMS Calcd for (M+H)+: C23H23N4O3S+: 435.1491, Found:
435.1486.
The title compound was synthesized following a similar proce-
dure as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm
1.27–1.46 (m, 1H) 1.60–1.87 (m, 5H) 2.81–2.97 (m, 4H) 3.33 (q,
J = 5.4 Hz, 2H) 3.40 (d, J = 11.5 Hz, 2H) 7.34 (dd, J = 8.8, 1.5 Hz, 1H)
7.57–7.69 (m, 2H) 7.76 (t, J = 7.8 Hz, 1H) 7.89 (d, J = 8.8 Hz, 1H)
8.07 (d, J = 7.6 Hz, 1H) 8.21 (s, 1H) 8.31 (d, J = 8.3 Hz, 1H) 8.55 (d,
J = 7.3 Hz, 1H) 8.78 (d, J = 8.5 Hz, 1H) 9.75 (br s, 1H) 10.61 (s, 1H)
14.08 (s, 1H); MS (ES+) m/e 463 (M+H)+; HRMS Calcd for (M+H)+:
4.41. N-(3-(Naphthalen-1-ylsulfonyl)-1H-indazol-7-yl)piperidine-
4-carboxamide HCl (23c)
C
25H27N4O3S+: 463.1798, Found: 463.1799.
The title compound was synthesized following a similar proce-
dure as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm
1.71–1.93 (m, 2H) 2.04 (d, J = 12.0 Hz, 2H) 2.75–3.06 (m, 3H) 3.32
(d, J = 12.4 Hz, 2H) 7.27 (t, J = 7.9 Hz, 1H) 7.51–7.88 (m, 5H) 8.07
(d, J = 7.8 Hz, 1H) 8.31 (d, J = 8.3 Hz, 1H) 8.36–8.53 (m, 1H) 8.57 (d,
J = 7.6 Hz, 1H) 8.66–8.77 (m, 1H) 8.79 (d, J = 8.5 Hz, 1H) 10.53 (s,
1H) 14.36 (s, 1H); MS (ES+) m/e 435 (M+H)+; HRMS Calcd for
(M+H)+: C23H23N4O3S+: 435.1491, Found: 435.1484.
4.36. 3-(Dimethylamino)-N-(3-(naphthalen-1-ylsulfonyl)-1H-
indazol-7-yl)propanamide HCl (22d)
The title compound was synthesized following a similar proce-
dure as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm
2.76 (d, J = 4.9 Hz, 6H) 2.99 (t, J = 7.1 Hz, 2H) 3.29–3.44 (m, 2H)
7.28 (t, J = 7.9 Hz, 1H) 7.55–7.86 (m, 5H) 8.07 (d, J = 8.1 Hz, 1H)
8.31 (d, J = 8.3 Hz, 1H) 8.58 (d, J = 7.6 Hz, 1H) 8.79 (d, J = 8.5 Hz,
1H) 9.90 (br s, 1H) 10.83 (s, 1H) 14.39 (s, 1H); MS (ES+) m/e 423
(M+H)+; HRMS Calcd for (M+H)+: C22H23N4O3S+: 423.1485, Found:
423.1485.
4.42. N-(3-(Naphthalen-1-ylsulfonyl)-1H-indazol-7-
yl)piperidine-3-carboxamide HCl (24a)
Thetitlecompoundwas synthesizedfollowingasimilarprocedure
as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm 1.61–1.76
(m, 2H) 1.76–1.89 (m, 1H) 2.00–2.18 (m, 1H) 2.81–2.96 (m, 1H)
2.95–3.13 (m, 2H) 3.13–3.22 (m, 1H) 3.29–3.44 (m, 1H) 7.28 (t,
J = 7.9 Hz, 1H) 7.56–7.70 (m, 3H) 7.72 (d, J = 8.3 Hz, 1H) 7.77
(t, J = 7.9 Hz, 1H) 8.07 (d, J = 8.1 Hz, 1H) 8.31 (d, J = 8.3 Hz, 1H) 8.58
(d, J = 7.3 Hz, 1H) 8.60–8.68 (m, 1H) 8.73–8.87 (m, 2H) 10.62 (s, 1H)
14.19 (s, 1H); MS (ES+) m/e 435 (M+H)+; HRMS Calcd for (M+H)+:
4.37. 3-(Diethylamino)-N-(3-(naphthalen-1-ylsulfonyl)-1H-
indazol-7-yl)propanamide HCl (22e)
The title compound was synthesized following a similar proce-
dure as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm
1.18 (t, J = 7.3 Hz, 6H) 2.93 (t, J = 7.0 Hz, 2H) 3.07–3.14 (m, 4H)
3.31–3.36 (m, 2H) 7.25 (t, J = 7.7 Hz, 1H) 7.55–7.76 (m, 5H) 8.03 (d,
J = 8.5 Hz, 1H) 8.28 (d, J = 8.2 Hz, 1H) 8.55 (d, J = 7.5 Hz, 1H) 8.76
(d, J = 8.4 Hz, 1H) 9.64 (b, 1H). MS (ES+) m/e 451 (M+H)+; HRMS Calcd
for (M+H)+: C24H27N4O3S+: 451.1798, Found: 451.1799.
C
23H23N4O3S+: 435.1485, Found: 435.1489.
4.43. 4-Nitro-benzoic acid methyl ester (25)
4.38. N-(3-(Naphthalen-1-ylsulfonyl)-1H-indazol-7-yl)-3-
(piperidin-1-yl)propanamide HCl (22f)
To a solution of 4-nitrobezoic acid (1.0 g, 7.3 mmol) in EtOAc
(10 ml) was added trimethyl silyl diazomethane (5 ml, 10.9 mmol)
dropwise. The mixture was then diluted with water, extracted with
EtOAc, washed with water (2ꢂ), brine (1ꢂ), dried over Na2SO4, and
concentrated under vacuum. The product was purified by flash
chromatography with 20% EtOAc/hexane to afford the title com-
pound as an off-white solid (0.8 g, 60%). MS (ES+) m/e 182 (MH+).
The title compound was synthesized following a similar proce-
dure as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm
1.27–1.47 (m, 1H) 1.58–1.89 (m, 5H) 2.84–2.95 (m, 2H) 2.97 (d,
J = 7.1 Hz, 2H) 3.30–3.39 (m, 2H) 3.43 (d, J = 11.5 Hz, 2H) 7.29 (t,
J = 7.9 Hz, 1H) 7.55–7.70 (m, 3H) 7.70–7.83 (m, 2H) 8.07 (d,
J = 8.1 Hz, 1H) 8.31 (d, J = 8.3 Hz, 1H) 8.58 (d, J = 7.3 Hz, 1H) 8.79
(d, J = 8.5 Hz, 1H) 9.59 (br s, 1H) 10.68 (s, 1H) 14.25 (s, 1H); MS
(ES+) m/e 463 (M+H)+; HRMS Calcd for (M+H)+: C25H27N4O3S+:
463.1798, Found: 463.1801.
4.44. 3-(Naphthalene 1-sulfonylmethyl)-4-nitro-benzoic acid
methyl ester (26)
A mixture of 4-nitro-benzoic acid methyl ester (0.8 g, 4.4 mmol)
and 1-chloromethane-sulfonyl-naphthalene (1.3 g, 5.3 mmol) was
stirred in THF (50 ml) at ꢁ78 °C, in a round bottom flask under nitro-
gen. A solution of 1 M potassium t-butoxide in THF was added drop-
wise (13 ml, 13 mmol) over a half an hour period. Temperature was
allowed to rise to ꢁ40 °C, and the reaction mixture was stirred at this
temperature for 5 h. The reaction mixture was poured into cold 2 N
HCl, extracted with EtOAc, dried over Na2SO4, and concentrated un-
der vacuum. The product was purified by normal phase HPLC using
as eluent 40% EtOAc/hexane to afford the title compound as an off-
white solid (1.5 g, 87%). MS (ES+) m/e 386 (MH+).
4.39. N-(3-(Naphthalen-1-ylsulfonyl)-1H-indazol-5-yl)piperidine-
4-carboxamide HCl (23a)
The title compound was synthesized following a similar proce-
dure as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm
1.76–1.93 (m, 2H) 1.93–2.06 (m, 2H) 2.60–2.77 (m, 1H) 2.93 (q,
J = 11.8 Hz, 2H) 3.35 (d, J = 12.8 Hz, 2H) 7.52–7.72 (m, 4H) 7.77 (t,
J = 7.9 Hz, 1H) 7.97–8.14 (m, 1H) 8.31 (d, J = 8.1 Hz, 1H) 8.37–
8.56 (m, 3H) 8.61–8.90 (m, 2H) 10.28 (s, 1H) 14.19 (s, 1H); MS
(ES+) m/e 435 (M+H)+; HRMS Calcd for (M+H)+: C23H23N4O3S+:
435.1491, Found: 435.1486.
4.45. 4-Amino-3-(naphthalene-1-sulfonylmethyl)-benzoic acid
methyl ester (27)
4.40. N-(3-(Naphthalen-1-ylsulfonyl)-1H-indazol-6-
yl)piperidine-4-carboxamide HCl (23b)
A mixture of 3-(naphthalene 1-sulfonylmethyl)-4-nitro-benzoic
acid methyl ester (1.5 g, 3.9 mmol) and 10% Pd/C in THF (10 ml)
and methanol (20 ml) was hydrogenated in a Parr hydrogenation
bottle (250 ml) at 52 psi overnight. The mixture was filtered
The title compound was synthesized following a similar proce-
dure as described for 37b. 1H NMR (400 MHz, DMSO-d6) d ppm

660
K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
through Celite, and the filtrate was concentrated under vacuum to
afford the title compound as an off-white solid (0.9 g, 64%). MS
(ES+) m/e 356 (MH+).
2.66 (t, J = 6.6 Hz, 2H) 3.3 t, J = 6.1 Hz, 2H 7.4–8.8 (m, 7H) 7.8–8.5
(m, 3H) 12.4 (s, 1H). MS (ES+) m/e 462 (MH+).
4.51. tert-Butyl 4-(3-iodo-1H-indazol-5-ylamino)piperidine-1-
carboxylate (40)
4.46. 3-(Naphthalen-1-sulfonyl)-1H-indazole-5-carboxylic acid
methyl ester (28)
A mixture of 3-iodo-1H-indazol-5-amine (7.0 g, 27.0 mmol),
1-N-Boc-4-piperdone (5.34 g, 27.0 mmol), acetic acid (3.1 ml) and
sodium triacetoxyborohydride (5.7 g, 27.0 mmol) in 1,2-dichloro-
ethane (90 ml) was stirred at rt for 1 h, neutralized with concen-
trated sodium carbonate solution, extracted with CH2Cl2 and
concentrated and purified by chromatography with 1–15% MeOH
in CH2Cl2 to provide the title compound (8.9 g, 74%). 1H NMR
(400 MHz, CDCl3) d 1.19–1.34 (m, 2H) 1.36 (s, 9H) 1.86 (dd, J = 13.0
and 3.0 Hz, 2H) 2.90–3.00 (m, 2H) 3.35–3.45 (m, 1H) 3.84 (d,
J = 7.9 Hz, 2H) 5.38 (d, J = 8.4 Hz, 1H) 6.26 (d, J = 1.5 Hz, 1H) 6.86
(dd, J = 9.0 and 2.0 Hz, 1H) 7.24 (d, J = 8.8 Hz, 1H). MS (ESꢁ) m/e
442 (MꢁH)ꢁ.
A mixture of 4-amino-3-(naphthalen-1-sulfonylmethyl)-ben-
zoic acid methyl ester (0.9 g, 2.5 mmol) in THF (5 ml) and 4 M
HCl (10 ml) was stirred in a round bottom flask, under nitrogen,
at 3 °C. A solution of sodium nitrite (0.18 g, 2.62 mmol) in H2O
(1 ml) was added dropwise. The reaction mixture was poured into
a cold solution of saturated sodium bicarbonate (100 ml) and ex-
tracted with EtOAc. The extracts were dried over Na2SO4, and con-
centrated under vacuum to afford the title compound as an off
white solid (0.82 g, 90%). MS (ES+) m/e 493 (MH+).
4.47. 1-(3-Chloro-benzyl)-2-(naphthalen-1-sulfonyl)-1H-indazole-
4.52. tert-Butyl 4-(3-(phenylthio)-1H-indazol-5-ylamino)
5-carboxylic acid methyl ester (29)
piperidine-1-carboxylate (41)
A
mixture of 3-(naphthalene-1-sulfonyl)-1H-indazole-5-car-
Under nitrogen, to a stirred solution of tert-butyl 4-(3-iodo-1H-
indazol-5-ylamino)piperidine-1-carboxylate 40 (0.3 g, 0.68 mmol)
in isopropanol (0.85 ml) was added CuI (0.013 mg, 0.07 mmol),
K2CO3 (0.187 g, 1.36 mmol) and ethylene glycol (0.084 g, 1.36 mmol)
followed by addition of benzenethiol (0.075 g, 67.8 mmol). The
resulting solution was stirred at 100 °C for 3 h, diluted with 20 ml
of 20% MeOH/CH2Cl2 and then passed through a pad of silica gel, con-
centrated to provide the title compound (0.288 g, 100%). 1H NMR
(400 MHz, CDCl3) d 1.12–1.14 (m, 2H) 1.37 (s, 9H) 1.76 (dd, J = 13.0
and 2.9 Hz, 2H) 2.75–2.85 (m, 2H) 3.20–3.30 (m, 1H) 3.79 (d,
J = 14.2 Hz, 2H) 5.40 (dd, J = 8.2 Hz, 1H) 6.32 (s, 1H) 6.84 (dd, J = 8.9
and 2.1 Hz, 1H) 7.09–7.11 (m, 3H) 7.13–7.15 (m, 2H) 7.32 (d,
J = 8.8 Hz, 1H). MS (ES+) m/e 426 (MH+).
boxylic acid methyl ester (0.82 g, 2.25 mmol), 3-chloro-benzyl bro-
mide (0.34 ml, 2.7 mmol), and cesium carbonate (0.87 g, 2.7 mmol)
in DMF (5 ml) was stirred together in a round bottom flask at room
temperature for 30 min. Reaction mixture was diluted with H2O,
extracted with EtOAc, washed with water (2ꢂ), brine (1ꢂ), dried
over Na2SO4, and concentrated under vacuum. The crude product
was purified by HPLC using as eluent 30% EtOAc/hexane to afford
the title compound as an off-white solid (1.01 g, 92%). MS (ES+)
m/e 367 (MH+).
4.48. 1-(3-Chloro-benzyl)-3-(naphthalen-1-sulfonyl)-1H-indazole-
5-carboxylic acid (2-dimethyl-amino-ethyl)-amide (30a)
To a solution of dimethyl ethylene diamine (0.02 ml, 0.2 mmol)
in THF (2 ml), cooled to 0 °C, was added LDA dropwise (0.15 ml,
0.3 mmol). To this mixture was then added a solution of 1-(3-
chloro-benzyl)-2-(naphthalene-1-sulfonyl)-1H-indazole-5-carbox-
ylic acid methyl ester (0.05 g, 0.1 mmol) in THF (1 ml). The mixture
was allowed to warm slowly to room temperature, diluted with
water, extracted with EtOAc (1ꢂ), CH2Cl2 (1ꢂ). The organics were
washed with brine (1ꢂ) and concentrated under vacuo to afford
the title compound (0.3 g, 20%). MS (ES+) m/e 547 (MH+).
4.53. 3-(Phenylthio)-N-(piperidin-4-yl)-1H-indazol-5-amine (42)
To tert-butyl 4-(3-(phenylthio)-1H-indazol-5-ylamino)piperi-
dine-1-carboxylate (0.03 g, 0.07 mmol), TFA was added and stirred
for 1 h at rt. The reaction was concentrated to provide the title
compound (.023 g, 0.07 mmol). MS (ES+) m/e 325 (M+H)+.
4.54. 3-(Phenylsulfonyl)-N-(piperidin-4-yl)-1H-indazol-5-amine
HCl (18e)
4.49. N-[2-(Dimethylamino)ethyl]-3-(1-naphthylsulfonyl)-1H-
indazole-5-carboxamide HCl (31a)
To a mixture of 3-(phenylthio)-N-(piperidin-4-yl)-1H-indazol-5-
amine (0.023 g, 0.07 mmol) in MeOH (5 ml) was added 2 N HCl
(2 ml) and the mixture was stirred for a few minutes, concentrated
and the residue was dissolved in methanol (1.41 ml) and water
(1.41 ml) followed by addition of oxone (0.113 g, 0.18 mmol). The
reaction was allowed to stir at rt for 30 min, concentrated to dryness
and purified by reverse-phase HPLC to provide the title compound
(0.025 g, 98%). WAY-319522 HCl 1H NMR (400 MHz, DMSO-d6) d
ppm 1.59–1.81 (m, 2H) 2.02–2.13 (m, 2H) 3.03 (q, J = 9.7 Hz, 2H)
3.32 (d, J = 13.0 Hz, 2H) 3.59–3.74 (m, 1H) 7.02–7.35 (m, 2H) 7.46–
7.57 (m, 1H) 7.60 (t, J = 7.2 Hz, 2H) 7.68 (t, J = 7.4 Hz, 1H) 7.98 (d,
J = 7.2 Hz, 2H) 8.73–8.90 (m, 1H) 8.89–9.03 (m, 1H) 14.11 (br s,
1H); MS (ES+) m/e 357 (M+H)+; HRMS Calcd for (M+H)+:
C18H21N4O2S+: 357.1379, Found: 357.1380.
A mixture of 1-(3-chloro-benzyl)-3-(naphthalen-1-sulfonyl)-
1H-indazole-5-carboxylic acid (2-dimethyl-amino-ethyl)-amide
(0.3 g, 0.04 mmol), DMSO (1 ml) and t-BuOH (0.2 ml) was stirred
at room temperature in a round bottom flask under oxygen atmo-
sphere. A solution of potassium t-butoxide (0.05 ml, 0.05 mmol)
was added dropwise and the reaction mixture was stirred for 1/
2 h and was quenched with saturated ammonium chloride, ex-
tracted with EtOAc, dried over Na2SO4, and concentrated under
vacuum. The crude compound was purified by reverse phase HPLC
to afford the title compound. MS (ES+) m/e 423 (MH+).
4.50. 3-(Naphthalen-1-ylsulfonyl)-N-(2-piperidin-1-ylethyl)-1H-
indazole-5-carboxamide HCl (31b)
4.55. 3-(3-Fluorophenylsulfonyl)-N-(piperidin-4-yl)-1H-indazol-
5-amine HCl (18f)
The title compound was prepared following the same procedure
as described for 31a using 1-(2-aminoethyl)-piperidine as a start-
ing material. 1H NMR (500 MHz, DMSO-d6) d 1.5–2.24 (m, 10H)
The title compound was synthesized using the same procedure as
described for 18e. 1H NMR (400 MHz, DMSO-d6) d ppm 1.59–1.85

K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
661
(m, 2H) 2.07 (d, J = 11.1 Hz, 2H) 2.92–3.13 (m, 2H) 3.32 (d,
4.61. N-(Piperidin-4-yl)-3-(4-(trifluoromethyl)phenylsulfonyl)-
J = 12.8 Hz, 2H) 3.70 (t, J = 9.9 Hz, 1H) 7.01–7.40 (m, 2H) 7.45–7.62
(m, 2H) 7.62–7.74 (m, 1H) 7.73–7.89 (m, 2H) 8.70–8.93 (m, 1H)
8.91–9.07 (m, 1H) 14.23 (br s, 1H). MS (ES+) m/e 375 (M+H)+; HRMS
Calcd for (M+H)+: C18H20FN4O2S+: 375.1285, Found: 375.1291.
1H-indazol-5-amine HCl (18l)
The title compound was synthesized using the same procedure as
described for 18e. 1H NMR (400 MHz, DMSO-d6) d ppm 1.50–1.84
(m, 2H) 2.07 (d, J = 13.0 Hz, 2H) 2.94–3.14 (m, 2H) 3.31 (d,
J = 12.8 Hz, 2H) 3.54–3.73 (m, 1H) 6.95–7.23 (m, 2H) 7.54 (d,
J = 9.0 Hz, 1H) 7.99 (d, J = 8.4 Hz, 2H) 8.18 (d, J = 8.4 Hz, 2H) 8.73–
8.91 (m, 1H) 8.90–9.03 (m, 1H) 14.23 (br s, 1H). MS (ES+) m/e 425
(M+H)+; HRMS Calcd for (M+H)+: C19H20F3N4O2S+: 425.1253, Found:
425.1255.
4.56. 3-(3-Chlorophenylsulfonyl)-N-(piperidin-4-yl)-1H-indazol-
5-amine HCl (18g)
The title compound was synthesized using the same procedure as
described for 18e. 1H NMR (400 MHz, DMSO-d6) d ppm 1.59–1.75 (m,
2H) 2.08 (d, J = 11.7 Hz, 2H) 2.99–3.13(m, 2H) 3.32 (d, J = 12.7 Hz, 2H)
3.60–3.76 (m, 1H) 6.99–7.22 (m, 2H) 7.51 (d, J = 8.8 Hz, 1H) 7.64 (t,
J = 8.1 Hz, 1H) 7.74–7.80 (m, 1H) 7.93 (d, J = 8.1 Hz, 1H) 7.97 (t,
J = 1.7 Hz, 1H) 8.69–9.01 (m, 2H) 14.15 (br s, 1H). MS (ES+) m/e 391
(M+H)+; HRMS Calcd for (M+H)+: C18H20ClN4O2S+: 391.0989, Found:
391.0989.
4.62. 3-(4-Methoxyphenylsulfonyl)-N-(piperidin-4-yl)-1H-
indazol-5-amine HCl (18m)
The title compound was synthesized using the same procedure as
described for 18e. 1H NMR (400 MHz, DMSO-d6) d ppm 1.56–1.86
(m, 2H) 2.07 (d, J = 11.8 Hz, 2H) 2.93–3.12 (m, 2H) 3.32 (d,
J = 12.3 Hz, 2H) 3.57–3.73 (m, 1H) 3.79 (s, 3H) 7.11 (d, J = 8.9 Hz,
2H) 7.13–7.24 (m, 1H) 7.23–7.39 (m, 1H) 7.55 (d, J = 8.6 Hz, 1H)
7.91 (d, J = 8.9 Hz, 2H) 8.74–8.91 (m, 1H) 8.90–9.04 (m, 1H) 14.06
(br s, 1H). MS (ES+) m/e 387 (M+H)+; HRMS Calcd for (M+H)+:
C19H23N4O3S+: 387.1485, Found: 387.1487.
4.57. N-(Piperidin-4-yl)-3-(m-tolylsulfonyl)-1H-indazol-5-amine
HCl (18h)
The title compound was synthesized using the same procedure
as described for 18e. 1H NMR (400 MHz, DMSO-d6) d ppm 1.60–
1.83 (m, 2H) 2.07 (d, J = 11.4 Hz, 2H) 2.96–3.11 (m, 2H) 3.32 (d,
J = 12.8 Hz, 2H) 3.56–3.76 (m, 1H) 6.98–7.42 (m, 2H) 7.43–7.53
(m, 2H) 7.56 (d, J = 8.6 Hz, 1H) 7.71–7.86 (m, 2H) 8.74–8.92 (m,
1H) 8.91–9.10 (m, 1H) 14.13 (br s, 1H). MS (ES+) m/e 371 (MH+).
4.63. 3-(Naphthalen-2-ylsulfonyl)-N-(piperidin-4-yl)-1H-indazol-
5-amine HCl (18n)
The title compound was synthesized using the same procedure as
described for 18e. 1H NMR (400 MHz, DMSO-d6) d ppm 1.63–1.89
(m, 2H) 2.06 (d, J = 11.5 Hz, 2H) 2.86–3.14 (m, 2H) 3.31 (d,
J = 12.7 Hz, 2H) 3.70 (t, J = 9.9 Hz, 1H) 7.19 (d, J = 3.9 Hz, 1H) 7.31–
7.50 (m, 1H) 7.57 (d, J = 8.5 Hz, 1H) 7.62–7.77 (m, 2H) 7.91 (dd,
J = 8.7, 1.8 Hz, 1H) 8.02 (d, J = 7.8 Hz, 1H) 8.11 (d, J = 8.8 Hz, 1H)
8.24 (d, J = 7.8 Hz, 1H) 8.75 (s, 1H) 8.79–8.95 (m, 1H) 8.96–9.09
(m, 1H) 14.19 (br s, 1H). MS (ES+) m/e 407 (M+H)+; HRMS Calcd for
(M+H)+: C22H23N4O2S+: 407.1535, Found: 407.1538.
4.58. 3-(4-Fluorophenylsulfonyl)-N-(piperidin-4-yl)-1H-indazol-
5-amine HCl (18i)
The title compound was synthesized using the same procedure as
described for 18e. 1H NMR (400 MHz, DMSO-d6) d ppm 1.64–1.82
(m, 2H) 2.08 (d, J = 11.1 Hz, 2H) 2.92–3.10 (m, 2H) 3.32 (d,
J = 12.5 Hz, 2H) 3.60–3.74 (m, 1H) 7.13–7.24 (m, 1H) 7.24–7.38 (m,
1H) 7.46 (t, J = 8.8 Hz, 2H) 7.57 (d, J = 8.8 Hz, 1H) 8.05 (dd, J = 8.8,
5.1 Hz, 2H) 8.77–8.94 (m, 1H) 8.93–9.08 (m, 1H) 14.18 (br s, 1H).
MS (ES+) m/e 375 (M+H)+; HRMS Calcd for (M+H)+: C18H20FN4O2S+:
375.1285, Found: 375.1285.
Acknowledgments
We thank Donald Herold, Sergio Anis, and Alvin Bach for their
discovery analytical chemistry support.
References and notes
4.59. 3-(4-Chlorophenylsulfonyl)-N-(piperidin-4-yl)-1H-indazol-
5-amine HCl (18j)
1. Monsma, F. J., Jr.; Shen, Y.; Ward, R. P.; Hamblin, M. W.; Sibley, D. R. Mol.
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The title compound was synthesized using the same procedure as
described for 18e. 1H NMR (400 MHz, DMSO-d6) d ppm 1.66–1.88
(m, 2H) 2.06 (d, J = 11.4 Hz, 2H) 2.90–3.12 (m, 2H) 3.32 (d,
J = 12.8 Hz, 2H) 3.60–3.77 (m, 1H) 7.13–7.28 (m, 1H) 7.26–7.46 (m,
1H) 7.59 (d, J = 8.6 Hz, 1H) 7.70 (d, J = 8.6 Hz, 2H) 7.98 (d,
J = 8.6 Hz, 2H) 8.74–8.95 (m, 1H) 8.95–9.09 (m, 1H) 14.25 (br s,
1H). MS (ES+) m/e 391 (M+H)+; HRMS Calcd for (M+H)+:
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Schwartz, J. C. Biochem. Biophys. Res. Commun. 1993, 193, 268.
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4. Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Lachowicz, J. E.;
Meltzer, H. Y.; Sibley, D. R.; Roth, B. L.; Hamblin, M. W. J. Neurochem. 1996, 66,
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4.60. 3-(4-Isopropylphenylsulfonyl)-N-(piperidin-4-yl)-1H-
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The title compound was synthesized using the same procedure as
described for 18e. 1H NMR (400 MHz, DMSO-d6) d ppm 1.18 (d,
J = 6.83 Hz, 6H) 1.55–1.78 (m, 2H) 2.07 (d, J = 11.47 Hz, 2H) 2.94
(spt, J = 6.80 Hz, 1H) 2.98–3.14 (m, 2H) 3.32 (d, J = 12.44 Hz, 2H)
3.57–3.74 (m, 1H) 6.98–7.23 (m, 2H) 7.39–7.57 (m, 3H) 7.88 (d,
J = 8.30 Hz, 2H) 8.66–8.81 (m, 1H) 8.80–8.95 (m, 1H) 13.99 (br s,
1H). MS (ES+) m/e 399 (M+H)+; HRMS Calcd for (M+H)+:
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C
21H27N4O2S+: 399.1848, Found: 399.1851.

662
K. G. Liu et al. / Bioorg. Med. Chem. 19 (2011) 650–662
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