Discovery and Preclinical Characterization of 3-((4-(4-Chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator for Psychiatric Indications

Article abstract of DOI:10.1021/acs.jmedchem.6b01858

Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore. Optimization of the core and aryl appendages was performed by scanning and matrix libraries synthesized by the multiple parallel synthesis approach. Biological evaluation of matrix libraries provided a number of potent, metabolically stable, and in vivo active compounds. One of these compounds, 25 showed high efficacy and safety in preclinical in vivo models; this allowed its nomination as a novel, nonacetylenic mGluR5 NAM clinical candidate. Compound 25 was advanced to first-in-man trials for the treatment of psychiatric conditions.

Full text of DOI:10.1021/acs.jmedchem.6b01858

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Article
Discovery and Preclinical Characterization of 3-((4-(4-
chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile,
a Novel Non-acetylenic Metabotropic Glutamate Receptor 5
(mGluR5) Negative Allosteric Modulator for Psychiatric Indications
János Galambos, Attila Bielik, Mikhail Krasavin, Zoltán Orgován, György Domány, Katalin Nógrádi,
Gábor Wágner, György T. Balogh, Zoltán Béni, János Koti, Zoltán Szakács, Amrita Bobok,
Sándor Kolok, Mónika L. Miko-Bakk, Mónika Vastag, Katalin Sághy, Judit Laszy, Attila Sándor
Halász, Ottilia Balázs, Krisztina Gál, István Greiner, Zsolt Szombathelyi, and György M Keser#
J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.6b01858 • Publication Date (Web): 17 Feb 2017
Downloaded from http://pubs.acs.org on February 18, 2017
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Journal of Medicinal Chemistry is published by the American Chemical Society.
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Discovery and Preclinical Characterization of 3-((4-(4-chlorophenyl)-7-
fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic
Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator
for Psychiatric Indications
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János Galambos,1 Attila Bielik,1 Mikhail Krasavin,2 Zoltán Orgován,3 György Domány,1* Katalin
Nógrádi,1 Gábor Wágner,1 György T. Balogh,1 Zoltán Béni,1 János Kóti,1 Zoltán Szakács,1 Amrita
Bobok,1 Sándor Kolok,1 Mónika L. Mikó-Bakk,1 Mónika Vastag,1 Katalin Sághy,1 Judit Laszy,1 Attila
Sándor Halász,1 Ottilia Balázs,1 Krisztina Gál,1 István Greiner,1 Zsolt Szombathelyi,1 György M.
Keserű3*
Gedeon Richter Plc, 19-21 Gyömrői út, Budapest, 1103 Hungary
Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospekt, Peterhof 198504
Russia
Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of
Sciences, 2 Magyar tudósok körútja, Budapest, 1117 Hungary.
Abstract
Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been
implicated as potential pharmacotherapy for a number of psychiatric diseases including anxiety and
depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic
moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high
throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead
compound with the minimal pharmacophore. Optimization of the core and aryl appendages was
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performed by scanning and matrix libraries synthesized by the multiple parallel synthesis approach.
Biological evaluation of matrix libraries provided a number of potent, metabolically stable and in vivo
active compounds. One of these compounds, 25 showed high efficacy and safety in preclinical in vivo
models this allowed its nomination as a novel, non-acetylenic mGluR5 NAM clinical candidate.
Compound 25 was advanced to first-in-man trials for the treatment of psychiatric conditions.
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Introduction
Metabotropic glutamate receptors (mGluRs) constitute the class C of G-protein coupled receptors
(GPCRs) and play a key role in glutamatergic signaling.1 This class of GPCRs consists of three subclasses
including groups I (mGluR1 and mGluR5), II (mGluR2 and mGluR3), and III (mGluR4, mGluR6, mGluR7
and mGluR8). Group I mGluRs are Gq coupled, located mainly postsynaptically and their activation
increases NMDA receptor activity and neuronal excitability. The inhibition of mGluR5 which is mostly
expressed in the striatum, hippocampus, amygdala, and frontal cortex is therefore considered as a
potential therapeutic intervention in a number of psychiatry indications including fragile X syndrome,2
anxiety,3 and depression.4 Due to the indirect enhancement of NMDA activity mGluR5 activators might
be effective in schizophrenia,5 can improve cognitive6 and memory performance.7 Since the orthosteric
glutamate site is highly conserved for all the mGluRs, most of the discovery programs are directed
toward allosteric modulators that would provide the necessary selectivity not only between but also
within the subclasses.8 In the case of mGluR5 these approaches yielded different chemotypes as
negative and positive allosteric modulators (NAMs and PAMs, respectively). Early mGluR5 NAMs were
rod-like compounds where terminal rings were connected typically by an acetylenic moiety. In fact,
compounds that reached the clinic up to now (ADX-10059,9 RG-7090,10 AFQ05611 and ADX-4862112) all
belong to this class of compounds (Figure 1). In more recent mGluR5 NAM chemotypes the terminal
rings are connected by 5- or 6-membered heterocycles as exemplified by AZD6538 and AZD927213 and
HTL1424214 (1) clinical candidates (Figure 1).
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Acetylenic chemotypes
4
F
Cl
5
6
N
NH2
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N
H
O
F
N
N
N
N
N
HO
H
O
N
F
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Basimglurant (RG-7090)
Raseglurant (ADX-10059)
Mavoglurant (AFQ056)
Dipraglurant (ADX-48621)
Non-acetylenic chemotypes
Cl
R1
F
F
N
N
N
N
CN
O
N
N
CN
AZD9272, R1=F
AZD6538, R1=CN
HTL14242 (1)
Figure 1. Clinical mGluR5 NAMs of acetylenic and non-acetylenic chemotypes
As a part of our research program for searching novel non-acetylenic chemotypes we identified a
morfolino-sulfoquinoline derivative (2) by screening our corporate compound deck (Figure 2).15 Based
on our previous experience with thieno[2,3-b]pyridines16,17 the original hit (2) was rapidly converted
to the 4-chlorophenyl derivative (3) in Region I, this showed improved potency but virtually the same
low metabolic stability in both rat and human microsomes (Figure 2).
2
3
Figure 2. The amino-sulfoquinoline HTS hit (2) and the phenyl-sulfoquinoline advanced hit (3)
Our most important objective during the optimization of 3 was therefore to improve the metabolic
stability while maintaining target potency of phenyl-sulfoquinolines. Optimization of GPCR allosteric
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modulators is a complex task due to multiple reasons.8 Structure-activity relationship of allosteric
modulators is commonly steep or flat,18 structural modifications might result in the switch between
NAMs and PAMs19 and the properties of allosteric sites often challenge the ADME properties of the
ligands. The latter situation frequently occurs when structural changes at metabolically vulnerable
moieties and attempts to improve the solubility are less tolerated by the SAR. In such cases iterative,
multidimensional parallel synthesis approaches20,21 might help to understand structure-activity and
structure-metabolism relationships. We herein report the successful implementation of this strategy
for the optimization of our phenyl-sulfoquinoline-based mGluR5 NAMs to clinical candidate 25, and
preclinical data that support its potential in psychiatry indications.
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Chemistry
4-Phenyl-3-aryl-sulfoquinolines were synthesized in five steps from substituted sodium arylsulfinates
(4). The arylsulfinates were first converted to methyl 2-(arylsulfonyl)acetates (5) with
ethylchloroacetate in DMF. The reaction of arylsulfonyl acetates (5) and triethyl orthoformate gave
methyl 3-ethoxy-2-(arylsulfonyl)-2-propenoates (6) that were cyclized to corresponding quinolinones
(8) with substituted anilines (7). Phenylsulfonyl-4(1H)-quinolinones (8) were chlorinated by POCl3 in
position 4 preparing the corresponding 4-chloro-3-phenylsulfonyl-quinolines (9) that were coupled
with boronic acids (10) in 1,4-dioxane using Pd(PPh3)4 and K2CO3 to give 4-phenyl-3-aryl-
sulfoquinolines (11) (Scheme 1).
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R1
O
O
i
O
ii
R1
O
R1
O
CH3
CH3
ONa
S
S
CH3
O
S
O
O
O
O
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H2N
R2
O
R1
iv
O
Cl
N
R1
O
S
7
S
O
R2
O
R2
iii
N
H
8
9
R3
(OH)2B
R3
R1
O
S
10
O
R2
v
N
11
Scheme 1. Synthesis of 4-phenyl-3-aryl-sulfoquinolines
i – DMF, ClCH2COOEt, 1 h at 80°C, 60-80%; ii – HC(OEt)3, 3 h at 150°C, 90-95%; iii – PhOPh, reflux 1 h,
35-55%; iv – POCl3, reflux 2-3 h, 90-95%; v – 1,4-dioxane, Pd(PPh3)4, K2CO3, 20h at 90oC, 50-90%.
Results and Discussion
Our optimization strategy involved a multiple parallel synthesis approach as applied for all the three
regions of 4-phenyl-3-aryl-sulfoquinolines (Figure 3).
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Figure 3. Implementation of the multiple parallel synthesis approach for the optimization mGluR5
NAMs. Retrosynthetic analysis of the sulfoquinoline scaffold at level 1 allowed us to identify three
regions (Regions I, II and III) for further evaluation. The preferred substituents in Region II (7-fluoro
and 8-fluoro) were identified by the scanning library at level 2. Next we explored Regions I and III by
the synthesis of matrix libraries 3a and 3b. Most promising compounds identified from the matrix
libraries were further optimized at level 4 to yield compounds profiled for candidate selection at level
5.
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Since our primary objective was to improve the metabolic stability the first step was that we
analyzed the metabolically vulnerable positions of 3 by SmartCyp.22 The most affected para-methyl
group in Region III was replaced by a fluorine substituent and metabolic hot spots of the modified
core were re-evaluated. Since SmartCyp suggested all of the metabolic hot spots in Region II (see
Supplementary Figure 1). The available positions of the quinoline core where mapped by the
scanning library (Figure 3, Table 1).
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Table 1. The effect of quinoline substituents on the binding affinity and metabolic stability of 4-
phenyl-3-aryl-sulfoquinolines prepared in the scanning library
rat mGlu5
binding
rat mGlu5
MMPEP displ.
at 1 uM (%)a
rat CL int
human CL int
Compound
R
(ml/min*g liver) a (ml/min*g liver) a
Ki (nM) a
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6-Cl,7-F
6-F,7-Cl
7-Cl, 8-F
8-F
43.7
48
n.d.
n.d.
0.34
0.57
0.01
0.06
0.40
0.89
0.20
0.04
0.01
0.01
0.09
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0.01
0.01
0.28
0.12
1.23
0.01
0.01
0.21
0.01
0.01
83.6
91.5
76.3
91.6
58.3
39.7
92.8
8.7
71.2
16
6-F
179.6
38.6
n.d.
7-F
6-Cl
6-CN
7-Cl
n.d.
110.4
n.d.
7-CN
6-Cl, 8-F
19
n.d.
a geometric mean, n ≥ 2 measurements
Scanning around the quinoline core revealed that the measured metabolic stabilities were in line
with the SmartCyp predictions. The introduction of halogens to positions 6, 7 and 8 of Region II
improves the metabolic stability in both species significantly. Similar to optimization programs
reported against other allosteric GPCR sites we found the “fluorine walk’’ useful to identify the most
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tolerant positions of the core.23 In the case of 7- and 8-fluoro derivatives the improved metabolic
stability went parallel to reasonable binding affinity towards the target. After we identified the
optimal positions for fluorine incorporation we aimed to find the best combination of Region I and
Region III substituents in terms of potency and metabolic stability. Consequently, at the next stage of
our optimization protocol we used matrix libraries (3a and 3b on Figure 3) to understand structure-
metabolism relationships around the 7- and 8-fluoroquinolineo cores. During these attempts we
mapped Regions I and III synthesizing two matrix libraries of 61 and 53 7-fluoro and 8-fluoro-
sulfoquinolines, respectively by parallel synthesis (Scheme 1). Library members were first evaluated
in metabolic stability assays using rat and human microsomes and also tested against mGluR5. Since
human metabolic stability data ran parallel to corresponding rat data we restrict our analysis to
human data (Figure 4).
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A. Matrix library of 7-fluoroquinoline derivatives
Intrinsic clearance, human (ml/min*g liver)
Region III
2-F
1.39
0.79 0.93
1.07
1.05
3-F
4-F
0.24 0.95 0.78 3.36 2.94 3.71 0.60 0.41 0.06 0.25 2.08 0.41 1.32
0.11 1.34 0.39 9.37 1.71 9.25 0.44 0.18 0.01 0.69 1.29 2.33 2.26
3-Cl
4-Cl
3-OMe
4-OMe
average
0.99 2.97
0.98 1.25 0.31
4.01 0.38 0.93 0.22 0.66 1.19 2.13 1.50
1.28 7.88 0.01 0.13 0.03 0.39
8.78 1.77 1.51 1.81
1.36
2.90
1.62
1.83
1.71
1.89 1.77 0.92
1.18 4.13 1.10 1.00 1.51 1.08
0.81 1.33 0.94 5.23 1.78 6.29 0.73 0.73 0.61 0.69 1.57 1.62
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B. 8-fluoroquinoline derivatives
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Intrinsic clearance, human (ml/min*g liver)
Region III
2-F
0.21
1.14 1.56 0.34 3.03 1.28 1.08 1.18 1.23 3.92 1.64
0.19 0.19 0.78 1.01 0.69 0.19 2.75 0.83
0.66
1.39 0.44 0.09 1.39
0.70
3-F
4-F
3-Cl
4-Cl
0.56 1.21 1.11 2.75 1.13 1.20 0.64 0.18 3.18 1.33
0.62 0.28 0.08 1.05 0.28 0.78 0.73 0.01 2.20 0.67
3-OMe
4-OMe
average
2.60 2.23
2.48 2.41
2.87
2.31 2.76
4.02 2.80
3.27 2.44
2.12 2.12 2.11 2.59
1.11 1.54 0.48 2.36 1.16 1.27 1.24 0.60 3.22
Figure 4. Metabolic stability driven optimization of Region I and III substituents around the
sulfoquinoline core. Panel A shows human intrinsic clearance data in the 7-fluoroquinoline library
(matrix library 3a). The library contains 61 derivatives carrying a range of substituents in Region I
(rows) and Region III (columns). Panel B shows human intrinsic clearance data in the 8-
fluoroquinoline library (matrix library 3b). The library contains 53 derivatives carrying a range of
substituents in Region I (rows) and Region III (columns). Cells are colored as a gradient from red (high
clearance) to green (low clearance).
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Analyzing the impact of the 7-fluoroquinoline substituents we concluded that 4-chloro, 4-fluoro and
3-fluoro substituents were beneficial in Region I, while methoxy groups introduced to positions 3 and
4 resulted in much less stable compounds. Although 4-chloro derivatives were somewhat better than
4-fluoro compounds this trend was reversed at position 3, showing 3-chloro derivatives as less stable
compounds as their corresponding fluoro analogues. Region III generally preferred disubstituted
analogues since difluoro, dichloro and mixed fluoro-chloro compounds showed better metabolic
stability as compared to mono-substituted compounds. The only exceptions were 3-fluoro and 3-
cyano substituents that gave similar metabolic stability as the disubstituted analogues. Position 3
seems to be crucial in this region since stable disubstituted analogues always contain a fluorine or
chlorine atom in this position. Otherwise 3,4- and 3,5-disubstitutions gave similar results. In contrast
to halogen substituents both methoxy and methyl derivatives were found to be metabolically less
stable in mono- and disubstituted scenarios, respectively. Structure-metabolism relationship was
found to be similar for 8-fluoroquinolines as both 4-chloro and 4-fluoro substituents were beneficial
in Region I. Methoxy substituents in positions 3 and 4 yielded significantly less stable compounds. 2-
fluoro derivatives were metabolically more stable and the 3-fluoro substituent seems to be less
favored than found in the 7-fluoroquinoline series. Preferred substituent patterns of Region III
showed high similarity to that observed for 7-fluoroquinolines. Again, 3-fluoro and 3-cyano
derivatives emerged from the mono-substituted analogues, while 3,4- and 3,5-dihalo substitution
gave compounds with acceptable metabolic stability. Methyl and methoxy substituents mostly
increased the metabolic vulnerability of 8-fluoroquinolines.
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Combining the results of this structure-metabolism analysis with the binding affinity data we selected
the most stable and mGluR5 active (Ki < 50 nM) library members and resynthesized them for in vivo
testing (Figure 3). The optimized set of 4-phenyl-3-aryl-sulfoquinolines was evaluated in the Vogel
punished drinking test after i.p. administration. Compounds showed reasonable MED (lower than 30
mg/kg) were also tested after p.o. administration (Table 2).
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Table 2. Best 4-phenyl-3-aryl-sulfoquinolines identified from the matrix libraries.
7
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20
Plasma
level at
Vogel
MEDb
(nM)
n.d.
71.0
Plasma
level at
Vogel
MEDc
(nM)
rat
mGluR5
human
mGluR5
Vogel
i.p.
MED
Vogel
p.o.
MED
rat CL
human CL
21
Cmpd
R1
R2
R3
(ml/min* (ml/min*
binding Ki functional
g liver) a
g liver) a
22
23
24
(nM)a
IC50 (nM) a
(mg/kg)
(mg/kg)
MPEP24
-
-
-
9.6
5.2
31
21
0.19
0.89
1.61
0.69
3
10e
3
3f
10e
3f
n.d.
25
4-F 7-F 3-Cl, 4-F
133
88.3
151
34.8
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
373
218
n.d.
n.d.
196d
n.d.
23
26
27
2824
29
4-F 7-F
3-CN
6.5
20
0.70
0.39
10e
208
4-Cl 7-F
3-F 7-F
4-F 7-F
4-F 8-F
4-F 8-F
4-F 7-F
3-F 7-F
4-F 7-F
3-CN
3,5-Cl2
3,5-F2
3,5-Cl2
3-F
3,5-Cl2
3,5-F2
3,4-F2
55.3
10.7
18
133
35
25
25
69
25
74
43
0.25
1.53
0.93
1.06
0.20
1.15
1.80
0.67
0.31
0.41
0.01
1.01
0.19
0.18
0.06
0.44
3e
30e
51.1
90.6
206d
119
1207
165c
63.0d
247d
0.5f
n.t.
>10f
n.t.
n.t.
n.t.
n.t.
n.t.
10e
3e
30
25
31
26
32
>30e
30e
27
33
34
6.8
28
31.6
11.5
32.6
19.1
30e
35
29
36
>30e
>30e
>30e
30
37
38
31
39
32
40
41
33
4-Cl 7-F 3-Cl, 4-F
8.3
27
0.45
0.39
30e
373
42
43
4-F 8-F
4-Cl 7-F
4-Cl 8-F
4-Cl 7-F
3,5-F2
3,5-Cl2
3,4-F2
3,4-F2
13.3
30.3
8.4
12
94
13
22
0.63
0.77
0.20
1.41
0.69
0.13
0.28
0.01
30e
30e
3e
151
377
59.7
n.d.
n.t.
n.t.
>30e
10e
34
44
35
45
46
36
47
17.1
10e
37
48
49
50
51
52
53
54
55
56
57
58
59
60
n.t. – not tested, n.d. – not determined, a geometric mean, n ≥ 2 measurements, b ~45 minutes after ip. administration, c ~75 minutes after p.o.
e
f
administration, d at the dose of 30 mg/kg, in suspension containing 5% Tween 80, in Type IV lipid formulation diluted with 70% d.w stabilized with 1%
HPMC
Based on in vivo evaluation we found five compounds that showed high anxiolytic efficacy in both i.p.
and p.o. administration. Since most of the present anxiolytics show memory impairment as a dose
limiting side effect we tested four compounds out of the five in the Morris water maze at a single
dose of 30 mg/kg (Table 3).
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Table 3. Effect of selected 4-phenyl-3-aryl-sulfoquinolines on learning performance as evaluated in
the Morris water maze test.
8
9
Therapeutic
index
(Morris MED/
Therapeutic
index
(plasma
levels)
≤9.1
Test
dose
(mg/kg)
Plasma
level
(nM)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound
23
24
25
33
Outcome
Vogel MED)
30a
30a
30a
30b
Slight impairment
Impairment
No impairment
Slight impairment
968
1280
986
≤10
10
>30
10
≤8.4
28.3
3.9
866
a
b
Type IV lipid formulation diluted with 70% d.w stabilized with 1% HPMC, Type IIIB lipid formulation diluted with 70% d.w
Interestingly we found, that except for compound 25 all the other compounds affected the learning
performance showing slight to moderate impairment at 30 mg/kg. Clinical signs together with
therapeutic indices calculated from both MED values and plasma levels obtained in the main effect
and the side effect animal models suggested compound 25 as the ultimate choice. The compound
was therefore nominated as a development candidate selected for further characterization.
Characterization of compound 25
Binding mode to mGluR5
The first step of the characterization of the development candidate involved the investigation of key
interactions formed in the binding site of mGluR5 (Figure 5). Since 4-phenyl-3-aryl-sulfoquinolines
differ significantly from earlier acetylenic mGluR5 NAMs we used the the high resolution X-ray
structure of compound 1 a non-acetylenic chemotype cocrystallized with mGluR5.14 Docking
calculations revealed that similar to compound 1 the sulfoquinoline core and the fluorine substituent
in Region II is located in a pocket formed by Pro6553.40, Tyr659, Ala8107.40, Ile6252.46, Ser6583.43, Gly624,
Gly6282.49 and Ser6543.39 (Ballesteros-Weinstein25 numbering in superscript). Direct comparison of
binding modes, however, showed that the extended conformation of 25 prevents its binding in the
lower part of the pocket occupied by 1. As a consequence, unlike to the Heptares compound the
quinolone nitrogen of compound 25 could not form hydrogen bond to Ser8097.39. Instead, the expected
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binding mode suggests that one of the sulfone oxygens of 25 makes a hydrogen bond with Ser8057.35
opposite to Ser8097.39. One of the most significant differences between the conformations of binding
site residues around 1 and mavoglurant is related to Trp7856.50. In the case of 1 this residue is rotated
out toward helix 5 and forms aromatic interactions with the ligand. Interactions with Trp7856.50 were
also crucial for our compound since the phenyl rings of both Regions I and III were found in aromatic
stacking with this residue. Compound 1 formed similar interactions with Phe7886.53 but this residue
seems to be less relevant in the binding of 25. The orientation of the 3-aryl substituent of the
sulfoquinoline core (Region III) is similar to that of the 3-chloro-5-cyanophenyl ring of 1 this allows
formation of a water mediated hydrogen bond between the 3-cyano substituent in Region III with the
3
4
5
6
7
8
9
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25
26
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backbone carbonyl of Val7405.40
.
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A.
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24
25
26
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B.
C.
Figure 5. The predicted binding mode of 25 (A), binding hot spot map (B) and lipophilic hot spots (C) of
its binding site. The color coding of the binding hot spot map (B) reflects the GE of all ligands described
in Table 3 and is projected on the protein atoms within 4 Å distance. The binding pocket surface was
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colored according to the maximum GE values for each protein atom. Oxygen, nitrogen, sulphur and
hydrogen atoms are colored red, blue, orange and white, respectively. Lipophilic hot spots (yellow
shaded surfaces on panel C) were identified by WaterFLAP26 at the binding site found in the X-ray
structure of mGluR5-compound 1 complex without the ligand (gray surface). Waters are color coded
to show the energetically most disfavored as red (>3.5 kcal/ mol), then yellow (2.2−3.5 kcal/mol), bulk
solvent as gray (−1 to 2.2 kcal/mol), and favored as blue (<−1 kcal/mol). GRID maps are contoured
(transparent solid) and colored in the following manner: CH3 methyl group probe in gray at 1 kcal/mol
defining the pocket surface and C1= probe (lipophilic) in yellow at −2.7 kcal/ mol. The predicted binding
mode of 25 (purple) is overlaid to identify the displaced water molecules (green circled).
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The predicted binding mode of 25 was validated by the hot spot analysis of the binding site using
structure−activity relationship (SAR) data available in Table 1 and 2. We used the group efficiency (GE)
concept27 to analyze the contributions of different parts of the ligand to its binding affinity. All ligands
with measured Ki values (Tables 1 and 2) were docked to the binding site identified for 25, the best
scored pose was selected and the GEs of all ligands were projected on the protein surface resulting in
different hot spots. Hot spot analysis (Figure 5 B) revealed that Region II substituents around the lower
part of the quinoline ring (positions 7 and 8) contribute most significantly to the binding affinity and
therefore identified as primary hotspot. The secondary hot spot is located around the benzenesulfonyl
ring (Region III) represented by positions 3 and 5. Finally, the phenyl ring at position 4 of the quinoline
core (Region I) fits well to the nearby lipophilic hot spot (Figure 5 C). WaterFLAP calculations showed
that the binding of 25 involves the displacement of water molecules in all regions. In Region II the 7-
chloro substituent of 25 reaches the lipophilic hot spot at the bottom of the binding site and more
importantly displaces the water molecule critical for receptor activation.28 Substituents at positions 3
and 4 around the 4-phenyl ring (in Region I) also displace energetically disfavored water molecules.
Finally, substituents at positions 3 and 5 around the upper phenyl group in Region III displace the
corresponding disfavored waters while the nitrile substituent forms a bridged H-bond to Val7405.40
.
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Primary in vitro pharmacology and in vitro ADME
7
8
9
Compound 25 is a potent and selective negative allosteric modulator at mGluR5 metabotropic
glutamate receptors (Table 4). Its potency on mGluR5 was assessed in comparison to mGluR1 in various
assays including recombinant human and native rat and human receptors. Moreover, functional
activity of the compound was characterized on recombinant human and native rat mGluR5 and native
rat mGluR1. [3H]-M-MPEP radioligand displacement studies29 were done using three types of
membranes prepared from (i) rat cerebrocortical tissue (ii) human mGluR5 expressing recombinant
cell line and (iii) post mortem human parietal cortical tissue. Selectivity of 25 to mGluR5 vs. mGluR1
was investigated in [3H]-R214127 binding assays30 with membranes prepared from (i) rat cerebellar
tissue (ii) human mGluR1 expressing recombinant cell line and (iii) post mortem human cerebellar
tissue. In conclusion, compound 25 binds with high affinity to the allosteric binding site of native (rat
and human) as well as recombinant (human) mGluR5 receptors and exhibits a selectivity of >50-fold
over native mGluR1 receptors. Functional studies in cells expressing mGluR5 or mGluR1 receptors
were performed by fluorometric calcium measurements with the group I specific agonist DHPG ((S)-
3,5-dihydroxyphenylglycine) in CHO cells expressing recombinant human mGluR5a receptors
(hmGluR5-CHO; EuroScreen), primary neuronal cultures prepared from neocortices of E17 rat embryos
(expressing predominantly mGluR5), and also from cerebelli of newborn rat pups (expressing
predominantly mGluR1). In conclusion, compound 25 behaves as a functional antagonist at both
mGluR5 and mGluR1 receptors with considerable selectivity for mGluR5 receptors. Broad selectivity
profiling against 68 receptors, ion channels at the test concentration of 1 μM revealed no significant
activity (<30 % effect) at any of the targets.
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11
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Penetration of compound 25 through MDCKII-MDR1 cell monolayers, a surrogate in vitro model of
brain penetrability, was measured for both inward and outward directions. The calculated apparent
inward permeability (Papp) value and permeability directional ratio (PDR, i.e. Pappoutward/Pappinward
)
are both reasonable and show that the compound can penetrate through membranes and is not a
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likely substrate of efflux transporters. The in vitro metabolism of compound 25 was investigated using
rat, dog and human liver microsomes. The amount metabolized was the highest in monkey liver
microsomes and similar among liver microsomes of human, mouse and rat. The potential of 24 to
inhibit CYP1A2, CYP2C9, CYP2D6 and CYP3A4 enzymes was investigated using human liver microsomes
and their specific probe substrate(s). The apparent IC50 of compound 25 for the inhibition of the
enzymes tested was higher than 10 μM, suggesting that 25 is not a potent inhibitor of these enzymes.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Summary of in vitro pharmacology and ADME data for 25
Property
Physicochemical
MW
Value
422.9
logD (pH 7.4, calculated)
tPSA
aqueous solubility (μg/mL, pH 7.4, measured)
mGluR5 binding (nM)
Rat native mGluR5 Ki
Human recombinant mGluR5 Ki
5.3
70.3
10
5.3
4.9
Male
Post mortem human mGluR5 Ki
Female
10.8
12.1
mGluR5 functional activity (nM)
Human recombinant mGluR5 IC50
Rat native mGluR5 IC50
13
19
Papp (nm/s) inward
115
PDR
0.74
0.25
0.27
0.31
99.73
99.75
99.61
Intrinsic clearance, (ml/min*g liver) Rat
Dog
Human
Plasma protein binding, (bound (%)) Rat
Dog
Human
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Preclinical disposition
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Detailed pharmacokinetic (PK) investigations were performed after single dose i.v. and oral
administration of 25 to Crl:CD(SD) rats and beagle dogs and a pilot single dose PK study was conducted
in Cynomolgus monkeys with oral (nasogastric) administration in different lipid based formulations.31
Disposition properties of the compound were also investigated in rats after per os administration of
14C-labelled compound 25 ([14C]-25). Table 5 shows the PK parameters for the unchanged compound
25 and summarizes the PK parameters for the total radioactivity (compound unchanged + metabolites)
after the administration of its 14C-labelled form.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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50
51
52
53
54
55
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57
58
59
60
Table 5. Mean pharmacokinetic parameters for 25
Sex
(No. of
animals)
Dose
Cl
Vd
t1/2 Tmax Cmax
+AUCtot
nM.h
Species
Route Formulation
mg/kg mL/h/kg L/kg h
h
nM
80% cosolvent
mixture/20%
d.w.
undiluted Type
IV lipid
formulation
707
M (n=3)
1674
856
12.4 5.13
iv.
0.5
4.5
0.5
1
--
--
1381
F (n=3)
9.6 7.79
Rat
Crl:CD(SD)
M (n=3)
7.06 0.75 369
6.30 0.75 650
2190
7297
p.o.
fed
--
--
F (n=3)
80% cosolvent
M (n=3)
F (n=3)
M (n=3)
F (n=3)
M (n=3)
F (n=3)
386
553
8.6 12.2 0.5 1542
9.2 11.8 0.5 1144
12.8 0.75 492
3074
2218
1859
1684
132#
87#
iv. inf. mixture/20%
d.w.
undiluted Type
IV lipid
*fasted
formulation
Dog
Beagle
p.o.
--
--
10.7 0.83 551
1.4# 1.7# 57#
undiluted Type
Cynom.
monkey
p.o.
IV lipid
&fasted
formulation
9
--
--
2.1# 1.3# 33#
# median, * from 1h prior to dose until 2h post dose, & from 2h prior to dose until 2h post dose +AUC0-8 in monkey study
Our results showed that the distribution volume was very similar in the rat and the dog (9-12 L/kg),
but with higher clearance in rat over dog (856-1674 mL/h/kg for the rat and 386-553 mL/h/kg for the
dog), resulting in lower half-life values (5-8 h) in the rat compared to dog (~12 h). The t1/2 of compound
25 in monkeys was even shorter (1-2 h), indicating substantially higher systemic clearance in this
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species. The pharmacokinetic parameters were similar between the genders, although female rats
seemed to show somewhat lower clearance than male rats. In contrast, female dog had higher
clearance than the male. These findings are in accordance with the in vitro metabolic stability data,
which show highest rate of metabolism in monkey liver microsomes followed by rat and human. The
terminal elimination half-life in the rat was similar for the unchanged 25 (~7 h after oral 4.5 mg/kg)
and the total [14C]-25 related radioactivity (~8 h after oral 50 mg/kg), suggesting that that there was
no long-persisting major metabolite.
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25
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In vivo pharmacology
Anxiolytic efficacy - Investigation of compound 25 in the Vogel punished drinking test was accompanied
with plasma level determinations from the same animals right after the test. The compound was
administered as a single dose in different lipid based formulations.31 Dose–response relationship of 25
was determined in four separate experiments; the pooled results are shown in Figure 6.
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25
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49
50
51
52
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60
Figure 6. Anxiolytic efficacy of 25 in the Vogel punished drinking test after single and repeated dose
p.o. administration. A. Anxiolytic effect of single doses of 25 in the Vogel assay (A) and plasma levels
measured right after the test (B). Mean±SEM values are given in (A), group sizes are shown inside the
columns. *, ** and ***: p<0.05, p<0.01 and p<0.001, respectively, vs. vehicle-treated group (ANOVA
followed by post-hoc Duncan-test). In (B), mean±SD values are plotted. B. Effect of repeatedly
administered 25 in the Vogel test. Means±SEM values are shown. Group size was 10. VEH/VEH: vehicle-
treated control group, VEH/25: single dose compound 25 treated group, 25/25: repeat dose compound
25 treated group. ** and ***: p<0.01 and p<0.001, respectively, vs. VEH/VEH. (ANOVA followed by
post-hoc Duncan-test).
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Compound 25 was active in the Vogel punished drinking test with a minimum effective dose of 0.5
mg/kg, with apparently dose-independent efficacy (ceiling effect) in the range of the 0.5-10 mg/kg.
Plasma concentrations of 25 increased approximately proportionally with increasing doses. For
assessment of plasma concentrations associated with maximum efficacy, doses of 0.5 and 1 mg/kg
yielded mean plasma concentrations of 34.8 nM and 99 nM, respectively. Impact of repeated
administration on the anxiolytic effect of 25 was investigated in the Vogel assay. The compound was
administered once a day for 19 days at the dose of 10 mg/kg p.o. A vehicle-treated group which only
received drug injection on Day 19 served as the first-dose-effect control group. Compound 25
produced statistically significant anxiolytic effects both after the first dosing and following 19-day-long
repeat-dose administration (0). Although plasma level of the compound was lower after repeated
dosing than after single dosing (513±127 nM vs. 787±323 nM; mean±SD), the anxiolytic efficacy rather
tended to increase indicating lack of development of tolerance to the anxiolytic effect of 25 at a
relatively high dose level.
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25
26
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The anxiolytic efficacy of 25 has been further demonstrated in ultrasonic vocalization test and
contextual fear-conditioning test. Compound 25 applied in the dose-range of 0.3–10 mg/kg p.o.
significantly and dose-dependently reduced ultrasonic vocalization with an ED50 value of 1.5 mg/kg. In
the contextual fearing test compound 25 in the dose-range of 0.5–3 mg/kg p.o. significantly and dose-
dependently reduced the freezing behavior with an ED50 value of 0.95 mg/kg. In conclusion, 25 shows
consistent in vivo efficacy at low doses (0.5-2 mg/kg, p.o.) in three rat models of anxiolytic activity.
CNS side effect profiling - The effect of 25 on spatial learning performance was investigated in the
Morris water maze paradigm at an oral dose of 30 mg/kg given 1 hour prior to the first daily trial.
Compound 25 did not affect the learning performance of rats. Plasma level of the compound measured
right after the last trial on Day 4 was 986 nM, which is about 30-fold higher than the reference
therapeutic plasma concentration in the Vogel assay (Table 3) assuring a considerably high therapeutic
index.
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The effect of 25 (0, 10, 30 and 50 mg/kg, p.o.) on spontaneous locomotor activity was tested in male
Wistar rats in a photocell-based activity monitor. Compound 25 dose-dependently inhibited
locomotion with about 50% inhibition at 50 mg/kg p.o. dose. The lower doses did not significantly
affect the ambulatory movement of rats. Therefore, the no observed adverse effect level in the study
was 30 mg/kg.
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17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
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43
44
45
46
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Benchmarking 25 with diazepam - For benchmarking, we compared 25 to diazepam, the gold standard
anxiolytic compound. Main effect and side effect profiles are shown in Table 6. The assay conditions
for diazepam were the same as described above for compound 25.
Table 6. Head-head comparison of 25 and diazepam in main and side effect pharmacology tests (doses
are p.o. unless otherwise stated).
25
plasma level
nM
diazepam
plasma level
nM
25 dose
mg/kg
diazepam dose
mg/kg
Effect
Test
Vogel test (MED)
USV (ED50)
Fear-conditioning
(ED50)
0.5
1.5
34.8
n.d.
2.5
7.8
BQL (<35)
n.d.
Anxiolytic
effect
0.95
n.d.
>10
n.d.
Morris water-
maze (MED)
SMA (ED50)
>30
50
986
n.d.
5 (i.p.)
9.7
n.d.
n.d.
Side effects
n.d. – not determined; MED: minimum effective dose; USV: ultrasonic vocalization; SMA: spontaneous motor activity
In general, 25 proved to be more potent than diazepam in the anxiolytic assays. Moreover, diazepam
shows sedative and learning impairing effects at doses 1-4 fold higher than those of its anxiolytic-like
activity. In contrast, 25 has about 30-fold therapeutic index between plasma levels associated with
therapeutic (anxiolytic) and side effects.
Conclusion
Optimization of an amino-sulfoquinoline HTS hit led to identification of a 4-phenyl-3-arylsulfiquinoline
lead. Extensive optimization around the sulfoquinoline core was supported by multiple parallel
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syntheses of scanning and matrix libraries that provided highly potent mGluR5 NAM compounds with
enhanced metabolic stability. Further characterization of these library members resulted in the orally
bioavailable compound 25 which showed efficacy in a preclinical model of anxiety after both single a
repeated dose administration. Being a potent and selective mGluR5 NAM with acceptable ADME
properties, clean off-target profile, and favorable preclinical in vivo efficacy results, 25 was nominated
as clinical candidate and after profiling in regulatory toxicological studies was advanced to phase 1
clinical trials. Clinical data on human pharmacokinetics, safety and tolerability will be reported in due
course.
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Experimental Section
General Experimental Methods.
All reactions were carried out under dry nitrogen. Commercially available reagents were used without
further purification. Solvents and gases were dried according to standard procedures. Organic solvents
were evaporated with reduced pressure using a rotary evaporator. Purity of final compounds was
assessed by HPLC with UV detection at 215 nm; all tested compounds were >95% purity. NMR spectra
were recorded on a Varian 500 MHz spectrometer equipped with a 1H{13C/15N} Triple Resonance 13C
Enhanced Salt Tolerant Cold Probe in DMSO-d6. Chemical shifts are referenced to TMS. HRMS analyses
were performed on a Finnigan MAT 95 XP mass spectrometer (Finnigan, Bremen, Germany). The
ionization method was EI and operated in positive ion mode. The ion source temperature was set at
220◦C, the applied ionization energy was 70 eV. Data acquisition and analysis were accomplished with
Xcalibur software version 2.0 (Thermo Fisher Scientific Inc.). The quinoline part, the benzenesulfonyl
moiety, and the third ring of the molecules are numbered as <1…8a>, <1’…6’> and <1’’…6’’ or 7’’
depending on the structure>, respectively. Melting points were determined in open glass capillaries
using Büchi 540 melting point apparatus and are uncorrected.
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General Procedure for the synthesis of 4-R3-aryl-R2-3-(R1- arylsulfonyl)-quinolines (Scheme 1)
STEP1: The mixture of ethylchloroacetate and sodium arylsulfinate (4) in DMF (1 mL/mmol) was stirred
and heated at 80°C for 2 h. The solution was diluted with water (3 mL/mmol). The separated oil was
extracted with chloroform and washed with water. The organic phase was evaporated in vacuo to give
methyl 2-(arylsulfonyl)acetates (5) in 60-80% yield. STEP2: An equimolar mixture of arylsulfonyl
acetate (5) and triethyl orthoformate was stirred at 150 °C for 3 h with simultaneous distillation of
ethanol, and then evaporated to dryness. The crude methyl 3-ethoxy-2-(arylsulfonyl)-2-propenoates
(6) were obtained in 90–95% yield and were used in the next step without purification. STEP3: The
mixture of 25 mmol of methyl 3-ethoxy-2-(arylsulfonyl)-2-propenoate (6) and 25 mmol of the
corresponding aniline (7) in 20 ml of diphenyl ether was heated at near reflux for 1 h. After cooling the
precipitate was filtered, washed with ether and crystallized from an appropriate solvent to give R2-3-
(R1-arylsulfonyl)-4(1H)-quinolinone (8) in 35-55% yield. STEP4: 10 mmol of R2-3-(R1-arylsulfonyl)-
4(1H)-quinolinone (8) in 50 mmol of POCl3 was refluxed for 2-3 h. Excess POCl3 was evaporated in
vacuo. The residue was extracted with chloroform and washed with water. The organic phase was
evaporated in vacuo yielding R2-4-chloro-3-(R1-arylsulfonyl)-quinoline (9) in 90-95%. STEP5: 0.2 mmol
of the corresponding R2-4-chloro-3-(R1-arylsulfonyl)-quinoline (9) and 0.3 mmol of R3C6H4B(OH)2 (10)
in 2 ml of 1,4-dioxane were stirred for 20 h at 90C with 1 mmol of K2CO3 and 0.01 mmol of Pd(PPh3)4.
After cooling, chloroform (10 mL) was added; the mixture was purified by chromatography on silica gel
and subsequent crystallization from methanol to give the final product as 4-R3-aryl-R2-3-(R1-
arylsulfonyl)-quinolines (11) in 50-90% yield. All 4-phenyl-3-aryl-sulfoquinolines reported were
prepared by the general procedure.
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4-(4-Chlorophenyl)-3-tosylquinoline hydrochloride (3): 4-(4-chlorophenyl)-3-tosylquinoline (40 mg,
0.102 mmol) - prepared according to the general procedure - was dissolved in ethyl acetate (15 ml)
then HCl solution in ethyl acetate (c = 1.6 M, 0.14 ml, 0.224 mmol) was added dropwise to the solution.
The precipitated solid was filtered, washed with ethyl acetate, and dried under vacuum. Yield: 35 mg
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(80%). Mp: 184-186 oC. 1H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.16-8.25 (m, 1H), 7.98 (ddd, J=8.4,
6.9, 1.4 Hz, 1H), 7.60-7.69 (m, 1H), 7.41-7.52 (m, 2H), 7.31-7.37 (m, 2H), 7.23-7.30 (m, 3H), 6.96 - 7.07
(m, 2 H), 2.36 (s, 3H). EI-HRMS: calcd for C22H16O2NClS [Mbase]+: 393.05848; found: 393.05831; delta= -
0.4 ppm. EI-MS m/z(rel int%): 393(100); 392(57); 400(8); 328(18); 294(8); 286(11); 254(14); 238(8);
226(14); 203(16); 176(18); 139(7); 36(2).
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6-Chloro-4-(4-chlorophenyl)-7-fluoro-3-((4-fluorophenyl)sulfonyl)quinoline (12): Mp: 172 C. H NMR
(500 MHz, DMSO-d6) δ ppm 9.67 (s, 1 H) 8.29 (d, J=10.0 Hz, 1 H) 7.46 - 7.55 (m, 4 H) 7.36 (d, J=7.8 Hz,
1 H) 7.27 - 7.34 (m, 2 H) 7.02 - 7.09 (m, 2 H). EI-HRMS: calcd for C21H11O2NCl2F2S [M]+: 448.98501;
found: 448.98395; delta= -2.4 ppm. EI-MS m/z(rel int%): 449(100); 448(58); 414(3); 384(10); 349(9);
306(14); 289(7); 278(11); 255(25); 228(9); 219(12); 193(6) 159(3); 143(5); 95(7).
7-Chloro-4-(4-chlorophenyl)-6-fluoro-3-((4-fluorophenyl)sulfonyl)quinoline (13): Mp: 173 oC decomp.
1H NMR (500 MHz, DMSO-d6) δ ppm 9.65 (s, 1 H) 8.57 (d, J=7.3 Hz, 1 H) 7.46 - 7.55 (m, 4 H) 7.27 -
7.35 (m, 1 H) 7.11 (d, J=10.0 Hz, 1 H) 6.98 - 7.06 (m, 2 H). EI-HRMS: calcd for C21H11O2NCl2F2S [M]+:
448.98501; found: 448.98429; delta= -1.6 ppm. EI-MS m/z(rel int%): 449(100); 448(55); 384(12);
349(8); 306(16); 290(7); 278(12); 255(23); 228(9); 219(11); 193(5) 159(3); 143(6); 95(7).
o
7-Chloro-4-(4-chlorophenyl)-8-fluoro-3-((4-fluorophenyl)sulfonyl)quinoline (14): Mp: 180 C decomp.
1H NMR (500 MHz, DMSO-d6) δ ppm 9.71 (s, 1 H) 7.78 (dd, J=9.3, 6.9 Hz, 1 H) 7.44 - 7.57 (m, 4 H) 7.27
- 7.35 (m, 1 H) 7.10 (dd, J=9.3, 1.4 Hz, 1 H) 6.97 - 7.07 (m, 2 H). EI-HRMS: calcd for C21H11O2NCl2F2S [M]+:
448.98501; found: 448.98385; delta= -2.6 ppm. EI-MS m/z(rel int%): 449(100); 448(47); 384(10); 350(7);
306(15); 290(7); 278(12); 255(24); 228(6); 219(11); 193(5) 159(3); 143(5); 95(7).
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4-(4-Chlorophenyl)-8-fluoro-3-((4-fluorophenyl)sulfonyl)quinoline (15): Mp: 169-170 C. H NMR (500
MHz, DMSO-d6) δ ppm 9.68 (s, 1 H) 7.85 (ddd, J=10.5, 7.8, 1.1 Hz, 1 H) 7.63 (td, J=8.2, 5.1 Hz, 1 H) 7.50
- 7.56 (m, 2 H) 7.44 - 7.50 (m, 2 H) 7.23 - 7.35 (m, 2 H) 7.09 (d, J=8.5 Hz, 1 H) 7.01 - 7.06 (m, 2 H). EI-
HRMS: calcd for C21H12O2NClF2S [M]+: 415.02398; found: 415.02359; delta= -1.0 ppm. EI-MS m/z(rel
int%): 415(100); 414(42); 350(13); 316(6); 272(10); 256(8); 255(10); 244(11); 221(18); 194(9); 143(3);
95(4).
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4-(4-Chlorophenyl)-6-fluoro-3-((4-fluorophenyl)sulfonyl)quinoline (16): Mp: 142-143 C. H NMR (500
MHz, DMSO-d6) δ ppm 9.62 (s, 1 H) 8.33 (dd, J=9.3, 5.4 Hz, 1 H) 7.94 (ddd, J=9.3, 8.1, 2.9 Hz, 1 H) 7.45
- 7.55 (m, 4 H) 7.25 - 7.35 (m, 2 H) 6.99 - 7.07 (m, 2 H) 6.89 (dd, J=9.8, 2.8 Hz, 1 H). EI-HRMS: calcd for
C21H12O2NClF2S [M]+: 415.02398; found: 415.02328; delta= -1.7 ppm. EI-MS m/z(rel int%): 415(100);
414(51); 350(15); 316(7); 272(11); 256(8); 255(8); 244(12); 221(22); 194(13); 143(3); 95(4).
4-(4-Chlorophenyl)-7-fluoro-3-((4-fluorophenyl)sulfonyl)quinoline (17): Mp: 168-169 oC. 1H NMR (500
MHz, DMSO-d6) δ ppm 9.65 (s, 1 H) 8.02 (dd, J=9.9, 2.7 Hz, 1 H) 7.59 (ddd, J=9.4, 8.3, 2.6 Hz, 1 H) 7.45
- 7.54 (m, 4 H) 7.35 (dd, J=9.3, 6.0 Hz, 1 H) 7.25 - 7.33 (m, 2 H) 7.00 - 7.07 (m, 2 H). EI-HRMS: calcd for
C21H12O2NClF2S [M]+: 415.02398; found: 415.02343; delta= -1.3 ppm. EI-MS m/z(rel int%): 415(100);
414(52); 350(15); 316(6); 272(16); 256(8); 255(7); 244(14); 221(20); 194(15); 143(3); 95(4).
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6-Chloro-4-(4-chlorophenyl)-3-((4-fluorophenyl)sulfonyl)quinoline (18): Mp: 196-198 C. H NMR (500
MHz, DMSO-d6) δ ppm 9.65 (s, 1 H) 8.26 (d, J=9.1 Hz, 1 H) 8.02 (dd, J=9.0, 2.4 Hz, 1 H) 7.47 - 7.55 (m, 4
H) 7.26 - 7.34 (m, 2 H) 7.18 (d, J=2.2 Hz, 1 H) 7.01 - 7.09 (m, 2 H). EI-HRMS: calcd for C21H12O2NCl2FS
[M]+: 430.99443; found: 430.99410; delta= -0.8 ppm. EI-MS m/z(rel.int.%): 431(100); 396(3); 366(10);
332(7); 288(9); 271(9); 260(10); 237(23); 210(10); 201(11); 175(6).
4-(4-Chlorophenyl)-3-((4-fluorophenyl)sulfonyl)quinoline-6-carbonitrile (19): Mp: 167-168 oC. 1H NMR
(500 MHz, DMSO-d6) δ ppm 9.77 (s, 1 H) 8.38 (d, J=8.6 Hz, 1 H) 8.29 (dd, J=8.7, 1.9 Hz, 1 H) 7.79 (d,
J=1.8 Hz, 1 H) 7.45 - 7.56 (m, 4 H) 7.27 - 7.35 (m, 1 H) 7.02 - 7.09 (m, 2 H). EI-HRMS: calcd for
C22H12O2N2ClFS [M]+: 422.02866; found: 422.02828; delta= -0.9 ppm. EI-MS m/z(rel int%): 422(100);
421(48); 387(13); 357(13); 323(10); 311(4); 279(10); 262(13); 251(8); 228(18); 201(14); 143(7); 95(8).
7-Chloro-4-(4-chlorophenyl)-3-((4-fluorophenyl)sulfonyl)quinoline (20): Mp: 194-196 oC. 1H NMR (500
MHz, DMSO-d6) δ ppm 9.65 (s, 1 H) 8.32 (d, J=2.2 Hz, 1 H) 7.69 (dd, J=9.1, 2.2 Hz, 1 H) 7.46 - 7.55 (m,
4 H) 7.26 - 7.34 (m, 3 H) 7.00 - 7.07 (m, 2 H). EI-HRMS: calcd for C21H12O2NCl2FS [M]+: 430.99443;
found: 430.99383; delta= -1.4 ppm. EI-MS m/z(rel int%): 431(100); 430(47); 366(10); 332(7); 320(4);
288(16); 272(7); 260(15); 237(21); 210(12); 201(11); 175(6); 174(6).
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4-(4-Chlorophenyl)-3-((4-fluorophenyl)sulfonyl)quinoline-7-carbonitrile (21): Mp: 222 C decomp. H
NMR (500 MHz, DMSO-d6) δ ppm 9.75 (s, 1 H) 8.72 - 8.93 (m, 1 H) 7.93 (dd, J=8.8, 1.6 Hz, 1 H) 7.52 -
7.57 (m, 2 H) 7.48 - 7.52 (m, 2 H) 7.42 (d, J=8.8 Hz, 1 H) 7.26 - 7.35 (m, 2 H) 7.02 - 7.10 (m, 2 H). EI-
HRMS: calcd for C22H12O2N2ClFS [M]+: 422.02866; found: 422.02767; delta= -2.3 ppm. EI-MS m/z(rel
int%): 422(100); 421(53); 357(15); 323(8); 311(5); 279(13); 263(7); 251(10); 228(16); 201(15); 143(9);
95(8).
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6-Chloro-4-(4-chlorophenyl)-8-fluoro-3-((4-fluorophenyl)sulfonyl)quinoline (22): Mp: 198-199 C. H
NMR (500 MHz, DMSO-d6) δ ppm 9.69 (s, 1 H) 8.11 (dd, J=10.0, 2.2 Hz, 1 H) 7.47 - 7.55 (m, 4 H) 7.27 -
7.36 (m, 2 H) 7.03 - 7.09 (m, 2 H) 7.01 (dd, J=2.1, 1.2 Hz, 1 H). EI-HRMS: calcd for C21H11O2NCl2F2S [M]+:
448.98501; found: 448.98629; delta=2.8 ppm. EI-MS m/z(rel int%): 449(100); 448(32); 414(3); 384(8);
350(7); 306(7); 289(10); 278(8); 255(21); 228(4); 219(11); 193(4) 159(3); 143(6); 95(7).
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3-((3-Chloro-4-fluorophenyl)sulfonyl)-7-fluoro-4-(4-fluorophenyl)quinoline (23): Mp: 176-177 C. H
NMR (500 MHz, DMSO-d6) δ ppm 9.67 (s, 1 H) 8.03 (dd, J=9.8, 2.7 Hz, 1 H) 7.60 (ddd, J=9.4, 8.3, 2.7 Hz,
1 H) 7.46 - 7.57 (m, 2 H) 7.39 - 7.42 (m, 1 H) 7.37 (dd, J=9.3, 6.0 Hz, 1 H) 7.22 - 7.33 (m, 1 H) 7.02 - 7.12
(m, 2 H). EI-HRMS: calcd for C21H11O2NClF3S [M]+: 433.01456; found: 433.01367; delta= -2.1 ppm. EI-
MS m/z(rel int%): 433(100); 368(10); 333(13); 288(9); 256(22); 240(29); 228(20); 212(14); 193(8).
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3-((7-Fluoro-4-(4-fluorophenyl)quinolin-3-yl)sulfonyl)benzonitrile (24): Mp: 182-183 C. H NMR (500
MHz, DMSO-d6) δ ppm 9.68 (s, 1 H) 8.10 (dt, J=7.8, 1.3 Hz, 1 H) 8.04 (dd, J=9.9, 2.7 Hz, 1 H) 7.69 - 7.75
(m, 2 H) 7.62 - 7.67 (m, 1 H) 7.60 (ddd, J=9.4, 8.3, 2.7 Hz, 1 H) 7.36 (dd, J=9.3, 6.0 Hz, 1 H) 7.21 - 7.29
(m, 1 H) 6.99 - 7.08 (m, 2 H). EI-HRMS: calcd for C22H12O2N2F2S [M]+: 406.05821; found: 406.05760;
delta= -1.5 ppm. EI-MS m/z(rel int%): 406(100); 341(22); 288(4); 256(13); 240(26); 228(13); 212(12);
193(7).
3-((4-(4-Chlorophenyl)-7-fluoroquinolin-3-yl)sulfonyl)benzonitrile (25): Mp: 209 oC. 1H NMR (500 MHz,
DMSO-d6) δ ppm 9.68 (s, 1 H) 8.11 (ddd, J=7.7, 1.4, 1.2 Hz, 1 H) 8.04 (dd, J=9.9, 2.6 Hz, 1 H) 7.73 - 7.78
(m, 2 H) 7.65 (td, J=7.8, 0.7 Hz, 1 H) 7.60 (ddd, J=9.3, 8.3, 2.7 Hz, 1 H) 7.43 - 7.50 (m, 2 H) 7.37 (dd,
J=9.3, 6.0 Hz, 1 H) 6.97 - 7.07 (m, 2 H). EI-HRMS: calcd for C22H12O2N2ClFS [M]+: 422.02866; found:
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422.02781; delta= -2.0 ppm. EI-MS m/z(rel int%): 422(100); 387(3); 357(15); 323(6); 272(11); 256(14);
244(10); 221(24); 194(16).
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3-((3,5-Dichlorophenyl)sulfonyl)-7-fluoro-4-(3-fluorophenyl)quinoline (26): Mp: 198-199 C. H NMR
(500 MHz, DMSO-d6) δ ppm 9.68 (s, 1 H) 8.05 (dd, J=9.9, 2.6 Hz, 1 H) 7.97 (t, J=1.9 Hz, 1 H) 7.57 - 7.67
(m, 1 H) 7.46 - 7.54 (m, 1 H) 7.39 - 7.45 (m, 2 H) 7.38 (d, J=1.8 Hz, 2 H) 6.88 - 6.98 (m, 2 H). EI-HRMS:
calcd for C21H11O2NCl2F2S [M]+: 448.98501; found: 448.98426; delta= -1.7 ppm. EI-MS m/z(rel int%):
449(100); 414(6); 384(14); 349(12); 288(10); 256(28); 240(43); 228(24); 212(17); 193(10).
3-((3,5-Difluorophenyl)sulfonyl)-7-fluoro-4-(4-fluorophenyl)quinoline (27): Mp: 162-164 oC. 1H NMR
(500 MHz, DMSO-d6) δ ppm 9.65 (s, 1 H) 8.04 (dd, J=9.9, 2.6 Hz, 1 H) 7.53 - 7.71 (m, 2 H) 7.39 (dd,
J=9.3, 6.0 Hz, 1 H) 7.22 - 7.30 (m, 1 H) 7.07 - 7.15 (m, 4 H). EI-HRMS: calcd for C21H11O2NF4S [M]+:
417.04411; found: 417.04397; delta= -0.3 ppm. EI-MS m/z(rel int%): 417(100); 416(32); 352(22);
288(5); 256(16); 240(32); 239(17); 228(16); 212(12); 193(7).
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3-((3,5-Dichlorophenyl)sulfonyl)-8-fluoro-4-(4-fluorophenyl)quinoline (28): Mp: 189-191 oC. 1H NMR
(500 MHz, DMSO-d6) δ ppm 9.69 (s, 1 H) 7.94 (t, J=1.9 Hz, 1 H) 7.87 (ddd, J=10.6, 7.8, 1.0 Hz, 1 H) 7.64
(td, J=8.2, 5.1 Hz, 1 H) 7.33 (d, J=1.9 Hz, 2 H) 7.24 - 7.31 (m, 1 H) 7.05 - 7.15 (m, 3 H). EI-HRMS: calcd
for C21H11O2NCl2F2S [M]+: 448.98501; found: 448.98676; delta=3.9 ppm. EI-MS m/z(rel int%):
449(100); 448(27); 414(4); 384(8); 350(6); 349(7); 288(6); 256(16); 240(30); 239(28); 228(17); 220(8);
212(10); 193(8).
8-Fluoro-4-(4-fluorophenyl)-3-((3-fluorophenyl)sulfonyl)quinoline (29): Mp: 123-124 oC. 1H NMR (500
MHz, DMSO-d6) δ ppm 9.69 (s, 1 H) 7.86 (ddd, J=10.5, 7.7, 1.0 Hz, 1 H) 7.64 (td, J=8.2, 5.1 Hz, 1 H)
7.47 - 7.56 (m, 2 H) 7.27 - 7.33 (m, 1 H) 7.20 - 7.27 (m, 1 H) 7.15 - 7.19 (m, 1 H) 7.11 (d, J=8.6 Hz, 1 H)
6.99 - 7.09 (m, 3 H). EI-HRMS: calcd for C21H12O2NF3S [M]+: 399.05354; found: 399.05255; delta= -2.5
ppm. EI-MS m/z(rel int%): 399(100); 334(17); 288(5); 256(12); 240(19); 239(19); 228(15); 220(5);
212(8); 193(5).
3-((3,5-Dichlorophenyl)sulfonyl)-7-fluoro-4-(4-fluorophenyl)quinoline (30): Mp: 182-184 oC. 1H NMR
(500 MHz, DMSO-d6) δ ppm 9.66 (s, 1 H) 8.04 (dd, J=9.8, 2.5 Hz, 1 H) 7.94 (t, J=1.8 Hz, 1 H) 7.61 (td,
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J=8.8, 2.6 Hz, 1 H) 7.39 (dd, J=9.3, 6.0 Hz, 1 H) 7.32 (d, J=1.8 Hz, 2 H) 7.24 - 7.31 (m, 2 H) 7.06 - 7.13
(m, 2 H). EI-HRMS: calcd for C21H11O2NCl2F2S [M]+: 448.98501; found: 448.98467; delta= -0.8 ppm. EI-
MS m/z(rel int%): 449(100); 448(38); 414(5); 384(10); 350(7); 349(10); 288(9); 256(24); 240(41);
239(24); 228(21); 220(5); 212(16); 193(9).
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3-((3,5-Difluorophenyl)sulfonyl)-7-fluoro-4-(3-fluorophenyl)quinoline (31): Mp: 170-171 oC. 1H NMR
(500 MHz, DMSO-d6) δ ppm 9.66 (s, 1 H) 8.05 (dd, J=9.8, 2.7 Hz, 1 H) 7.66 (tt, J=9.2, 2.2 Hz, 1 H) 7.62
(ddd, J=9.2, 8.4, 2.7 Hz, 1 H) 7.48 (td, J=8.0, 6.0 Hz, 1 H) 7.35 - 7.44 (m, 2 H) 7.07 - 7.21 (m, 2 H) 6.86 -
7.00 (m, 2 H). EI-HRMS: calcd for C21H11O2NF4S [M]+: 417.04411; found: 417.04384; delta= -0.7 ppm.
EI-MS m/z(rel int%): 417(100); 416(41); 352(27); 288(5); 256(17); 240(30); 239(18); 228(17); 212(11);
193(7).
3-((3,4-Difluorophenyl)sulfonyl)-7-fluoro-4-(44-fluorophenyl)quinoline (32): Mp: 159-161 oC. 1H NMR
(500 MHz, DMSO-d6) δ ppm 9.66 (s, 1 H) 8.03 (dd, J=9.9, 2.6 Hz, 1 H) 7.60 (ddd, J=9.3, 8.4, 2.7 Hz, 1 H)
7.51 - 7.58 (m, 1 H) 7.46 (ddd, J=9.8, 7.4, 2.3 Hz, 1 H) 7.37 (dd, J=9.4, 6.0 Hz, 1 H) 7.23 - 7.32 (m, 3 H)
7.05 - 7.12 (m, 2 H). EI-HRMS: calcd for C21H11O2NF4S [M]+: 417.04411; found: 417.04373; delta= -0.9
ppm. EI-MS m/z(rel int%): 417(100); 416(47); 352(21); 288(8); 256(17); 240(25); 239(16); 228(17);
212(11); 193(6).
3-((3-Chloro-4-fluorophenyl)sulfonyl)-4-(4-chlorophenyl)-7-fluoroquinoline (33): Mp: 143-144 oC. 1H
NMR (500 MHz, DMSO-d6) δ ppm 9.67 (s, 1 H) 8.03 (dd, J=9.9, 2.6 Hz, 1 H) 7.60 (ddd, J=9.4, 8.3, 2.7 Hz,
1 H) 7.48 - 7.57 (m, 4 H) 7.39 (dd, J=7.0, 2.2 Hz, 1 H) 7.37 (dd, J=9.3, 6.4 Hz, 1 H) 7.02 - 7.09 (m, 2 H).
EI-HRMS: calcd for C21H11O2NCl2F2S [M]+: 448.98501; found: 448.98643; delta=3.2 ppm. EI-MS m/z(rel
int%): 449(100); 448(47); 384(8); 349(12); 272(21); 256(15); 244(17); 221(29); 194(20).
3-((3,5-Difluorophenyl)sulfonyl)-8-fluoro-4-(4-fluorophenyl)quinoline (34): Mp: 177-179 oC. 1H NMR
(500 MHz, DMSO-d6) δ ppm 9.68 (s, 1 H) 7.87 (ddd, J=10.5, 7.8, 1.0 Hz, 1 H) 7.58 - 7.71 (m, 2 H) 7.21 -
7.34 (m, 1 H) 7.08 - 7.16 (m, 6 H). EI-HRMS: calcd for C21H11O2NF4S [M]+: 417.04411; found:
417.04398; delta= -0.3 ppm. EI-MS m/z(rel int%): 417(100); 416(24); 352(15); 288(3); 256(9); 240(23);
239(22); 228(13); 220(6); 212(7); 193(5).
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