6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines: A1 adenosine receptor agonist allosteric enhancers having improved potency

Article abstract of DOI:10.1021/jm049132j

Allosteric enhancers (AEs) of the A₁ adenosine receptor (A ₁AR) have potential as drugs for treating neurological, cardiovascular, and renal diseases. This report describes the synthesis and evaluation of a series of 6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines that exhibited AE activity at the A₁AR. Palladium-mediated condensation of arylboronic acids with 5-bromoindan-1-one generated arylindanones 2a-aj for iodine-catalyzed condensation with thiourea, generating 2-aminothiazolium salts 3a-aj. Binding studies using membranes from cells stably expressing human A ₁ARs, A_2AARs, or A₃ARs evaluated AE activity and receptor subtype selectivity. The EC₅₀ of the AE activities of compounds 3m-o, 3x, and 3ae were 2.2, 1.5, 0.9, 1.0, and 3.0 μM, respectively, substantially lower than that of the well characterized 2-amino-3-aroylthiophene (PD 81,723), >10 μM. The new compounds also have substantially higher maximal AE activity. These compounds had no AE activity at the A_2AAR and only minimal activity at the A₃AR. 2005 American Chemical Society.

Full text of DOI:10.1021/jm049132j

J. Med. Chem. 2005, 48, 5131-5139
5131
6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines: A1 Adenosine Receptor Agonist
Allosteric Enhancers Having Improved Potency
Mahendra D. Chordia,† Molly Zigler,† Lauren J. Murphree,‡ Heidi Figler,§ Timothy L. Macdonald,†
Ray A. Olsson,# and Joel Linden*,§
Departments of Chemistry, Pharmacology, and Medicine (Cardiology), University of Virginia, Charlottesville, Virginia 22901,
and Suncoast AHA Chapter Cardiovascular Research Laboratory, Department of Internal Medicine, University of South
Florida, Tampa, Florida 33612
Received October 28, 2004
Allosteric enhancers (AEs) of the A1 adenosine receptor (A1AR) have potential as drugs for
treating neurological, cardiovascular, and renal diseases. This report describes the synthesis
and evaluation of a series of 6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines that exhibited AE
activity at the A1AR. Palladium-mediated condensation of arylboronic acids with 5-bromoindan-
1-one generated arylindanones 2a-aj for iodine-catalyzed condensation with thiourea, generat-
ing 2-aminothiazolium salts 3a-aj. Binding studies using membranes from cells stably
expressing human A1ARs, A2AARs, or A3ARs evaluated AE activity and receptor subtype
selectivity. The EC50 of the AE activities of compounds 3m-o, 3x, and 3ae were 2.2, 1.5, 0.9,
1.0, and 3.0 µM, respectively, substantially lower than that of the well characterized 2-amino-
3-aroylthiophene (PD 81,723), >10 µM. The new compounds also have substantially higher
maximal AE activity. These compounds had no AE activity at the A2AAR and only minimal
activity at the A3AR.
Scheme 1. Synthesis of
Introduction
6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamine Hydroiodidea
Adenosine activates the A1 adenosine receptor (A1-
AR) in many organs, notably the central nervous
system, where it exerts neuromodulatory activity,1 in
the heart, where it exerts negative chronotropic, dromo-
tropic, and atrial inotropic actions,2 and in the kidney,
where it participates in tubuloglomerular feedback.3
Although potent and highly selective A1AR agonists
have been known for nearly 20 years, none is available
for clinical use perhaps because conventional agonists
have significant cardiac and renal effects and are poorly
accessible to the central nervous system.
All tissues of the body release adenosine constantly,
but because cellular uptake and incorporation into the
adenylate pool is very efficient,4 adenosine concentra-
tions are usually below the level that activates adenos-
ine receptors. However, metabolic stress, especially
hypoxia, increases adenosine and adenine nucleotide
release and simultaneously inhibits adenosine kinase,5
thereby raising the local adenosine concentration.
A1AR agonist allosteric enhancers amplify the action of
adenosine by stabilizing the activated agonist-recep-
tor-G protein ternary complex6,7 that forms when local
adenosine concentrations increase. Accordingly, they act
predominantly at sites and at times of elevated endo-
genous adenosine levels. In other words, their action is
site- and event-specific and therefore less likely to cause
side effects by indiscriminately activating A1ARs through-
out the body.
a Reagents and conditions: (a) Pd(OAc)2, K2CO3, Bu4NBr, H2O,
70-80 °C; (b) I2, thiourea, DMF, or EtOH, heating.
The 2-amino-3-aroylthiophene allosteric enhancers
discovered by Bruns and his colleagues8,9 have been
shown to enhance adenosine actions in heart and thus
could be antiarrythmic,10-12 to potentiate ischemic
preconditioning13 and thus could be cardioprotective,
and to mitigate allodynia14 and thus apparently are
accessible to the central nervous system and could be
useful in managing chronic pain. Despite such evidence
of potential as drugs, these agents have drawbacks.
They are aromatic amines and so have carcinogenic risk.
More importantly, they are unstable, undergoing oxida-
tion in DMSO in vitro and perhaps rapid metabolism
in vivo.15
* To whom correspondence should be addressed. Phone:
1-434-924-5600. Fax: 1-434-924-2828. E-mail: jlinden@virginia.edu.
† Department of Chemistry, University of Virginia.
‡ Department of Pharmacology, University of Virginia.
§ Department of Medicine (Cardiology), University of Virginia.
# University of South Florida.
We recently reported that 2-aminothiazole derivatives
have A1AR allosteric enhancer activity.16 Here, we
10.1021/jm049132j CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/09/2005

5132 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16
Chordia et al.
Table 1. Biological Evaluation of 6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamine Hydroiodide Salts 3a-aj
AE score (%) at 50 µMa
EC50 @ A1 antagonistb (µM)
max AE score (%)b
compd
Ar
A1
A2a
A3
A1
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
3y
3z
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
H
8.2 ( 1.5
36.6 ( 1.2
59.2 ( 2.7
4.9 ( 1.0
42.8 ( 1.8
54.4 ( 2.1
36.7 ( 1.5
22.7 ( 1.8
10.0 ( 1.8
4.0 ( 1.5
0.0
0.0
2.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
3.4
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.2
0.0
0.0
0.3
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.8
0.0
1.6
0.0
11.4
3.6
3.6
11.8
0.0
1.0
1.0
1.0
1.0
1.8
18.0
3.4
24.8
0.0
0.0
6.6
0.0
0.0
0.0
0.0
0.0
10.1
1.9
0.8
0.0
2.9
0.0
0.0
4.2
4.5
0.0
1.8
3.8
11.9
5.0
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
90.2
86.7
81.8
49.7
ND
57.0
ND
ND
51.0
ND
ND
82.7
ND
ND
ND
91
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
2.2
ND
34.4
ND
13.2
ND
ND
ND
ND
36.7
36.7
43.5
19.3
13.0
8.8
2-CH3
3-CH3
2-F
3-F
4-F
2-Cl
3-Cl
3-OH
4-OH
2-OCH3
38.0 ( 2.2
64.0 ( 4.7.
87.0 ( 2.0
83.0 ( 2.6
81.0 ( 7.6
40.1 ( 2.1
13.0 ( 2.9
50.1 ( 1.0
15.8 ( 1.9
8.9 ( 1.1
47.7 ( 1.6
52.0 ( 1.1
10.5 ( 1.0
82.0 ( 10.6
73.0 ( 2.8
23.3 ( 2.4
64.5 ( 2.6
82.0 ( 7.5
45.3 ( 4.6
44.0 ( 2.3
61.2 ( 3.5
38.6( 3.2
24.4 ( 3.9
32.0 ( 2.6
68.8 ( 5.7
51.0 ( 2.8
20.0( 2.2
3-OCH3
4-OCH3
4-OPh
1.5
4-N,N-(CH3)2
2-NO2
0.9
6.3
>10
5.1
>10
>10
7.3
>10
>10
1.0
12.5
8.3
8.3
3-NO2
2-CF3
ND
ND
ND
ND
30.1
8.7
19.2
16.0
11.8
18.0
11.6
8.0
10.0
13.0
4.2
ND
11.4
18.2
ND
ND
3-CF3
4-CF3
2,5-(CH3)2
3,4-(CH3)2
3,5-(CH3)2
3,4-(OCH3)2
2,4-(OCH3)2
3,4,5-(OCH3)3
2,3,4-(OCH3)2
3,4-OCH2O-
3,4-Cl2
>10
>10
>10
6.8
22.6
19.3
65.6
ND
ND
ND
ND
ND
ND
ND
3,5-Cl2
ND
2,3-C4H4
3.0
3,4-C4H4
>10
>10
>10
>10
>10
>10
6-OMe-3,4-C4H4
2-thiophenyl
3-thiophenyl
2-benzofuranyl
PD 81,723
a AE score activity at a single dose of 50 µM from two to three experiments, (SEM when N ) 3. b Curve fitting was used to calculate
maximal AE activity and EC50 values only for compounds with EC50 < 10 µM. Parameters are calculated from two to three dose-response
curves. ND ) not determined because EC50 > 10 µM.
describe the synthesis and allosteric enhancer activities
of new 6-arylindeno[1,2-d]thiazoles; some are active at
the low micromolar to submicromolar range.
Chemistry
Scheme 1 details the two-step synthesis of the target
compounds. The palladium-catalyzed coupling17 of aryl-
boronic acids with 5-bromo-1-indanone, 1, generated
5-arylindane-1-ones 2a-aj in yields between 62% and
84%. They reacted with thiourea18 to afford target
compounds 3a-aj as the powdery hydroiodide salts in
yields between 62% and 85%.
Figure 1. Concentration dependence of AE activity at the A1-
AR of selected 2-aminothiazolium salts.
Results and Discussion
Table 1 summarizes the results of in vitro assays for
agonist allosteric enhancer activity at the A1AR, A2A
compounds with EC50 < 10 µM. For compounds with
EC50 > 10 µM we could not accurately calculate the
maximum response, so we report the score at 50 µM,
the maximum concentration used. Compounds 3m-o,
3x, and 3ab had maximal scores greater than 80% and
EC50 less than 10 µM. Additionally, compounds 3p, 3r,
3u, and 3ae had modest efficacy scores, 40-58%, but
EC50 values between 3 and 7 µM. As a basis for
-
AR, and A3AR. For the assessment of A1AR enhancer
activity, we used a previously described activity score7,19
ranging from 0% to 100% that reflects the ability of a
compound to retard the dissociation of the agonist-
receptor-G protein complex. We used curve fitting
(Figure 1) to calculate the EC50 and maximal score of

6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5133
The results of this study and our previous report16
indicate that 2-aminothiazole hydroiodide salts are
active as AEs. However, a recent report22 indicates that
free bases of 2-aminothiazoles prepared by base treat-
ment of hydroiodide salts and purification by silica gel
column chromatography are inactive. Using the same
method of purification, we confirmed that free bases of
compounds 3l, 3m, and 3o in fresh solutions are weakly
active as AEs. However, the AE activity in solutions of
these compounds in DMF, DMSO, or acetonitrile in-
creases after 4 h and increases further to a constant
activity equivalent to that of the hydroiodine salts after
12 h. When free bases 3l and 3m are dissolved in
deuterated solvents such as DMSO-d6, DMF-d4, and
acetonitrile-d3 and monitored for several hours, no
Table 2. Comparison of AE Activities of Selected
6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines at Rat and Human
A1ARs
activity score (%) @ 50 µMa
compd
human
rat
3m
3n
72.0 ( 1.3
46.2 ( 7.7
67.9 ( 2.7
83.9 ( 2.8
90.7 ( 4.0
32.3 ( 4.2
19.8 ( 2.0
31.7 ( 2.6
39.1 ( 6.2
48.8 ( 2.9
3o
3x
3ab
a Data are the mean values of duplicate assays.
Table 3. Inhibition of Agonist Equilibrium Binding Selected
6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines at Human A1AR and
A3AR
inhibition of agonist binding by 10 µM AE (%)a
1
apparent change in H NMR was observed along with
compd
hA1AR
hA3Ar
the increase in AE activity. The reason for this increase
in AE activity of the free bases over time is under
investigation.
3m
3n
25.2 ( 3.2
27.6 ( 4.3
23.1 ( 2.9
18.8 ( 4.1
10.5 ( 3.3
37.6 ( 0.9
28.2 ( 2.7
38.6 ( 6.2
45.0 ( 2.9
22.5 ( 1.5
3o
Although the panel of aminothiazoles characterized
to date does not provide detailed information about
structure-activity rules, a few trends are evident.
Electron-donating phenyl substituents, especially in the
para position, supported activity (compounds 3m-o, 3x,
and 3ab), and conversely, electron-withdrawing sub-
stituents tended to reduce activity. A large aryl sub-
stituent (compounds 3ae-ag, 3aj) neither promoted nor
diminished AE activity.
There is some evidence that the 2-aminoindenothia-
zoles and the 2-amino-3-aroylthiophenes might have
similar docking modes in the allosteric site. Whereas
the AE activity of the 2-aminothiophenes depended on
both the 2-amino and the 3-aroyl groups, these amino-
thiazoles lack a substituent that corresponds to the aroyl
group. However, superimposing the two heterocycles
suggests that the thiazole nitrogen could serve as a
surrogate for the aroyl carbonyl, acting, for example,
as a hydrogen-bond acceptor. The aryl group of the
2-amino-3-aroylthiophenes can occupy a position near,
but not overlapping, the benzene moiety of the indeno-
thiazole (Figure 2). Finally, Bruns has suggested9 that
the AE activity of a 2-amino-3-aroylthiophene is due to
the planarity of the molecule, conferred by a hydrogen
bond between the 2-amino and the aroyl carbonyl
groups. By analogy with another 6:5:6 tricyclic, 9H-
fluorene, a planar molecule,23 these indeno[1,2-d]thia-
zoles are probably also planar, which would support the
Bruns model.
3x
3ab
a Data are the mean values of duplicate assays.
comparison, 50 µM 2-amino-3-aroylthiophene (PD 81,
723) has an allosteric enhancer (AE) score of 20 and an
EC50 greater than 10 µM. AE activity at the A2AAR was
negligible, but compounds 3c, 3f, 3m, 3o, 3x, and 3aj
had modest activity at the A3AR, their scores ranging
between 10% and 25%. Such a result might reflect a
similar, though obviously not identical, allosteric site
in the hA1 and hA3 receptors, which show substantial
homology in their amino acid sequences.20
In addition to their allosteric enhancing activity, some
of the 2-amino-3-aroylthiophenes are competitive an-
tagonists. Since allosteric enhancers do not influence
antagonist binding to receptor, antagonist activity can
be measured independently of enhancer activity by
using antagonist radioligands. All the title compounds
had weak antagonist activity, inhibiting the binding of
the A1AR antagonist [3H]8-cyclopentyl-1,3-dipropyl-
xanthine from 4% to 44%. There was no correlation
between allosteric enhancer and competitive antagonist
activities.
Pharmacological studies frequently use the rat, so we
examined the AE and antagonist activities of 3m-o, 3x,
and 3ab at the rA1AR. Table 2 summarizes the results,
which show that each was less active at the rat than at
the human receptor.
Because some aminothiophenes are A3AR antago-
nists,21 the characterization of 3m-o, 3x, and 3ab
included assessment of A3AR antagonist activity. Since
none of the aminothiazoles increased equilibrium bind-
ing of [125I]ABA (ABA is N6-3-aminobenzyl)adenosine)
to the A3AR, antagonist activity could be estimated on
the basis of the potency of these compounds to compete
for equilibrium [125I]ABA binding.8 At 10 µM, these
compounds inhibited radioligand binding to a greater
extent at the A3AR than at the A1AR (Table 3), but in
all cases the inhibition was less than 50%.
Conclusion
In conclusion, we report the preparation and evalu-
ation of new 6-arylindenothiazoles for their allosteric
enhancer activity at the human A1 adenosine receptor.
Several of the new compounds were more potent A1AR
agonist enhancers than known 2-aminothiophenes and
some of the aminothiazoles reported previously. Unlike
the 2-aminothiophenes, these 2-aminoindenothiazoles
in DMSO do not appear to be susceptible to oxidation.
However, both the aminothiazoles, and the aminothio-
phenes, are aromatic, so future work must assess their
carcinogenic potential.
Because the instability of the 5-alkyl-2-aminothio-
phenes and the possibility that C-8 of these indenothia-
zoles might also be a site of oxidation, we examined their
stability, finding them stable in DMSO solutions for 2-3
Experimental Section
5-Bromoindanone was from Acros Organics, and palladium
acetate was from Strem Chemicals. Other reagents and
chemicals were of the highest purity offered by Aldrich, Acros
1
months, as evidenced by unchanged H NMR spectra
and consistent AE activity.

5134 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16
Chordia et al.
Figure 2. Superimposition of a 2-aminoindeno[1,2-d]thiazole (left, blue) on a 2-amino-3-benzoylthiophene (right, red). Also shown
is chem3D MM2 minimized overlay of models with electron density map. Note the proximity of the thiazole N and the benzoyl
carbonyl and the phenyl moieties of the indene and the benzoyl groups.
Organics, or Lancaster and were used without further puri-
fication. Suzuki coupling reactions were carried out in freshly
deoxygenated, deionized water continuously bubbled with
nitrogen. 1H NMR spectra were recorded on Varian Unity
300 MHz spectrometer. 13C NMR was recorded on either a
General Electric GN 300 or a Varian Unity 300 spectrometer
working at 75 MHz. The chemical shifts are reported as ppm.
13C NMR data were proton-decoupled. Sample purity and mass
spectral analyses for new 6-arylindanone derivatives were
performed on an HP GCD plus GC-MS system. A Finnigan
Matt TSQ 7000 spectrometer provided electron spray ioniza-
tion mass spectra. Melting points were recorded on a Thomas-
Hoover capillary melting point apparatus and are uncorrected.
Atlantic Microlab Inc., Norcross, GA, performed the elemental
analyses on some of the target compounds, while other samples
were analyzed in house on a Perkin-Elmer series II 2400
CHNS analyzer, which agreed within (0.4% of the calculated
composition. In other instances, high-resolution MS and HPLC
in two systems evaluated the identity and purity of the
compounds.
General Procedure for Suzuki Coupling: Synthesis
of 5-Arylindan-1-ones (2a-aj). A mixture of 5-bromoindan-
1-one (1.0 mmol), the appropriate arylboronic acid (1.1 mmol),
tetrabutylammonium bromide (1.0 mmol), and K2CO3 (8-
10 mmol) was suspended in freshly nitrogen-purged deionized
water (3.0 mL) and purged with nitrogen for an additional 20
min. Pd(OAc)2 (2.5 mg, 0.01 mmol, ∼1 mol %) was added, and
the resulting suspension was stirred with heating for 2-3 h
on an oil bath at 70 °C. After the solution had cooled to room
temperature it was diluted with water (10 mL) and extracted
twice with CH2Cl2 (15 mL). The combined extracts were
washed once with brine, dried over Na2SO4, and evaporated
under reduced pressure to yield crude residue. Purification of
residue consisted of chromatography on silica, eluting with a
gradient of ethyl acetate-hexane that began with 10% and
ended with 30% ethyl acetate. Evaporation of fractions con-
taining product gave the 5-arylindan-1-one as a solid.
5-Phenyl-2,3-dihydroindene-1-one (2a). Mp 104-5 °C.
1H NMR (CDCl3): δ 2.75 (t, J ) 6.4 Hz, 2H, CH2), 3.21 (t, J )
6.4 Hz, 2H, CH2), 7.25-7.51 (m, 3H, ArH), 7.61 (d, J )
8.0 Hz, 1H, ArH), 7.64 (dd, J ) 8.4 Hz, 2H, ArH), 7.68 (s, 1H,
ArH), 7.83 (d, J ) 8.1 Hz, 1H, ArH).
(d, J ) 7.5 Hz, 1H, ArH), 7.36 (t, J ) 7.2 Hz, 1H, ArH), 7.43
(d, J ) 6.9 Hz, 1H, ArH), 7.60 (d, J ) 7.8 Hz, 1H, ArH), 7.67
(s, 1H, ArH), 7.81 (d, J ) 7.8 Hz, 1H, ArH). 13C NMR (CDCl3):
δ 21.4, 25.8, 36.4, 123.9, 124.5, 1125.0, 126.7, 128.1, 128.8,
129.0, 135.8, 138.5, 140.1, 147.8, 155.7, 206.5. MS (ESI) m/z:
222 (M+).
5-(2-Fluorophenyl)-2,3-dihydroindene-1-one (2d). Yield
1
68%, mp 90 °C. H NMR (CDCl3): δ 2.73 (m, J ) 6.6 Hz, 2H,
CH2), 3.19 (t, J ) 5.7 Hz, 2H, CH2), 7.16 (dd, J ) 1.2, 8.1 Hz,
1H, ArH), 7.24 (dd, J ) 7.5, 8.1 Hz, 1H, ArH), 7.35 (m, 1H,
ArH), 7.40 (m, 1H, ArH), 7.50 (d, J ) 8.1 Hz, 1H, ArH), 7.65
(s, 1H, ArH), 7.82 (d, J ) 8.1 Hz, 1H, ArH). 13C NMR (CDCl3):
δ 25.7, 36.4, 116.1 and 116.4 (d), 123.6, 125.8, 124.5, 127.2,
128.4, 130.0 and 129.9 (d), 130.6, 136.2, 142.2, 155.2, 157.9,
161.1, 206.5. MS (ESI) m/z: 226 (M+).
5-(3-Fluorophenyl)-2,3-dihydroindene-1-one (2e). Yield
1
71%, mp 114-5 °C. H NMR (CDCl3): δ 2.73 (m, J ) 6.6 Hz,
2H, CH2), 3.18 (t, J ) 5.7 Hz, 2H, CH2), 7.08 (m, 1H, ArH),
7.30 (dt, J ) 2.4, 9.9 Hz, 1H, ArH), 7.36-7.46 (m, 2H, ArH),
7.55 (dd, J ) 1.5, 8.1 Hz, 1H, ArH), 7.64 (d, J ) 1.5 Hz, 1H,
ArH), 7.80 (d, J ) 8.1 Hz, 1H, ArH). 13C NMR (CDCl3): δ 25.8,
36.4, 114.1 and 114.4 (d), 114.9 and 115.2 (d), 123.0, 124.1,
125.1, 126.6, 130.4 and 130.3 (d), 136.3, 142.3, 146.1, 155.8,
161.4 and 164.7 (d), 206.3. MS (ESI) m/z: 226 (M+).
5-(4-Fluorophenyl)-2,3-dihydroindene-1-one (2f). Yield
1
65%, mp 93-4 °C. H NMR (CDCl3): δ 2.73 (m, J ) 6.6 Hz,
2H, CH2), 3.19 (t, J ) 5.7 Hz, 2H, CH2), 7.17 (t, J ) 8.1 Hz,
2H, ArH), 7.53-769 (m, 4H, ArH), 7.81 (d, J ) 8.1 Hz, 1H,
ArH). 13C NMR (CDCl3): δ 25.7, 36.3, 115.6 and 115.9 (d),
123.9, 124.8, 126.4, 129.0 and 129.3 (d), 135.8, 136.1, 146.4,
155.8, 161.2 and 164.5 (d), 206.3. MS (ESI) m/z: 226 (M+).
5-(2-Chlorophenyl)-2,3-dihydroindene-1-one (2g). Yield
1
72%, mp 76 °C. H NMR (CDCl3): δ 2.72 (m, J ) 6.6 Hz, 2H,
CH2), 3.18 (t, J ) 6.0 Hz, 2H, CH2), 7.29-7.40 (m, 3H, ArH),
7.42 (dd, J ) 0.9, 7.8 Hz, 1H, ArH), 7.48 (m, 1H, ArH), 7.52
(brs, 1H, ArH), 7.79 (d, J ) 7.8 Hz, 1H, ArH). 13C NMR
(CDCl3): δ 25.7, 36.3, 123.2, 126.9, 127.5, 128.9, 129.1, 130.0,
131.0, 132.1, 136.1, 139.5, 145.7, 154.9, 206.4. MS (ESI) m/z:
242, 244 (M+).
5-(3-Chlorophenyl)-2,3-dihydroindene-1-one (2h). Yield
74%, mp 111 °C. 1H NMR (CDCl3): δ 2.72 (m, J ) 6.6 Hz, 2H,
CH2), 3.17 (t, J ) 5.7 Hz, 2H, CH2), 7.32-7.38 (m, 2H, ArH),
7.47 (dt, J ) 2.1, 6.3, 1H, ArH), 7.53 (dd, J ) 0.9, 8.1 Hz, 1H,
ArH), 7.57 (t, J ) 2.1 Hz, 1H, ArH), 7.62 (brs, 1H, ArH), 7.79
(d, J ) 7.8 Hz, 1H, ArH). 13C NMR (CDCl3): δ 25.7, 36.4, 124.0,
125.1, 125.5, 126.5, 127.4, 128.1, 130.1, 134.7, 136.3, 141.9,
145.9, 155.7, 206.3. MS (ESI) m/z: 242, 244 (M+).
5-(2-Methylphenyl)-2,3-dihydroindene-1-one (2b). Yield
1
84%, mp 87 °C. H NMR (CDCl3): δ 2.28 (s, 3H, CH3), 2.73
(m, J ) 6.6 Hz, 2H, CH2), 3.19 (t, J ) 6.6 Hz, 2H, CH2), 7.21-
7.35 (m, 5H, ArH), 7.42 (s, 1H, ArH), 7.80 (d, J ) 7.8 Hz, 1H,
ArH). 13C NMR (CDCl3): δ 20.3, 25.8, 36.4, 123.3, 125.8, 127.2,
127.9, 128.7, 129.4, 130.4, 135.0, 135.6, 140.9, 148.7, 155.2,
206.6. MS (ESI) m/z: 222 (M+).
5-(3-Hydroxyphenyl)-2,3-dihydroindene-1-one (2i). Yield
1
74%, mp 185-6 °C. H NMR (CDCl3): δ 2.75 (m, 2H, CH2),
5-(3-Methylphenyl)-2,3-dihydroindene-1-one (2c). Yield
3.19 (t, J ) 5.7 Hz, 2H, CH2), 6.91 (dd, J ) 2.4, 8.1 Hz, 1H,
ArH), 7.12 (t, J ) 1.8 Hz, 1H, ArH), 7.18 (d, J ) 7.5 Hz, 1H,
ArH), 7.34 (t, J ) 7.8 Hz, 1H, ArH), 7.56 (dd, J ) 0.9, 8.1 Hz,
1
79%, mp 92 °C. H NMR (CDCl3): δ 2.44 (s, 3H, CH3), 2.74
(m, J ) 6.6 Hz, 2H, CH2), 3.20 (t, J ) 6.6 Hz, 2H, CH2), 7.23

6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5135
1H, ArH), 7.65 (s, 1H, ArH), 7.81 (d, J ) 7.8 Hz, 1H, ArH).
MS (ESI) m/z: 224 (M+).
Hz, 1H, ArH), 7.59 (t, J ) 7.2 HZ, 1H, ArH), 7.77 (d, J ) 7.5
Hz, 1H, ArH), 7.78 (d, J ) 7.5 Hz, 1H, ArH). 13C NMR
(CDCl3): δ 25.6, 36.3, 122.9, 126.0, 127.1, 127.9, 128.4, 131.4,
136.3, 140.2, 146.2, 154.6, 206.4. MS (ESI) m/z: 253 (M+).
5-(3-Trifluoromethylphenyl)-2,3-dihydroindene-1-
one (2s). Yield 75%, mp 120 °C. 1H NMR (CDCl3): δ 2.70
(m, J ) 5.7 Hz, 2H, CH2), 3.17 (t, J ) 5.7 Hz, 2H, CH2), 7.55
(t, J ) 7.8 Hz, 2H, ArH), 7.63 (d, J ) 8.4 Hz, 1H, ArH), 7.64
(brs, 1H, ArH), 7.77 (t, J ) 8.1 Hz, 2H, ArH), 7.84 (d, J )
1.8 Hz, 1H, ArH). 13C NMR (CDCl3): δ 25.7, 36.3, 124.0, 124.7,
125.1, 126.5, 129.3, 130.6, 136.4, 140.8, 145.7, 155.8, 206.2.
MS (ESI) m/z: 253 (M+).
5-(4-Hydroxyphenyl)-2,3-dihydroindene-1-one (2j). Yield
70%, mp 212-3 °C. 1H NMR (CDCl3 + DMSO-d6): δ 2.57 (m,
2H, CH2), 3.04 (t, J ) 5.7 Hz, 2H, CH2), 6.82 (dd, J ) 1.8,
8.4 Hz, 2H, ArH), 7.35 (dd, J ) 2.1, 8.4 Hz, 2H, ArH), 7.41
(dd, J ) 1.8, 8.4 Hz, 2H, ArH), 7.48 (d, J ) 1.8 Hz, 1H, ArH),
7.61 (d, J ) 8.1 Hz, 1H, ArH). 13C NMR (CDCl3 + DMSO-d6):
δ 25.0, 35.7, 115.3 × 2, 122.9, 123.4, 125.1, 127.7 × 2, 134.2,
146.7, 155.2, 157.3, 205.6. MS (ESI) m/z 224 (M+).
5-(2-Methoxyphenyl)-2,3-dihydroindene-1-one (2k). Yield
1
69%, mp 114-5 °C. H NMR (CDCl3): δ 2.73 (m, J ) 6.6 Hz,
2H, CH2), 3.19 (t, J ) 6.6 Hz, 2H, CH2), 3.83 C 7.02 (d, J )
8.4 Hz, 1H, ArH), 7.07 (dd, J ) 1.2, 7.5 Hz, 1H, ArH), 7.31-
7.41 (m, 2H, ArH), 7.54 (dd, J ) 1.8, 8.1 Hz, 1H, ArH), 7.61
(brs, 1H, ArH), 7.79 (d, J ) 8.1 Hz, 1H, ArH). 13C NMR
(CDCl3): δ 25.8, 36.4, 55.5, 111.2, 120.8, 123.1, 127.5, 129.1,
129.5, 129.6, 130.7, 135.6, 145.3, 155.0, 156.3, 206.7. MS (ESI)
m/z: 238 (M+).
5-(4-Trifluoromethylphenyl)-2,3-dihydroindene-1-
one (2t). Yield 74%, mp 118 °C. 1H NMR (CDCl3): δ 2.76 (m,
J ) 6.6 Hz, 2H, CH2), 3.22 (t, J ) 5.7 Hz, 2H, CH2), 7.60 (dd,
J ) 1.5, 7.8 Hz, 1H, ArH), 7.68 (d, J ) 1.5 Hz, ArH), 7.73 (brs,
4H, ArH), 7.85 (d, J ) 7.8 Hz, 1H, ArH). 13C NMR (CDCl3): δ
25.8, 36.4, 124.2 × 2, 125.4, 125.8, 126.8, 127.7 × 2, 130.0,
136.6, 143.7, 146.0, 155.8, 206.2. MS (ESI) m/z: 253 (M+).
5-(2,5-Dimethylphenyl)-2,3-dihydroindene-1-one (2u).
Yield 84%, mp 114 °C. 1H NMR (CDCl3): δ 2.23 (s, 3H, CH3),
2.36 (s, 3H, CH3), 2.74 (m, J ) 6.6 Hz, 2H, CH2), 3.19 (t, J )
6.3 Hz, 2H, CH2), 7.05 (s, 1H, ArH), 7.12 (dd, J ) 1.5, 9.0 Hz,
1H, ArH), 7.19 (d, J ) 7.8 Hz, 1H, ArH), 7.33 (dd, J ) 1.2,
7.8 Hz, 1H, ArH), 7.41 (d, J ) 1.2 Hz, 1H, ArH), 7.89 (d, J )
7.8 Hz, 1H, ArH). 13C NMR (CDCl3): δ 19.8, 20.8, 25.7, 36.3,
123.2, 127.2, 128.5, 128.7, 130.1, 130.4, 131.8, 135.3, 135.5,
140.7, 148.8, 155.1, 206.6. MS (ESI) m/z: 236 (M+).
5-(3,4-Dimethylphenyl)-2,3-dihydroindene-1-one (2v).
Yield 81%, mp 111 °C. 1H NMR (CDCl3): δ 2.23 (s, 3H, CH3),
2.36 (s, 3H, CH3), 2.75 (m, 2H, CH2), 3.19 (t, J ) 6.0 Hz, 2H,
CH2), 7.05 (s, 1H, ArH), 7.12 (d, J ) 8.4 Hz, 2H, ArH), 7.19 (d,
J ) 7.8 Hz, 1H, ArH), 7.33 (d, J ) 7.8 Hz, 1H, ArH), 7.42 (s,
1H, ArH), 7.79 (d, J ) 7.8 Hz, 1H, ArH). 13C NMR (CDCl3): δ
19.8, 21.3, 25.7, 36.3, 123.2, 126.7, 128.5, 128.7, 130.1, 130.4,
131.8, 135.3, 135.5, 140.7,148.8, 155.1, 206.6. MS (ESI) m/z:
236 (M+).
5-(3-Methoxyphenyl)-2,3-dihydroindene-1-one (2l). Yield
1
72%, mp 103-4 °C. H NMR (CDCl3): δ 2.74 (m, J ) 6.6 Hz,
2H, CH2), 3.20 (t, J ) 6.6 Hz, 2H, CH2), 3.88 (s, 3H, OCH3),
6.95 (ddd, J ) 0.9, 1.8, 8.1 Hz, 1H, ArH), 7.15 (t, J ) 1.8, Hz,
1H, ArH), 7.20 (ddd, J ) 0.9, 1.5, 8.1 Hz, 1H, ArH), 7.39
(t, J ) 7.5, Hz, 1H, ArH), 7.59 (dd, J ) 1.5, 7.8 Hz, 1H, ArH),
7.67 (d, J ) 1.5 Hz, 1H, ArH), 7.82 (d, J ) 8.1 Hz, 1H, ArH).
13C NMR (CDCl3): δ 25.8, 36.4, 55.3, 113.1, 113.6, 119.9, 124.0,
125.1, 126.7, 129.9, 136.0,141.6, 147.5, 155.7, 159.9, 206.5. MS
(ESI) m/z: 238 (M+).
5-(4-Methoxyphenyl)-2,3-dihydroindene-1-one (2m).
Yield 76%, mp 154-5 °C. 1H NMR (CDCl3) δ 2.73 (m, 2H, CH2),
3.18 (t, J ) 5.7 Hz, 2H, CH2), 3.86 (s, 3H, OCH3), 7.01 (d, J )
8.7 Hz, 2H, ArH), 7.56 (brd, J ) 8.4 Hz, 1H, ArH), 7.58
(d, J ) 8.7 Hz, 2H, ArH), 7.63 (s, 1H, ArH), 7.80 (d, J )
8.4 Hz, 1H, ArH). Partial 13C NMR (CDCl3): δ 25.8, 36.5, 55.3,
114.3 × 2, 124.0, 126.2, 128.6 × 2, 135.4, 146.7, 155.2, 157.3,
206.1. MS (ESI) m/z: 238 (M+).
5-(4-Phenoxyphenyl)-2,3-dihydroindene-1-one (2n). Yield
5-(3,5-Dimethylphenyl)-2,3-dihydroindene-1-one (2w).
Yield 84%, mp 107-8 °C. 1H NMR (CDCl3): δ 2.40 (s, 6H, CH3
× 2), 2.73 (m, J ) 6.6 Hz, 2H, CH2), 3.19 (t, J ) 6.3 Hz, 2H,
CH2), 7.06 (s, 1H, ArH), 7.24 (d, J ) 1.8 Hz, 2H, ArH), 7.58
(dd, J ) 1.6, 7.8 Hz, 1H, ArH), 7.66 (d, J ) 1.6 Hz, 1H, ArH),
7.80 (d, J ) 8.1 Hz, 1H, ArH). 13C NMR (CDCl3): δ 21.3, 25.8,
36.4, 123.8, 125.0, 125.2 × 2, 126.7, 129.9, 135.7, 138.4 × 2,
140.0, 147.9, 155.7, 206.6. MS (ESI) m/z: 236 (M+).
1
80%, mp 142-3 °C. H NMR (CDCl3): δ 2.73 (m, J ) 6.6 Hz,
2H, CH2), 3.19 (t, J ) 6.6 Hz, 2H, CH2), 7.06-7.13 (m, 4H,
ArH), 7.16 (d, J ) 8.7 Hz, 1H, ArH), 7.35-7.41 (m, 2H, ArH),
7.56-7.63 (m, 3H, ArH), 7.65 (brs, 1H, ArH), 7.81 (d, J )
8.1 Hz, 1H, ArH). MS (ESI) m/z: 300 (M+).
5-(4-N,N-Dimethylaminophenyl)-2,3-dihydroindene-1-
1
one (2o). Yield 64%, mp 217-8 °C. H NMR (CDCl3): δ 2.71
(m, J ) 6.6 Hz, 2H, CH2), 3.02 (s, 6H, N-CH3 × 2), 3.16
(t, J ) 6.3 Hz, 2H, CH2), 6.81 (d, J ) 8.4 Hz, 2H, ArH), 7.55
(dd, J ) 1.8, 7.8 Hz, 1H, ArH), 7.57 (d, J ) 8.4 Hz, 2H, ArH),
7.63 (dd, J ) 0.6, 8.1 1H, ArH), 7.77 (d, J ) 8.1 Hz, 1H, ArH).
13C NMR (CDCl3): δ 25.8, 36.5, 114.0, 115.0, 117.8, 123.9,
125.0, 126.7, 129.8, 135.9, 141.3, 146.8, 147.9, 155.7, 206.6.
MS (ESI) m/z: 251 (M+).
5-(3,4-Dimethoxyphenyl)-2,3-dihydroindene-1-one (2x).
1
Yield 75%, mp 175 °C. H NMR (CDCl3): δ 2.73 (m, J ) 6.0
Hz, 2H, CH2), 3.19 (t, J ) 6.6 Hz, 2H, CH2), 3.94 (s, 3H, OCH3),
3.97 (s, 3H, OCH3), 6.97 (d, J ) 8.4 Hz, 1H, ArH), 7.14 (d, J )
2.1 Hz, 1H, ArH), 7.21 (dd, J ) 2.1, 8.4 Hz, 1H, ArH), 7.57
(brd, J ) 7.8 Hz, 1H, ArH), 7.64 (d, J ) 0.6 Hz, 1H, ArH),
7.80 (d, J ) 7.8 Hz, 1H, ArH). MS (ESI) m/z: 236 (M+).
5-(2,4-Dimethoxyphenyl)-2,3-dihydroindene-1-one (2y).
Yield 68%, mp 129 °C. 1H NMR (CDCl3): δ 2.71 (m, J )
6.0 Hz, 2H, CH2), 3.17 (t, J ) 6.0 Hz, 2H, CH2), 3.81 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 6.57 (brs, 1H, ArH), 6.59 (dd, J )
2.4, 7.5 Hz), 7.26 (d, J ) 7.4 Hz, 1H, ArH), 7.51 (dd, J ) 1.5,
7.8 Hz, 1H, ArH), 7.58 (brs, 1H, ArH), 7.76 (d, J ) 8.1 Hz, 1H,
ArH). 13C NMR (CDCl3): δ 25.7, 36.4, 55.4, 55.5, 98.9, 104.7,
122.4, 123.0, 127.2, 128.9, 131.3, 135.1, 145.1, 155.1, 157.4,
160.6, 206.7. MS (ESI) m/z: 236 (M+).
5-(2-Nitrophenyl)-2,3-dihydroindene-1-one (2p). Yield
68%, mp 124 °C. 1H NMR (CDCl3): δ 2.71 (m, J ) 6.0 Hz, 2H,
CH2), 3.16 (t, J ) 6.0 Hz, 2H, CH2), 7.28 (dd, J ) 1.2, 7.5 Hz,
1H, ArH), 7.41 (d, J ) 2.1 Hz, 1H, ArH), 7.43 (d, J ) 7.8 Hz,
1H, ArH), 7.54 (dt, J ) 1.5, 7.8 Hz, 1H, ArH), 7.65 (dt, J )
1.5, 7.8 Hz, 1H, ArH), 7.77 (d, J ) 8.1 Hz, 1H, ArH), 7.92 (dd,
J ) 1.2, 8.1 Hz, 1H, ArH). 13C NMR (CDCl3): δ 25.6, 36.2,
123.8, 124.3, 126.4, 127.3, 128.9, 131.6, 132.6, 135.6, 136.6,
143.9, 148.7, 155.3, 206.2. MS (ESI) m/z: 253 (M+).
5-(3-Nitrophenyl)-2,3-dihydroindene-1-one (2q). Yield
79%, mp 147 °C. 1H NMR (CDCl3): δ 2.77 (m, J ) 6.0 Hz, 2H,
CH2), 3.24 (t, J ) 6.0 Hz, 2H, CH2), 7.63 (ddd, J ) 4H, ArH),
7.68 (d, J ) 8.1 Hz, 1H, ArH), 7.73 (d, J ) 0.6 Hz, 1H, ArH),
7.87 (d, J ) 8.1 Hz, 1H, ArH), 7.96 (ddd, J ) 1.2, 1.8, 7.5 Hz,
1H, ArH), 8.27 (ddd, J ) 1.2, 3.6, 8.1 Hz, 1H, ArH), 8.49
(t, J ) 1.8 Hz, 1H, ArH). 13C NMR (CDCl3): δ 25.8, 36.4, 122.3,
122.9, 124.4, 125.4, 126.7, 129.9, 133.3, 136.9, 141.9, 144.8,
148.7, 155.9, 206.2. MS (ESI) m/z: 253 (M+).
5-(2-Trifluoromethylphenyl)-2,3-dihydroindene-1-
one (2r). Yield 70%, mp 112 °C. 1H NMR (CDCl3): δ 2.75
(m, J ) 5.7 Hz, 2H, CH2), 3.19 (t, J ) 5.7 Hz, 2H, CH2), 7.32
(d, J ) 7.5 Hz, 2H, ArH), 7.43 (s, 1H, ArH), 7.51 (t, J ) 7.5
5-(3,4,5-Trimethoxyphenyl)-2,3-dihydroindene-1-one
(2z). Yield 76%, mp 161 °C. 1H NMR (CDCl3): δ 2.75 (m, J )
6.0 Hz, 2H, CH2), 3.21 (t, J ) 6.3 Hz, 2H, CH2), 3.91 (s, 3H,
OMe), 3.94 (s, 6H, OMe × 2), 6.81 (s, 2H, ArH), 7.57 (d, J )
8.7 Hz, 1H, ArH), 7.63 (brs, 1H, ArH), 7.81 (d, J ) 8.4 Hz, 1H,
ArH). 13C NMR (CDCl3): δ 25.8, 36.4, 56.1, 60.8, 104.5, 123.7,
124.8, 126.4, 135.6, 135.7, 138.1, 147.4, 153.3, 155.6, 206.1.
MS (ESI) m/z: 298 (M+).
5-(2,3,4-Trimethoxyphenyl)-2,3-dihydroindene-1-one
(2aa). Yield 72%, mp 158-9 °C. 1H NMR (CDCl3): δ 2.71 (m,
J ) 6.0 Hz, 2H, CH2), 3.17 (t, J ) 5.7 Hz, 2H, CH2), 3.68 (s,
3H, OMe), 3.90 (s, 3H, OMe), 3.92 (s, 6H, OMe), 6.75 (d, J )
8.4 Hz, 1H, ArH), 7.05 (d, J ) 8.7 Hz, 1H, ArH), 7.50 (dd, J )

5136 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16
Chordia et al.
1.2, 8.4 Hz, 1H, ArH), 7.59 (brs, 1H, ArH), 7.76 (d, J ) 7.8 Hz,
1H, ArH). 13C NMR (CDCl3): δ 25.6, 36.2, 55.8, 60.8, 60.9,
107.3, 123.0, 124.7, 126.9, 128.4, 135.2, 142.3, 144.7151.2,
153.6, 155.0, 206.5. MS (ESI) m/z: 298 (M+).
5-(3,4-Methylenedioxyphenyl)-2,3-dihydroindene-1-
one (2ab). Yield 74%, mp 171-2 °C. 1H NMR (CDCl3): δ 2.73
(m, J ) 6.6 Hz, 2H, CH2), 3.18 (t, J ) 6.0 Hz, 2H, CH2), 6.02
(s, 2H, OCH2O), 6.90 (dd, J ) 1.5, 7.5 Hz, 1H, ArH), 7.10 (brs,
1H, ArH), 7.12 (dd, J ) 1.8, 7.8 Hz, 1H, ArH), 7.52 (brd, J )
8.1 Hz, 1H, ArH), 7.59 (brs, 1H, ArH), 7.78 (d, J ) 8.1 Hz, 1H,
ArH). 13C NMR (CDCl3): δ 25.8, 36.4, 101.3, 107.7, 108.7,
121.2, 124.0, 124.6, 126.4, 134.4, 135.6, 147.3, 147.9, 148.3,
155.8, 206.4. MS (ESI) m/z: 298 (M+).
(152 mg, 2 mmol), and iodine (279 mg, 1.1 mg-at.) in 2 mL of
absolute ethanol was heated for 3 h in an open vessel in a
105 °C oil bath. The alcohol was evaporated; more ethanol
(2 mL) was added, and the mixture was taken to dryness. The
dark residue was washed with ether (5 mL × 3), and the
washings were discarded. The residue was dissolved in hot
water (∼3 mL) with vigorous stirring; solid product separated
on cooling to room temperature. The solid was filtered and
washed with warm water and finally with ether (∼5 × 2 mL).
The solid was vacuum-dried. Occasionally, obtaining an ana-
lytical sample required reprecipitation from hot water.
6-(Phenyl)-8H-indeno[1,2-d]thiazol-2-ylamine Hydro-
iodide (3a). Yield 89%. Anal. (C16H13IN2S) C, H, N. 1H NMR
(DMSO-d6): δ 3.85 (s, 2H, CH2), 7.35 (dt, J ) 1.2, 7.2 Hz, 1H,
ArH), 7.46 (t, J ) 8.1 Hz, 2H, ArH), 7.60 (d, J ) 8.1 Hz, 2H,
ArH), 7.65-7.70 (m, 3H, ArH), 7.85 (brs, 1H, ArH), 8.80 (brs,
NH3). 13C NMR (DMSO-d6): δ 33.9, 118.5, 122.5, 123.4, 125.6,
126.6 × 2, 127.4, 129.0 × 2, 132.5, 137.5, 140.0, 143.8, 146.2,
173.9. MS (ESI) m/z: 264 (M+).
6-(2-Methylphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3b). Yield 84%. Anal. (C17H15IN2S)
C, H, N. 1H NMR (DMSO-d6): δ 2.23 (s, 3H, CH3), 3.84 (s, 2H,
CH2), 7.19-7.32 (m, 4H, ArH), 7.34 (d, J ) 7.8 Hz, 1H, ArH),
7.52 (s, 1H, ArH), 7.61 (d, J ) 7.8 Hz, 1H, ArH), 9.00 (brs,
NH3). 13C NMR (DMSO-d6): δ 20.2, 33.9, 117.8 br, 122.4, 125.8,
125.9, 127.7 br, 129.5 br, 130.3 br, 130.5 br, 132.0, 134.8, 138.7,
141.2, 143.8, 145.4, 174.0. MS (ESI) m/z: 278 (M+).
6-(3-Methylphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3c). Yield 79%. Anal. (C17H15IN2S)
C, H, N. 1H NMR (DMSO-d6): δ 2.35 (s, 3H, CH3), 3.85 (s, 2H,
CH2), 7.14 (d, J ) 7.5, 1H, ArH), 7.29 (t, J ) 7.5 Hz, 1H, ArH),
7.46 (d, J ) 7.8 Hz, 1H, ArH), 7.49 (s, 1H, ArH), 7.62 (d, J )
8.1 Hz, 1H, ArH), 7.66 (d, J ) 9.0 Hz, 1H, ArH), 7.83 (s, 1H,
ArH), 9.26 (brs, NH3). 13C NMR (DMSO-d6): δ 21.1, 34.1, 118.5,
122.3, 123.4, 123.7, 125.5, 127.3, 128.0, 128.8, 132.0, 137.7,
138.0, 139.8, 142.7, 146.1, 173.9. MS (ESI) m/z: 278 (M+).
6-(2-Fluorophenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3d). Yield 68%. Anal. (C16H12FIN2S)
C, H, N. 1H NMR (DMSO-d6): δ 3.87 (s, 2H, CH2), 7.25-7.34
(m, 2H, ArH), 7.37-7.44 (m, 1H, ArH), 7.54 (t, J ) 7.8 Hz,
2H, ArH), 7.65 (d, J ) 8.1 Hz, 1H, ArH), 7.73 (s, 1H, ArH),
9.00 (brs, NH3). 13C NMR (DMSO-d6): δ 21.1 × 2, 34.1, 118.5,
122.3, 123.5, 124.5 × 2, 125.5, 128.9, 132.0, 137.9, 138.0 × 2,
139.9, 143.0, 146.1, 174.0. MS (ESI) m/z: 282 (M+).
5-(3,4-Dichlorophenyl)-2,3-dihydroindene-1-one (2ac).
1
Yield 62%, mp 151 °C. H NMR (CDCl3): δ 2.75 (m, J ) 6.0
Hz, 2H, CH2), 3.21 (t, J ) 6.3 Hz, 2H, CH2), 7.45 (dd, J ) 2.4,
8.4, 1H, ArH), 7.54, (d, J ) 8.1 Hz, 1H, ArH), 7.63 (d, J ) 0.9
Hz, 1H, ArH), 7.72 (d, J ) 2.4 Hz, 1H, ArH), 7.83 (d, J ) 8.1
Hz, 1H, ArH). 13C NMR (CDCl3): δ 25.8, 36.4, 124.3, 125.0,
126.4, 126.6, 129.2, 130.8, 132.5, 133.1, 136.6, 140.1, 144.9,
155.8, 206.3. MS (ESI) m/z: 276, 278, 280 (M+).
5-(3,5-Dichlorophenyl)-2,3-dihydroindene-1-one (2ad).
1
Yield 64%, mp 170 °C. H NMR (CDCl3): δ 2.75 (m, J ) 6.0
Hz, 2H, CH2), 3.21 (t, J ) 6.3 Hz, 2H, CH2), 7.40 (dd, J ) 1.8,
2.1 Hz, 1H, ArH), 7.50, (m, 2H, ArH), 7.55 (d, J ) 8.1 Hz, 1H,
ArH), 7.64 (d, J ) 0.6 Hz, 1H, ArH), 7.83 (d, J ) 8.1 Hz, 1H,
ArH). 13C NMR (CDCl3): δ 23.7, 36.3, 124.2, 125.1, 125.8,
126.5, 128.0, 135.4, 143.0, 144.5, 155.7, 206.7. MS (ESI) m/z:
276, 278, 280 (M+).
5-(Naphth-1-yl)-2,3-dihydroindene-1-one (2ae). Yield
68%, mp 155 °C. 1H NMR (CDCl3): δ 2.78 (m, 2H, CH2), 3.24
(t, J ) 5.7 Hz, 2H, CH2), 7.42-7.56 (m, 5H, ArH), 7.60 (brs,
1H, ArH), 7.82-7.95 (m, 4H, ArH). 13C NMR (CDCl3): δ 25.6,
36.2, 123.0, 124.9, 125.1, 125.6, 126.0, 126.6, 127.8, 129.1,
130.7, 133.3, 135.6, 138.7, 147.0, 154.9, 206.0. MS (ESI) m/z:
258 (M+).
5-(Naphth-2-yl)-2,3-dihydroindene-1-one (2af). Yield
72%, mp 168 °C. 1H NMR (CDCl3): δ 2.77 (m, 2H, CH2), 3.24
(t, J ) 6.6 Hz, 2H, CH2), 7.50-7.65 (m, 2H, ArH), 7.60-7.80
(m, 2H, ArH), 7.81 (d, J ) 0.6 Hz, 1H, ArH), 7.85-7.94 (m,
3H, ArH), 7.96 (d, J ) 8.4 Hz, 1H, ArH), 8.10 (d, J ) 1.5 Hz,
1H, ArH). 13C NMR (CDCl3): δ 25.9, 36.5, 123.9, 125.1, 126.4,
126.8, 127.5, 128.2, 128.5, 132.8, 133.3, 135.8, 137.2, 147.3,
155.7, 206.4. MS (ESI) m/z: 258 (M+).
5-(6-Methoxynaphth-2-yl)-2,3-dihydroindene-1-one(2ag).
6-(3-Fluorophenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3e). Yield 71%. Anal. (C16H12FIN2S)
C, H, N. 1H NMR (DMSO-d6): δ 3.86 (s, 2H, CH2), 7.17 (tt,
J ) 1.5, 8.1 Hz, 1H, ArH), 7.45-7.56 (m, 3H, ArH), 7.62 (d,
J ) 8.1 Hz, 1H, ArH), 7.72 (dd, J ) 1.8, 8.1 Hz, 1H, ArH),
7.90 (s, 1H, ArH), 9.00 (brs, NH3). 13C NMR (DMSO-d6): δ 34.1,
113.0 and 113.3, 113.8 and114.1, 118.5, 122.6, 122.9, 123.4,
125.7, 130.7 and 130.8, 132.7, 135.9, 142.3, 143.0, 146.1, 161.0
and 164.2, 173.8. MS (ESI) m/z: 282 (M+).
6-(4-Fluorophenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3f). Yield 65%. Anal. (C16H12FIN2S)
C, H, N. 1H NMR (DMSO-d6): δ 3.84 (s, 2H, CH2), 7.17 (t, J )
8.7 Hz, 1H, ArH), 7.59 (d, J ) 7.8 Hz, 1H, ArH), 7.65 (d, J )
7.8 Hz, 1H, ArH), 7.70-7.75 (m, 2H, ArH), 7.81 (s, 1H, ArH),
8.80 (brs, NH3). 13C NMR (DMSO-d6): δ 33.4, 115.4, 115.7,
118.1, 122.7, 123.2, 125.3, 128.4, 128.9, 129.0, 133.3, 136.0,
136.5, 146.1, 163.2, 173.6. MS(ESI) m/z: 282 (M+). HRMS calcd
for C16H12N2FS, exact mass 283.070 52; found m/z, 283.070 82.
6-(2-Chlorophenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3g). Yield 65%. Anal. (C16H12ClIN2S)
C, H, N. 1H NMR (DMSO-d6): δ 3.85 (s, 2H, CH2), 7.35-7.46
(m, 4H, ArH), 7.57 (dt, J ) 1.8, 7.8 Hz, 1H, ArH), 7.61 (brs,
1H, ArH), 7.63 (d, J ) 7.5 Hz, 1H, ArH), 9.00 (brs, NH3). 13C
NMR (DMSO-d6): δ 34.1, 117.9, 122.9, 125.9, 127.5, 128.2,
129.2, 129.8, 131.3, 131.5, 132.3, 136.1, 139.6, 142.5, 145.2,
173.9. MS (ESI) m/z: 298, 300 (M+).
1
Yield 72%, mp not determined. H NMR (CDCl3): δ 2.76 (m,
2H, CH2), 3.22 (t, J ) 6.6 Hz, 2H, CH2), 3.95 (s, 3H, OCH3),
7.16-7.25 (m, 2H, ArH), 7.55-7.86 (m, 6H, ArH), 8.03 (s, 1H,
ArH). 13C NMR (CDCl3): δ 25.8, 36.4, 55.2, 105.5, 119.4, 124.0,
124.9, 125.7, 126.3, 126.6, 127.4, 128.9, 129.8, 134.2, 135.1,
147.5, 155.9, 158.1, 206.6. MS (ESI) m/z: 288 (M+).
5-(Thiophen-2-yl)-2,3-dihydroindene-1-one (2ah). Yield
68%, mp 111 °C. 1H NMR (CDCl3): δ 2.72 (m, J ) 6.6 Hz, 2H,
H2), 3.17 (t, J ) 6.6 Hz, 2H, CH2), 7.12 (dd, J ) 3.6, 5.1 Hz,
1H, ArH), 7.38 (dd, J ) 0.9, 5.1 Hz,1H, ArH), 7.45 (dd, J )
0.9, 3.6 Hz, 1H, ArH), 7.63 (dd, J ) 1.5, 8.17 Hz, 1H, ArH),
7.69 (m, 1H, ArH), 7.75 (d, J ) 8.1 Hz, 1H, ArH). MS (ESI)
m/z: 214 (M+).
5-(Thiophen-3-yl)-2,3-dihydroindene-1-one (2ai). Yield
65%, mp 154 °C. 1H NMR (CDCl3): δ 2.73 (m, J ) 6.6 Hz, 2H,
CH2), 3.18 (t, J ) 5.7 Hz, 2H, CH2), 7.44 (brd, J ) 2.1 Hz, 2H,
ArH), 7.59 (t, J ) 2.1 Hz, 1H, ArH), 7.68 (brs, 1H, ArH), 7.78
(d, J ) 8.1 Hz, 1H, ArH). 13C NMR (CDCl3): δ 25.7, 36.4, 122.3,
124.0, 124.1, 125.8, 126.2, 126.7, 135.7, 141.2, 141.7, 155.9,
206.3. MS (ESI) m/z: 214 (M+).
5-(Benzofuran-2-yl)-2,3-dihydroindene-1-one (2aj). Yield
72%, mp not determined. 1H NMR (CDCl3): δ 2.74 (m, J )
6.6 Hz, 2H, CH2), 3.18 (t, J ) 6.0 Hz, 2H, CH2), 7.18 (s, 1H,
ArH), 7.23-7.29 (m, 2H, ArH), 7.34 (dt, J ) 1.5, 8.4 Hz, 1H,
ArH), 7.54 (brd, J ) 8.4 Hz, 1H, ArH), 7.62 (brd, J ) 7.8 Hz,
1H, ArH), 7.83 (ABd, J ) 8.1 Hz, 2H, ArH), 7.98 (s, 1H, ArH).
MS (ESI) m/z: 248 (M+).
6-(3-Chlorophenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3h). Yield 67%. Anal. (C16H12ClIN2S)
1
6-Phenyl-8H-indeno[1,2-d]thiazol-2-ylamine (3a-aj).
General Method B. A mixture of 2a-aj (1 mmol), thiourea
C, H, N. H NMR (DMSO-d6): δ 3.86 (s, 2H, CH2), 7.40 (brd,
J ) 7.8 Hz, 1H, ArH), 7.49 (dd, J ) 7.5, 8.1 Hz, 1H, ArH),

6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5137
7.63 (d, J ) 8.1 Hz, 1H, ArH), 7.67 (dt, J ) 7.8 Hz, 1H, ArH),
7.70-7.76 (m, 2H, ArH), 7.91 (brs, 1H, ArH), 9.00 (brs, NH3).
13C NMR (DMSO-d6): δ 34.1, 118.5, 122.9, 123.5, 125.2, 125.7,
126.3, 127.1, 130.7, 132.7, 133.7, 135.8, 142.0, 142.8, 146.1,
173.9. MS (ESI) m/z: 298, 300 (M+).
d6): δ 33.1, 117.9, 123.8, 124.1, 124.3, 126.6, 128.6, 131.8,
132.8, 133.3, 135.1, 145.9, 148.9, 173.5. MS (ESI) m/z: 309
(M+).
6-(3-Nitrophenyl)-8H-indeno[1,2-d]thiazol-2-ylamine
Hydroiodide (3q). Yield 71%. Anal. (C16H12IN3O2S) C, H, N.
1H NMR (DMSO-d6): δ 3.88 (s, 2H, CH2), 7.66 (d, J ) 8.1 Hz,
1H, ArH), 7.75 (d, J ) 8.1 Hz, 1H, ArH), 7.81 (dd, J ) 1.8,
8.1 Hz, 1H, ArH), 8.00 (s, 1H, ArH), 8.19 (dt, J ) 2.4, 8.4 Hz,
2H, ArH), 8.46 (t, J ) 1.8, 1H, ArH), 8.98 (brs, NH3). 13C NMR
(DMSO-d6): δ 34.1, 118.6, 120.9, 122.0, 123.5, 123.6, 126.0,
130.5, 133.1, 133.4, 134.9, 141.5, 143.3, 146.3, 148.4, 174.0.
MS (ESI) m/z: 309 (M+).
6-(2-Trifluoromethylphenyl)-8H-indeno[1,2-d]thiazol-
2-ylamine Hydroiodide (3r). Yield 81%. Anal. (C17H12F3-
IN2S) C, H, N. 1H NMR (DMSO-d6): δ 3.82 (s, 2H, CH2), 7.29
(d, J ) 8.1 Hz, 1H, ArH), 7.42 (d, J ) 7.5 Hz, 1H, ArH), 7.47
(s, 1H, ArH), 7.57 (d, J ) 7.8 Hz, 1H, ArH), 7.62 (d, J )
7.8 Hz, 1H, ArH), 7.72 (t, J ) 7.5 Hz, 1H, ArH), 7.83 (d, J )
7.2 Hz, 1H, ArH). Partial 13C NMR (DMSO-d6): δ 33.6, 117.4,
123.0, 125.3, 126.1, 127.5, 128.0, 132.2, 133.4, 136.3, 140.6,
145.0, 173.8. MS (ESI) m/z: 309 (M+).
6-(3-Trifluoromethylphenyl)-8H-indeno[1,2-d]thiazol-
2-ylamine Hydroiodide (3s). Yield 79%. Anal. (C17H12F3-
IN2S) C, H, N. 1H NMR (DMSO-d6): δ 3.87 (s, 2H, CH2), 7.63
(d, J ) 8.1 Hz, 2H, ArH), 7.71 (m, 2H, ArH), 7.77 (dd, J ) 1.5,
8.1 Hz, 2H, ArH), 7.96 (s, 1H, ArH), 7.99 (s, 1H, ArH), 8.02 (t,
J ) 5.1 Hz, 1H, ArH), 8.90 (brs, 3H, NH3). 13C NMR (DMSO-
d6): δ 34.1, 118.6, 123.0, 123.2, 123.7, 123.9, 125.9, 129.5,
130.1, 130.6, 133.0, 135.7, 141.0, 143.2, 146.3, 174.0. MS (ESI)
m/z: 332 (M+).
6-(4-Trifluoromethylphenyl)-8H-indeno[1,2-d]thiazol-
2-ylamine Hydroiodide (3t). Yield 74%. Anal. (C17H12F3-
IN2S) C, H, N. 1H NMR (DMSO-d6): δ 3.85 (s, 2H, CH2), 7.61
(d, J ) 8.1 Hz, 2H, ArH), 7.74 (dd, J ) 1.8, 7.8 Hz, 1H, ArH),
7.80 (d, J ) 8.4 Hz, 2H, ArH), 7.91 (d, J ) 8.1 Hz, 2H, ArH),
7.92 (d, J ) 1.2 HZ, 1H, ArH), 8.50 (s, NH3). Partial 13C NMR
(DMSO-d6): δ 33.6, 118.4, 123.5, 125.7, 125.9, 127.3 × 2, 134.4,
135.3, 144.1, 146.3, 173.7. MS (ESI) m/z: 332 (M+).
6-(2,5-Dimethylphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3u). Yield 72%. Anal. (C18H17IN2S)
C, H, N. 1H NMR (DMSO-d6): δ 2.18 (s, 3H, CH3), 2.28 (s, 3H,
CH3), 3.84 (s, 2H, CH2), 7.02 (s, 1H, ArH), 7.07 (d, J ) 7.8 Hz,
1H, ArH), 7.17 (d, J ) 7.8 Hz, 1H, ArH), 7.31 (dd, J ) 1.5, 7.8
Hz, 1H, ArH), 7.51 (s, 1H, ArH), 7.61 (d, J ) 8.1 Hz, 1H, ArH).
13C NMR (DMSO-d6): δ 19.8, 20.5 , 34.0, 117.9, 122.2, 125.8,
127.9, 128.0, 130.2, 130.3, 131.5, 134.8, 138.9, 140.9, 142.7,
145.3, 174.0. MS (ESI) m/z: 292 (M+).
6-(3,4-Dimethylphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3v). Yield 81%. Anal. (C18H17IN2S)
C, H, N. 1H NMR (DMSO-d6): δ 2.17 (s, 3H, CH3), 2.28 (s, 3H,
CH3), 3.82 (s, 2H, CH2), 7.01 (brs, 1H, ArH), 7.06 (d, J ) 7.5
Hz, 1H, ArH), 7.17 (d, J ) 7.8 Hz, 1H, ArH), 7.31 (dd, J ) 1.2,
7.8 Hz, 1H, ArH), 7.49 (s, 1H, ArH), 7.59 (d, J ) 7.5 Hz, 1H,
ArH). 13C NMR (DMSO-d6): δ 19.8, 20.6 , 34.0, 117.9, 122.3,
125.8, 127.8, 128.0, 130.2, 130.4, 131.6, 131.8, 134.9, 138.9,
140.9, 143.5, 145.4, 174.0. MS (ESI) m/z: 292 (M+).
6-(3-Hydroxyphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3i). Yield 74%. Anal. (C16H13IN2OS)
1
C, H, N. H NMR (DMSO-d6): δ 3.86 (s, 2H, CH2), 6.75 (dd,
J ) 2.1, 8.1 Hz, 1H, ArH), 7.04 (d, J ) 2.1 Hz, 1H, ArH), 7.09
(d, J ) 7.5 Hz, 1H, ArH), 7.25 (t, J ) 8.1 Hz, 1H, ArH), 7.61
(s, 2H, ArH), 7.78 (s, 1H, ArH), 9.00 (brs, NH3). 13C NMR
(DMSO-d6): δ 34.1, 113.4, 114.4, 117.5, 118.5, 122.3, 123.4,
125.5, 130.0, 132.0, 137.8, 141.4, 142.5, 146.1, 157.8, 173.9.
MS (ESI) m/z: 280 (M+).
6-(4-Hydroxyphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3j). Yield 71%. Anal. (C16H13IN2OS)
C, H, N. 1H NMR (DMSO-d6): δ 3.82 (s, 2H, CH2), 6.84 (d,
J ) 8.4 Hz, 2H, ArH), 7.51 (d, J ) 8.4 Hz, 2H, ArH), 7.55 (m,
2H, ArH), 7.75 (s, 1H, ArH), 9.00 (brs, NH3). 13C NMR (DMSO-
d6): δ 33.8, 115.7 × 2, 118.3, 121.8, 122.7, 124.6, 126.9, 127.7
× 2, 130.7, 131.7, 137.6, 146.1, 157.0, 173.8. MS (ESI) m/z:
280 (M+).
6-(2-Methoxyphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3k). Yield 75%. Anal. (C17H15IN2OS)
1
C, H, N. H NMR (DMSO-d6): δ 3.76 (s, 3H, OCH3), 3.82 (s,
2H, CH2), 7.02 (t, J ) 7.5 Hz, 1H, ArH), 7.11 (d, J ) 7.5 Hz,
1H, ArH), 7.29 (dd, J ) 1.5, 7.5 Hz, 1H, ArH), 7.32 (dd, J )
7.2, 8.1 Hz, 1H, ArH), 7.45 (dd, J ) 1.5, 8.1 Hz, 1H, ArH),
7.57 (d, J ) 8.1 Hz, 1H, ArH), 7.63 (brs, 1H, ArH), 9.00 (brs,
NH2). 13C NMR (DMSO-d6): δ 33.9, 55.5, 111.7, 117.7, 120.8,
122.1, 126.0, 128.0, 128.9, 129.6, 130.4, 131.6, 135.7, 143.1,
145.0, 156.1, 173.9. MS (ESI) m/z: 294 (M+).
6-(3-Methoxyphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3l). Yield 74%. Anal. (C17H15IN2OS)
1
C, H, N. H NMR (DMSO-d6): δ 3.82 (s, 3H, OCH3), 3.86 (s,
2H, CH2), 6.92 (dt, J ) 1.8, 8.1 Hz, 1H, ArH), 7.21 (t, J ) 1.5
Hz, 1H, ArH), 7.25 (dd, J ) 0.9, 7.8 Hz, 1H, ArH), 7.37 (t, J )
7.8 Hz, 1H, ArH), 7.61 (d, J ) 8.1 Hz, 1H, ArH), 7.69 (dd, J )
1.5, 7.8 Hz, 1H, ArH), 7.87 (brs, 1H, ArH), 9.00 (brs, NH2).
13C NMR (DMSO-d6): δ 34.1, 55.1, 112.0, 113.0, 118.4, 118.9,
122.5, 123.5, 125.7, 130.0, 132.3, 137.5, 141.4, 142.9, 146.1,
159.7, 173.9. MS (ESI) m/z: 294 (M+).
6-(4-Methoxyphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3m). Yield 72%. Anal. (C17H15IN2OS)
1
C, H, N. H NMR (DMSO-d6): δ 3.78 (s, 3H, OCH3), 3.85 (s,
2H, CH2), 7.02 (dd, J ) 2.1, 6.9 Hz, 2H, ArH), 7.60-7.65 (m,
4H, ArH), 7.81(brs, 1H, ArH), 9.00 (brs, NH3). 13C NMR
(DMSO-d6): δ 34.0, 55.2, 114.3, 114.4 × 2, 118.4, 121.9, 122.9,
124.9, 127.7 × 2, 131.5, 132.2, 137.3, 146.1, 158.8, 173.9. MS
(ESI) m/z: 294 (M+).
6-(4-Phenoxyphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3n). Yield 81%. Anal. (C22H17IN2OS)
C, H, N. 1H NMR (DMSO-d6): δ 3.85 (s, 2H, CH2), 7.04-7.10
(m, 4H, ArH), 7.16 (dt, J ) 0.9, 7.2 Hz, 1H, ArH), 7.38-7.45
(m, 2H, ArH), 7.58-7.75 (m, 4H, ArH), 7.84 (s, 1H, ArH), 8.99
(brs, NH3). 13C NMR (DMSO-d6): δ 34.1, 118.5, 118.8 × 2,
118.9 × 2, 122.3, 123.2, 123.7, 125.3, 128.2 × 2, 130.1 × 2,
131.9, 135.0, 136.9, 142.8, 146.2, 156.3, 173.9. MS (ESI) m/z:
356 (M+).
6-(4-N,N-Dimethylaminophenyl)-8H-indeno[1,2-d]thia-
zol-2-ylamine Hydroiodide (3o). Yield 75%. 1H NMR (DMSO-
d6): δ 3.08 (s, 6H, NMe2), 3.86 (s, 2H, CH2), 7.24 (brd, 2H,
ArH), 7.67 (ABd, J ) 7.5 Hz, 2H, ArH), 7.72 (d, J ) 8.4 Hz,
2H, ArH), 7.86 (s, 1H, ArH), 9.05 (brs, NH3). 13C NMR (DMSO-
d6): δ 34.2, 43.9 × 2, 118.4, 118.6 × 2, 122.4, 123.2, 125.3,
127.8 × 3, 131.9, 136.6, 142.4, 144.7, 146.2, 174.0. HRMS calcd
for C18H17N3S, exact mass 307.114 32; found m/z, 307.121 76.
6-(2-Nitrophenyl)-8H-indeno[1,2-d]thiazol-2-ylamine
Hydroiodide (3p). Yield 79%. Anal. (C16H12IN3O2S) C, H, N.
1H NMR (DMSO-d6): δ 3.78 (s, 2H, CH2), 7.27 (dd, J ) 1.5,
7.5 Hz, 1H, ArH), 7.49 (d, J ) 1.5 Hz, 1H, ArH), 7.50 (d, J )
8.1 Hz, 1H, ArH), 7.58 (dd, J ) 0.9, 7.5 Hz, 1H, ArH), 7.61
(dt, J ) 1.2, 7.8 Hz, 1H, ArH), 7.76 (dt, J ) 1.5, 7.5 Hz, 1H,
ArH), 7.97 (dd, J ) 1.2, 7.8 Hz, 1H, ArH). 13C NMR (DMSO-
6-(3,5-Dimethylphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3w). Yield 84%. Anal. (C18H17IN2S)
C, H, N. 1H NMR (DMSO-d6): δ 2.31 (s, 6H, CH3 × 2), 3.84 (s,
2H, CH2), 6.97 (brs, 1H, ArH), 7.28 (brs, 2H, ArH), 7.59 (d, J
) 8.1 Hz, 1H, ArH), 7.64 (dd, J ) 1.5, 7.8 Hz, 1H, ArH), 7.82
(s, J ) 7.5 Hz, 1H, ArH). 13C NMR (DMSO-d6): δ 21.1 × 2,
34.1, 118.5, 122.3, 123.5, 124.5 × 2, 125.5, 128.9, 132.0, 137.9,
138.0 × 2, 139.9, 143.0, 146.1, 174.0. MS (ESI) m/z: 292 (M+).
6-(3,4-Dimethoxyphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3x). Yield 68%. Anal. (C18H17IN2O2S)
1
C, H, N. H NMR (DMSO-d6): δ 3.78 (s, 3H, OCH3), 3.84 (s,
5H, CH2 and CH3), 7.03 (d, J ) 8.1 Hz, 1H, ArH), 7.21 (dd,
J ) 1.8, 8.1 Hz, 1H, ArH), 7.24 (s, 1H, ArH), 7.58 (d, J ) 7.8
Hz, 1H, ArH), 7.66 (dd, J ) 1.5, 8.1 Hz, 1H, ArH), 7.8d (s, 1H,
ArH), 9.00 (brs, NH3). 13C NMR (DMSO-d6): δ 34.1, 55.6 × 2,
110.2, 112.1, 118.4, 118.7, 122.0, 123.1, 125.1, 131.5, 132.6,
137.6, 143.0, 146.1, 148.4, 149.0, 173.9. MS (ESI) m/z: 324
(M+).

5138 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16
Chordia et al.
6-(2,4-Dimethoxyphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3y). Yield 68%. Anal. (C18H17IN2O2S)
6-(6-Methoxynaphth-2-yl)-8H-indeno[1,2-d]thiazol-2-
1
ylamine Hydroiodide (3ag). Yield 71%. H NMR (DMSO-
1
C, H, N. H NMR (DMSO-d6): δ 3.76 (s, 3H, OCH3), 3.80 (s,
d6): δ 3.88 (s, 2H, CH2), 7.19 (dd, J ) 2.4, 8.7 Hz, 1H, ArH),
7.34 (d, J ) 2.4 Hz, 1H, ArH), 7.62 (d, J ) 8.4 Hz, 1H, ArH),
7.78-7.92 (m, 4H, ArH), 7.98 (s, 1H, ArH), 8.17 (s, 1H, ArH).
13C NMR (DMSO-d6): δ 33.9, 55.2, 105.7, 118.5, 118.9, 122.4,
123.3, 124.9, 125.3, 125.5, 127.3, 128.7, 129.6, 132.4, 133.4,
134.9, 137.3, 144.3, 146.2, 157.4, 173.8. HRMS calcd for
C21H17N2OS, exact mass 345.106 16; found m/z, 345.105 71.
6-(Thiophen-2-yl)-8H-indeno[1,2-d]thiazol-2-ylamine
Hydroiodide (3ah). Yield 74%. Anal. (C14H11IN2S2) C, H, N.
1H NMR (DMSO-d6): δ 3.85 (s, 2H, CH2), 7.56-7.61 (m, 2H,
ArH), 7.65 (dd, J ) 3.0, 4.8 Hz, 1H, ArH), 7.74 (dd, J ) 1.2,
7.8 Hz, 1H, ArH), 7.69 (dd, J ) 1.5, 7.8 Hz, 1H, ArH), 7.89
(dd, J ) 1.5, 6.0 Hz, 1H, ArH), 7.93 (brs, 1H, ArH), 9.04 (brs,
NH2). 13C NMR (DMSO-d6): δ 34.0, 118.4, 120.8, 122.1, 122.8,
124.9, 126.1, 127.2, 131.7, 132.6, 141.2, 143.0, 146.1, 173.9.
MS (ESI) m/z: 270 (M+). HRMS calcd for C14H11N2OS2, exact
mass 271.036 36; found m/z, 271.036 87.
3H, OCH3), 3.81 (s, 2H, CH2), 6.61 (dd, J ) 1.8, 8.1 Hz, 1H,
ArH), 6.66 (s, 1H, ArH), 7.23 (d, J ) 81, 1H, ArH), 7.42 (dd,
J ) 1.5, 7.8 Hz, 1H, ArH), 7.55 (d, J ) 7.8, 1H, ArH), 7.60 (s,
1H, ArH), 9.00 (brs, NH3). 13C NMR (DMSO-d6): δ 33.9, 55.3,
55.6, 98.9, 105.3, 117.6, 121.7, 122.2, 125.9, 127.8, 130.9, 131.1,
135.7, 143.1, 145.0, 157.1, 160.0, 173.9. MS (ESI) m/z: 324
(M+).
6-(3,4,5-Trimethoxyphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3z). Yield 64%. Anal. (C19H19IN2O3S)
C, H, N. 1H NMR (DMSO-d6): δ 3.69 (s, 3H, OCH3), 3.86 (brs,
8H, OCH3 × 2, CH2), 6.95 (s, 2H, ArH), 7.25 (brs, NH3), 7.61
(d, J ) 7.8 Hz, 1H, ArH), 7.72 (dd, J ) 1.5, 7.8 HZ, 1H, ArH),
7.91 (s, 1H, ArH). 13C NMR (DMSO-d6): δ 34.0, 56.0 × 2, 60.1,
104.0 × 2, 118.3, 122.3, 123.5, 125.6, 132.1, 135.7, 137.0, 137.7,
143.3, 146.0, 153.2 × 2, 173.9. MS (ESI) m/z: 354 (M+).
6-(2,3,4-Trimethoxyphenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3aa). Yield 72%. Anal. (C19H19-
6-(3-Thiophenyl)-8H-indeno[1,2-d]thiazol-2-ylamine Hy-
1
droiodide (3ai). Yield 68%. Anal. (C14H11IN2S2) C, H, N. H
1
IN2O3S) C, H, N. H NMR (DMSO-d6): δ 3.58 (s, 3H, OCH3),
NMR (DMSO-d6): δ 3.84 (s, 2H, CH2), 7.56-7.61 (m, 2H, ArH),
7.65 (dd, J ) 3.0, 4.8 Hz, 1H, ArH), 7.74 (dd, J ) 1.2, 7.8 Hz,
1H, ArH), 7.69 (dd, J ) 1.5, 7.8 Hz, 1H, ArH), 7.89 (dd, J )
1.5, 6.0 Hz, 1H, ArH), 7.93 (brs, 1H, ArH), 9.04 (brs, NH2).
13C NMR (DMSO-d6): δ 34.0, 118.4, 120.8, 122.2, 122.8, 124.9,
126.1, 127.2, 131.9, 132.6, 141.2, 143.4, 146.1, 173.9. MS (ESI)
m/z: 270 (M+).
3.78 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.83 (s, 2H, CH2), 6.89
(d, J ) 8.1 Hz, 1H, ArH), 7.06 (d, J ) 8.1 Hz, 1H, ArH), 7.45
(dd, J ) 1.5, 7.8, 1H, ArH), 7.58 (d, J ) 7.8 Hz, 1H, ArH), 7.62
(s, 1H, ArH), 9.00 (brs, NH3). 13C NMR (DMSO-d6): δ 34.0,
55.9, 60.4, 60.7, 108.2, 117.9, 122.0, 124.6, 125.6, 127.4, 127.6,
131.1, 135.4, 142.0, 142.8, 145.2, 150.8, 152.9, 173.9. MS (ESI)
m/z: 354 (M+).
6-(Benzofuran-2-yl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3aj). Yield 63%. Anal. (C18H13IN2OS)
C, H, N. 1H NMR (DMSO-d6): δ 3.88 (s, 2H, CH2), 7.21-7.31
(m, 2H, ArH), 7.40 (s, 1H, ArH), 7.58 (d, J ) 7.8 Hz, 1H, ArH),
7.61-7.70 (m, 1H, ArH), 7.92 (d, J ) 7.8 Hz, 1H, ArH), 8.06
(s, 1H, ArH), 9.05 (brs, NH2). 13C NMR (CDCl3): δ 34.1, 101.9,
111.0, 118.6, 121.1, 121.2, 123.2, 123.5, 123.7, 124.5, 126.9,
128.9, 133.4, 143.3, 146.1, 154.1, 155.2, 173.9. MS (ESI) m/z:
304 (M+).
6-(3,4-Methylenedioxyphenyl)-8H-indeno[1,2-d]thiazol-
2-ylamine Hydroiodide (3ab). Yield 65%. Anal. (C17H13-
IN2O2S) C, H, N. 1H NMR (DMSO-d6): δ 3.84 (s, 2H, CH2),
6.05 (s, 2H, OCH2O), 6.99 (d, J ) 8.1, 1H, ArH), 7.17 (dd, J )
1.8, 8.1 Hz, 1H, ArH), 7.26 (d, J ) 1.8 Hz, 1H, ArH), 7.60 (dd,
J ) 1.5, 7.8 Hz, 2H, ArH), 7.80 (s, 1H, ArH), 9.10 (brs, NH2).
13C NMR (DMSO-d6): δ 34.1, 101.1, 107.0, 108.6, 118.4, 120.2,
122.0, 123.2, 125.2, 131.5, 134.1, 137.4, 142.5, 146.0, 146.7,
147.9, 173.9. MS (ESI) m/z: 308 (M+).
6-(3,4-Dichlorophenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3ac). Yield 62%. Anal. (C16H11Cl2-
IN2S) C, H, N. 1H NMR (DMSO-d6): δ 3.85 (s, 2H, CH2), 7.62
(d, J ) 7.8 Hz, 1H, ArH), 7.69 (dd, J ) 1.8, 7.8 Hz, 1H, ArH),
7.91 (d, J ) 0.9 Hz, 1H, ArH), 7.94 (t, J ) 1.2, 1H, ArH). 13C
NMR (DMSO-d6): δ 34.2, 118.5, 123.1, 123.4, 125.7, 126.6,
128.2, 129.9, 130.9, 131.6, 132.8, 134.7, 140.4, 142.5, 146.1,
173.9. MS (ESI) m/z: 332, 334, 336 (M+).
6-(3,5-Dichlorophenyl)-8H-indeno[1,2-d]thiazol-2-
ylamine Hydroiodide (3ad). Yield 65%. Anal. (C16H11Cl2-
IN2S) C, H, N. 1H NMR (DMSO-d6): δ 3.85 (s, 2H, CH2), 7.57
(t, J ) 2.1 Hz, 1H, ArH), 7.61 (d, J ) 7.5 Hz, 1H, ArH), 7.71-
7.78 (m, 3H, ArH), 7.94 (brs, 1H, ArH). 13C NMR (DMSO-d6):
δ 34.1, 118.5, 123.4, 123.6, 125.1 × 2, 125.9, 126.5, 133.2, 134.3,
134.6 × 2, 142.7, 143.3, 146.1, 173.9. MS (ESI) m/z: 332, 334,
336 (M+).
Assay of AE Activity. Stock solutions of 3a-aj were in
DMSO. Binding assays employed membranes from CHO-K1
cells stably expressing the hA1AR or from HEK 293 cells
expressing the hA2AAR or hA3AR. Agonist radioligands were
[
125I]ABA (ABA is N6-3-aminobenzyl)adenosine) for the A1AR
and the A3AR and [125I]N6-[2(4-aminophenyl)ethyladenosine])
for the A2AAR. The assay of AE activity consisted of three
phases: (1) formation of the agonist-A1AR-G protein ternary
complex, (2) stabilization of that complex by the AE, and (3)
dissociation of the complex by adding a combination of an
A1AR antagonist to compete with agonist at the orthosteric
site and GTPγS to accelerate dissociation by displacing GDP
from the G protein. The assay employed membranes from
CHO-K1 cells stably expressing the hA1AR. For agonist
binding to equilibrium, the incubation mixture consisted of
10 mM HEPES, pH 7.2, containing 0.5 mM MgCl2, 1 U/mL
adenosine deaminase, 0.5 nM [125I]ABA, and 10 µg of mem-
brane protein (Bmax ≈ 4 pmol/mg protein) in a final volume of
100 µL. After 90 min at room temperature, the addition of
50 µL of a 0.3 mM solution of a candidate AE (50 µM final)
initiated stabilization of the ternary complex. Five minutes
later, the addition of 50 µL of a solution of 400 µM 8-cyclo-
pentyltheophylline and 200 µM GTPγS initiated the dissocia-
tion of the ternary complex. After 10 min for dissociation,
filtering through a 96-well multiscreen Millipore filter plate,
washing, drying, and counting 125I activity allowed measure-
ment of the residual bound radioligand. The percentage of
specifically bound agonist remaining after 10 min of dissocia-
tion served as a score of AE activity, as calculated by the
formula
6-(Naphth-1-yl)-8H-indeno[1,2-d]thiazol-2-ylamine Hy-
1
droiodide (3ae). Yield 67%. Anal. (C20H15IN2S) C, H, N. H
NMR (DMSO-d6): δ 3.89 (s, 2H, CH2), 7.45 (dd, J ) 1.5, 7.5,
1H, ArH), 7.49 (s, 1H, ArH), 7.52 (dd, J ) 1.8, 3.0 Hz, 1H,
ArH), 7.55 (m, 1H, ArH), 7.58 (d, J ) 7.2, 1H, ArH), 7.64 (s,
1H, ArH), 7.69 (d, J ) 7.5 Hz, 1H, ArH), 7.81 (d, J ) 8.1 Hz,
1H, ArH), 7.94 (d, J ) 8.1 Hz, 1H, ArH), 7.99 (d, J ) 7.8 Hz,
1H, ArH), 9.01 (brs, NH2). 13C NMR (DMSO-d6): 34.1, 118.1,
122.6, 125.2, 125.5, 125.9, 126.4, 126.5, 127.0, 127.6, 128.4,
128.7, 130.8, 132.1, 133.4, 137.4, 139.3, 142.8, 145.6, 174.0.
MS (ESI) m/z: 344 (M+).
6-(Naphth-2-yl)-8H-indeno[1,2-d]thiazol-2-ylamine Hy-
1
droiodide (3af). Yield 79%. Anal. (C20H15IN2S) C, H, N. H
NMR (DMSO-d6): δ 3.90 (s, 2H, CH2), 7.45-7.59 (m, 3H,
Ar1H, H), 7.69 (d, J ) 8.1 Hz, 1H, ArH), 7.86 (dd, J 7.5 Hz,
2H, ArH), 7.93 (d, J ) 8.4 Hz, 1H, ArH), 7.95-8.02 (m, 2H,
ArH), 8.24 (s, 1H, ArH), 9.20 (brs, NH2). 13C NMR (DMSO-
d6): δ 33.9, 118.4, 122.5, 123.5, 124.8, 125.0, 125.7, 125.9,
126.3, 127.3, 128.0, 128.3, 132.0, 132.2, 133.2, 137.1, 133.2,
143.0, 146.1, 173.8. MS (ESI) m/z: 344 (M+).
B - Bo
AE activity (%) ) 100 ×
Beq - Bo
where B is the residual binding (cpm) bound at the end of
10 min of dissociation in the presence of an AE, Bo is the
residual binding (cpm) at the end of 10 min of dissociation in

6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5139
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Molecular biology and regulation of nucleoside and nucleobase
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the absence of an AE, and Beq is the cpm bound at the end of
90 min of equilibration. A score of 0% indicates the lack of AE
activity, and a score of 100% indicates no dissociation of the
ternary complex in <10 min, the maximal possible allosteric
effect. To initiate dissociation from the A2A or A3 receptors,
100 µM ZM241385 or BW-1433, respectively, was added along
with GTPγS. Table 1 reports the mean and standard error of
two to three separate assays, each in triplicate.
EC50 of Allosteric Enhancer Activity. These assays
differed from the screening assays only in that the concentra-
tion of candidate AE varied over a range of 10 nM to 50 µM.
The analysis program (Graph Pad) estimated EC50, the
concentration producing half-maximum AE activity from data
on the activity score and AE concentration. Table 1 reports
the mean and standard error of two to three separate assays,
each in triplicate.
Assay of A1AR Antagonist Activity. Assays of antago-
nism of equilibrium binding by allosteric enhancers used
membranes from CHO-K1 cells expressing the hA1AR. Assays,
in triplicate, consisted of mixing 50 µL aliquots of membrane
suspensions (15 µg of protein) in 10 mM HEPES, pH 7.4,
containing 1 mM EDTA, 1 U/mL adenosine deaminase, and
4 nM [3H]CPX with 50 µL of either 200 µM enhancer dissolved
in HEPES buffer containing 10% methyl sulfoxide or, as
controls, HEPES containing 10% DMSO. Additional aliquots
of membrane suspension mixed with 50 µL of 200 µM NECA
in HEPES-10% DMSO served for measurements of unspecific
binding. Incubation for 3 h at room temperature established
binding equilibrium. Filtration through Whatman GF/C mem-
branes separated free and bound radioligand. The membranes
were washed three times and dried, and 3H activity was
measured by liquid scintillation spectrometry. Inhibition was
expressed as the percentage of control specific binding. Table
1 reports the mean ( standard error of two to three separate
assays, each in triplicate.
Assay of A1AR and A3AR Antagonist Activity by
Competition for Radioligand Binding. The assays for
antagonism of the allosteric enhancers rely on competition for
equilibrium radioligand binding and used membranes from
CHO-K1 cells expressing hA1AR or from HEK293 cells ex-
pressing hA3AR. The membranes were resuspended at 0.5 mg/
mL in 10 mM HEPES, pH 7.4, containing 1 mM EDTA,
1 U/mL adenosine deaminase, 5 mM MgCl2, and 2 nM
[3H]CPX (for A1 receptors) or 0.5 nM [125I]ABA (for A3 recep-
tors). Fifty-microliter aliquots of membrane solution (in trip-
licate) were added to 50 µL of HEPES buffer containing
20 µM allosteric enhancer, vehicle (DMSO), or 100 µM NECA
to define nonspecific binding. Incubation for 3 h at room
temperature established equilibrium binding. Filtering through
a 96-well multiscreen Millipore filter plate, washing, drying,
and counting 125I activity allowed measurement of the residual
bound radioligand separated by filtration. Inhibition was
expressed as the percentage of control specific binding.
Acknowledgment. NIH Grant R01-HL-56111 sup-
ported this research.
Supporting Information Available: Elemental analysis
in table form. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) Goblyos, A.; Santiago, S. N.; Pietra, D.; Mulder-Krieger, T.; von
Frijtag Drabbe, K. J.; Brussee, J.; Ijzerman, A. P. Synthesis and
biological evaluation of 2-aminothiazoles and their amide deriva-
tives on human adenosine receptors. Lack of effect of 2-amino-
thiazoles as allosteric enhancers. Bioorg. Med. Chem. 2005, 13,
2079-2087.
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