Synthesis and biological study of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3] triazolo[1,5-a]pyrimidines as potent and selective serotonin 5-HT6 receptor antagonists

Article abstract of DOI:10.1016/j.bmc.2010.05.051

A number of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a] pyrimidines were prepared and their 5-HT₆ receptor binding affinity and ability to inhibit the functional cellular responses to serotonin were evaluated. 3-[(3-Chlorophenyl)sulfonyl]-N-(tetrahydrofuran-2-ylmethyl)thieno[2, 3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{5,26} appeared to be the most active in a functional assay (IC₅₀ = 29.0 nM) and 3-(phenylsulfonyl)-N-(2-thienylmethyl) thieno[2,3-e][1,2,3]triazolo[1,5-a] pyrimidin-5-amine 2{1,28} demonstrated the greatest affinity in a 5-HT ₆ receptor radioligand binding assay (K_i = 1.7 nM). A screening of 5-HT_2A and 5-HT_2B receptor affinity revealed that 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines are highly selective 5-HT₆ receptor ligands.

Full text of DOI:10.1016/j.bmc.2010.05.051

Bioorganic & Medicinal Chemistry 18 (2010) 5282–5290
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and biological study of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazol-
o[1,5-a]pyrimidines as potent and selective serotonin 5-HT6 receptor
antagonists
Alexandre V. Ivachtchenko a,b, Elena S. Golovina a, Madina G. Kadieva a, Angela G. Koryakova a,
b
d
b
Sergiy M. Kovalenko c, Oleg D. Mitkin a, , Ilya M. Okun , Irina M. Ravnyeyko , Sergey E. Tkachenko ,
*
Oleg V. Zaremba d
a Chemical Diversity Research Institute, 114401 Khimki, Moscow Reg, Russia
b ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121, USA
c Institute of Combinatorial Organic Chemistry, Kharkiv, Ukraine
d National Pharmaceutical University, Kharkiv, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
A number of 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines were prepared and their 5-
HT6 receptor binding affinity and ability to inhibit the functional cellular responses to serotonin were
evaluated. 3-[(3-Chlorophenyl)sulfonyl]-N-(tetrahydrofuran-2-ylmethyl)thieno[2,3-e][1,2,3]triazolo[1,5-
a]pyrimidin-5-amine 2{5,26} appeared to be the most active in a functional assay (IC50 = 29.0 nM) and
3-(phenylsulfonyl)-N-(2-thienylmethyl) thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{1,28}
demonstrated the greatest affinity in a 5-HT6 receptor radioligand binding assay (Ki = 1.7 nM). A screening
of 5-HT2A and 5-HT2B receptor affinity revealed that 3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]
pyrimidines are highly selective 5-HT6 receptor ligands.
Received 16 March 2010
Revised 13 May 2010
Accepted 18 May 2010
Available online 24 May 2010
Keywords:
Thieno[2,3-e][1,2,3]triazolo[1,5-
a]pyrimidines
Ó 2010 Elsevier Ltd. All rights reserved.
5-HT6 Receptor
5-HT6 Antagonist
1. Introduction
antagonists.16 Such models assist in the elaboration of new phar-
macologically active compounds.
5-HT6 receptor, one of seven (5-HT1–5-HT7) families of seroto-
nin receptors, belongs to G-protein coupled receptors and is
positively linked to adenylyl cyclase via GS-protein.1 In spite of
the fact that it was discovered more than 10 years ago, it’s physio-
logical functions are still under debate.2 Almost exclusive localiza-
tion of 5-HT6R within the CNS in regions that play key roles in
modulating cognitive processes and neurotransmitter release3,4 to-
gether with high 5-HT6R affinity for several antipsychotics5 sug-
gest this receptor as an attractive target for drug development.6,7
This interest inspired the discovery of a number of highly active
and selective ligands and even clinical candidates among 5-HT6
antagonists for treating CNS disorders,8 such as Alzheimer’s dis-
ease9–12 and schizophrenia.13
Consistent with this,17 during the combined virtual screening,
which includes the construction of HipHop pharmacophore model
and recursive partitioning technique, it was found that 3-(phenyl-
sulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines (PSTTP’s),
Another well-known attractive feature of 5-HT6R antagonists is
their ability to suppress appetite, which may be used for the devel-
opment of safe and more effective anti-obesity drugs.7,14,15
On the basis of a sufficient number of ligands, several authors
have described pharmacophore modeling studies for 5-HT6R
Figure 1. The best HipHop pharmacophore model (cyan: hydrophobic groups;
green: hydrogen bond acceptor feature with a vector in the direction of the putative
hydrogen donor; orange: aromatic ring; and red: positive ionizable group)17 and
the most 5-HT6R active PSTTP.
* Corresponding author. Tel.: +7 495 225 1189; fax: +7 495 626 9780.
E-mail addresses: mod@chemdiv.com, enegeld@yahoo.com (O.D. Mitkin).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.05.051

A. V. Ivachtchenko et al. / Bioorg. Med. Chem. 18 (2010) 5282–5290
5283
Cl
investigation of PSTTP as a template for highly effective and selec-
tive 5-HT6R ligands.
S
S
N
N
a
O
O
S
O
N
N
S
O
N
N
2. Chemistry
23%
R1
N
N
N
In this paper we report a new combinatorial library (CL) of 466
substituted PSTTP’s and biological study of PSTTP’s as potent and
selective 5-HT6R antagonists.
b
4
1 {1-9}
R2
R3
N
36%
SEt
Parallel liquid-phase synthesis of a CL of PSTTP’s 2 was based on
5-chloro-PSTTP’s 1{1–9} (Scheme 1). The reaction of 5-chloro-
PSTTP’s 1{1–9} with amines 3{1–90} (Chart 1), was carried out in
DMF in the presence of Et3N. The reaction products 2{1–9,1–90}
were isolated with a yield of 70–90% by adding water to precipitate
solids and subsequent recrystallization from methanol.
PSTTP 4 and 5-ethylthio-PSTTP 5 were obtained by hydrogena-
tion of 5-chloro-PSTTP 1{1} and by treatment of 5-chloro-PSTTP
1{1} with KSEt in DMF, respectively.
The resulting CL (Fig. 2) included three 5-amino- and 44 5-alkyl-
amino-PSTTP’s (2A), 95 5-benzylamino- (2B), 29 5-heteroarylmeth-
ylamino- (2C), 23 5-cycloalkylamino- (2D), 185 5-arylamino- (2E)
and 87 5-azaheterocyclyl-PSTTP’s (2F). Some representatives of this
series of compounds are presented in Tables 1–8.
S
S
N
c
O
S
O
O
N
N
70-90%
S
O
N
N
R1
N
5
N
2 {1-9,1-90}
1{1-9}, 2{1-9,1-90}: R1 = H, 4-Me, 4-Et, 4-i-Pr, 3-Cl, 4-Cl, 4-Br, 2,5-di-Me,
3,4-di-Me; NR2R3 = amino groups (see Chart 1).
Scheme 1. Parallel liquid-phase synthesis of combinatorial libraries of PSTTP’s.
Reagents and conditions: (a) H2, Pd/C, rt, MeOH/benzene, 12 h; (b) KSEt, DMF, rt,
1 h; (c) R2R3NH 3{1–90}, DMF, Et3N, 100–120 °C, 1 h.
containing substituted amino groups in position 5, are promising
5-HT6R ligands (Fig. 1). The present work is focused on a detailed
NH3, i-PrNH2, n-BuNH2, i-PrCH2CH2NH2, MeOCH2CH2NH2, Me2NCH2CH2NH2, MeOCH2CH2CH2NH2,
1
2
3
4
5
6
7
O
N
CH2CH2CH2NH2,
12
CH2CH2NH2,
EtOCH2CH2CH2NH2, i-PrOCH2CH2CH2NH2,
CH2CH2CH2NH2,
10
8
9
11
O
Me
O
R
O
O
CH(CH3)NH2,
CH2NH2,
26
CH2CH2NH2, CH2CH(CH3)NH2,
13 14
CH2NH2,
25
CH2NH2,
27
CH2NH2,
15-23
24
N
N
Me
Me
S
CH(CH3)NH2,
NH2,
32
CH2NH2,
28
NH2,
33
CH2NH2,
29
NH2,
34
CH2NHCH3,
30
NH2,
35
31
NMe2
Me
R
4-Me2N-C6H4
Ph
Ph
S
N
Me
Me
Et
Et
Me
Et
Me
N
N
H
N
H
N
H
N
H
N
H
NH2,
H
NH2
67
36-66
68
69
70
71
72
73
CO2Et CONH
Me
2 O
O
CO2Et
Me
3-Py
Me
N
H
N
N
H
N
N
H
N
N
N
H
N
H
H
H
H
H
74
75
76
77
78
79
80
81
82
Ph
Me
N
Ph
Et
N
N
O
S
N
H
N
H
N
H
N
H
N
N
H
N
H
N
H
H
83
84
85
86
87
88
89
90
Chart 1. Building blocks 3{1–90}. 3{15–23}: R = H {15}, 2-Cl {16}, 2-MeO {17}, 3-Cl {18}, 3-MeO {19}, 4-MeO {20}, 4-F {21}, 4-Cl {22}, 3,4-di-MeO {23}. 3{36–66}: R = H {36}, 2-
MeO {37}, 2-EtO {38}, 3-Me {39}, 3-Et {40}, 3-MeO {41}, 3-MeS {42}, 3-F {43}, 3-CF3 {44}, 4-Me {45}, 4-MeO {46}, 4-Et {47}, 4-EtO {48}, 4-i-Pr {49}, 4-F {50}, 4-Cl {51}, 4-AcNH
{52}, 2,3-di-Me {53}, 2,4-di-Me {54}, 2,4-di-MeO {55}, 2,5-di-Me {56}, 2,5-di-MeO {57}, 3,4-di-Me {58}, 3,4-di-MeO {59}, 3-Cl-4-F {60}, 3-Me-6-MeO {61}, 3,5-di-Me {62}, 3,5-
di-MeO {63}, 3-Cl-4-Me {64}, 3-Cl-4-MeO {65}, 3-Cl-5-Me {66}.

5284
A. V. Ivachtchenko et al. / Bioorg. Med. Chem. 18 (2010) 5282–5290
R4
R3
R2
Hetaryl
N
N
R2
R2
S
N
N
R 3
N
N
N
O
S
O
S
S
N
N
O
O
S
R1
N
N
S
R1
R1
R2,R3 = H,Alk
N
N
O
O
N
N
2A
2B
2C
Ar
N
HN
( )
Azaheterocyclyl
HN
N
n
S
S
S
N
O
N
O
S
O
O
S
N
N
S
N
R1
N
R1
O
N
R1
N
O
N
N
2E
2F
2D
Figure 2. Basic templates included in the combinatorial library of PSTTP’s.
Table 1
Table 2
Biological data of 5-amino-PSTTP’s 2A as 5-HT6R antagonists in functional assay
Biological data of 5-benzylamino-PSTTP’s 2B as 5-HT6R antagonists in functional
assay
Compds 2A
R1
R2
R3
IC50 (lM)
Compds 2B
R1
R2
R3
R4
IC50 (lM)
2{1,2}
2{1,3}
2{1,5}
2{1,7}
2{1,11}
H
H
H
H
H
H
H
4-Me
4-Me
4-Me
4-Et
4-Et
4-Et
4-Et
4-Et
4-i-Pr
4-i-Pr
4-i-Pr
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
4-Cl
4-Cl
4-Cl
4-Br
4-Br
i-Pr
Bu
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Et
H
H
H
H
H
H
H
H
Me
H
H
Et
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.37
0.069
0.19
0.26
1.16
1.08
0.87
0.58
1.49
0.96
1.60
>5.00
>5.00
1.05
1.90
>5.00
>5.00
>5.00
0.69
0.47
0.060
0.068
0.11
0.78
0.15
0.82
1.22
0.58
1.20
2.17
>5.00
0.61
>5.00
1.22
0.35
0.86
0.86
1.29
0.67
1.22
0.75
0.046
1.57
2.38
0.68
2{1,15}
2{1,16}
2{1,17}
2{1,19}
2{1,21}
2{1,22}
2{1,24}
2{1,25}
2{1,71}
2{2,15}
2{2,17}
2{2,18}
2{2,19}
2{2,21}
2{2,24}
2{2,25}
2{2,72}
2{4,16}
2{5,17}
2{5,21}
2{5,24}
2{5,71}
2{5,72}
2{6,15}
2{6,17}
2{6,24}
2{6,71}
2{6,72}
2{7,17}
2{7,24}
2{7,71}
2{7,72}
2{8,24}
2{8,71}
2{8,72}
2{9,16}
2{9,17}
2{9,21}
2{9,71}
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Et
H
H
H
H
Me
Et
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
H
Me
H
H
H
Me
H
H
Me
H
H
H
H
H
H
2-Cl
2-MeO
3-MeO
4-F
4-Cl
H
3,4-CH2O2
H
H
2-MeO
3-Cl
3-MeO
4-F
0.059
0.032
0.29
1.37
0.69
1.17
0.037
0.29
0.17
0.26
0.58
0.12
2.21
0.74
0.18
1.25
0.30
1.83
0.78
0.48
0.15
0.92
0.54
0.27
1.15
0.28
1.19
0.57
0.93
0.54
1.95
0.58
0.17
1.48
1.10
0.60
0.47
0.52
1.33
2-MeO-Et
3-MeO-Pr
PhCH2CH2
PhCH2CH(CH3)
Me2NCH2CH2
3-Me-Bu
2-MeO-Et
PhCH2CH2
i-Pr
3-Me-Bu
3-MeO-Pr
PhCH2CH2
Et
*
2{1,14}
2{1,70}
2{2,4}
2{2,5}
2{2,11}
2{3,2}
2{3,4}
2{3,7}
2{3,11}
2{3,69}
2{4,3}
2{4,4}
2{4,5}
2{5,1}
2{5,2}
2{5,3}
2{5,4}
2{5,5}
2{5,6}a
2{5,7}
2{5,11}
2{5,69}
2{5,70}
2{6,2}
2{6,5}
2{6,7}
2{7,1}
2{7,7}
2{8,1}
2{8,2}
2{8,4}
2{8,5}
2{8,7}
2{8,11}
2{8,12}
2{9,2}
2{9,4}
2{9,5}
2{9,7}
2{9,14}
H
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-i-Pr
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
4-Cl
4-Cl
4-Cl
4-Cl
Bu
H
3-Me-Bu
2-MeO-Et
H
i-Pr
Bu
3-Me-Bu
2-MeO-Et
Me2NCH2CH2
3-MeO-Pr
PhCH2CH2
Et
Me2NCH2CH2
i-Pr
2-MeO-Et
3-MeO-Pr
H
3,4-CH2O2
H
2-Cl
2-MeO
4-F
H
H
H
H
2-MeO
H
H
H
2-MeO
H
H
H
Me
Et
H
4-Cl
4-Br
4-Br
4-Br
H
Me
Et
H
Me
Et
H
H
H
Me
3-MeO-Pr
H
i-Pr
4-Br
2,5-di-Me
2,5-di-Me
2,5-di-Me
2,5-di-Me
2,5-di-Me
2,5-diMe
2,5-di-Me
3,4-di-Me
3,4-di-Me
3,4-di-Me
3,4-di-Me
3,4-di-Me
2,5-di-Me
2,5-di-Me
2,5-di-Me
3,4-di-Me
3,4-di-Me
3,4-di-Me
3,4-di-Me
H
H
H
3-Me-Bu
2-MeO-Et
3-MeO-Pr
PhCH2CH2
PhCH2CH2CH2
i-Pr
3-Me-Bu
2-MeO-Et
3-MeO-Pr
PhCH2CH(CH3)
2-Cl
2-MeO
4-F
H
H
Key building blocks, 5-chloro-PSTTP’s 1{1–9}, were obtained on
the basis of 3-amino-thiophene-2-carboxylic acid methyl ester 6.
Azide 7 was prepared by the standard method from 6; based-
catalyzed condensation of 7 with arylsulfonylacetonitriles 8{1–9}
a
As hydrochloride.

A. V. Ivachtchenko et al. / Bioorg. Med. Chem. 18 (2010) 5282–5290
5285
Table 3
Table 6
Biological data of 5-heteroarylmethylamino-PSTTP’s 2C as 5-HT6R antagonists in
Biological data of 5-azaheterocyclyl-PSTTP’s 2F as 5-HT6R antagonists in functional
functional assay
assay
Compds 2C
R1
R2
Heteroaryla
IC50
(
lM)
Compds 2F
R1
Azaheterocyclyl
IC50 (lM)
2{1,26}
2{1,27}
2{1,28}
2{1,29}
2{1,30}
2{2,26}
2{2,27}
2{2,28}
2{5,26}
2{5,27}
2{5,28}
2{5,29}
2{6,26}
2{6,27}
2{6,28}
2{7,26}
2{8,26}
2{8,28}
2{9,27}
2{9,28}
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2-THFu
2-Fu
2-Th
3-Py
3-Py
2-THFu
2-Fu
2-Th
2-THFu
2-Fu
2-Th
0.063
0.040
0.11
0.26
0.50
0.25
0.50
0.22
0.029
0.19
0.15
1.25
0.48
0.41
0.65
1.62
0.89
0.71
0.77
0.090
2{1,77}
2{1,82}
2{5,77}
2{5,79}
2{5,83}
2{5,84}
2{8,76}
2{8,79}
2{8,84}
2{8,86}
H
H
3-Cl
3-Cl
3-Cl
3-Cl
2,5-di-Me
2,5-di-Me
2,5-di-Me
2,5-di-Me
3-Methylpiperidin-1-yl
4-Aminocarbonylpiperidin-1-yl
3-Methylpiperidin-1-yl
4-Methylpiperidin-1-yl
Azepan-1-yl
Morpholin-4-yl
Piperidin-1-yl
4-Methylpiperidin-1-yl
Morpholin-4-yl
1-Methylpiperazin-4-yl
2.03
1.99
2.00
1.12
1.54
1.04
1.52
1.99
1.93
1.34
H
4-Me
4-Me
4-Me
3-Cl
3-Cl
3-Cl
3-Cl
4-Cl
4-Cl
4-Cl
3-Py
2-THFu
2-Fu
Table 7
Biological data of PSTTP’s 2 as 5-HT6R ligands in radioligand binding assay
2-Th
4-Br
2-THFu
2-THFu
2-Th
2-Fu
2-Th
2,5-di-Me
2,5-di-Me
3,4-di-Me
3,4-di-Me
R2
5-HT6R
IC50
Ki
(nM)
S
N
(nM)
R1
R2
O
a
S
N
N
3-Py—pyridine-3-yl, 2-THFu—tetrahydrofuran-2-yl, 2-Th—thiophen-2-yl.
R1
O
N
2A{1,2}
2A{1,6}
2A{1,68}
2A{1,70}
2A{7,4}
H
H
H
H
4-
Br
i-PrNH
Me2NCH2CH2NH
Me2N
Me2NCH2CH2NMe
3-Me-BuNH
65.0
30.2
Table 4
>300.0
>30.0
>300.0
34.3
Biological data of 5-cycloalkylamino-PSTTP’s 2D as 5-HT6R antagonists in functional
assay
15.9
46
Compds 2D
n
R1
IC50 (lM)
2{1,32}
2{1,33}
2{1,34}
2{2,32}
2{2,33}
2{2,34}
2{5,32}
2{5,33}
2{5,34}
2{6,33}
2{8,32}
2{9,33}
2{9,34}
1
2
3
1
2
3
1
2
3
2
1
2
3
H
H
H
4-Me
4-Me
4-Me
3-Cl
3-Cl
3-Cl
0.14
0.20
0.17
2.03
0.73
0.79
0.17
0.069
0.14
0.96
0.59
0.82
0.35
2A{8,1}
2A{8,2}
2B{1,31}
2,5- NH2
di-
Me
2,5- i-PrNH
di-
Me
H
99.1
28.3
13.2
Adamantan-1-yl-
CH(Me)NH
BnNMe
221.0 103.0
2B{1,71}
2B{5,71}
H
5.0
7.5
2.3
3.5
4-Cl
3-
Cl
4-
Br
H
BnNMe
2,5-di-Me
3,4-di-Me
3,4-di-Me
2B{7,25}
2C{1,26}
Benzo[1,3]dioxol-5-
yl-CH2NH
Tetrahydrofuran-2-
yl-CH2NH
62.1
17.5
28.8
8.1
2C{1,27}
2C{1,28}
H
H
Furan-2-yl-CH2NH
Thiophen-2-yl-
CH2NH
6.1
3.6
2.8
1.7
Table 5
Biological data of 5-anilino-PSTTP’s 2E as 5-HT6R antagonists in functional assay
2C{1,29}
2C{1,30}
H
H
Pyridin-3-yl-CH2NH
Pyridin-3-yl-
CH2NMe
Pyridin-3-yl-
CH2NMe
Cyclopentyl-NH
Cyclohexyl-NH
3,5-
Dimethyladamantan-
1-yl-NH
>30.0
>30.0
Compds 2E
R1
Ar
IC50 (lM)
2{1,36}
2{1,44}
2{1,50}
2{1,67}
2{2,39}
2{2,40}
2{2,43}
2{2,53}
2{3,39}
2{4,39}
2{4,41}
2{4,53}
2{4,58}
2{5,36}
2{5,44}
2{5,45}
2{5,50}
2{5,56}
2{6,37}
2{6,53}
2{7,56}
2{7,58}
2{9,41}
2{9,51}
2{9,66}
H
H
H
H
Ph
ꢀ5.00
0.82
2C{5,29}
3-
Cl
H
H
H
31.7
14.7
3-CF3-C6H4
4-F-C6H4
Benzothiazol-2-yl
3-Me-C6H4
3-Et-C6H4
0.60
>5.00
*
2D{1,32}
2D{1,33}
2D{1,35}
11.9
6.9
56.7
5.5
3.2
26.3
4-Me
4-Me
4-Me
4-Me
4-Et
4-i-Pr
4-i-Pr
4-i-Pr
4-i-Pr
3-Cl
3-Cl
3-Cl
3-Cl
3-Cl
4-Cl
4-Cl
4-Br
4-Br
5.22
1.38
3.81
0.59
1.75
0.59
0.90
1.00
1.11
0.92
1.07
1.21
2.50
0.74
1.15
0.80
2.01
1.35
0.86
1.43
2.26
3-F-C6H4
2,3-di-Me-C6H3
3-Me-C6H4
3-Me-C6H4
3-MeO-C6H4
2,3-di-Me-C6H3
3,4-di-Me-C6H3
Ph
3-CF3-C6H4
4-Me-C6H4
4-F-C6H4
2,5-di-Me-C6H3
2-MeO-C6H4
2,3-di-Me-C6H3
2,5-di-Me-C6H3
3,4-di-Me-C6H3
3-MeO-C6H4
4-Cl-C6H4
2F{1,75}
H
Pyrrolidin-1-yl
188.0
87.5
afforded 3-arylsulfonyl-4H-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyr-
imidin-5-ones 9{1–9}. Applied arylsulfonylacetonitriles 8{1–9},
along with an unsubstituted one 8{1}, were 4-methyl- 8{2}, 4-
ethyl- 8{3}, 4-i-propyl- 8{4}, 3-chloro- 8{5}, 4-chloro- 8{6}, 4-bro-
mo- 8{7}, 2,5-dimethyl- 8{8}, and 3,4-dimethylphenylsulfonyl-ace-
tonitrile 8{9}. Thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-ones
9{1–9} were transformed to desired 5-chloro-PSTTP’s 1{1–9} by
the action of POCl3 in the presence of Et3N (Scheme 2).
Unfortunately, the 1H NMR spectra of 3-arylsulfonyl-4H-thie-
no[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-ones 9{1–9} (e.g., 9{1})
indicate two sets of signals, suggesting the existence of two tauto-
meric forms. The last are in line with the data of IR spectroscopy
3,4-di-Me
3,4-di-Me
3,4-di-Me
3-Cl-5-Me-C6H3

5286
A. V. Ivachtchenko et al. / Bioorg. Med. Chem. 18 (2010) 5282–5290
Table 8
PSTTP 1{1} with IC50 = 0.57
5-unsubstituted PSTTP 4 with IC50 = 3.0
l
M and the least active antagonist is
M.
The activity of 5-amino-PSTTP’s 2A (Table 1) strongly depends
on the nature of the substituents and ranges from IC50 = 0.046
to IC50 >5.0 M. For example, in a series of 5-amino-3-(3-chloro-
% of radioligands displacement from the complexes with serotonin receptors using
M PSTTP’s 2 in radioligand binding assay
l
1
l
Serotonin receptor
PSTTP’s
lM
l
2B{1,71}
2B{5,71}
% Displacement
benzenesulfonyl)-PSTTP’s 2A{5,1–7; 5,11; 5,69–70} the activity
changes 20-fold: the most active antagonists are 5-butylamino-
5-HT1A
5-HT1B
5-HT2A
5-HT2B
5-HT2C
5-HT3
5-HT4
5-HT6
5-HT7
2
1
15
12
2
ꢁ7
33
103
ꢁ2
9
3
PSTTP 2A{5,3} with IC50 = 0.060
PSTTP 2A{5,4} with IC50 = 0.068
antagonist is 5-diethylamino-PSTTP 2A{5,69} with IC50 = 1.22
Activity of other 5-amino-3-(3-chlorobenzenesulfonyl)-PSTTP’s
decreases in the series, presented below, from IC50 = 0.11 M to
IC50 = 0.82 M.
2A{5,5} > 2A{5,7} > 2A{5,2} > 2A{5,70} > 2A{5,1} > 2A{5,6} > 2A
{5,11} = 0.11 M > 0.15 M > 0.47 M > 0.58 M > 0.69 M > 0.78 -
M > 0.82 M, respectively.
The nature and position of the substituents in the benzenesulfo-
l
M and 5-(3-methylbutylamino)-
M, while the least active
M.
50
46
15
ꢁ3
41
106
6
l
l
l
l
l
l
l
l
l
l
l
indicating the presence of valent vibration band of the amide car-
bonyl group at 1670 cmꢁ1. Note that a similar signal at 1670 cmꢁ1
is reported18 in the IR spectrum of 3-bromo-4H-thieno[2,3-
e][1,2,3]triazolo[1,5-a]pyrimidin-5-one.
nyl fragment (Table 1) also strongly influence on activity. For
example, in a series of 5-(2-methoxyethylamino)-PSTTP’s 2A{1–
2,5;4–6,5;8–9,5} transition from 3-benzenesulfonyl derivative
2A{1,5} with IC50 = 0.19
derivative 2A{5,5} with IC50 = 0.11
However, substitution of position 4 of this moiety by chlorine
(2A{6,5}), IC50 = 2.2 M), methyl (2A{2,5}, IC50 = 1.49 M) or iso-
propyl group (2A{4,5}, IC50 >5.0 M) or incorporation of two
substituents (2A{8–9,5}) considerably reduces the activity. The
most active antagonists in this series of PSTTP’s 2A were 3-ben-
zenesulfonyl derivative 2A{1,5} and 3-(3-chlorobenzenesulfonyl)
derivative 2A{5,5}. As an exception appears 3-(3,4-dim-
l
M
to 3-(3-chlorobenzenesulfonyl)
O
OH
l
M slightly increases activity.
S
S
NH
N
O
S
O
O
S
O
l
l
Ph
Ph
N
N
N
N
N
l
N
For the reaction with 5-chloro-PSTTP’s 1{1–9} (Scheme 1) the
following amines were used (Chart 1): ammonia 3{1}, primary
amines: alkylamines 3{2–30}, cycloalkylamines 3{31–35}, anilines
3{36–66}, 2-aminobenzotiazole 3{67} and secondary amines: dial-
kylamines 3{68–74}, pyrrolidine 3{75}, piperidines 3{76–82}, aze-
pane 3{83}, morpholine 3{84}, thiomorpholine 3{85}, piperazines
3{86–88}, 4-phenyl-1,2,3,6-tetrahydropyridine 3{89}, and 2,3-
dihydro-1H-indole 3{90}.
ethylbenzenesulfonyl) derivative 2A{9,4} with IC50 = 0.046 lM.
In the series of 5-benzylamino-PSTTP’s 2B (Table 2) the most
promising compounds are 3-benzenesulfonyl- 2B{1,15–16; 1,24}
and 3-(3,4-dimethylbenzenesulfonyl)- 2B{9,16} with IC50 = 0.032–
0.059
l
M. The most active 5-HT6R antagonist is 2-chlorobenzyla-
M. The least active 5-
mino-PSTTP 2B{1,16} with IC50 = 0.032
l
HT6R antagonist is 5-(2-methoxybenzylamino)-3-(p-tolylsulfo-
nyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine 2B{2,19} with
3. Biological assays
IC50 = 2.21 lM.
Screening of 5-HT6R antagonistic activity of PSTTP’s 2 was per-
The activity of 5-heteroarylmethylamino-PSTTP’s 2C (Table 3) is
similar to that of 5-benzylamino-PSTTP’s 2B (Table 2). Among 5-
(tetrahydrofuran-2-ylmethylamino)-PSTTP’s 2C {1–2,26; 5–8,26}
the most active 5-HT6R antagonist is 3-(3-chlorobenzenesulfonyl)
formed in concentrations of 5 lM and 10 lM by testing in vitro the
ability to inhibit the functional cellular responses to serotonin.
Stimulation of cells (HEK293) stably expressing recombinant hu-
man 5-HT6R by serotonin activates adenylyl cyclase, which cata-
lyzes the synthesis of cAMP, the level of which is estimated with
the help of LANCE19 technology. PRX-07034 and SB-742457 were
used as standards of comparison. For 148 compounds that inhib-
derivative 2C{5,26} with IC50 = 0.029
antagonist is 3-(4-bromobenzenesulfonyl) derivative 2C{7,26} with
IC50 = 1.62 M. In the series of 5-(furan-2-ylmethylamino)-PSTTP’s
2C{1–2,27; 5–6,27; 8–9,27}, PSTTP 2C{1,27} with IC50 = 0.04 M is
lM, while the least active
l
l
ited the synthesis of cAMP at 5
mined IC50 (Tables 2–8).
lM by more than 50%, we deter-
the most active, and in a row of 5-(thiophen-2-ylmethylamino)-
PSTTP’s 2C{1–2,28; 5–6,28; 8–9,28}, PSTTP 2C{9,28} with
Inhibition of the hERG Potassium Ion Channel in a patch clamp
assay and screening of 5-HTR activity of PSTTP’s in a competitive
radioligand binding assay were performed by MDS Pharma
Services.20
IC50 = 0.090 lM is the most active.
Among 5-cycloalkylamino-PSTTP’s 2D (Table 4) again the
most promising antagonists are 3-(3-chlorobenzenesulfonyl)
compounds 2D{5,32–34}. For example, 5-cyclohexylamino-3-(3-
chlorobenzenesulfonyl) derivative 2D{5,33} with IC50 = 0.069
is 10.6 times more active than 3-(4-methylbenzenesulfonyl)
analogue 2D{2,33} with IC50 = 0.73 M and 14 times more active
than 3-(4-chlorobenzenesulfonyl) analogue 2D{6,33} with IC50
= 0.96 M.
lM
4. Results and discussion
l
Among of PSTTP’s 1{1}, 4, and 5 the most active 5-HT6R antag-
onists are 5-ethylthio-PSTTP 5 with IC50 = 0.51
l
M and 5-chloro-
l
O
CO2Me
S
S
CO2Me
NH2
a
c
b
NH
N
S
O
S
O
1{1-9}
75-80%
Ar
80-90%
70-90%
N
N
N3
7
9{1-9}
6
Scheme 2. Synthesis of 5-chloro-PSTTP’s 1{1–9}. Reagents and conditions: (a) NaNO2, H2O, 18% aq HCl, 0.5 h at 25 °C; (b) ArSO2CH2CN 8{1–9}, EtONa, 20 h reflux; (c) POCl3,
Et3N, 12 h reflux.

A. V. Ivachtchenko et al. / Bioorg. Med. Chem. 18 (2010) 5282–5290
5287
5-anilino-PSTTP’s 2E (Table 5) don’t have any significant 5-HT6R
antagonistic activity (the highest IC50 is about 0.6 M).
Finally, in a series of 5-azaheterocyclyl-PSTTP’s 2F (Table 6)
activity does not get better than IC50 = 1.04 M, which corresponds
to 5-(morpholin-4-yl)-3-(3-chlorobenzenesulfonyl)-thieno[2,3-
e][1,2,3]triazolo[1,5-a]pyrimidine 2F{5,84}.
The findings described above allowed us to select the most ac-
tive antagonists with IC50 <100.0 nM: 5-alkylamino- 2A{1,3; 5,3–
4}, 5-benzylamino- 2B{1,15–16; 1,24; 9,16}, 5-heterocyclylmeth-
ylamino 2C{1,26–27; 5,26; 9,28}, and 5-cycloalkylamino-3-ben-
zenesulfonyl-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine 2D{5,33}
(Fig. 3).
Using radioligand binding assay, we studied the selectivity of
two potent PSTTP’s, namely 2B{1,71; 5,71} on a panel of serotonin
receptors (Fig. 4). The data for displacement of radioligands from
their complexes with serotonin receptors are presented in Table
8. Except for some interactions of PSTTP 2B{5,71} with a 5-HT2AR
(50%) and 5-HT2BR (46%), these ligands display a high selectivity
towards 5-HT6R.
l
l
In a patch clamp assay, two of the studied 5-HT6R antagonists
demonstrated very weak inhibition of hERG Potassium Ion Chan-
nel, (ꢀ20% inhibition at 15.0
lM and 30 lM, respectively, for
2B{1,71} and 2B{5,71}. (Fig. 5)
We also have studied the activity of some PSTTP’s in a radioli-
gand binding assay. As it follows from Table 7, the most active
5-HT6R ligands (Fig. 4) are 5-heterocyclylmethylamino- 2C{1,26–
28}, 5-(N-benzyl-N-methylamino)- 2B{1,71; 5,71}, and 5-cyclo-
alkylamino-PSTTP’s 2D{1,32–33} with Ki <10 nM. The most active
ligands identified in radioligand binding assays are in good
agreement with the most active antagonists identified in terms
of functional assay.
5. Conclusions
In summary, a number of new potent and selective 5-HT6 recep-
tor antagonists were developed. Of particular note are the com-
pounds with benzyl, heteroarylmethyl or tetrahydrofurylmethyl
moiety at the N-5 atom and unsubstituted or with m-chlorine atom
in the phenylsulfonyl portion such as 2B{1,15–16}, 2B{1,24},
2B{9,16}, 2C{1,26–28}, 2C{1,32–33}, and 2C{5,26}. The most
Me
Cl
HN
N
Me
HN
N
Me
HN
N
Me
Me
S
NH
NH
NH
Cl
Cl
S
S
S
S
S
N
N
N
N
N
N
O
O
O
O
O
O
S
S
S
O
S
S
S
N
N
N
N
N
N
O
O
N
N
N
N
O
O
O
N
N
N
N
N
2B{1,15}: IC50 = 59.2 nM
2B{1,24}: IC50 = 36.7 nM.
2B{1,16}:IC50 = 32.0 nM
2A{1,3}: IC50 = 68.7 nM.
2A{5,4}: IC50 = 68.0 nM
2A{5,3}: IC50 = 60.3 nM
O
S
O
O
Cl
NH
NH
NH
NH
NH
HN
Me
Me
Cl
Cl
S
S
S
S
S
S
N
N
N
N
N
N
O
O
O
O
O
O
Me
Me
S
S
N
S
N
S
N
S
S
N
N
N
O
O
O
N
N
N
N
O
O
O
N
N
N
N
N
N
N
N
2B{9,16}: IC50 = 59.5 nM
2C{5,26}: IC50 = 29.0 nM
2C{1,26}: IC50 = 62.9 nM.
2C{1,27}: IC50 = 40.4 nM
2C{9,28}: IC50 = 90.3 nM
2D{5,33}: IC50 = 68.6 nM
Figure 3. The most active 5-HT6R antagonists of PSTTP’s combinatorial library in functional assay.
S
O
Me
NH
N
N
NH
NH
S
S
S
S
N
N
N
N
O
S
O
O
O
>
>
>
>
S
S
N
N
N
N
N
S
N
N
O
O
O
N
N
O
N
N
2C{1,28}: Ki = 1.7 nM
2B{1,71}: Ki = 2.3 nM
2D{1,33}: Ki = 3.2 nM
2C{1,27}: Ki = 2.8 nM
O
Me
NH
NH
N
N
Cl
S
S
S
N
N
N
O
O
O
>
>
>
S
S
N
N
N
N
S
O
O
O
N
N
N
N
2C{1,26}: Ki = 8.1 nM
2D{1,32}: Ki = 5.5 nM
2B{5,71}: Ki = 8.1 nM
Figure 4. The most active 5-HT6R ligands of PSTTP’s combinatorial library in radioligand binding assay.

5288
A. V. Ivachtchenko et al. / Bioorg. Med. Chem. 18 (2010) 5282–5290
CO3, H2O, dried and evaporated. Yields of products 1{1–9} as
slightly colored solids were 70–90%.
6.1.2.1. 5-Chloro-(3-phenylsulfonyl)thieno[2,3-e][1,2,3]triazol-
o[1,5-a]pyrimidine 1{1}. ESI-MS m/z 351. 1H NMR (DMSO-d6,
400 MHz) d 8.76 (d, J = 5.2 Hz, 1H), 8.28 (d, J = 5.6 Hz, 1H), 8.06
(m, 2H), 7.72 (m, 1H), 7.65 (m, 2H).
6.1.3. (3-Phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-
a]pyrimidine 4
To a solution of 5-chloro-3-phenylsulfonyl-thieno[2,3-e][1,2,3]
triazolo[1,5-a]pyrimidine 1{1} (304.5 mg, 0.87 mmol) in a mixture
of 60 mL of MeOH and 20 mL of benzene, Pd/C (10%, 100 mg) was
added and stirred for 24 h in an atmosphere of H2. The mixture was
filtered through Celite and concentrated under vacuum. Product 4
was isolated by HPLC to yield 63.2 mg (23%) as white powder. Mp:
217–218 °C. ESI-MS m/z 317. 1H NMR (DMSO-d6, 400 MHz) d 9.65
(s, 1H), 8.73 (d, J = 5.2 Hz, 1H), 8.23 (dd, J1 = 5.6 Hz, J2 = 0.4 Hz, 1H),
8.09 (m, 2H), 7.70 (m, 1H), 7.63 (m, 2H). 13C NMR (DMSO-d6,
Figure 5. Inhibition of hERG Potassium Ion Channel PSTTP’s 2 in a patch clamp
assay.
promising antagonists are compounds 2C{5,26} and 2C{1,28}. Fur-
ther investigation of the therapeutic potential of 3-(phenylsulfo-
nyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidines is in progress.
75 MHz)
d 151.88, 141.58, 141.16, 139.16, 138.48, 135.55,
134.02, 129.63, 127.23, 125.06, 115.70.
6. Experimental
6.1.4. 5-Ethylthio-(3-phenylsulfonyl)thieno[2,3-e][1,2,3]
triazolo[1,5-a]pyrimidine 5
6.1. General experimental
To a solution of KSEt (209 mg, 2.09 mmol) in 10 mL DMSO the
chloro-derivative 1{1} (609 mg, 1.74 mmol) was added portion-
wise and the mixture was stirred at room temperature for 1 h.
The resulting mixture was poured into water and extracted with
EtOAc. The organic layer was separated, dried over Na2SO4 and
concentrated under vacuum. Product 5 was isolated by column
chromatography, eluent benzene/AcOEt = 50:1. The yield of PSTTP
5 as white solid was 236 mg (36%). Mp: 190–192 °C. ESI-MS m/z
377. 1H NMR (CDCl3, 400 MHz) d 8.25 (m, 2H), 8.05 (q, J = 5.2 Hz,
2H), 7.60 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 8 Hz, 2H), 3.58 (q,
J = 7.2 Hz, 2H), 1.60 (t, J = 7.2 Hz, 3H).
LC–MS analyses were performed with
a
Shimadzu HPLC
equipped with a Waters XBridge C18 3.5
l
m (4.6 ꢂ 150 mm) col-
umn, mass detector PE SCIEX API 150 EX and spectrophotometric
detector Shimadzu (220 and 254 nm). According to LC–MS data,
purity of the compounds obtained exceeded 98.0%. 1H NMR spectra
were recorded on a Varian (400 MHz, 27 °C) using DMSO-d6 and
CDCl3 as solvents. IR spectra of PSTTP 9{1} were recorded on a Spe-
cord 75 IR in nujol.
5-HT6R binding activities of synthesized PSTTP’s were deter-
mined in a radioligand binding assay using a panel of eight seroto-
nin receptors.21
6.1.5. General procedure for the synthesis of (3-phenylsulfonyl)
thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amines 2
To a solution of the chloro- derivative 1{1–9} (1 mmol) in 2 mL
of anhydrous DMF and 1 mL of Et3N, amine 3{1–90} (1.1 mmol)
was added and the mixture was heated at 120 °C for 1 h. After cool-
ing, 10 mL of H2O was added. Separated solid was filtered off and
purified by recrystallization from methanol. Yields of PSTQ’s 2 as
white to creamy crystalline powders were 70–90%.
6.1.1. General procedure for synthesis of (3-phenylsulfonyl)-4H-
thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-one 9{1–9}
To a stirred solution of EtONa (0.5 g, 21.7 mmol of Na in 15 mL
of EtOH), 2-phenylsulfonylacetonitrile 8{1–9} (9.5 mmol) was
added. After 20 min a solution of methyl 3-azido-2-thiophenecarb-
oxylate 7 (1.13 g, 6.1 mmol) in 50 mL of EtOH was added for
40 min, then the mixture was heated under reflux for 20 h. The
reaction mixture was concentrated in vacuo, treated with H2O
and extracted with CHCl3. Product 9{1–9} precipitated from the
aqueous layer after acidification (pH 2) with concd HCl, was col-
lected by filtration and washed with H2O. Yields of products 9{1–
9} as creamy crystalline powders were 80–90%.
6.1.5.1. N-Isopropyl-(3-phenylsulfonyl)thieno[2,3-e][1,2,3]triaz-
olo[1,5-a]pyrimidin-5-amine 2{1,2}. Mp: 205–207 °C. ESI-MS
m/z 373. 1H NMR (DMSO-d6, 400 MHz) d 8.61 (d, J = 7.2 Hz, 1H),
8.38 (d, J = 5.6 Hz, 1H), 8.08 (d, J = 6.4 Hz, 2H), 7.95 (d, J = 5.2 Hz,
1H), 7.67 (m, 1H), 7.59 (m, 2H), 7.57 (sep, J = 6.8 Hz, 1H), 1.29 (d,
J = 6.8 Hz, 6H). 13C NMR (DMSO-d6, 75 MHz) d 152.56, 141.69,
141.11, 138.02, 136.43, 133.55, 130.17, 129.32, 127.08, 116.16,
114.12, 43.13, 21.73.
6.1.1.1. (3-Phenylsulfonyl)-4H-thieno[2,3-e][1,2,3]triazolo[1,5-
a]pyrimidin-5-one 9{1}. IR (nujol) 1670 cmꢁ1. ESI-MS m/z 333.
1H NMR (DMSO-d6, 400 MHz) d 8.43, 8.39 (2d, J = 5.2 Hz, 1H),
8.16, 8.05 (2d, J = 7.6 Hz, 2H), 7.92, 7.51 (2d, J = 5.2 Hz, 1H), 7.73
(m, 1H), 7.66 (m, 2H).
6.1.5.2. N,N-Dimethyl-N0-[(3-Phenylsulfonyl)thieno[2,3-e][1,2,3]
triazolo[1,5-a]pyrimidin-5-yl]ethane-1,2-diamine dihydrochlo-
ride 2{1,6}. Mp: 206–208 °C. ESI-MS m/z 416. 1H NMR (DMSO-d6,
400 MHz) d 9.90 (s,1H), 9.17 (t, J = 5.2 Hz, 1H), 8.45 (d, J = 5.6 Hz,
1H), 8.05 (m, 2H), 8.03 (d, J = 5.6 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H),
7.64 (t, J = 8 Hz, 2H), 3.95 (m, 2H), 3.44 (m, 2H), 2.89 (s, 6H). 13C
6.1.2. General procedure for the synthesis of 5-chloro-(3-phenyl-
sulfonyl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine 1{1–9}
A solution of 3-phenylsulfonyl-4H-thieno[2,3-e][1,2,3]triazol-
o[1,5-a]pyrimidin-5-one 9{1–9} (1.75 mmol) in 12 mL of Et3N
was cooled in an ice-bath (0–5 °C), 8 mL of POCl3 were added
and the mixture was heated under reflux for 12 h. After cooling,
the reaction mixture was poured into crushed ice and quickly
extracted with CHCl3. The CHCl3 extract was washed with 6% NaH-
NMR (DMSO-d6, 75 MHz)
d 153.82, 141.78, 141.01, 138.02,
137.06, 133.62, 130.44, 129.55, 126.94, 116.00, 114.67, 55.55,
42.61, 36.21.

A. V. Ivachtchenko et al. / Bioorg. Med. Chem. 18 (2010) 5282–5290
5289
6.1.5.3. N-(2-Phenylethyl)-(3-phenylsulfonyl)thieno[2,3-e][1,2,-
3]triazolo[1,5-a]pyrimidin-5-amine 2{1,11}. Mp: 254–256 °C
(dec). ESI-MS m/z 435. 1H NMR (DMSO-d6, 400 MHz) d 8.98 (t,
J = 4.8 Hz, 1H), 8.38 (d, J = 5.2 Hz, 1H), 8.08 (d, J = 7.2 Hz, 2H),
7.98 (d, J = 5.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 8 Hz,
2H), 7.33 (m, 4H), 7.22 (t, J = 6.8 Hz, 1H), 3.77 (m, 2H), 3.03 (t,
J = 7.2 Hz, 2H). 13C NMR (DMSO-d6, 75 MHz) d 153.41, 141.96,
141.28, 139.30, 138.02, 136.43, 133.50, 130.31, 129.29, 128.78,
128.47, 126.90, 126.30, 116.26, 114.21, 42.84, 34.23.
(DMSO-d6, 75 MHz) d 151.21, 141.80, 140.33, 138.81, 137.77,
137.55, 133.63, 133.13, 131.22, 131.19, 131.03, 129.44, 126.88,
121.91, 120.42, 116.25, 114.78, 19.11.
6.1.5.10. N-1,3-Benzothiazol-2-yl-3-(phenylsulfonyl)thieno[2,3-
e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{1,67}. Mp: 272–
274 °C. ESI-MS m/z 465. 1H NMR (DMSO-d6, 400 MHz) d 8.49 (d,
J = 5.2 Hz, 1 H), 8.19 (m, 2H), 8.08 (d, J = 5.2 Hz, 1H), 8.02 (m,
1H), 7.64 (m, 4H), 7.52 (m, 2H), 7.38 (m, 1H).
6.1.5.4. N-(1-Phenylethyl)-3-(phenylsulfonyl)thieno[2,3-e][1,2,3]
triazolo[1,5-a]pyrimidin-5-amine 2{1,24}. Mp: 230–232 °C.
6.1.5.11. 3-Phenylsulfonyl-N,N-dimethylthieno[2,3-e][1,2,3] tria-
zolo[1,5-a]pyrimidin-5-amine 2{1,68}. Mp: 234–236 °C. ESI-MS
m/z 359. 1H NMR (DMSO-d6, 400 MHz) d 8.49 (d, J = 5.6 Hz, 1H),
8.08 (m, 2H), 7.99 (d, J = 5.2 Hz, 1H), 7.63 (m, 3H), 3.49 (s, 6H).
ESI-MS m/z 435. 1H NMR (DMSO-d6, 400 MHz)
d 9.22 (d,
J = 7.6 Hz, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 5.2 Hz, 1H),
7.92 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.52 (d, J = 7.6 Hz,
2H), 7.43 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 7.2 Hz, 2H), 7.29 (t,
J = 7.6 Hz, 1H), 5.60 (m, 1H), 1.62 (d, J = 7.6 Hz, 3H). 13C NMR
(DMSO-d6, 75 MHz) d 152.59, 143.93, 141.94, 141.03, 138.21,
136.74, 133.34, 130.28, 129.29, 128.46, 127.00, 126.73, 126.42,
116.19, 114.00, 50.29, 21.89.
6.1.5.12. N-Benzyl-N-methyl-3-(phenylsulfonyl)thieno[2,3-e] [1,
2,3]triazolo[1,5-a]pyrimidin-5-amine
3
2{1,71}. Mp: 235–
237 °C. ESI-MS m/z 435. 1H NMR (DMSO-d6, 400 MHz) d 8.51 (d,
J = 5.6 Hz, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 7.2 Hz, 2H),
7.60 (m, 1H), 7.40 (m, 7H), 5.18 (s, 2H), 3.58 (s, 3H).
6.1.5.5. 3-Phenylsulfonyl-N-(tetrahydrofuran-2-ylmethyl)thie-
no[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{1,26}. Mp:
221–223 °C. ESI-MS m/z 415. 1H NMR (DMSO-d6, 400 MHz) d
8.98 (t, J = 5.6 Hz, 1H), 8.38 (d, J = 5.6 Hz, 1H), 8.06 (d, J = 7.2 Hz,
2H), 7.97 (d, J = 5.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.59 (t,
J = 8 Hz, 2H), 4.15 (m, 1H), 3.83 (m, 1H), 3.67 (m, 1H), 3.61 (m,
2H), 1.96 (m, 1H), 1.88 (m, 2H), 1.68 (m, 1H).
6.1.5.13. 3-(Phenylsulfonyl)-5-pyrrolidin-1-ylthieno[2,3-e] [1,2,
3]triazolo[1,5-a]pyrimidine 2{1,75}. Mp: 233–235 °C. ESI-MS
m/z 386. 1H NMR (DMSO-d6, 400 MHz) d 8.48 (d, J = 5.6 Hz, 1H),
8.09 (m, 2H), 7.99 (d, J = 5.6 Hz, 1H), 7.63 (m, 3H), 4.12–3.64 (br
m, 4H), 2.19–1.92 (br m, 4H).
6.1.5.14. 3-(Phenylsulfonyl)-5-piperidin-1-ylthieno[2,3-e][1,2,3]
triazolo[1,5-a]pyrimidine 2{1,76}. Mp: 221–223 °C. ESI-MS m/z
400. 1H NMR (DMSO-d6, 400 MHz) d 8.49 (d, J = 5.2 Hz, 1H), 8.04
(m, 3H), 7.67 (m, 1H), 7.61 (m, 2H), 4.03(m, 4H), 1.71 (m, 6H).
6.1.5.6. N-Cyclopentyl-3-(phenylsulfonyl)thieno[2,3-e][1,2,3]tri-
azolo[1,5-a]pyrimidin-5-amine 2{1,32}. Mp: 235–237 °C. ESI-
MS m/z 399. 1H NMR (DMSO-d6, 400 MHz) d 8.69 (d, J = 6.8 Hz,
1H), 8.38 (d, J = 5.6 Hz, 1H), 8.08 (d, J = 7.6 Hz, 2H), 7.96 (d,
J = 5.2 Hz, 1H), 7.67 (m, 1H), 7.59 (m, 2H), 4.53 (m, 1H), 2.06 (m,
2H), 1.77 (m, 2H), 1.65 (m, 4H). 13C NMR (DMSO-d6, 75 MHz) d
152.89, 141.60, 140.94, 137.83, 136.30, 133.42, 130.15, 129.15,
126.98, 115.97, 114.00, 52.93, 31.63, 23.93.
6.1.5.15. 5-(3-Methylpiperidin-1-yl)-3-(phenylsulfonyl)thieno
[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine
2{1,77}. Mp:
192–
194 °C. ESI-MS m/z 414. 1H NMR (DMSO-d6, 40 MHz) d 8.48 (d,
J = 5.6 Hz, 1H), 8.05 (m, 2H), 8.02 (d, J = 5.6 Hz, 1H), 7.67 (m, 1H),
7.60 (m, 2H), 4.62 (m, 1H), 4.55 (m, 1H), 3.36 (m, 1H), 3.09 (dd,
J1 = 13.2 Hz, J2 = 10.4 Hz, 1H), 1.84 (m, 2H), 1.74 (m, 1H), 1.54 (m,
1H), 1.32 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H). 13C NMR (DMSO-d6,
6.1.5.7. N-Cyclohexyl-3-(phenylsulfonyl)thieno[2,3-e][1,2,3]tri-
azolo[1,5-a]pyrimidin-5-amine 2{1,33}. Mp: 228–230 °C. ESI-
MS m/z 413. 1H NMR (DMSO-d6, 400 MHz) d 8.61 (d, J = 7.2 Hz,
1H), 8.38 (d, J = 5.6 Hz, 1H), 8.08 (d, J = 7.2 Hz, 2H), 7.95 (d,
J = 5.6 Hz, 1H), 7.68 (m, 1H), 7.58 (m, 2H), 4.13 (m, 1H), 1.98 (m,
2H), 1.87 (m, 2H), 1.72 (m, 1H), 1.43 (m, 4H), 1.22 (m, 1H). 13C
75 MHz)
d 153.25, 141.74, 140.17, 139.35, 136.57, 133.59,
129.97, 129.35, 127.00, 116.11, 112.39, 66.41, 54.11, 47.67, 32.30,
31.21, 24.88.
6.1.5.16. 5-Azepan-1-yl-3-(phenylsulfonyl)thieno[2,3-e][1,2,3]
triazolo[1,5-a]pyrimidine 2{1,83}. Mp: 211–214 °C. ESI-MS m/z
414. 1H NMR (DMSO-d6, 400 MHz) d 8.50 (d, J = 5.6 Hz, 1H), 8.06
(d, J = 7.2 Hz, 2H), 8.01 (d, J = 5.6 Hz, 1H), 7.67 (t, J = 6.8 Hz, 1H),
7.60 (t, J = 7.6 Hz, 2H), 4.01 (t, J = 5.6 Hz, 4H), 1.89 (m, 4H), 1.54
(m, 4H).
NMR (DMSO-d6, 75 MHz)
136.50, 133.62, 130.14, 129.17, 127.10, 116.15, 114.08, 50.63,
31.66, 25.34, 25.13.
d 152.49, 141.63, 141.05, 138.07,
6.1.5.8. N-Phenyl-3-(phenylsulfonyl)thieno[2,3-e][1,2,3]triazolo
[1,5-a]pyrimidin-5-amine 2{1,36}. Mp: 259–261 °C (dec). ESI-
MS m/z 408. 1H NMR (DMSO-d6, 400 MHz) d 10.43 (s, 1H), 8.49
(d, J = 5.2 Hz, 1H), 8.06 (d, J = 5.6 Hz, 1H), 8.01 (d, J = 7.2 Hz, 2H),
7.96 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 8.0 Hz,
2H), 7.50 (t, J = 8.0 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H). 13C NMR
(DMSO-d6, 75 MHz) d 151.41, 141.58, 140.34, 138.64, 138.36,
137.30, 133.50, 130.88, 129.25, 128.58, 126.82, 124.65, 122.36,
116.11, 114.64.
6.1.5.17. 5-(4-methylpiperazin-1-yl)-3-(phenylsulfonyl)thieno
[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine
2{1,86}. Mp:
247–
249 °C. ESI-MS m/z 415. 1H NMR (DMSO-d6, 400 MHz) d 8.52 (d,
J = 5.6 Hz, 1H), 8.05 (m, 3H), 7.68 (m, 1H), 7.61 (m, 2H), 4.04 (m,
4H), 2.54 (m, 4H), 2.27 (s, 3H).
6.1.5.18. 5-(2,3-Dihydro-1H-indol-1-yl)-3-(phenylsulfonyl)thie-
no[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine 2{1,90}. Mp: 263–
265 °C. ESI-MS m/z 434. 1H NMR (DMSO-d6, 400 MHz) d 9.98 (d,
J = 8.4 Hz, 1H), 8.59 (d, J = 5.6 Hz, 1H), 8.09 (d, J = 5.6 Hz, 1H),
8.04 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz,
2H), 7.34 (m, 2H), 7.14 (t, J = 6.8 Hz, 1H), 4.76 (t, J = 8.0 Hz, 2H),
3.36 (m, 2H).
6.1.5.9. 3-(3-Chloro-4-methylphenylsulfonyl)-N-phenylthieno
[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine
2{1,64}. Mp:
262–264 °C. ESI-MS m/z 443. 1H NMR (DMSO-d6, 400 MHz) d
10.46 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.06
(m, 3H), 7.80 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 7.65 (m, 1H), 7.57
(t, J = 7.6 Hz, 2H), 7.44 (d, J = 8.4 Hz, 1H), 2.38 (s, 3H). 13C NMR

5290
A. V. Ivachtchenko et al. / Bioorg. Med. Chem. 18 (2010) 5282–5290
6.1.5.19. 3-(4-Ethylphenylsulfonyl)-5-thiomorpholin-4-ylthieno
8.51 (d, J = 5.6 Hz, 1H), 8.04 (d, J = 5.6 Hz, 1H), 8.00 (s, 1H), 7.91
(d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 8.4 Hz, 1H),
7.40 (m, 2H), 7.36 (m, 3H), 5.17 (s, 2H), 3.56 (s, 3H).
[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine
2{3,85}. Mp:
206–
208 °C. ESI-MS m/z 446. 1H NMR (DMSO-d6, 400 MHz) d 8.53 (d,
J = 5.6 Hz, 1H), 8.05 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H),
7.45 (d, J = 8.4 Hz, 2H), 4.33 (m, 4H), 2.82 (m, 4H), 2.65 (q,
J = 8.0 Hz, 2H), 1.15 (t, J = 8.0 Hz, 3H).
6.1.5.27. 3-(4-Chlorophenylsulfonyl)-5-(1,4-dioxa-8-azaspiro[4,5]-
dec-8-yl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine 2{6,82}. Mp:
233–235 °C. ESI-MS m/z 493. 1H NMR (DMSO-d6, 400 MHz) d 8.51 (d,
J = 5.6 Hz, 1H), 8.04 (m, 3H), 7.69 (m, 2H), 4.07 (m, 4H), 3.97 (s, 4H),
1.82 (m, 4H).
6.1.5.20. 3-(4-Ethylphenylsulfonyl)-5-(4-phenyl-3,6-dihydro-
pyridin-1(2H)-yl)thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine 2
{3 ,89}. Mp: 223–225 °C. ESI-MS m/z 502. 1H NMR (DMSO-d6,
400 MHz) d 8.54 (d, J = 5.6 Hz, 1H), 8.05 (d, J = 5.6 Hz, 1H), 8.00
(d, J = 8.4 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H),
7.38 (t, J = 7.2 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 6.39 (m, 1H), 4.72
(m, 2H), 4.25 (t, J = 5.6 Hz, 2H), 2.77 (m, 2H), 2.64 (q, J = 7.2 Hz,
2H), 1.13 (t, J = 7.6 Hz, 3H).
6.1.5.28. 3-(4-Chlorophenyl)sulfonyl)-5-morpholin-4-ylthieno
[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine
2{6,84}. Mp:
202–
204 °C. ESI-MS m/z 437. 1H NMR (DMSO-d6, 400 MHz) d 8.54 (d,
J = 5.6 Hz, 1H), 8.05 (m, 3H), 7.69 (m, 2H), 4.03 (t, J = 4.8 Hz, 4H),
3.81 (t, J = 5.2 Hz, 4H). 13C NMR (DMSO-d6, 75 MHz) d 154.00,
140.23, 139.86, 139.36, 138.53, 136.92, 129.80, 129.48, 128.99,
115.93, 112.54, 65.65, 46.81.
6.1.5.21. 3-(4-Isopropylphenylsulfonyl)-5-thiomorpholin-4-ylthi-
eno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine 2{4,85}. Mp: 206–
208 °C (dec). ESI-MS m/z 460. 1H NMR (DMSO-d6, 400 MHz) d
8.53 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 5.6 Hz, 1H) 7.96 (d, J = 8.4 Hz,
2H), 7.49 (d, J = 8.4 Hz, 2H), 4.33 (m, 4H), 2.95 (sep, J = 6.4 Hz,
1H), 2.82 (m, 4H), 1.17 (d, J = 6.8 Hz, 6H). 13C NMR (DMSO-d6,
6.1.5.29. 3-(4-Bromophenylsulfonyl)thieno[2,3-e][1,2,3]triazolo
[1,5-a]pyrimidin-5-amine 2{7,1}. Mp: 275–277 °C. ESI-MS m/z
410. 1H NMR (DMSO-d6, 400 MHz) d 8,42 (M, 3H), 7,98 (d,
J = 5.2 Hz, 1H), 7.95 (d, J = 9.2 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H). 13C
75 MHz)
d 154.49, 153.25, 139.65, 139.39, 139.01, 136.78,
NMR (DMSO-d6, 75 MHz)
d 155.48, 141.67, 141.33, 138.28,
130.59, 127.26, 127.25, 116.03, 112.58, 49.98, 33.39, 26.16, 23.33.
136.93, 132.38, 128.84, 128.57, 127.29, 116.09, 113.69.
6.1.5.22. 3-(3-Chlorophenylsulfonyl)thieno[2,3-e][1,2,3]triazol-
o[1,5-a]pyrimidin-5-amine 2{5,1}. Mp: 253–255 °C. ESI-MS m/z
366. 1H NMR (DMSO-d6, 400 MHz) d 8.45 (s, 2H), 8.42 (d,
J = 5.6 Hz, 1H), 7.99 (m, 3H), 7.74 (m, 1H), 7.64 (t, J = 7.6 Hz, 1H).
6.1.5.30. 3-(2,5-Dimethylphenylsulfonyl)thieno[2,3-e][1,2,3] triaz
olo[1,5-a]pyrimidin-5-amine 2{8,1}. Mp: 251–253 °C. ESI-MS
m/z 359. 1H NMR (DMSO-d6, 400 MHz) d 8.41 (d, J = 5.2 Hz, 1H),
8.33 (s, 2H), 7.98 (d, J = 5.2 Hz, 1H), 7.92 (m, 1H), 7.35 (m, 1H),
7.22 (m, 1H), 2.37 (s, 6H). 13C NMR (DMSO-d6, 75 MHz) d 155.24,
141.48, 139.56, 138.25, 136.74, 135.79, 134.31, 133.91, 132.39,
129.36, 128.63, 116.11, 113.64, 20.37, 19.16.
6.1.5.23. N0-[3-(3-Chlorophenylsulfonyl)thieno[2,3-e][1,2,3]tria-
zolo[1,5-a]pyrimidin-5-yl]-N,N-dimethylethane-1,2-diamine
dihydrochloride 2{5,6}. Mp: 204–206 °C. ESI-MS m/z 437. 1H
NMR (DMSO-d6, 400 MHz) d 10.09 (s, 1H), 8.60 (d, J = 5.6 Hz, 1H),
8.07 (d, J = 5.6 Hz, 1H), 8.02 (m, 2H), 7.69 (m, 1H), 7.63 (m, 2H),
4.29 (t, J = 6.0 Hz, 2H), 3.66 (s, 3H), 3.50 (q, J = 6.0 Hz, 2H), 2.91
(d, J = 4.8 Hz, 6H). 13C NMR (DMSO-d6, 75 MHz) d 153.93, 143.56,
141.27, 138.06, 137.17, 133.97, 133.63, 131.77, 129.66, 126.37,
125.72, 115.98, 114.76, 55.42, 42.56, 36.23.
References and notes
1. Barnes, N. M.; Sharp, T. Neuropharmacology 1999, 38, 1083.
2. Hoyer, D.; Martin, G. R. Behav. Brain Res. 1996, 73, 263.
3. Sebben, M.; Ansanay, H.; Bockaert, J.; Dumuis, A. Neuroreport 1994, 5, 2553.
4. Roberts, J. C.; Reavill, C.; East, S.; Harrison, P. J.; Pate, S.; Routledge, C.; Leslie, R.
A. Brain Res. 2002, 934, 49.
5. Woolley, M. L.; Marsden, C. A.; Fone, K. C. F. Curr. Drug Targets CNS Neurol.
Disord. 2004, 3, 59.
6. Dawson, L. A.; Nguyen, H. Q.; Li, P. Neuropsychopharmacology 2001, 25,
662.
7. Holenz, J.; Pauwels, P. J.; Díaz, J. L.; Mercè, R.; Codony, X.; Buschmann, H. Drug
Discovery Today 2006, 11, 283.
8. Liu, K. G.; Robichaud, A. J. Drug Dev. Res. 2009, 70, 145.
9. Geldenhuys, W. J.; Van der Schyf, C. J. Curr. Top. Med. Chem. 2008, 8, 1035.
10. Gerard, R.; Schaffhauser, H. Curr. Top. Med. Chem. 2010, 10, 207.
11. http://clinicaltrials.gov/ct2/show/NCT00348192.
6.1.5.24. 3-(3-Chlorophenylsulfonyl)-N-(4-fluorobenzyl)thieno
[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine
2{5,21}. Mp:
246–248 °C. ESI-MS m/z 474. 1H NMR (DMSO-d6, 400 MHz) d
9.43 (t, J = 6.0 Hz, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.99 (m, 2H), 7.92
(m, 1H), 7.72 (m, 1H), 7.53 (m, 3H), 7.16 (m, 2H), 4.77 (d,
J = 6.4 Hz, 2H). 13C NMR (DMSO-d6, 75 MHz) d 162.57, 160.16,
153.37, 143.54, 141.29, 138.12, 136.64, 134.50, 134.47, 133.79,
133.39, 131.37, 130.06, 129.98, 129.36, 126.24, 125.39, 116.18,
115.15, 114.93, 114.11, 43.54.
12. Tkachenko, S.; Ivachtchenko, A.; Khvat, A.; Okun, I.; Lavrovsky, Y.; Salimov R.
Abstracts of Papers, 9th International Conference AD/PD, Prague, Czech
Republic, Mar 11–15, 2009, 945.
13. http://www.biospace.com/news_story.aspx?NewsEntityId=141148.
14. Davies, S. L.; Silvestre, J. S.; Guitart, X. Drugs Future 2005, 30, 479.
15. Heal, D. J.; Smith, S. L.; Fisas, A.; Codony, X.; Buschmann, H. Pharmacol. Ther.
2008, 117, 207.
16. López-Rodríguez, M. L.; Bellinda Benhamú, B.; de la Fuente, T.; Sanz, A.; Pardo,
L.; Campillo, L. J. Med. Chem. 2005, 48, 4216.
17. Kim, H.-J.; Doddareddy, M. R.; Choo, H.; Cho, Y. S.; No, K. T.; Park, W.-K.; Pae, A.
N. J. Chem. Inf. Model. 2008, 48, 197.
18. Westerlund, C. J. Heterocycl. Chem. 1980, 17, 1771.
19. Kasila, P.; Harney H. http://las.perkinelmer.com/Content/RelatedMaterials/
Posters/PST_LANCEcAMPGasGaiCoupledReceptors.pdf.
20. http://www.mdsps.com/Services.
6.1.5.25. 3-(3-Chlorophenylsulfonyl)-N-(pyridin-3-ylmetnyl)thi-
eno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine 2{5,29}. ESI-MS
m/z 457. 1H NMR (DMSO-d6, 400 MHz) d 9.76 (m, 1H), 9.04 (s, 1H),
8.82 (d, J = 4.8 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.44 (d, J = 5.2 Hz, 1H),
8.97 (m, 4H), 7.63 (t, J = 6.8 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 4.92 (d,
J = 4.8 Hz, 2H).
6.1.5.26. N-Benzyl-3-(3-chlorophenylsulfonyl)-N-methylthieno
[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-amine
2{5,71}. Mp:
21. Okun, I.; Tkachenko, S. E.; Khvat, A.; Mitkin, O.; Kazey, V.; Ivachtchenko, A. V.
Curr. Alzheimer Res. 2010, 7, 97.
203–205 °C. ESI-MS m/z 470. 1H NMR (DMSO-d6, 400 MHz) d