Novel 4-aryl-pyrido[1,2-c ]pyrimidines with dual SSRI and 5-HT1A activity. Part 4

Article abstract of DOI:10.1016/j.ejmech.2014.10.069

This project describes the synthesis, pharmacological and pharmacodynamic tests on two series of novel derivatives of 2H-pyrido[1,2-c]pyrimidine with potential binary binding to 5-HT_1A receptors and SSRI + serotonin transporters. The influence of piperidinyl-indole (8.1-8.7) and tetrahydropyridinyl-indole (8.8-8.32) residues and indole 5-position substituents (R₃ Combining double low line Br, Cl, F) present in the pharmacophore element of ligands on their binding to both molecular targets was tested.A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed and compounds with a high binding affinity were identified: K_i 5-HT_1A Combining double low line 12.4 nM; K_i SERT Combining double low line 15.6 nM 8.1; K_i 5-HT_1A Combining double low line 5.6 nM; K_i SERT Combining double low line 20.7 nM 8.7, while the presence of a tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT_1AR. The presence of chlorine (R₃) in this series resulted in a notable reduction in binding to both targets (5-HT_1A and SERT). Selected compounds had their metabolic stability in a first-pass test (human liver microsomes, NADPH) determined in vitro, and R₁ and R₂ substituents present on the terminal residue of pyrido[1,2-c]pyrimidine were recognized as having an impact on stability.

Full text of DOI:10.1016/j.ejmech.2014.10.069

Accepted Manuscript
Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT activity. Part 4
1A
Andrzej Chodkowski, Martyna Z. Wróbel, Jadwiga Turło, Jerzy Kleps, Agata Siwek,
Gabriel Nowak, Mariusz Belka, Tomasz Bączek, Aleksander P. Mazurek, Franciszek
Herold
PII:
S0223-5234(14)00997-0
10.1016/j.ejmech.2014.10.069
EJMECH 7477
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 2 April 2014
Revised Date: 22 October 2014
Accepted Date: 23 October 2014
Please cite this article as: A. Chodkowski, M.Z. Wróbel, J. Turło, J. Kleps, A. Siwek, G. Nowak,
M. Belka, T. Bączek, A.P. Mazurek, F. Herold, Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual
SSRI and 5-HT activity. Part 4, European Journal of Medicinal Chemistry (2014), doi: 10.1016/
1A
j.ejmech.2014.10.069.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
R2
R2
R1
O
R1
O
F
R3
N
N
N
N
N
N
O
O
8.1-7
8.8-32
N
N
H
H
R =H, F, Cl, CH , OCH
R = H, F, Cl,CH , OCH
R = F, Br, Cl
3
1
3
3
2
3
3
Graphical Abstract. The general structure of final compounds.

ACCEPTED MANUSCRIPT
Novel 4-aryl-pyrido[1,2-c]pyrimidines
with dual SSRI and 5-HT activity. Part 4.
1
A
a
a,
a
a
b
Andrzej Chodkowski , Martyna Z. Wróbel *, Jadwiga Turło , Jerzy Kleps , Agata Siwek
b,c
d
d
e,f
Gabriel Nowak , Mariusz Belka , Tomasz Bączek , Aleksander P. Mazurek , Franciszek
a,
Herold *
a
Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy,
Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland
b
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College,
9
Medyczna Street, 30-688 Kraków, Poland
Institute of Pharmacology, Polish Academy of Sciences,
2 Smętna Street, 31-343 Kraków, Poland
c
1
d
Department of Pharmaceutical Chemistry,
Faculty of Pharmacy with Subfaculty of Laboratory Medicine,
Medical University of Gdańsk
1
07 Al. Gen. J. Hallera Street , 80-416 Gdańsk, Poland
e
Department of Drug Chemistry, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland
f
National Medicines Institute, 30/34 Chełmska Street, 00-725 Warszawa, Poland
Abstract
This project describes the synthesis, pharmacological and pharmacodynamic tests on
two series of novel derivatives of 2H-pyrido[1,2-c]pyrimidine with potential binary binding to
5
-HT1A receptors and SSRI+ serotonin transporters. The influence of piperidinyl-indole (8.1-
.7) and tetrahydropyridinyl-indole (8.8-8.32) residues and indole 5-position substituents (R3
8
=
Br, Cl, F) present in the pharmacophore element of ligands on their binding to both
molecular targets was tested.
A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed
and compounds with a high binding affinity were identified: K 5-HT = 12.4 nM; K SERT
i
1A
i
=
15.6 nM 8.1; K 5-HT = 5.6 nM; K SERT = 20.7 nM 8.7, while the presence of a
i 1A i
tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT R.
1
A
The presence of chlorine (R ) in this series resulted in a notable reduction in binding to both
3
targets (5-HT1A and SERT). Selected compounds had their metabolic stability in a first-pass
test (human liver microsomes, NADPH) determined in vitro, and R and R substituents
1
2
present on the terminal residue of pyrido[1,2-c]pyrimidine were recognized as having an
impact on stability.
Keywords: antidepressants, pyrido[1,2-c]pyrimidines, dual 5-HT /SERT activity , ADME
1
A
1

ACCEPTED MANUSCRIPT
Abbreviations: SERT, 5-HT-T, serotonin transporter; SAR, structure-activity relationship; 5-
HT, serotonin; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetraline; Ki, inhibitor constant;
TMS, tetramethylsilane; NADPH, dihydronicotinamide-adenine dinucleotide phosphate;
HRMS, high resolution mass spectrometry; SSRIs, selective serotonin inhibitors; ADME,
adsorption-distribution-metabolism-elimination
*
corresponding
author,
e-mail:
martynawrobel.wum@gmail.com,
franciszek.herold@wum.edu.pl
1
. Introduction
Depression is now the fourth most common disorder in the world and by 2020 it is
expected to become the second most common [1]. Disorders in monoaminergic
neurotransmission connected to serotonin and noradrenaline play a key role in the
pathomechanism of depression. This has been confirmed by the fact that most drugs used in
the pharmacotherapy of depression assume the serotoninergic system as their molecular target
[
2]. The recent introduction of selective serotonin reuptake inhibitors (SSRIs) such as
fluoxetine, escitalopram, paroxetine, sertraline and more is considered a breakthrough in the
treatment of depression. They also manifest greater selectivity, which reduces undesirable
effects and results in high therapeutic indices [3]. Unfortunately, this group of medications
has its shortcomings, as only every third patient reacts to treatment and the latency period
extends over 4 to 6 weeks due to slow desensitization of autoreceptors [4]. One hypothesis
suggests that the delay in the onset of action is due to a negative feedback control exerted by
5
-HT1A autoreceptors on nerve terminal serotonin release [5]. According to this hypothesis,
the onset of action is initiated only when this impulse flow is restored following
desensitization of 5-HT1A autoreceptors, and a coincident increase in the postsynaptic
serotonin level is achieved [6,7].
Research conducted by Artigas [8] and Blier [9] focused on the co-administration of 5-HT1A
antagonist (pindolol) and SSRI, which aimed at reducing the latency period. The
inconvenience of this research consisted of its lack of antagonist selectivity to 5-HT1A
autoreceptors, with a simultaneous antagonism of postsynaptic receptors. A subsequent
direction of SSRI+ research pointed to connecting the effects of SSRI with a pre- and
postsynaptic agonist that would generate an increase in serotoninergic transmission through
acceleration of 5-HT1A autoreceptor desensitization [9,10]. This line of inquiry led to the
®
introduction of vilazodone (Viibryd ) for the treatment of depression [11]. The research
described in that work concentrated on the synthesis of novel derivatives of pyrido-pyrimidine
2

ACCEPTED MANUSCRIPT
from the SSRI+ group with affinity for 5-HT1A receptors and serotonin transporter (SERT),
with piperidinyl-indole and tetrahydropyridinyl-indole residues in their structure. This was
expected to increase their degree of affinity for SERT, since those residues are proven to
manifest inhibitory activity towards SERT [12-15].
Research directed at discovering ligands with binary binding (5-HT1A and SERT) and
appropriate functional activity for 5-HT1A receptors (pre- and postsynaptic agonism) among
novel derivatives of pyrido[1,2-c]pyrimidine has been carried out in our laboratory for a
number of years. It is associated with investigating a new generation of antidepressants from
the SSRI+ group. Earlier work in the mentioned research described a series of derivatives of
pyrido[1,2-c]pyrimidine with 3-(piperidin-4-yl)-1H-indole or 3-(1,2,3,6-tetrahydropyridin-4-
yl)-1H-indole residues in the pharmacophore element. A series of compounds with a high
degree of binding to both molecular targets and a suitable functional profile with 5-HT1A
receptor binding (pre- and postsynaptic agonism) was obtained [16-18]. It is worth
emphasizing that presynaptic agonism of the 5-HT1A receptor accelerates autoreceptor
desensitization, which in turn reduces the latency period. On the other hand, postsynaptic
agonism of 5-HT1A receptors can improve neurotransmission in the serotoninergic system
[
19]. The analysis covered the impact of the degree of hydrogenation of the terminal part of
the pyrido[1,2-c]pyrimidine structure and the function of benzene ring substituents (ortho and
para) at the 4-position on the binding of ligands to 5-HT and SERT [16-18].
1
A
Pursuing the research within the SSRI+ group, we have focused on derivatives of 2H-
pyrido[1,2-c]pyrimidine series with binary binding (5-HT1A and SERT) exhibiting agonistic
activity (pre- and postsynaptic) to 5-HT R. The aim of the research was to determine the
1
A
impact of substituents (Cl, Br, F) the 5-position (R ) of the indole present in the
3
pharmacophore portion of each ligand (Fig. 1) on the degree of affinity to both molecular
targets. In addition, the impact of piperidinyl and tetrahydropyridinyl residues also present in
the pharmacophore element was analysed. Examination of how R and R substituents in the
1
2
terminal portion of the ligands influences their metabolic stability in a first-pass test with a
microsomal fraction from human liver tissue in the presence of NADPH also constituted a
part of the project.
3

ACCEPTED MANUSCRIPT
R2
R1
O
R3
N
N
N
O
N
H
Fig. 1. General structure of pyrido[1,2-c]pyrimidines with dual 5-HT /SERT activity
1
A
2
. Results and Discussion
2
.1 Chemistry
Final compounds 8.1-8.32 were obtained via multi-step synthesis according to Scheme 1. The
starting (2a-i, 3a-i, 4a-i, 5a-i, 6a, 6 and 7a-c) and final compounds (8.1 - 8.32) were
synthesized according to procedures described in our previous paper [16-18]. All new
1
13
compounds (6a and 8.1-32) were characterized by physical constants, HRMS, H, and C
NMR spectroscopy.
4

ACCEPTED MANUSCRIPT
a
Scheme 1 . The synthesis pathways of the investigated compounds.
R2
R2
R1
R1
CN
i
ii
iii
CONH2
CN
N
N
R2
R1
1
a - i
R2
2 a - i
3 a - i
R2
R1
O
R1
O
iv
N
NH
N
N
Br
O
O
5
a - i
4
a - i
F
F
R3
v
v
vi
NBn
NH
NH
N
N
N
H
H
H
6
a
6
7 a - c
R2
R2
R1
O
R1
O
F
R3
N
N
N
N
N
N
O
O
8
.1-7
8.8-32
N
N
H
H
R =H, F, Cl, CH , OCH
R = H, F, Cl,CH , OCH
R = F, Br, Cl
3
1
3
3
2
3
3
a
Reagents and conditions: (i) 2-bromopyridine, KOH, DMSO, ꢀ; (ii) H SO , CH COOH, ꢀ; (iii) diethyl carbonate, EtONa,
2
4
3
EtOH abs., ꢀ; (iv) 1,4-dibromobutane, K CO , acetone, ꢀ; (v) acetionitrile, K CO , KI, ꢀ: (vi) 10% Pd/C, CH OH,
2
3
2
3
3
The work resulted in obtaining a number of novel derivatives of 4-aryl-pyrido[1,2-
c]pyrimidine with a 5-fluoro-3-(piperidin-4-yl)-1H-indole structure in the pharmacophore part
and 5-fluoro, 5-chloro and 5-bromo derivatives of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-
indole (Scheme 1). The aryl substituent the in 4-aryl-pyrido[1,2-c]pyrimidine configuration
5

ACCEPTED MANUSCRIPT
constituted a benzene ring for compounds 8.1, 8.8, 8.17 and 8.25, whereas in other derivatives
the substituents on this ring featured: -F (8.5, 8.13, 8.21, 8.30), -Cl (8.6, 8.14, 8.22), -OCH3
(
8.7, 8.16, 8.24, 8.32), or -CH (8.15, 8.23, 8.31) in the ortho position, and -F (8.4, 8.12, 8.20,
3
8
.29), -Cl (8.3, 8.11, 8.28), -OCH (8.10, 8.19, 8.27), or -CH (8.2, 8.9, 8.18, 8.26) in the para
3 3
position.
2
.2 In vitro studies
The test results on the binding of compounds 8.1-8.32 to 5-HT and 5-HT-T receptors
1
A
allowed for analyse as to how receptor affinity is influenced by: substituents on the indole
portion (-F, -Cl, -Br substituents in the 5-position of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-
indole), the degree of saturation of the pyridine ring of the 3-(piperidin-4-yl)-1H-indole
structure and ortho and para position substituents on the aryl ring of pyrido[1,2-c]pyrimidine.
Binding results for ligands 8.1-8.32 to 5-HT1A receptors confirmed very high affinity for
compounds 8.7 (K = 5.6nM), 8.5 (K = 9.2nM), 8.1 (K = 12.4nM), 8.4 (K = 12.8nM) and 8.6
i
i
i
i
(
K = 15.9nM). The degree of affinity for the remaining derivatives ranged from high to
i
average, with K values between 23.1 nM and 295.0 nM (in order of increasing K : 8.27, 8.30,
i
i
8
8
.32, 8.2, 8.25, 8.28, 8.31, 8.22, 8.29, 8.10, 8.3, 8.21, 8.24, 8.20, 8.13, 8.8, 8.17, 8.14, 8.26,
.9, 8.23, 8.12, 8.16, 8.11, 8.18, 8.19, and 8.15; Table 1). Analysis of the impact of indole
substituents on binding to 5-HT1A receptors, in turn, indicated that derivatives featuring a
fluorine atom at 5-position of the 3-(piperidin-4-yl)-1H-indole structure (HHPI) or a bromine
atom at 5-position of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (THPI) exhibit either very
high or high affinity. The presence of either a fluorine or chlorine atom at the 5-position of the
3
-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (THPI) structure in a derivative was confirmed
to cause a drop in the degree of binding to 5-HT receptors. A substitution on the aryl ring of
1
A
pyrido[1,2-c]pyrimidine, on the other hand, may be said to cause reduced receptor affinity for
derivatives with –CH (8.2, 8.9, 8.18, 8.26) or -Cl (8.3, 8.11, 8.28) groups in the para position
3
and –CH (8.15, 8.23, 8.31) in the ortho position in relation to other ligands with analogous
3
HHPI or THPI structures in the pharmacophore element.
The results on binding of the proteins to the serotonin transporter 5-HT-T
demonstrated the very high affinity of compounds 8.13 (K =3.9 nM), 8.14 (K =5.2 nM), 8.12
i
i
(
K =11.3 nM), 8.10 and 8.1 (K = 15.6 nM). Affinity values for the remaining compounds
i
i
ranged from high to poor, i.e. between 19.4 nM and 1.2 ꢁM (in order of increasing K : 8.4,
i
8
8
.7, 8.16, 8.3, 8.5, 8.8, 8.2, 8.9, 8.11, 8.15, 8.6, 8.19, 8.17, 8.27, 8.20, 8.29, 8.18, 8.21, 8.24,
.23, 8.22, 8.30, 8.25, 8.31, 8.26, 8.28 and 8.32).
6

ACCEPTED MANUSCRIPT
By looking at the effect of indole substituents on binding to the 5-HT-T serotonin
transporter protein, it can be stated that ligands featuring a fluorine atom at the 5-position of
3
-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (THPI) or 3-(piperidin-4-yl)-1H-indole (HHPI)
had similarly high affinity, while K values for derivatives with a bromine or chlorine atom at
i
the 5-position of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (THPI) ranged from average to
high. Substitution on the aryl ring of pyrido[1,2-c]pyrimidine, in turn, resulted in relatively
higher affinity for derivatives with -OCH (8.10, 8.19, 8.27) or fluorine (8.4, 8.12, 8.20, 8.29)
3
in the para position. The remaining derivatives showed higher values of Ki.
Table 1 SERT and 5-HT1A receptor binding affinities of 3-(piperidin-4-yl)-1H-indole derivatives (HHPI) and 3-(1,2,3,6-
tetrahydropyridin-4-yl)-1H-indole derivatives (THPI).
R1
H
R2
H
R3
F
K 5-HT [nM]
K SERT [nM]
i
1A
i
8
8
8
8
8
8
8
8
8
.1
.2
.3
.4
.5
.6
.7
.8
.9
HHPI
HHPI
HHPI
HHPI
HHPI
HHPI
HHPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
THPI
12.4
15.6
27.4
25.5
19.4
25.7
88.6
20.7
27.1
30.3
15.6
58.2
11.3
3.9
H
CH
Cl
F
F
38.5
3
H
F
84.4
H
F
12.8
F
H
F
9.2
Cl
OCH
H
H
F
15.9
H
F
5.6
3
H
F
117.7
153.2
81.7
H
CH
F
3
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
.10
.11
.12
.13
.14
.15
.16
.17
.18
.19
.20
.21
.22
.23
.24
.25
.26
H
OCH
Cl
F
3
F
H
F
265.1
219.7
115.5
127.3
295.0
251.5
125.8
267.1
277.5
106.4
97.1
H
F
F
H
F
Cl
H
F
5.2
CH
H
F
58.8
20.8
322.0
408.4
311.8
329.4
435.0
774.4
739.6
717.9
839.7
949.4
3
OCH
H
H
F
3
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
H
CH
3
H
OCH
F
3
H
F
H
Cl
H
74.4
CH
H
212.5
97.8
3
OCH
H
H
3
H
40.1
H
CH
144.9
3
7

ACCEPTED MANUSCRIPT
8
8
8
8
8
8
.27
.28
.29
.30
.31
.32
H
H
OCH
Cl
F
3
Br
Br
Br
Br
Br
Br
THPI
THPI
THPI
THPI
THPI
THPI
23.1
61.6
79.1
32.5
71.5
33.1
326.5
1000.0
403.6
835.8
879.5
1200.0
H
F
H
CH
H
3
OCH
H
3
From our early investigation it appeared that docking of 4-(1-H-indol-3-yl)piperidine
drivatives to the 5-HT1A receptor is predetermined by basic moiety of the compound and
aromatic part interacting with Asp3.32 and Phe6.52 residues in the receptor [17, 18]. In
SERT interaction model the Asp fragment was crucial for anchoring protonated nitrogen of
fully flexible ligands to the serotonin transporter. The flexibility originates from alkyl spacer
of the ligand. For unsubsituted indole ring moieties it is likely the NH group of indole ring
can point towards the interior of binding pocket at the 5-HT receptor. Here the 5-position of
1
A
indole ring is substituted with fluorine atom. It is known that the charge distribution around
fluorine atom is very similar to that of -OH group, present also naturally in serotonine.
Therefore hydrogen bonding is likely to be formed in the smaller binding sub-pocket outlined
by transmembrane helices (TMHs) 1-3 and 7. Thus the 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-
indole (THPI) or 3-(piperidin-4-yl)-1H-indole (HHPI) have high affinity both for 5-HT1A
receptor and SERT. The replacement of fluorine atom with bromine or chlorine diminishes
significantly possible hydrogen bond formation due to electron charge distribution and steric
changes in those derivatives. The phenyl ring in position 4 of the 5,6,7,8-tetrahydro-
pyrido[1,2-c]pyrimidine moiety can be stacked between Phe3.28 and Tyr2.64 residues. This
interaction can be distorted by steric hindrance, e.g. –OCH substituent or twisted phenyl ring
3
due to interaction between negative charge distribution around fluorine atom and loin electron
pairs of –OCH group. Therefore para substituted derivatives are more likely to be bound
3
without additional distortion of yielding higher receptor affinity (8.10, 8.19, 8.27) and (8.12,
8
.20, 8.29).
In the SERT the pyridopyrimidine moiety is placed to putative low affinity binding site [20,
1]. For ligand docked do far close interaction with Asp981.45 in TMH1 was observed.
2
However, the steric hindrance of Ph3556.53 also has to be considered. In addition steric
interaction of pyridopyrimidine and Arg1042.52 in TMH1 can affect the ligand affinity for
SERT moiety. It was established that the presence of the 3-(piperidin-4-yl)-1H-indole residue
or its 5-methoxy and 5-fluoro derivatives as well as the ortho or para substitution with –
8

ACCEPTED MANUSCRIPT
OCH /–CH and -F groups in phenyl ring in position 4 of the 5,6,7,8-tetrahydro-pyrido[1,2-
3
3
c]pyrimidine moiety, are at an advantage with regard to binding affinity. It was also found
that the degree of saturation of the 5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine system has no
influence on the binding activity for both 5-HT receptor and SERT compared to unsaturated
1
A
pyrido[1,2-c]pyrimidine derivatives. The same structural and electronic effects like in 5-HT1A
receptor binding are characteristic for SERT protein binding (see Table 1).
2
.3 ADME studies
ADME (absorption-distribution-metabolism-elimination) studies are now an integral
part of most preclinical projects directed toward obtaining potential drugs possessing not only
high activity against a selected molecular target but also desirable pharmacokinetic properties
[
22, 23].
Drug metabolism is particularly important because biotransformation reactions can cause a
decrease or loss of pharmacological activity [24]. For drugs administrated orally, the first-pass
effect is a phenomenon of drug metabolism whereby the concentration of a drug is greatly
reduced before it reaches the systemic circulation, affecting its efficacy. The liver is the organ
responsible for the majority of drug bioconversion, so high throughput methods to study
metabolic reactions carried out by liver tissue were developed. The microsome assay,
performed in vitro, is a standard procedure in metabolic stability testing because it is
relatively cheap, easy to handle and involves studying biotransformation against the enzymes
most relevant to xenobiotics – cytochromes P450 [25, 26]. In vitro incubation of a potential
drug in the presence of liver microsomes and NADPH coupled to drug determination by LC-
MS techniques ensures sensitive, specific, and reliable results [27, 28].
Metabolic stability
The results of a metabolic stability study in the presence of pooled human liver microsomes
and NADPH are shown in Table 2.
Table 2 Metabolic stability of studied compounds.
ID
.8
Unchanged drug at 60 min
63.36%
HLM t(1/2) [min]
81.97
8
8
8
8
8
.11
.15
.16
.18
50.24%
60.24
60.52%
75.76
67.92%
94.34
64.33%
84.75
9

ACCEPTED MANUSCRIPT
8
8
8
.24
.25
.29
55.65%
63.18%
51.36%
67.57
81.97
61.72
About 50–65% of each compound remained unchanged after 60 min of incubation, which in
comparison to a similar study focused on arylpiperazine derivatives of Tandon et al [29]
seems a satisfactorily high value. These experiments revealed only small differences in
stability between the studied derivatives but some structure-metabolic stability relationships
can still be noted (Fig. 2). The most labile compounds were 8.11 and 8.29, which both contain
hydrogen in the R position and halogens in R and R (Fig. 2).
1
2
3
1
00
94.34
90
80
70
60
50
40
30
20
10
0
84.75
8
1.97
81.97
7
5.76
6
7.57
6
1.72
6
0.24
8
.8
8.11
8.15
8.16
8.18
8.24
8.25
8.29
Studied final compounds
Fig. 2. HLM t/1/2 [min] of studied compounds.
The displacement of halogen by hydrogen in R resulted in greater metabolic stability
2
(derivatives 8.8 and 8.25, respectively). This suggests that the incorporation of chlorine or
fluorine in the R position can activate derivatives to some metabolic reactions. On the other
2
hand, the most stable compound, 8.16, possesses a methoxy- moiety in the R position.
1
Comparing the stability of 8.16 to that of the 8.15 derivative, which contains a methyl
substituent instead of a -OCH group, it could be concluded that –OCH possesses stabilizing
3
3
properties. Nevertheless, stabilizing properties of methoxy moiety are not present in the case
of 8.24, implying a more complex mechanism of metabolic stabilization.
3
. Conclusion
1
0

ACCEPTED MANUSCRIPT
By extending the research within the group of 2H-pyrido[1,2-c]pyrimidine derivatives,
ligands with binary binding to the 5-HT1A receptor and serotonin transporter (SERT), two
series, 8.1-8.7 and 8.8-8.32, have been obtained. The results of receptor binding tests
confirmed that ligands featuring a piperidinyl-indole residue in the pharmacophore element
(8.1-8.7) manifest very high degrees of binding to both molecular targets; compound 8.1 (Ki
5
-HT =12.4 nM, K SERT=15.6 nM) and compound 8.7 (K 5-HT =5.6 nM, K SERT=20.7
1
A
i
i
1A
i
nM). The presence of a tetrahydropyridinyl-indole residue (8.8-8.32) reduces binding to 5-
HT , while Cl substituents in R reduce binding to both 5-HT and SERT. The presence of
1
A
3
1A
F in R , in turn, results in an increased binding to SERT. In vitro tests for metabolic stability
3
in a first-pass test (human liver microsomes, NADPH) run on selected compounds led to the
conclusion that R and R substituents present on the pyrido-pyrimidine element of the
1
2
terminal molecule benefit stability.
4
4
4
. Experimental protocols
.1 Chemistry
.1.1 General remarks
Melting points were determined on an Electrothermal 9100 apparatus with open
capillary tubes and are uncorrected. Infrared spectra were recorded on a Shimadzu FT IR-
1
13
8
4
300 spectrometer. H and C NMR spectra were obtained on a Bruker AVANCE DMX
00WB instrument in CDCl (chemical shifts are reported in δ units). Coupling constants (J)
3
are in hertz (Hz); the internal reference was TMS. The following abbreviations are used to
describe peak patterns when appropriate: s (singlet), bs (broad singlet), d (doublet), dd
(
double doublet), t (triplet), td (triple doublet), ps (pseudotriplet), 4d (quartet of doublets), m
multiplet), * - peak patterns under DMSO. For the two-dimensional experiments, the pulse
(
sequences, acquisition, and processing parameters were taken from the standard Bruker
software library. ESI-HRMS spectra were obtained on a Marimer (PE Biosystems)
instrument.
Flash column chromatography was carried out on Merck Silica gel 60 (230–400 mesh
ASTM) using the solvent methylene chloride/methanol (99:1, 97:3, 95:5, v/v). Thin layer
chromatography was run on Merck Silica gel 60 F254 plates with a mobile phase of dioxane,
toluene, ethanol, and 25% NH OH (6.0:3.2:0.5:0.2, v/v). Compounds were visualized by UV
4
light (254 nm). Room temperature refers to 20–25°C. The purity (>95%) and homogeneity of
the compounds were routinely confirmed by TLC on Merck plates (Kieselgel 60 F254) and
1
H NMR spectra.
1
1

ACCEPTED MANUSCRIPT
4
.1.2 The starting compounds 2a-i, 3a-i, 4a-i, 5a-i were obtained according to procedures
described in [16-18,30,31]
4
.1.3 Procedure for the synthesis of N-benzyl-5-fluoro-3-(piperidin-4-yl)-1H-indole (6a) and
-fluoro-3-(piperidin-4-yl)-1H-indole (6).
5
The starting compound 6 can be obtained by two different methods.
First method: metallic sodium (0.2 mol) was slowly added to methanol (100 ml). The mixture
was stirred under argon at room temperature until all the sodium had reacted. Next, N-benzyl-
4
-piperidone (0.1 mol) and 5-fluoro-1H-indol (0.05 mol) was added and the reaction mixture
was refluxed with stirring for about 24 h. The reaction completion time was determined
chromatographically (TLC). The reaction mixture was cooled and poured into 500 ml of
water with ice. The crude product was collected and crystallized from ethyl acetate to give
º
compound 6a (yield: 65.0 %, m.p.: 162–163 C).
+
HRMS (ESI) calculated for C H FN : 307.1605 (M+H) found 307.1607.
20
20
2
1
H NMR (500 MHz) δ: 2.54 (m, CbH ), 2.73 (t, CeH ), 3.23 (pk, CaH ), 3.67 (s, CH ), 6.09
2
2
2
2
3
4
3
3
4
(
m, CbH), 6.91 (td, J =9.0, J=2.4,C6”H), 7.14 (d, J=2.4, C2”H), 7.23 (dd, J=8.8, J
H-F
H-
3
F=4.6, C7”H), 7.27 (m, C4’H), 7.34 (m, C3’H, C5’H), 7.40 (pd, J=7.6, C2’H, C6’H), 7.50
3
4
(
dd, J =10.2, J=2.4,C4”H), 8.35 (bs, NH).
H-F
1
3
*
C NMR (500 MHz) δ: 29.0 (Cd), 49.9 (Ce), 53.2 (Ca), 62.9 (CH ), 105.8 (d , 2J=24.4, C4”),
2
2
3
4
1
10.5 (d*, J=26.4, C6”), 111.8 (d*, J=9.7, C7”), 118.2 (d*, J=4.4, C3”), 119.3 (C2”), 123.0
3
(
Cb), 125.5 (d*, J=9.7, C3”a), 127.1 (Cc), 128.2 (C2’, C6’), 129.3 (C3’, C5’), 129.5 (C4’),
1
1
33.3 (C7”a), 138.3 (C1’), 158.1 (d*, J=234.4, C5”).
N-benzyl-5-fluoro-3-(piperidin-4-yl)-1H-indole (6a) and 0.6 g 10% Pd/C in 300 ml of
methanol were hydrogenated with debenzylation under 1 atm at 40°C during 8 h. After
filtration of the catalyst and concentration of the filtrate, the crude product was crystallized
from ethyl acetate to give compound 6.
º
The title compound 6 was isolated as a white powder (yield: 66.1%; m.p.: 208–209 C).
Second method: The starting compound 6 was obtained according to previously described
procedures [32].
4
.1.4 Preparation of 5-substitued-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole (7a-c).
The starting compound 7a-c was obtained according to procedures described in
[
12,15,32].
1
2

ACCEPTED MANUSCRIPT
4
.1.5 General procedure for the synthesis of 4-aryl-pyrido[1,2-c]pyrimidine-1,3-dione
derivatives (8.1-32).
Appropriate substrates, i.e. bromobutylpyrido[1,2-c]pyrimidine-derivatives 5a-i
0.0026 mol) and (1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indoles 7a-c (0.0026 mol) or 5-fluoro-
(
3
-(piperidin-4-yl)-1H-indole (6) as well as K CO (0,005 mol), 70 ml of acetonitrile and a
2 3
catalytic amount of KI was stirred and refluxed for 4–5 h. Reaction time was monitored using
TLC. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The
crude residue was purified by crystallization from acetonitrile or by flash chromatography
using a mixture of CH Cl /MeOH (97:3 v/v). Proper fractions were identified by TLC and
2
2
evaporated to dryness to give an analytically pure compound in each case 8.1-32.
.1.5.1 2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-4-phenyl-pyrido[1,2-
4
c]pyrimidine-1,3-dione (8.1)
The title compound was isolated as a yellow powder, crystallization from diethyl ether, yield:
º
6
2.5% m.p. 145 - 147 C
+
HRMS (ESI) calculated for C H FN O : 511.2518 (M+H) found 511.2518.
31
32
4
2
1
x
3
x
H-NMR (500MHz) δ: 1.87 (C3 H , q, J=6.8), 1.98 (C2 H ,q ), 2.09 (CbH , CdH ,pd ),
2
2
ax
ax
x
2
.36 (CbH , CdH , pd), 2.79 (C4 H ,bps), 3.07 ( CaH , CeH , pt), 2.95 (CcH, pt), 3.48
eq eq 2 ax ax
x
3
3
3
4
(
CaH , CeH , bps), 4.21 (C1 H , t, J=6.8), 6.43 (C7H, m, J =7.6, J =6.3, J=1.5), 6.89
eq eq 2 1 2
3
3
4
(
C5H, C6”H, m), 6.94 (C6H, 4d, J =8.3, J =6.3, J=1.2), 7.02 (C2”H, ps), 7.17 (C4”H, dd,
1 2
3
4
3
4
J =9.5, J=2.4), 7.27-7.33 (C2’H, C6’H, C7”H, m), 7.38 (C4’H, tt, J=7.3, J=1.5), 7.44
H-F
3
4
3
4
5
(
C3’H, C5’H, tt, J=7.1, J=1.0), 8.35 ( C8H, dt, J=7.6, J= J=1.0), 8.54 (NH, bs).
1
3
x
x
x
C-NMR (500MHz) δ: 21.1 (C3 ), 24.7 (C2 ), 29.7 (Cb, Cd), 31.3 (Cc), 40.9 (C1 ), 53.2
x
2
2
(
C4 , Ca, Ce), 103.3 (C4”, d* J=23.4), 104.6 (C4), 110.4 (C6”, d*, J=26.3), 111.1 (C7),
3
3
1
12.2, (C7”, d*, J=9.38), 118,2 (C3”), 121.5 (C5), 122.3 (C2”), 126.5 (C3”a, d*, J=9.8),
1
28.0 (C8, C4’), 128.9 (C3’, C5’), 131.3 (C2’, C6’, C7”a), 132.8 (C6), 144.0 (C4a), 148.9
1
1
(
C1), 157.6 (C5”, d*, J=234.4), 157.6 (C5”, d*, J=234.4), 160.5 (C3).
4
.1.5.2 2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-4-(4-methylphenyl)-
pyrido[1,2-c]pyrimidine-1,3-dione (8.2)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol,
º
yield: 73.0% m.p. 180 - 181 C
+
HRMS (ESI) calculated for C H FN O : 525.2660 (M+H) found 525.2650.
32
34
4
2
1
3

ACCEPTED MANUSCRIPT
1
x
x
HNMR (500 MHz) δ: 1.70 (C3 H ,q), 1.80 (C2 H q), 1.90 ( CbH , CdH ,pt),
2
2 ,
ax
ax
x
3
2
.03 (CbH , CdH ,pd), 2.23 (CaH ,CeH ,pt), 2.39 (C3H, s), 2.56 (C4 H ,t, J=7.6), 2.79
eq
eq
ax
ax
2
x
3
(
CcH, tt), 3.14 (CaH ,CeH ,pd), 4.20 (C1 H ,t, J=7.3), 6.37 (C7H, m), 6.90 (C5H, C6H,
eq eq 2
3
3
C4”H, m), 7.00 (C2”H, d, J=2.0), 7.20 (C3’H, C5’H, d, J=8.0), 7.25 (C6”H, C7”H, m), 8.07
3
(
NH, bs), 8.32 (C8H, d, J=7.6)
1
3
x
x
C-NMR (500 MHz) δ: 21.3 (CH3), 23.9 (C3 ), 25.4 (C2 ), 32.3 (Cb, Cd), 33.1
x
x
2
(
Cc), 42.2 (C1 ), 54.2 (Ca, Ce), 58.4 (C4 ), 103.9 (C4”, d*, J=23.4), 104.9 (C4), 110.3 (C6”,
2
3
d*, J=26.4), 110.6 (C7), 111.8 (C7”a, d*, J=9.7), 121.2 (C3”), 121.6 (C5), 121.6 (C2”),
3
1
27.0 (C3”a, d*, J=8.0), 127.9 (C8), 129.5 (C3’, C5’), 129.7 (C1’), 131.0 (C2’, C6’), 132.2
1
(
C6), 132.8 (C7”a), 137.6 (C4’), 143.5 (C4a), 149.0 (C1), 157.5 (C5”, d*, J=234.4), 160.35
C1);
(
4
.1.5.3
2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-4-(4-chlorophenyl)-
pyrido[1,2-c]pyrimidine-1,3-dione (8.3)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol,
º
yield: 66.0 % m.p. 160 - 162 C
+
HRMS (ESI) calculated for C H FClN O : 545.2114 (M+H) found 545.2135.
31
31
4
2
1
x
x
HNMR (500 MHz) δ: 1.75 (C3 H , q), 1.82 (C2 H , q), 1.97 (CbH , CdH , pt),
2
2
ax
ax
x
3
2
.06 (CbH , CdH , pd), 2.31 (CaH , CeH pt), 2.63 (C4 H , t, J=7.5), 2.83 (
eq eq ax ax , 2
3
3
x
3
CcH, tt, J =12.0, J
=3.5), 3.20 (CaH , CeH , pd), 4.20 (C1 H , t, J=6.5), 6.43 (C7H,
ex ex 2
ax-ax
ax-eq
3
3
4
3
4
5
3
m, J =7.5, J =6.5, J=1.2), 6.88 (C5H, dt, J=9.5, J= J=1.0), 6.93 (C6”H, td, J =9.0,
1
2
H-F
4
3
3
4
3
J=2.5), 6.96 (C6H, dt, J =9.5, J =6.0, J=1.0), 7.02 (C2”H, d, J=2.0), 7.23-7.30 (C4”H,
1
2
3
4
3
C7”H, m), 7.42 (C2’H, C6’H, dt, J=9.0, J=2.0), 8.12 (NH, bs), 8.36 (C8H, dt, J=7.5,
4
5
J= J=1.0)
4
.1.5.4
2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-4-(4-fluorophenyl)-
pyrido[1,2-c]pyrimidine-1,3-dione (8.4)
The title compound was isolated as a yellow powder, crystallization from diethyl ether, yield:
º
7
5,0% m.p. 106-107 C
+
HRMS (ESI) calculated for C H F N O : 529,2410 (M+H) found 529,2427.
31
31
2
4
2
1
x
HNMR (500 MHz) : 1.64 (C3 H , m), 1.79 (CdH , m), 2.01 (CbH , CdH , pd),
2
ax
eq
eq
1
4

ACCEPTED MANUSCRIPT
x
3
3
3
2
.10 (CaH , CeH , td), 2.43 (C4 H , t, J=7.8,), 2.75 (CcH, tt, J =12.1, Jax-eq=3.4,), 3.05
ax
ax
2
ax-ax
x
3
3
3
4
(
CaH , CeH , pb), 4.19 (C1 H , t, J=7.6), 6.39 (C7H, m, J =7.6, J =6.3, J=1.5), 6.86 (C-
ex
ex
2
1
2
3
4
5
3
5
H, dt, J=9.0, J= J=1.0), 6.92 (C-6H, C-6”H, m), 6.99 (C2”H, d, J=2.4), 7.13 (C3’H, C5’H,
3
4
5
m), 7.22-7.32 (C4”H, C7”H, m), 7.96 (NH, bs), 8.34 (C8H, dt, J=7.3, J= J=1.0)
1
3
x
x
x
CNMR (500 MHz) δ: 24.6 (C3 ), 25.7 (C2 ), 32.9 (Cb, Cd), 33.5 (Cc), 42.6 (C1 ), 54.4 (Ca,
x
2
2
Ce), 58.8 (C4 ), 103.8 (C4), 104.0 (C4”, d*, J=23.4), 110.2 (C6”, d*, J=25.9), 110.7 (C7),
3
2
1
11.7 (C7’’, d*, J=9.7), 115.8 (C3’, C5’, d*, J=21.5), 121.2 (C5), 121.5 (C2”), 121.9 (C3”),
3
4
1
27.1 (C3”a, d*, J=9.8), 128.1 (C8), 128.7 (C1’, d*, J=3.4), 132.9 (C7”a), 133.0 (C2’, C6’,
3
1
d*, J=7.8), 143.7 (C4a), 148.9 (C1), 157.6 (C-5”, d*, J=234.4), 160.2 (C3), 162.3 (C4’, d*,
1
J=247.1)
4
.1.5.5
2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-4-(2-fluorophenyl)-
pyrido[1,2-c]pyrimidine-1,3-dione (8.5)
The title compound was isolated as a yellow powder, crystallization from diethyl ether, yield:
º
5
6.0% m.p. 112 - 113 C
+
HRMS (ESI) calculated for C H F N O : 529.2410 (M+H) found 529.2402.
31
31
2
4
2
1
x
x
H NMR (500 MHz) δ: 1.70 (C3 H , q), 1.81 (C2 H , m), 1.89 ( CaH , CeH , pt ),
2
2
ax
ax
x
3
3
2
.03 (CbH , CdH , pd ), 2.21 (CaH , pt) 2.43 (C4 H , t, J=7.8), 2.75 (CcH, tt, Jax-ax=12.1,
eq eq ax 2
3
x
3
3
Jax-eq=3.4,), 3.05 (CaHex, CeHex, pb), 4.19 (C1 H , t, J=7.6), 6.39 (C7H, m, J =7.6,
2
1
3
3
3
4
3
4
5
J =6.3, J=1.5), 6.86 (C5H, dt, J=9.0, J= J=1.0), 6.92 (C6H, C6”H, m), 6.99 (C2”H, d,
2
J=2.4), 7.13 (C3’H, C5’H, m), 7.22-7.32 (C4”H, C7”H, m), 7.96 (NH, bs), 8.34 (C8H, dt,
4
5
J=7.3, J= J=1.0)
1
3
x
x
x
C NMR (500 MHz) δ: 24.6 (C3 ), 25.7 (C2 ), 32.9 (Cb, Cd), 33.5 (Cc), 42.6 (C1 ), 54.4
x
2
2
(
(
(
(
(
Ca, Ce), 58.8 (C4 ), 103.8 (C4), 104.0 (C4”, d*, J=23.4), 110.2 (C6”, d*, J=25.9), 110.7
3
2
C7), 111.7 (C7’’, d*, J=9.7), 115.8 (C3’, C5’, d*, J=21.5), 121.2 (C5), 121.5 (C2”), 121.9
3
4
C3”), 127.1 (C3”a, d*, J=9.8), 128.1 (C8), 128.7 (C1’, d*, J=3.4), 132.9 (C7”a), 133.0
3
1
C2’, C6’, d*, J=7.8), 143.7 (C4a), 148.9 (C1), 157.6 (C5”, d*, J=234.4), 160.2 (C3), 162.3
1
C4’, d*, J=247.1)
4
.1.5.6
2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-4-(2-chlorophenyl)-
pyrido[1,2-c]pyrimidine-1,3-dione (8.6)
1
5

ACCEPTED MANUSCRIPT
The title compound was isolated as a yellow powder, crystallization from ethanol, yield:
º
6
2.0% m.p. 140.2 – 143.6 C
+
HRMS (ESI) calculated for C H FClN O : 545.2114 (M+H) found 545.2135.
31
31
4
2
1
x
x
HNMR (500MHz) δ: 1.85 (C3 H , q), 1.88 (C2 H , q), 2.09 (CbH , CdH , bps),
2
2
ax
ax
x
2
.17 (CbH , CdH , pt), 2.55 (C4 H , t), 2.89 (CaH , CeH , CcH, m), 3.34 (CaH , CeH ,
eq eq 2 ax ax eq eq
x
3
3
4
bps), 4.22 (C1 H , m), 5.52 (C3’H, m), 6.46 (C7H, m, J =7.3, J =6.1, J=1.5), 6.56 (C5H, dt,
2
1
2
3
4
5
3
4
3
3
4
J=9.3, J= J=1.0), 6.92 (C6”H, td, J=9.0, J=2.4), 7.00 (C6H, 4d, J =9.5, J =6.3, J=1.2),
1
2
3
3
4
7
.03 (C2”H, d, J=2.2), 7.20 (C4”H, dd, J =9.8, J=2.5), 7.24-7.40 (C6’H, C7”H, m), 8.22
H-F
3
4
5
(
NH, bs), 8.39 (C8H, dt, J=7.6, J= J=1.0)
1
3
x
x
C NMR (500MHz) δ: 22.0 (C3 ), 25.0 (C2 ), 30.8 (Cb, Cd), 32.1 (Cc), 36.7 and 53,4
x
x
2
(
Ca, Ce), 41.2 (C1 ), 57.5 (C4 ), 102,0 (C4), 103.6 (C4”, d*, J=23.4), 110.4, (C6”, d*,
2
3
J=26.3), 111.1 (C7), 112.0 (C7”, d*, J=9.8), 119.6 (C3”), 121.1 (C5), 122.0 (C2”), 126.7
3
(
C3”a, d*, J=9.8), 127.5 (C5’), 128.2 (C8), 129.9 (C4’), 130.1 (C3’), 131.8 (C7”a), 132.8
1
(
C1’), 133.5 (C6, C6’), 135.8 (C2’), 144.2 (C4a), 148.9 (C1), 157.7 (C5”, d*, J=234.9),
1
59.8 (C3).
4
.1.5.7
2-{4-[4-(5-fluoro-1H-indol-3-yl)-piperidin-1-yl]-butyl}-4-(2-methoxyphenyl)-
pyrido[1,2-c]pyrimidine-1,3-dione (8.7)
The title compound was isolated as a yellow powder, crystallization from diethyl ether, yield:
º
6
9.5 % m.p. 123 - 126 C
+
HRMS (ESI) calculated for C H FN O : 541.2610 (M+H) found 541.2631.
32
34
4
3
1
x
x
H NMR (500MHz) δ: 1.69 (C3 H , q), 1.80 (C2 H , q), 1.88 (CbH , CdH , pt), 2.02
2
2
ax
ax
x
3
3
(
CbH , CdH , pd), 2.19 (C4 H , t), 2.53 (CaH , CeH , pt), 2.77 (CcH, tt, J =12.0, J
eq eq 2 ax ax ax-ax ax-
x
3
eq=3.4), 3.11 (CaH , CeH , pd), 3.76 (OCH , s), 4.20 (C1 H , t, J=7.6), 6.36 (C7H, m,
eq
eq
3
2
3
4
4
3
3
4
3
4
5
3
3
J =7.6, J =6.3, J=1.5), 6.63 (C5H, dt, J=9.5, J= J=1.0), 6.87 (C6H, 4d, J =9.5, J =6.3,
1
2
1
2
3
4
3
J=1.2), 6.92 (C6”H, td, J =9.0, J=2.4), 7.00 (C3’H, C2”H, m), 7.04 (C5’H, td, J=7.3,
H-F
3
4
J=1.0), 7.21 (C4”H, dd, J =7.6, J=1.7), 7.23-7.28 (C3’H, C2”H, m), 7.37 (C4’H, 4d,
H-F
3
4
3
4
5
J =8.3, J =7.6, J=1.7), 8.03 (NH, bs), 8.32 (C8H, dt, J=7.3, J= J=1.2).
1
2
1
3
x
x
x
C NMR (500MHz) δ: 24.0 (C3 ), 25.5 (C2 ), 32.5 (Cb, Cd), 33.2 (Cc), 42.2 (C1 ), 54.2 (Ca,
x
2
2
Ce), 55.6 (OCH ), 58.5 (C4 ), 101.3 (C4), 103.9 (C4”, d*, J=23.5), 110.3 (C6”, d*, J=26.3),
3
1
6

ACCEPTED MANUSCRIPT
3
1
10.5 (C7), 111.4 (C3’), 111.7 (C7”, d*, J=9.3), 119.0 (C3”), 121.0 (C5’), 121.5 (C1’), 121.6
3
(
(
(
C2”), 122.0 (C5), 127.0 (C3”a, d*, J=9.2), 127.9 (C8), 129.7 (C4’), 131.9 (C7”a), 132.8
1
C6), 133.0 (C6’), 143.7 (C4a), 149.2 (C1), 157.6 (C5”, d*, J=234.4), 157.9 (C2’), 160.0
C3).
4
.1.5.8
2-{4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-
phenyl-pyrido[1,2-c]pyrimidine-1,3-dione (8.8)
The title compound was isolated as a yellow powder, crystallization from diethyl ether, yield:
º
5
0.67 % m.p. 118-119 C
+
HRMS (ESI) calculated for C H O N F: 509.2353 (M+H) found 509.2363.
31
30
2
4
1
3
H NMR ( CDCl ,500 MHz) : 6.85-6.94 (C5H,C6H,C6``H, m), 6.39 (C7H, m,
3
3
4
3
3
4
J =7.5, J =6.0, J=2.0), 8.33 (C8H, d, J=7.5), 7.31 (C2`H,C6`H, dt, J=7.0, J=1.0), 7.39-7.48
1
2
3
x
3
x
(
C3`H,C5`H,C4``H, m), 7.35 (C4`H, tt, J=7.0), 4.21 (C1 H , t, J=7.0), 1.83 (C2 H , q,
2 2
3
x
3
x
3
J=7.5), 1.76 (C3 H , q, J=7.5), 2.69 (C4 H , t, J=7.5), 3.30 (CaH , bs), 5.95 (CbH, bs),
2
2
2
3
3
3
4
2
=
.
.52 (CdH , bs), 2.81 (CeH , t, J=5.5), 7.05 (C2``H, d, J=2.0), 7.26 (C7``H, dd, J=8.5, J
2
2
H-F
4.5), 9.05 (NH, bs)
1
3
C NMR (CDCl , 125MHz ) : 149.2 (C1), 160.6 (C3), 105.0 (C4), 144.0 (C4a), 121.7 (C5),
3
1
32.8 (C6), 111.1 (C7), 128.1 (C8), 133.0 (C1’), 131.5 (C2’, C6’), 129.0 (C3’, C5’), 128.2
x
x
x
x
(
C4’), 42.3 (C1 ), 25.5 (C2 ), 23.8 (C3 ), 57.6 (C4 ), 52.5 (Ca), 116.6 (Cb), 130.0 (Cc), 29.9
3
(
Cd), 50.2 (Ce), 123.9 (C2”), 117.1 (C3”, d* ), 125.4 (C3”a, d*, J=9.8 ), 105.7 (C4”, d*,
2
1
2
3
J=24.4 ), 158.3 (C5”, d*, J=233.9 ), 110.6 (C6”, d*, J=25.9 ), 112.4 (C7”, d*, J=9.3),
1
33.6 (C7”a)
4
.1.5.9
2-{4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(4-
methylphenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.9)
The title compound was isolated as a yellow powder, crystallization from diethyl ether, yield:
º
6
9.8 % m.p. 115-116 C
+
HRMS (ESI) calculated for C H O N F: 523.2509 (M+H) found 523.2495.
32
32
2
4
1
3
3
H NMR ( CDCl ,500 MHz) : 6.84-6.92 (C5H,C6H,C6``H, m), 6.36 (C7H, m,
3
3
4
3
J =7.5, J =5.5, J=2.0), 8.31 (C8H, d, J=7.5), 7.23 (C2`H,C6`H,C7”H), 7.18 (C3`H,C5`H , d,
1
2
x
3
x
3
x
3
J=8.5), 4.21 (C1 H , t, J=7.0), 1.82 (C2 H , q, J=7.5), 1.73 (C3 H , q, J=7.0), 2.63
2
2
2
1
7

ACCEPTED MANUSCRIPT
x
3
3
(
7
.
C4 H , t, J=7.5), 3.26 (CaH , bs), 5.99 (CbH, bs), 2.45 (CdH , bs), 2.75 (CeH , t, J=5.5),
2
2
2
2
3
4
.04 (C2``H, s), 7.43 (C4``H, dd, J =10.5, J=2.0), 2.36 (CH , s ), 9.06 (NH, bs)
H-F
3
1
3
C NMR (CDCl , 125MHz ) : 148.9 (C1), 160.4 (C3), 104.8 (C4), 143.6 (C4a), 121.6 (C5),
3
1
32.3 (C6), 110.7 (C7), 127.9 (C8), 131.0 (C1’), 129.5 (C2’, C6’), 129.7 (C3’, C5’), 137.6
x
x
x
x
(
C4’), 42.2 (C1 ), 25.3 (C2 ), 23.9 (C3 ), 57.6 (C4 ), 52.6 (Ca), 117.1 (Cb, C3”), 129.7 (Cc),
3
2
2
9.7 (Cd), 50.0 (Ce), 123.5 (C2”), 125.2 (C3”a, d*, J=9.8 ), 105.5 (C4”, d*, J=23.9 ), 158.0
1
2
3
(
C5”, d*, J=233.9 ), 110.2 (C6”, d*, J=26.3 ), 112.0 (C7”, d*, J=10.3), 133.4 (C7”a), 21.3
CH3)
(
4
.1.5.10
2-{4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(4-
methoxyphenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.10)
The title compound was isolated as a yellow powder, crystallization from diethyl ether, yield:
º
6
7.4 % m.p. 111 - 112 C
+
HRMS (ESI) calculated for C H O N FNa: 561.2278 (M+Na) found 561.2270.
32
31
3
4
1
H NMR (see supplementary materials) ( CDCl ,500 MHz) : 6.85-6.91 (C5H,C6H,C6``H,
3
3
3
4
3
m), 6.36 (C7H, m, J =7.5, J =5.0, J=2.5), 8.31 (C8H, d, J=7.5), 7.21 (C2`H,C6`H, dt,
1
2
3
4
3
4
x
3
x
J=8.5, J=2.0), 6.95 (C3`H,C5`H , dt, J=8.5, J=2.0), 4.21 (C1 H , t, J=7.5), 1.82 (C2 H ,
2
2
3
x
3
x
3
q, J=7.5), 1.71 (C3 H , q, J=7.5), 2.60 (C4 H , t, J=7.5), 3.23 (CaH , bs), 6.01 (CbH, bs),
2
2
2
3
3
3
2
.49 (CdH , bs), 2.73 (CeH , t, J=5.5), 7.06 (C2``H, d, J=2.0), 7.45 (C4``H, dd, J =10.5,
2 2 H-F
4
3
4
J=2.5), 7.24 (C7``H, dd, J =8.5, J =4.5), 3.81 (OCH , s ), 8.98 (NH, bs)
H-F
3
1
3
C NMR (see supplementary materials) (CDCl , 125MHz ) : 148.9 (C1), 160.5 (C3), 104.5
3
(C4), 143.6 (C4a), 121.6 (C5), 132.2 (C6), 110.7 (C7), 127.9 (C8), 124.8 (C1’), 132.4 (C2’,
x
x
x
x
C6’), 114.3 (C3’, C5’), 159.2 (C4’), 42.3 (C1 ), 25.5 (C2 ), 24.2 (C3 ), 57.7 (C4 ), 52.7 (Ca),
1
17.7 (Cb), 129.7 (Cc), 28.3 (Cd), 50.1 (Ce), 123.5 (C2”), 117.4 (C3”, d*) 125.3 (C3”a, d*,
3
2
1
2
J=9.8 ), 105.5 (C4”, d*, J=24.4 ), 158.0 (C5”, d*, J=233.9 ), 110.2 (C6”, d*, J=26.3 ),
3
1
12.0 (C7”, d*, J=9.3), 133.4 (C7”a), 55.3 (OCH )
3
4
.1.5.11
2-{4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(4-
chlorophenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.11)
The title compound was isolated as a yellow powder, crystallization from diethyl ether, yield:
º
7
1.4 % m.p. 124 - 125 C
1
8

ACCEPTED MANUSCRIPT
+
HRMS (ESI) calculated for C H O N FCl: 543.1963 (M+H) found 543.1964.
31
29
2
4
1
3
3
3
4
H NMR ( CDCl ,500 MHz) : 6.85 (C5H, d, J=10.0), 6.94 (C6H, 4d, J =9.5, J =6.0, J=1.0),
3
1
2
3
3
4
3
3
6
.40 (C7H, m, J =7.5, J =6.0, J=1.5), 8.34 (C8H, d, J=7.5), 7.39 (C2`H,C6`H, dt, J=8.5,
1 2
4
x
3
x
3
J=2.0), 7.22-7.28 (C3`H,C5`H,C7``H, m), 4.20 (C1 H ,t, J=7.5), 1.82 (C2 H , q, J=7.5),
2
2
x
3
x
3
3
1
.72 (C3 H ,q , J=7.5), 2.61 (C4 H ,t, J=7.5), 3.25 (CaH , d, J=0.5), 6.02 (CbH, bs), 2.51
2 2 2
3
3
3
(
CdH , bs), 2.75 (CeH ,t, J=4.5), 7.08 (C2``H, d, J=1.5), 7.45 (C4``H, dd, J =10.5,
2 2 H-F
4
3
4
J=2.0), 6.89 (C6``H, td, J=9.0, J=2.5), 8.86 (NH, bs)
1
3
C NMR (CDCl , 125MHz ) : 148.8 (C1), 160.0 (C3), 103.5 (C4), 143.7 (C4a), 121.0 (C5),
3
1
33.0 (C6), 110.9 (C7), 128.1 (C8), 131.3 (C1’), 129.0 (C2’, C6’), 132.7 (C3’, C5’), 133.7
x
x
x
x
(
C4’), 42.3 (C1 ), 25.4 (C2 ), 24.1 (C3 ), 57.7 (C4 ), 52.7 (Ca), 117.7 (Cb), 129.7 (Cd), 50.1
3
2
(
Ce), 123.4 (C2”), 117.4 (C3”, d*) 125.3 (C3”a, d*, J=9.8 ), 105.6 (C4”, d*, J=23.9 ), 158.1
1
2
3
(
C5”, d*, J=234.4 ), 110.3 (C6”, d*, J=26.3 ), 112.0 (C7”, d*, J=9.7), 112.0 (C7``, d*,
3
J=9.7), 133.3 (C7”a)
4
.1.5.12
2-{4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(4-
fluorophenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.12)
The title compound was isolated as a yellow powder, crystallization from diethyl ether, yield:
º
6
1.6 % m.p. 115 - 116 C
+
HRMS (ESI) calculated for C H O N F : 527.2258 (M+H) found 527.2245.
31
29
2
4 2
1
3
3
3
H NMR ( CDCl ,500 MHz) : 6.84 (C5H, d, J=9.5), 6.92 (C6H, td, J=9.0), 6.39 (C7H, t,
3
3
J=6.5), 8.33 (C8H, d, J=7.5), 7.27 (C2`H,C6`H,C7``H, m), 7.12 (C3`H,C5`H, m), 4.20
x
3
x
3
x
3
x
3
(
C1 H ,t, J=7.5), 1.83 (C2 H , q, J=7.5), 1.72 (C3 H ,q , J=7.5), 2.60 (C4 H ,t, J=7.5),
2 2 2 2
3
3
.24 (CaH , bs), 6.02 (CbH, bs), 2.51 (CdH , bs), 2.75 (CeH ,t, J=5.5), 7.10 (C2``H, d,
2 2 2
3
3
3
4
J=2.0), 7.45 (C4``H, d, J =10.0), 6.89 (C6``H, td, J=9.0, J=2.5), 8.84 (NH, bs)
H-F
1
3
C NMR (CDCl , 125MHz ) : 148.9 (C1), 160.2 (C3), 103.7 (C4), 143.8 (C4a), 121.1 (C5),
3
4
3
1
33.8 (C6), 110.8 (C7), 128.1 (C8), 128.6 (C1’, d*, J=3.4), 133.0 (C2’, C6’, d*, J=7.8), 115.8
2
1
x
x
x
(
C3’, C5’, d*, J=21.5), 162.3 (C4’, d*, J=247.0), 42.4 (C1 ), 25.4 (C2 ), 24.2 (C3 ), 57.8
x
(
C4 ), 52.8 (Ca), 117.9 (Cb), 129.6 (Cc), 29.7 (Cd), 50.1 (Ce), 123.3 (C2”), 117.5 (C3”, d*)
3
2
1
1
25.3 (C3”a, d*, J=9.7 ), 105.6 (C4”, d*, J=24.4), 158.0 (C5”, d*, J=234.0 ), 110.3 (C6”,
2
3
3
d*, J=26.4 ), 112.0 (C7”, d*, J=9.8), 112.0 (C7``, d*, J=9.8), 133.3 (C7”a)
1
9

ACCEPTED MANUSCRIPT
4
.1.5.13
2-{4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(2-
fluorophenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.13)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 45.8 % m.p. 122 - 124 C
+
HRMS (ESI) calculated for C H F N O : 527.2244 (M+H) found 527.2258.
31
30
2
4
2
1
3
3
3
H NMR ( CDCl ,500 MHz) : 6.73 (C5H, d, J=9.0 ), 6.97 (C6H, 4d, J =9.5, J =6.0 ), 6.42
3
1
2
3
3
3
3
4
(
C7H, m, J =7.0, J =6.5 ), 8.36 (C8H, dt, J=7.5 ), 7.16 (C3’H, J=9.0, J=1.0 ), 7.37 (C4’H,
1
2
3
4
3
4
x
3
m ), 7.22 (C5’H, td, J=7.5, J=1.5 ), 7.32 (C6’H, td, J=7.5, J=2.0 ), 4.22 (C1 H , t, J=7.5 ),
2
x
3
x
3
x
3
1
.83 (C2 H , q, J=7.5 ), 1.72 (C3 H , q, J=7.5 ), 2.60 (C4 H , t, J=7.5 ), 3.24 (CaH , bs ),
2 2 2
3
3
6
.03 (CbH, bs ), 2.53 (CdH , bs ), 2.74 (CeH , t, J=5.5 ), 7.13 (C2”H, d, J=2.0 ), 7.46
2
2
3
4
3
4
3
4
(
C4”H, dd, J =10.0, J=2.5 ), 6.90 (C6”H, td, J=9.0, J=2.5), 7.26 (C7”H, dd, J=9.0, J
H-F
H-
F=4.5), 8.91 (NH, bs )
1
3
C NMR (CDCl , 125MHz ) : 149.1 (C1), 159.8 (C3), 98.5 (C4), 144.3 (C4a), 121.7 (C5),
3
1
33.3 (C6), 111.0 (C7), 128.3 (C8), 120.5 (C1’, d* ), 161.1 (C2’, d* ), 116.2 (C3’, d* ), 130.3
x
x
x
x
(
C4’, d* ), 124.6 (C5’, d* ), 133.6 (C6’, d* ), 42.5 (C1 ), 25.6 (C2 ), 24.3 (C3 ), 57.9 (C4 ),
2.9 (Ca), ∼ 118.3 (Cb), 129.8 (Cc), 28.7 (Cd), 50.3 (Ce), 123.4 (C2”), 117.8 (C3”, d* ), 125.5
5
(
C3”a, d* ), 105.8 (C4”, d* ), 158.2 (C5”, d* ), 110.5 (C6”, d* ), 112.1 (C7”, d* ), 133.5
C7”a)
(
4
.1.5.14
2-{4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(2-
chlorophenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.14)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 65.0 % m.p. 119 – 120 C
+
HRMS (ESI) calculated for C H FClN O : 543.1963 (M+H) found 543.1959.
31
29
4
2
1
3
3
4
5
3
H NMR ( CDCl ,500 MHz) : 6.54 (C5H, dt, J=9.5, J= J=1.0 ), 6.96 (C6H, 4dt, J =9.5,
3
1
3
3
3
4
5
J =7.0 ), 6.43 (C7H, m, J =9.5, J =7.0 ), 8.37 (C8H, dt, J=7.5, J= J=1.0 ), 7.49 (C3’H, m
2
1
2
x
3
x
3
)
, 7.24-7.34 (C4’H, C5’H, C6’H, m), 4.22 (C1 H , t, J=7.0 ), 1.84 (C2 H , q, J=7.0 ), 1.72
2 2
x
3
x
3
3
(
C3 H , t, J=7.0 ), 2.61 (C4 H , t, J=7.5 ), 3.24 (CaH , d, J=2.0 ), 6.01 (CbH, t ), 2.51
2
2
3
3
3
(
CdH , bs ), 2.74 (CeH , t, J=6.0 ), 7.09 (C2”H, d, J=2.0 ), 7.44 (C4”H, dd, J =10.0,
2
2
H-F
4
3
4
3
4
J=2.5 ), 6.88 (C6”H, td, J=9.0, J=2.5), 7.25 (C7”H, dd, J=9.0, J =4.5), 8.96 (NH, bs )
H-F
2
0

ACCEPTED MANUSCRIPT
1
3
C NMR (CDCl , 125MHz ) : 149.2 (C1), 159.8 (C3), 102.4 (C4), 144.2 (C4a), 121.3 (C5),
3
1
33.6 (C6), 111.2 (C7), 128.4 (C8), 132.0 (C1’), 136.0 (C2’), 130.2 (C3’), 130.0 (C4’), 127.6
x
x
x
x
(
C5’), 133.5 (C6’), 42.5 (C1 ), 25.7 (C2 ), 24.2 (C3 ), 57.9 (C4 ), 52.9 (Ca), 117.9 (Cb),
29.9 (Cc), 28.6 (Cd), 50.3 (Ce), 123.7 (C2”), 117.6 (C3”, d* ), 125.5 (C3”a, d* ), 105.3
C4”), 158.3 (C5”, d* ), 110.5 (C6”, d* ), 112.3 (C7”, d* ), 133.6 (C7”a)
1
(
4
.1.5.15
2-{4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(2-
methylphenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.15)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 63.4 % m.p. 116 - 118 C
+
HRMS (ESI) calculated for C H FN O : 523.2517 (M+H) found 523.2509.
32
33
4
2
1
3
4
5
H NMR ( CDCl ,500 MHz) : 6.54 (C5H, dt, J=9.0, J= J=1.0 ), 6.88 (C6H, C6”H, m ), 6.38
3
3
3
3
4
5
3
4
(
)
(
)
(
C7H, m, J =7.5, J =6.0 ), 8.33 (C8H, dt, J=7.0, J= J=1.0 ), 7.12 (C3’H, dd, J=7.0, J=1.5
1 2
x
3
x
3
, 7.24-7.33 (C4’H, C5’H, C6’H, m), 4.23 (C1 H , t, J=7.0 ), 1.84 (C2 H , q, J=7.5 ), 1.71
2
2
x
x
3
3
C3 H , m ), 2.59 (C4 H , t, J=7.5 ), 3.22 (CaH , d, J=2.5 ), 6.02 (CbH, bs ), 2.47 (CdH , bs
2
2
2
3
3
3
4
, 2.71 (CeH , t, J=5.5 ), 7.03 (C2”H, d, J=2.5 ), 7.46 (C4”H, dd, J =10.5, J=2.5 ), 7.22
2
H-F
3
4
C7”H, dd, J=8.5, J =5.0), 2.14 (CH , s ), 8.96 (NH, bs )
H-F
3
1
3
C NMR (CDCl , 125MHz ) : 149.2 (C1), 159.9 (C3), 104.1 (C4), 143.7 (C4a), 121.5 (C5),
3
1
32.7 (C6), 110.8 (C7), 128.5 (C8), 132.2 (C1’), 138.6 (C2’), 131.7 (C3’), 128.1 (C4’), 126.5
x
x
x
x
(
C5’), 130.7 (C6’), 42.4 (C1 ), 25.6 (C2 ), 24.3 (C3 ), 57.9 (C4 ), 53.0 (Ca), 118.1 (Cb),
29.8 (Cc), 28.6 (Cd), 50.2 (Ce), 123.6 (C2”), 117.5 (C3”, d* ), 125.4 (C3”a, d* ), 105.7
C4”), 158.2 (C5”, d* ), 110.3 (C6”, d* ), 112.1 (C7”, d* ), 133.5 (C7”a), 19.7 (CH3)
1
(
4
.1.5.16
2-{4-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(2-
methoxyphenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.16)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 52.4 % m.p. 120 - 122 C
+
HRMS (ESI) calculated for C H FN O : 539.2457 (M+H) found 539.2458.
32
33
4
3
1
3
4
5
H NMR ( CDCl ,500 MHz) : 6.62 (C5H, dt, J=9.5, J= J=1.0 ), 6.87 (C6H, C6”H, m ), 6.37
3
3
3
3
4
5
3
(
C7H, m, J =7.5, J =6.6 ), 8.32 (C8H, dt, J=7.5, J= J=1.0 ), 6.96 (C3’H, d, J=8.5 ), 7.35
1 2
2
1

ACCEPTED MANUSCRIPT
3
3
3
4
3
4
(
C4’H, 4d, J =8.5, J =7.5 ), 7.02 (C5’H, td, J=7.5, J=1.0 ), 7.20 (C6’H, dd, J=7.5, J=2.0
1 2
x
x
3
x
3
x
3
)
, 4.21 (C1 H , m ), 1.83 (C2 H , q, J=7.5 ), 1.73 (C3 H , q, J=7.5 ), 2.63 (C4 H , t, J=7.5
2
2
2
3
)
, 3.26 (CaH , bs ), 5.98 (CbH, bs ), 2.49 (CdH , bs ), 2.75 (CeH , t, J=5.0 ), 7.04 (C2”H, d,
2 2 2
3
3
4
3
4
J=1.0 ), 7.43 (C4”H, dd, J =10.0, J=2.0 ), 7.24 (C7”H, dd, J=8.5, J =5.0), 3.72 (OCH ,
H-F
H-F
3
s ), 9.14 (NH, bs )
1
3
C NMR (CDCl , 125MHz ) : 149.3 (C1), 160.2 (C3), 101.3 (C4), 143.9 (C4a), 122.1 (C5),
3
1
33.1 (C6), 110.8 (C7), 128.0 (C8), 121.5 (C1’), 158.1 (C2’), 111.6 (C3’), 129.9 (C4’), 121.1
x
x
x
x
(
C5’), 132.3 (C6’), 42.3 (C1 ), 25.5 (C2 ), 24.0 (C3 ), 57.7 (C4 ), 52.7 (Ca), 117.2 (Cb),
1
1
29.9 (Cc), 28.2 (Cd), 50.1 (Ce), 123.8 (C2”), (C3”), 125.4 (C3”a, d* ), 105.6 (C4”, d* ),
58.2 (C5”, d* ), 110.4 (C6”, d* ), 112.3 (C7”, d* ), 133.6 (C7”a), 55.8 (OCH3)
4
.1.5.17
2-{4-[4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-
phenyl-pyrido[1,2-c]pyrimidine-1,3-dione (8.17)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 53.3 % m.p. 164 - 166 C
+
HRMS (ESI) calculated for C H ClN O : 525.2057 (M+H) found 525.2063.
31
30
4
2
1
4
3
3
H NMR (see supplementary materials) ( DMSO ,500 MHz) : 7.76 (C5H, dt, J=9.5,
5
3
3
4
J= J=1.0 ), 7.11 (C6H, C6”H, m ), 6.55 (C7H, m, J =7.5, J =5.5, J=1.5 ), 8.29 (C8H, dt,
1
2
4
5
3
4
J=7.5, J= J=1.0 ), 7.28 (C2’, C6’H, dt, J=7.0, J=1.5 ), 7.44 (C3’H, C5’H, C2”H, m ), 7.36
3
4
x
3
x
3
x
(
C4’H, tt, J=7.5, J=1.5 ), 4.03 (C1 H , t, J=7.0 ), 1.63 (C2 H , q, J=7.0 ), 1.54 (C3 H , q,
2 2 2
3
x
3
3
J=7.0 ), 2.41 (C4 H , t, J=7.0 ), 3.08 (CaH , d, J=3.0 ), 6.06 (CbH, t ), 2.47 (CdH , ps ),
2
2
3
3
3
3
2
)
.61 (CeH , t, J=6.0 ), 7.77 (C4”H, d, J=2.0 ), 7.39 (C7”H, d, J=8.5 ), 11.30 (NH, d, J=2.0
2
1
3
C NMR (see supplementary materials) (DMSO , 125MHz ) : 148.4 (C1), 159.1 (C3), 103.2
(C4), 143.1 (C4a), 120.3 (C5), 133.3 (C6), 111.0 (C7), 127.2 (C8), 133.5 (C1’), 131.2 (C2’,
x
x
x
x
C6’), 128.3 (C3’, C5’), 127.9 (C4’), 41.5 (C1 ), 25.0 (C2 ), 24.0 (C3 ), 57.5 (C4 ), 52.6 (Ca),
18.3 (Cb), 125.5 (Cc), 28.5 (Cd), 50.0 (Ce), 124.3 (C2”), 115.7 (C3”), 128.9 (C3”a ), 119.0
C4”), 123.8 (C5”), 121.1 (C6”), 113.1 (C7”), 135.3 (C7”a)
1
(
4
.1.5.18
2-{4-[4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(4-
methylphenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.18)
2
2

ACCEPTED MANUSCRIPT
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 50.2 % m.p. 158 - 159 C
+
HRMS (ESI) calculated for C H ClN O : 539.2042 (M+H) found 539.2088.
32
32
4
2
1
3
4
5
H NMR ( DMSO ,500 MHz) : 6.76 (C5H, dt, J=9.5, J= J=1.0 ), 7.09 (C6H, C6”H, m ),
3
3
4
3
4
5
6
.54 (C7H, m, J =7.5, J =6.5, J=1.0 ), 8.27 (C8H, dt, J=7.5, J= J=1.0 ), 7.24 (C2’, C6’H,
1 2
3
3
x
3
x
3
dt, J=8.0 ), 7.15 (C3’H, C5’H, dt, J=8.0 ), 4.02 (C1 H , t, J=7.5 ), 1.67 (C2 H , q, J=7.0 ),
2
2
x
3
x
3
3
1
.53 (C3 H , q, J=7.0 ), 2.42 (C4 H , t, J=7.5 ), 3.08 (CaH , d, J=2.0 ), 6.06 (CbH, t ), 2.47
2 2
3
3
3
(
CdH , ps ), 2.61 (CeH , t, J=5.5 ), 7.44 (C2”H, d, J=3.0 ), 7.77 (C4”H, d, J=2.0 ), 7.39
2 2
3
3
(
C7”H, d, J=8.5 ), 2.34 (CH , s ), 11.30 (NH, d, J=2.0 )
3
1
3
C NMR (DMSO , 125MHz ) : 148.4 (C1), 159.2 (C3), 103.1 (C4), 143.0 (C4a), 120.5 (C5),
1
33.3 (C6), 111.0 (C7), 127.8 (C8), 130.2 (C1’), 129.0 (C2’, C6’), 131.0 (C3’, C5’), 136.4
x
x
x
x
(
(
(
C4’), 41.5 (C1 ), 25.0 (C2 ), 24.0 (C3 ), 57.4 (C4 ), 52.6 (Ca), 118.2 (Cb), 125.5 (Cc), 28.5
Cd), 50.0 (Ce), 124.3 (C2”), 115.7 (C3”), 129.0 (C3”a ), 119.0 (C4”), 123.8 (C5”), 121.1
C6”), 113.1 (C7”), 135.3 (C7”a), 20.7 (CH3)
4
.1.5.19
2-{4-[4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(4-
methoxyphenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.19)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 59.4 % m.p. 172 - 177 C
+
HRMS (ESI) calculated for C H ClN O : 555.2142 (M+H) found 555.2177.
32
32
4
3
1
3
4
5
H NMR ( DMSO ,500 MHz) : 6.77 (C5H, dt, J=9.5, J= J=1.0 ), 7.09 (C6H, C6”H, m ),
3
3
4
3
4
5
6
.56 (C7H, m, J =7.5, J =6.5, J=1.5 ), 8.26 (C8H, dt, J=7.5, J= J=1.0 ), 7.19 (C2’, C6’H,
1 2
3
2
3
4
x
3
dt, J=9.0, J=2.0 ), 6.99 (C3’H, C5’H, dt, J=9.0, J=2.0 ), 4.02 (C1 H , t, J=7.0 ), 1.67
2
x
3
x
3
x
3
3
(
C2 H , q, J=7.0 ), 1.53 (C3 H , q, J=7.0 ), 2.41 (C4 H , t, J=7.0 ), 3.08 (CaH , d, J=3.0 ),
2
2
2
3
3
6
.06 (CbH, t ), 2.47 (CdH , ps ), 2.60 (CeH , t, J=5.5 ), 7.44 (C2”H, d, J=2.5 ), 7.77 (C4”H,
2 2
3
3
d, J=2.0 ), 7.39 (C7”H, d, J=8.5 ), 3.79 (OCH , s ), 11.30 (NH, bs )
3
1
3
C NMR (DMSO , 125MHz ) : 148.4 (C1), 159.3 (C3), 103.0 (C4), 143.0 (C4a), 120.5 (C5),
1
33.2 (C6), 110.9 (C7), 127.8 (C8), 125.1 (C1’), 132.3 (C2’, C6’), 113.8 (C3’, C5’), 158.4
x
x
x
x
(
(
(
C4’), 41.5 (C1 ), 24.9 (C2 ), 24.0 (C3 ), 57.5 (C4 ), 52.7 (Ca), 118.3 (Cb), 125.5 (Cc), 28.5
Cd), 50.0 (Ce), 124.3 (C2”), 115.7 (C3”), 128.9 (C3”a ), 119.0 (C4”), 123.8 (C5”), 121.1
C6”), 113.1 (C7”), 135.3 (C7”a), 55.0 (OCH3)
2
3

ACCEPTED MANUSCRIPT
4
.1.5.20
2-{4-[4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(4-
fluorophenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.20)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 49.6 % m.p. 169 - 173 C
+
HRMS (ESI) calculated for C H ClN O F: 543.1963 (M+H) found 543.1937.
31
29
4
2
1
3
3
4
5
3
H NMR ( DMSO ,500 MHz) : 6.76 (C5H, dt, J=9.5, J= J=1.0 ), 7.13 (C6H, 4d, J =9.5,
1
4
3
3
4
3
4
5
J =6.5, J=1.5 ), 6.56 (C7H, m, J =7.5, J =6.5, J=1.5 ), 8.30 (C8H, dt, J=7.5, J= J=1.0 ),
2
1
2
x
3
x
3
7
.31 (C2’, C6’H, m ), 6.26 (C3’H, C5’H, m ), 4.03 (C1 H , t, J=7.0 ), 1.68 (C2 H , q, J=7.0
2 2
x
3
x
3
3
)
, 1.54 (C3 H , q, J=7.0 ), 2.41 (C4 H , t, J=7.0 ), 3.08 (CaH , d, J=3.0 ), 6.06 (CbH, t ),
2
2
3
3
3
2
7
.47 (CdH , ps ), 2.60 (CeH , t, J=5.5 ), 7.44 (C2”H, d, J=2.5 ), 7.77 (C4”H, d, J=2.0 ),
2 2
3
4
3
5
.10 (C6”H, dd, J=9.0, J=2.0), 7.38 (C7”H, dd, J=9.0, J=0.5 ), 11.30 (NH, bs )
1
3
C NMR (DMSO , 125MHz ) : 148.3 (C1), 159.2 (C3), 102.1 (C4), 143.3 (C4a), 120.2 (C5),
4
3
1
1
5
1
33.7 (C6), 111.0 (C7), 128.0 (C8), 129.5 (C1’, d*, J=3.0), 133.3 (C2’, C6’, d*, J=8.0 ),
2
1
x
x
x
15.2 (C3’, C5’, d*, J=21.2), 161.3 (C4’, d*, J=244.1 ), 41.6 (C1 ), 24.9 (C2 ), 24.0 (C3 ),
x
7.5 (C4 ), 52.7 (Ca), 118.3 (Cb), 125.5 (Cc), 28.5 (Cd), 50.0 (Ce), 124.3 (C2”), 115.7 (C3”),
28.9 (C3”a ), 119.0 (C4”), 123.8 (C5”), 121.1 (C6”), 113.1 (C7”), 135.3 (C7”a)
4
.1.5.21
2-{4-[4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(2-
fluorophenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.21)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 57.5 % m.p. 145 - 148 C
+
HRMS (ESI) calculated for C H ClN O F: 543.1963 (M+H) found 543.1922.
31
29
4
2
1
H NMR (see supplementary materials) ( DMSO ,500 MHz) : 6.61 (C5H, C7H, m), 7.20
3
3
4
3
4
5
(
C6H, 4d, J =9.5, J =6.5, J=1.5 ), 8.33 (C8H, dt, J=7.5, J= J=1.0 ), 7.29 (C3’H, C5’H, m
1 2
x
3
x
3
)
, 7.45 (C4’H, C2”H, m ), 7.32 (C6’H, m ), 4.03 (C1 H , t, J=7.0 ), 1.69 (C2 H , q, J=7.0 ),
2 2
x
3
x
3
3
1
.54 (C3 H , q, J=7.0 ), 2.43 (C4 H , t, J=7.0 ), 3.09 (CaH , d, J=2.5 ), 6.06 (CbH, t ), 2.48
2 2
3
3
3
4
(
CdH , ps ), 2.61 (CeH , t, J=5.5 ), 7.78 (C4”H, d, J=2.0 ), 7.10 (C6”H, dd, J=8.5, J=2.0),
2 2
3
7
.39 (C7”H, d, J=8.5 ), 11.30 (NH, bs )
2
4

ACCEPTED MANUSCRIPT
1
3
C NMR (see supplementary materials) (DMSO , 125MHz ) : 148.3 (C1), 158.6 (C3), 96.6
2
(
C4), 143.6 (C4a), 120.1 (C5), 134.4 (C6), 111.2 (C7), 128.1 (C8), 120.6 (C1’, d*, J=16.1),
1
2
3
1
60.4 (C2’, d*, J=245.1), 115.7 (C3’, d*, J=22.1), 130.0 (C4’, d*, J=8.0), 124.4 (C5’, d*,
4
3
x
x
x
x
J=3.4), 133.6 (C6’, d*, J=3.0) 41.6 (C1 ), 24.9 (C2 ), 23.9 (C3 ), 57.4 (C4 ), 52.6 (Ca),
1
18.2 (Cb), 125.5 (Cc), 28.5 (Cd), 50.0 (Ce), 124.3 (C2”), 115.7 (C3”), 128.9 (C3”a ), 119.0
(C4”), 123.8 (C5”), 121.1 (C6”), 113.1 (C7”), 135.3 (C7”a)
4
.1.5.22
2-{4-[4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(2-
chlorophenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.22)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 54.0 % m.p. 183 - 188 C
+
HRMS (ESI) calculated for C H Cl N O : 559.1667 (M+H) found 559.1695
31
29
2
4
2
1
3
3
4
5
3
H NMR ( DMSO ,500 MHz) : 6.44 (C5H, dt, J=9.0, J= J=1.0), 7.19 (C6H, 4d, J =9.5,
1
4
3
3
4
3
4
5
J =6.0, J=1.5 ), 6.61 (C7H, m, J =7.5, J =6.0, J=1.5), 8.34 (C8H, dt, J=7.5, J= J=1.0), ),
2
1
2
x
x
7
,
.44 (C3’H, C5’H, C2”H, m ), 7.59 (C4’H, m), 7.34 (C6’H, m), 4.04 (C1 H , m), 1.69 (C2 H
2 2
3
x
3
x
3
3
q, J=7.0 ), 1.53 (C3 H , q, J=7.0 ), 2.42 (C4 H , t, J=7.0 ), 3.08 (CaH , d, J=2.5 ), 6.05
2
2
3
3
(
CbH, t ), 2.47 (CdH , ps ), 2.60 (CeH , t, J=5.5 ), 7.77 (C4”H, d, J=2.0 ), 7.10 (C6”H, dd,
2 2
3
4
3
J=8.0, J=2.0), 7.39 (C7”H, d, J=8.5), 11.23 (NH, bs )
1
3
C NMR (DMSO , 125MHz ) : 148.4 (C1), 158.4 (C3), 100.7 (C4), 143.3 (C4a), 120.0 (C5),
1
34.4 (C6), 111.2 (C7), 128.0 (C8), 132.1 (C1’), 134.9 (C2’), 129.7 (C3’), 129.4 (C4’), 127.4
x
x
x
x
(
C5’), 133.7 (C6’), 41.4 (C1 ), 24.9 (C2 ), 23.9 (C3 ), 57.4 (C4 ), 52.6 (Ca), 118.3 (Cb),
25.5 (Cc), 28.5 (Cd), 50.0 (Ce), 124.3 (C2”), 115.7 (C3”), 128.9 (C3”a ), 119.0 (C4”), 123.8
C5”), 121.1 (C6”), 113.1 (C7”), 135.3 (C7”a)
1
(
4
.1.5.23
2-{4-[4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(2-
methylphenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.23)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 49.0 % m.p. 196 - 198 C
+
HRMS (ESI) calculated for C H ClN O : 539.2042 (M+H) found 539.2081.
32
32
4
2
2
5

ACCEPTED MANUSCRIPT
1
3
4
5
H NMR ( DMSO ,500 MHz) : 6.42 (C5H, dt, J=9.5, J= J=1.0), 7.19 (C6H, C3’H, C6’’H, m
3
3
4
3
4
5
)
, 6.56 (C7H, m, J =7.5, J =6.5, J=1.5), 8.30 (C8H, dt, J=7.5, J= J=1.0), 7.31 (C4’H,
1 2
x
x
3
x
C6’H, m ), 7,24 (C5’H, m ), 4.04 (C1 H , m), 1.69 (C2 H , q, J=7.0 ), 1.53 (C3 H , q,
2
2
2
3
x
3
3
J=7.5 ), 2.42 (C4 H , t, J=7.5 ), 3.08 (CaH , d, J=2.5 ), 6.06 (CbH, t ), 2.47 (CdH , ps ),
2
2
3
3
3
2
.60 (CeH , t, J=5.5 ), 7.45 (C2’’H, d, J=2.5), 7.77 (C4”H, d, J=2.0 ), 7.39 (C7”H, d,
2
3
5
J=8.5, J=0.5), 2.07 (CH ), 11.23 (NH, bs )
3
1
3
C NMR (DMSO , 125MHz ) : 148.5 (C1), 158.7 (C3), 102.4 (C4), 143.0 (C4a), 120.3 (C5),
1
33.6 (C6), 110.8 (C7), 127.9 (C8), 132.8 (C1’), 138.2 (C2’), 131.6 (C3’), 127.8 (C4’), 125.9
x
x
x
x
(
C5’), 130.0 (C6’), 41.4 (C1 ), 24.9 (C2 ), 23.9 (C3 ), 57.4 (C4 ), 52.6 (Ca), 118.3 (Cb),
25.5 (Cc), 28.5 (Cd), 50.0 (Ce), 124.3 (C2”), 115.7 (C3”), 128.9 (C3”a ), 119.0 (C4”), 123.8
C5”), 121.1 (C6”), 113.1 (C7”), 135.3 (C7”a), 19.1 (CH3)
1
(
4
.1.5.24
2-{4-[4-(5-chloro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(2-
methoxyphenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.24)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 52.6 % m.p. 128 - 131 C
+
HRMS (ESI) calculated for C H ClN O H: 555.2142 (M+H) found 555.2172.
32
31
4
3
1
3
3
4
5
3
H NMR ( DMSO ,500 MHz) : 6.43 (C5H, dt, J=9.5, J= J=1.0), 6.88 (C6H, 4d, J =9.0,
1
4
3
3
4
3
4
5
J =6.5, J=1.0), 6.37 (C7H, m, J =7.5, J =6.5, J=1.5), 8.31 (C8H, dt, J=8.5, J= J=1.0),
2
1
2
3
4
3
4
3
4
7
.08 (C3’H , dd, J=8.5, J=2.0), 7,36 (C4’H, td, J=8.0, J=1.5), 7.03 (C5’H, td, J=8.0, J=1.0
3
4
x
x
3
x
)
, 7.20 (C6’H, dd, J=7.5, J=1.5), 4.21 (C1 H , m), 1.83 (C2 H , q, J=7.5), 1.72 (C3 H , q,
2 2 2
3
x
3
J=7.5 ), 2.61 (C4 H , t, J=7.5 ), 3.24 (CaH , ps ), 6.03 (CbH, t ), 2.47 (CdH , ps ), 2.73
2
2
3
3
4
3
(
CeH , t, J=5.5 ), 7.03 (C2’’H, d, J=1.0), 7.76 (C4”H, d, J=2.0), 6.97 (C6’’H, d, J=8.5),
2
3
7
.24 (C7”H, d, J=8.5), 3.73 (OCH ,s), 9.02 (NH, bs )
3
1
3
C NMR (DMSO , 125MHz ) : 149.1 (C1), 160.1 (C3), 101.2 (C4), 143.8 (C4a), 121.9 (C5),
1
33.0 (C6), 110.6 (C7), 127.9 (C8), 121.5 (C1’), 158.0 (C2’), 111.5 (C3’), 129.7 (C4’), 121.0
x
x
x
x
(
C5’), 132.1 (C6’), 42.2 (C1 ), 25.4 (C2 ), 24.0 (C3 ), 57.7 (C4 ), 52.7 (Ca), 118.1 (Cb),
25.6 (Cc), 28.4 (Cd), 50.1 (Ce), 129.5 (C2”), 117.1 (C3”), 126.1 (C3”a ), 120.0 (C4”), 123.0
C5”), 122.2 (C6”), 112.5 (C7”), 135.2 (C7”a), 55.6 (OCH3)
1
(
2
6

ACCEPTED MANUSCRIPT
4
.1.5.25
2-{4-[4-(5-bromo-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-
phenyl-pyrido[1,2-c]pyrimidine-1,3-dione (8.25)
The title compound was isolated as a yellow powder, crystallization from absolute ethanol
º
yield: 67.0 % m.p. 200 - 205 C
+
HRMS (ESI) calculated for C H N O Br: 569.1552 (M+H) found 569.1558.
3
1
30
4
2
1
3
3
4
H NMR ( CDCl ,500 MHz) 6.88 (C5H, C6H, m), 6.38 (C7H, m, J =7.5, J =5.0, J=2.5 ),
3
1
2
3
3
3
8
.32 (C8H, d, J=7.5 ), 7.30 (C2’H, C6’H, d, J=7.5 ), 7.43 (C3’H, C5’H, t, J=7.5 ), 7.35
3
x
3
x
3
x
3
(
C4’H, t, J=7.5 ), 4.22 (C1 H , t, J=7.5 ), 1.83 (C2 H , q, J=7.5 ), 1.69 (C3 H , q, J=7.5
2 2 2
x
3
3
)
, 2.52 (C4 H , t, J=7.5 ), 3.17 (CaH , d, J=2.5 ), 6.08 (CbH, t ), 2.40 (CdH , ps ), 2.64
2
2
3
3
3
3
(
CeH , t, J=5.5 ), 6.97 (C2”H, d, J=2.5 ), 7.96 (C4”H, d, J=1.5 ), 7.21 (C6”H, dd, J=8.5,
2
4
3
J=1.5), 7.17 (C7”H, d, J=8.5), 8.97 (NH, bs )
1
3
C NMR (CDCl , 125 MHz) : 148.9 (C1), 160.2 (C3), 104.8 (C4), 143.6 (C4a), 121.4 (C5),
3
1
32.5 (C6), 110.8 (C7), 127.8 (C8), 132.8 (C1’), 131.2 (C2’, C6’), 128.8 (C3’, C5’), 127.9
x
x
x
x
(
(
(
C4’), 42.5 (C1 ), 25.5 (C2 ), 24.6 (C3 ), 58.0 (C4 ), 53.2 (Ca), 119.3 (Cb), 126.8 (Cc), 28.9
Cd), 50.2 (Ce), 122.7 (C2”), 113.1 (C3”), 129.4 (C3”a ), 123.1 (C4”), 117.2 (C5”), 124.6
C6”), 112.7 (C7”), 135.4 (C7”a)
4
.1.5.26
2-{4-[4-(5-bromo-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(4-
methylophenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.26)
The title compound was isolated as a orange powder, crystallization from acetonitril, yield:
º
5
1.0 %; m.p. 296 - 299 C
+
HRMS (ESI) calculated for C H N O NaBr: 605.1528 (M+Na) found 605.1524.
31
32
4
2
1
3
3
4
H NMR ( CDCl ,500 MHz) 6.90 (C5H, C6H, m), 6.38 (C7H, m, J =7.5, J =5.0, J=2.0 ),
3
1
2
3
4
5
8
.32 (C8H, d, J=7.7, J= J=1.0), 7.30 (C2’H, C6’H), 7.23 (C6”H, C7”H, m), 7.19 (C3’H,
3
x
3
x
x
x
C5’H, d, J=7.0 ), 4.21 (C1 H , t, J=7.0 ), 1.83 (C2 H , q ), 1.75 (C3 H , q), 2.67 (C4 H , t
2
2
2
3
)
, 3.30 (CaH , ps ), 6.02 (CbH, ps ), 2.55 (CdH , ps ), 2.81 (CeH , ps ), 7.05 (C2”H, d, J=2.0
2 2 2
), 7.90 (C4”H, ps ), 8.86 (NH, bs ), 2.37 (CH3)
1
3
C NMR (CDCl , 125 MHz) : 149.0 (C1), 160.4 (C3), 104.8 (C4), 143.6 (C4a), 121.6 (C5,
3
Cb), 132.3 (C6), 110.7 (C7), 127.9 (C8), 129.7 (C1’), 131.0 (C2’, C6’), 129.5 (C3’, C5’),
2
7

ACCEPTED MANUSCRIPT
x
x
x
x
1
5
1
37.6 (C4’), 42.1 (C1 ), 25.3 (C2 ), 23.9 (C3 ), 57.6 (C4 ), 52.5 (Ca), 126.7 (Cc), 19.7 (Cd),
0.0 (Ce), 122.8 (C2”), 113.3 (C3”), 129.4 (C3”a ), 123.0 (C4”), ~117.0 (C5”), 124.9 (C6”),
12.9 (C7”), 135.4 (C7”a), 21.3 (CH3)
4
.1.5.27.
2-{4-[4-(5-bromo-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(4-
methoxyphenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.27)
The title compound was isolated as a white powder, crystallization from acetonitril yield: 90.1
º
%
m.p. 142-145 C
+
HRMS (ESI) calculated for C H N O NaBr: 621.1477 (M+Na) found 621.1462.
32
31
4
3
1
3
3
4
H NMR (CDCl , 500 MHz) : 6.87 (C5H, C6H, m ), 6.36 (C7H, m, J =11.5, J =7.5, J=4.0
3
1
2
3
4
5
)
, 8.30 (C8H, dt, J=7.5, J= J=1.0 ), 7.10-7.22 (C2’H, C6’H, C6”H, C7”H, m ), 6.94 (C3’H,
3
4
x
3
x
3
x
C5’H, dt, J=8.5, J=1.5 ), 4.22 (C1 H , t, J=7.5 ), 1.83 (C2 H , q, J=7.5 ), 1.68 (C3 H , q,
2
2
2
3
x
3
3
J=7.5 ), 2.52 (C4 H , t, J=7.5 ), 3.16 (CaH , d, J=2.0 ), 6.06 (CbH, t ), 2.35 (CdH , ps ),
2
2
3
3
3
2
.62 (CeH , t, J=6.0 ), 6.91 (C2”H, d, J=2.0 ), 7.98 (C4”H, d, J=1.5 ), 3.79 (OCH , s ), 9.33
2 3
(NH, bs )
1
3
C NMR (CDCl , 125 MHz) : 148.9 (C1), 160.5 (C3), 104.4 (C4), 143.6 (C4a), 121.5 (C5),
3
1
32.3 (C6), 110.7 (C7), 127.8 (C8), 124.7 (C1’), 132.3 (C2’, C6’), 114.2 (C3’, C5’), 159.1
x
x
x
x
(
(
(
C4’), 42.5 (C1 ), 25.5 (C2 ), 24.5 (C3 ), 58.0 (C4 ), 53.1 (Ca), 119.0 (Cb), 126.8 (Cc), 28.8
Cd), 50.2 (Ce), 123.0 (C2”), 113.0 (C3”), 129.4 (C3”a ), 123.0 (C4”), 116.9 (C5”), 124.5
C6”), 112.8 (C7”), 135.5 (C7”a), 55.3 (OCH3)
4
.1.5.28
2-{4-[4-(5-bromo-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-butyl}-4-(4-
chlorophenyl)-pyrido[1,2-c]pyrimidine-1,3-dione (8.28)
The title compound was isolated as a white powder, crystallization from acetonitril, yield:
º
5
9.6 % ; m.p. 220-228 C
+
HRMS (ESI) calculated for C H N O ClBr: 603.1162 (M+H) found 603.1183.
31
29
4
2
1
3
3
4
5
3
H NMR (CDCl , 500 MHz) : 6.87 (C5H, dt, J=9.5, J= J=1.0 ), 6.95 (C6H, 4d, J =9.5,
3
1
4
3
3
4
3
J =6.5, J=1.0 ), 6.41 (C7H, m, J =7.5, J =6.5, J=1.5 ), 8.35 (C8H, dt, J=7.5 ), 7.40 (C2’,
2
1
2
3
4
x
3
C6’H, dt, J=8.5, J=2.0 ), 7.20-7.28 (C3’H, C5’H, C6”H, C7”H, m ), 4.21 (C1 H , t, J=7.5
2
x
x
x
3
)
, 1.82 (C2 H , q ), 1.71 (C3 H , q ), 2.59 (C4 H , t, J=7.5 ), 3.24 (CaH , ps ), 6.07 (CbH, ps
2 2 2
3
)
, 2.52 (CdH , ps ), 2.74 (CeH , t, J=5.5 ), 7.07 (C2”H, ps ), 7.94 (C4”H, ps ), 8.72 (NH, bs )
2
2
2
8