N-Methylanilide and N-methylbenzamide derivatives as phosphodiesterase 10A (PDE10A) inhibitors

Article abstract of DOI:10.1016/j.bmc.2013.07.030

PDE10A is a recently identified phosphodiesterase with a quite remarkable localization since the protein is abundant only in brain tissue. Based on this unique localization, research has focused extensively on using PDE10A modulators as a novel therapeutic approach for dysfunction in the basal ganglia circuit including Parkinson's disease, Huntington's disease, schizophrenia, addiction and obsessive compulsive disorder. Medicinal chemistry efforts identified the N-methyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-isonicotinamide (8) as a nanomolar PDE10A inhibitor. A subsequent Lead-optimization program identified analogous N-methylanilides and their corresponding N-methylbenzamides (29) as potent PDE10A inhibitors, concurrently some interesting and unexpected binding modes were identified.

Full text of DOI:10.1016/j.bmc.2013.07.030

Bioorganic & Medicinal Chemistry 21 (2013) 6053–6062
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
N-Methylanilide and N-methylbenzamide derivatives
as phosphodiesterase 10A (PDE10A) inhibitors
a
a
b
b
John Paul Kilburn a, , Jan Kehler , Morten Langgård , Mette N. Erichsen , Sebastian Leth-Petersen ,
⇑
Mogens Larsen c, Claus Tornby Christoffersen d, Jacob Nielsen e
a H. Lundbeck A/S, Department of Medicinal Chemistry, DK-2500 Valby, Denmark
b Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, DK-2100 Copenhagen, Denmark
c LEO Pharma A/S, Department of Medicinal Chemistry, DK-2750 Ballerup, Denmark
d H. Lundbeck A/S, Department of Molecular Pharmacology, DK-2500 Valby, Denmark
e H. Lundbeck A/S, Department of Molecular Neurobiology, DK-2500 Valby, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 April 2013
Revised 9 July 2013
Accepted 12 July 2013
Available online 23 July 2013
PDE10A is a recently identified phosphodiesterase with a quite remarkable localization since the protein
is abundant only in brain tissue. Based on this unique localization, research has focused extensively on
using PDE10A modulators as a novel therapeutic approach for dysfunction in the basal ganglia circuit
including Parkinson’s disease, Huntington’s disease, schizophrenia, addiction and obsessive compulsive
disorder. Medicinal chemistry efforts identified the N-methyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-iso-
nicotinamide (8) as a nanomolar PDE10A inhibitor. A subsequent Lead-optimization program identified
analogous N-methylanilides and their corresponding N-methylbenzamides (29) as potent PDE10A inhib-
itors, concurrently some interesting and unexpected binding modes were identified.
Keywords:
Phosphodieasterase 10A inhibitors
Schizophrenia
Ó 2013 Elsevier Ltd. All rights reserved.
Antipsychotics
Molecular modeling
MPO
1. Introduction
Parkinson’s disease, Huntington’s disease, schizophrenia, addiction
and obsessive compulsive disorder.4
The cyclic nucleotides cyclic adenosine monophosphate (cAMP)
and cyclic guanosine monophosphate (cGMP) are ubiquitous intra-
cellular messengers responsible for mediation of the biological re-
sponse of a variety of extracellular signals, including hormones,
light and neurotransmitters.1 In neurons, the response includes
the activation of cAMP- and cGMP-dependent kinases and subse-
quent phosphorylation of proteins involved in acute regulation of
synaptic transmission as well as in neuronal differentiation and
survival.2,3
Early studies on the relative selective PDE inhibitor papaverine
(Fig. 1) indicated a possible link between antipsychotic activity and
PDE10A inhibition.4d,8 Subsequent studies have yielded several
new compound classes that selectively inhibit PDE10A, notably
MP-10 (3, Fig. 1), which is currently under clinical evaluation for
N
O
N
N
N
O
The phosphodiesterases (PDEs) are a family of bimetallic hydro-
lase enzymes that inactivate cAMP/cGMP by catalytic hydrolysis of
the 30-ester bond, forming the inactive 50-monophosphate.1,3 Phos-
phodiesterase 10A (PDE10A) is a basal ganglia specific hydrolase
that can degrade both cAMP and cGMP. Based on the unique local-
ization of PDE10A with predominant expression in the medium
spiny neurons of the striatal complex, research has focused on
the use of PDE10A modulators as a novel therapeutic approach
for diseases with dysfunction in the basal ganglia circuit including
O
N
N
N
O
O
N
N
O
O
N
O
1, papaverine
2, PQ10
3, MP-10
N
N
N
O
O
N
N
O
N
N
4
8
Figure 1. Some published PDE10A inhibitors 1,4d 2,5b 3,6 4,7 and the novel N-
methylanilide lead 8.
⇑
Corresponding author. Tel.: +45 30833215.
E-mail address: jpk@lundbeck.com (J.P. Kilburn).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.07.030

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J. P. Kilburn et al. / Bioorg. Med. Chem. 21 (2013) 6053–6062
the treatment of schizophrenia.4,5 Preclinical evidence suggests
that a PDE10A inhibitor could provide anti-psychotic, pro-cogni-
tive and negative symptom efficacy.4,5
In our search for PDE10A inhibitors, we decided to investigate
the possibilities of identifying chemotypes with an MP10-like
structure and binding properties. In our pursuit we discovered that
substituted N-methylanilides were potent and selective inhibitors
of PDE10A. The first compound 8 (Fig. 1, Table 1) was a PDE10A
inhibitor with similar potency as papaverine. Compound 8 was
an attractive starting point for several reasons: it was metaboli-
cally stable (HClint 1.1 L/min, human liver blood flow = 1.4 L/
H
N
R1
H
N
R1
NH2
b
a
Route 1
O
R2
O
O
HO
HO
6
5
c
R3
N
R1
NH
a then b
O
Route 2
R2
O
Route 2: where R3 = CH3-
or b then a
HO
min), it had no Herg activity (IC50 >50 lM), it had a good selectivity
Scheme 1. Synthesis of N-substituted anilides. Procedures: (a) R1COCl, Et3N, THF or
R1COOH, EDCꢀHCl, HOBt, DIPEA, DMF; (b) R2CH2Cl, K2CO3, CH3CN; (c) R3I, NaH, DMF.
for PDE10A compared to other PDEs (PDEx >50), good penetration
into the brain (B/P rat = 0.6) and it showed in vivo activity in a
model for antipsychotic activity with a potency (ED50 = 60 mg/kg)
similar to that of papaverine. However, 8 was considered to lack
potency when compared to MP-10, which in the same antipsy-
chotic model exhibits an ED50 of 1.8 mg/kg.
Table 2
R3 investigations
R3
A recent report9 on the correlation between physical chemical
properties and CNS druglike molecules has suggested the multipa-
rameter optimization (MPO) algorithm to predict the correlation
between physico-chemical properties and CNS druglike properties
based on historical compounds. Compounds are rated on a scale
from one to six, above four being a good score. The algorithm is
based on six physicochemical parameters: lipophilicity in form of
the calculated partition coefficient (cLogP), the calculated distribu-
tion coefficient (cLogD) at pH 7.4, molecular weight (MW), topo-
logical polar surface area (TPSA), number of hydrogen bond
donors (HBD) and the most basic center (pKa). A lead optimization
program founded on compound 8 was initiated with the aim of
increasing potency and using the MPO algorithm as a tool for selec-
tion of compounds.
O
N
N
O
N
a
Compound
R3
IC50 (nM)
7
8
H
CH3
33% Inh @ 2
250
lM
9
10
C2H5
C4H9
750
660
a
Values are means of two experiments with a standard deviation of 30%.
Next, we investigated the SAR at the R1 substituent while main-
taining R2 and R3 constant as the 2-quinoline (R2) and methyl (R3).
The results of which are shown in Table 3.
2. Results and discussion
PDE10A affinity was diminished by a factor of 2 when the
4-pyridyl (8) was substituted with a phenyl (11) at the R1 position.
More surprising was the significant affinity loss of the pyridyl-
regioisomers 12 and 13. Several analogues were prepared to inves-
tigate the limitations of the binding pocket: Compound 14, a 6,5
bicyclic system, demonstrated the apparent relatively large vol-
ume available in the PDE10A binding pocket. Fusing the 6,5 system
(15) yielded the first two-digit nanomolar inhibitor of PDE10A in
this series. Inverting the system to a 5,6 bicyclic system yielded
the most potent compounds 20 and 21.
Synthesis protocols employed for substituted N-methylanilides
are outlined in Scheme 1.
In one approach (Route 1), O-alkylation of starting material
4-aminophenol employing standard Williamson0s ether synthesis
conditions yielded anilines 5. Acylation of 5 employing acid chlo-
rides or carboxylic acids under standard amide bond forming con-
ditions, yielded anilides of general formula 6 and final compound
7. N-alkylation using alkyl iodides and sodium hydride as base
yielded the final compounds. In a second approach (Route 2) N-
methyl-4-aminophenol (R3 = methyl) was acylated then O-alkyl-
ated as previously described. The sequence of these two reactions
could be reversed depending on the focus of compound generation
to yield the objective N-methylanilides.
Investigations were now directed towards R2. The parent com-
pounds selected were 8 due to its high MPO score and compound
15 due to its high ligand efficiency and lack of requirement for pro-
tecting group chemistry. A total of 20 compounds were synthes-
ised and a representative sample of those are shown in Table 4.
All of the analogues synthesised were inferior in potency to the
parent 2-quinolinyl substituted compounds.
Due to the conformational similarity of this compound series to
the previously described clinical candidate MP-10, we decided to
try to get a deeper understanding of the binding by studying X-
ray crystal structures of complexes between MP-10 and the cata-
lytic domain of PDE10A. In the PDE10A-MP10 complex, the pyra-
zole ring provides an appropriate angle for the molecule to
extend into both the Q1 (pyridine binding) and Q2 (quinoline bind-
ing) pockets (Fig. 2).
Preliminary investigations were directed towards the role of R3,
while R1 and R2 were held constant as the 4-pyridyl (R1) and
2-quinoline (R2), respectively. Interestingly the secondary amide
analogue 7 with R3 = H was markedly less potent than the original
hit 8. Similarly, the ethyl- and butyl-analogues 9 and 10 had dimin-
ished affinities (Table 2).
Table 1
IC50 of compounds 1, 2, 3, 4 and 8 for the inhibition of PDE10A enzyme
a
Compound
PDE10A IC50 (nM)
A possible explanation for the reduction in potency of the pri-
mary amide 7 may be the that N–H anilides are almost exclusively
in trans conformation, whereas N-methyl anilides are found almost
exclusively in the cis conformation.10 Thus, the cis conformation of
N-methyl anilides may provide a conformational isostere for the
pyrazole ring in MP-10 (Fig. 2).
1, papaverine
2, PQ10
3, MP10
4
8
210
64
2.6
32
250
a
Values are means of three experiments with a standard deviation of 30%.

J. P. Kilburn et al. / Bioorg. Med. Chem. 21 (2013) 6053–6062
6055
Table 3
SAR investigations on diversity point R1
O
N
N
R1
O
a
Compound
R1
PDE10A inhibition at 2
88
lM (%)
PDE10A IC50 (nM)
MPO score
5.51
LEa
N
N
8
250
660
ND
0.32
0.30
ND
11
12
96
62
4.49
5.51
13
14
27
98
ND
5.51
4.01
ND
N
N
N
N
460
0.26
S
15
16
103
101
31
88
3.95
4.49
0.33
0.29
N
S
S
N
N
17
18
103
102
87
24
4.49
3.41
0.29
0.32
N
N
N
N
19
20
99
110
4.41
0.29
N
N
N
101
100
13
12
4.41
4.41
0.33
0.33
N
N
N
N
21
N
a
ND is not determined.
In order to clarify the binding motif of the N-methyl anilides,
divalent metals opposite of MP-10. This unexpected binding mode
provides possible explanations of the SAR data. The higher potency
of the 4-pyridyl (8) compared to the 2- and 3-pyridyl (12 and 13)
may be due to the nitrogen in the 4-pyridyl being presented to-
wards the water molecules encompassing the divalent metals.
The X-ray studies also explains why bulky groups are tolerated
as they extrude out of the binding pocket and why compounds
compounds 8 and 19 were co-crystallized with PDE10A (Fig. 3).
The X-ray structures confirmed the predicted binding of the
quinoline moiety in the Q2 binding pocket similarly to MP-10.
The N-methyl amide also provides the expected cis conformation,
but unexpectedly the R1 substituents of compound 8 and 19 are
presented out of the Q1 binding pocket directed towards the

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J. P. Kilburn et al. / Bioorg. Med. Chem. 21 (2013) 6053–6062
Table 4
SAR investigations on diversity point R2
Compound
Structure
PDE10A inhibition at 2
lM (%)
PDE10A IC50 (nM)
1600
MPO score
5.99
LE
O
N
22
N
N
88
0.29
O
N
O
N
N
23
24
25
O
90
98
1600
920
61
5.03
4.55
4.31
0.28
0.28
0.32
S
N
O
N
N
N
O
O
O
S
S
N
N
O
N
N
104
Figure 2. Left: illustration of the principle of the binding mode of MP-10. Right: X-ray crystal structure of MP-10 in complex with PDE10A determined by H. Lundbeck A/S
(Not published, crystal structure almost identical to that of PDB 3HR1).5d
20 and 21 which present their pyridyl nitrogens towards the water
enveloped divalent metals are highly potent PDE10A inhibitors.
We hypothesized that compounds 8 and 19 might be oriented
differently than predicted by MP10 studies because the configura-
tion of the amide bond enhanced the hydrogen bond between the
N-methyl moieties to the N–H of Gln-726 forcing the R1 substitu-
ent out of the binding pocket. Consequently, we decided to invert
the amide bond to address the possible binding orientation of
the corresponding N-methylbenzamides.
Synthesis strategies employed for substituted N-methylbenza-
mides are outlined in Scheme 2. The final compounds 26–32 were
prepared from the intermediate 4-(quinolin-2-ylmethoxy)-benzoic
acid11 either directly via amide bond formation with N-methyl
substituted amines or through amide bond formation with primary
amines followed by N-methylation with methyl iodide.
MP10-like binding mode in this case. The cis conformation of the
amide bond presents the R1 substituent into the Q1 binding pocket
and an overlay of the two co-crystal structures (MP10 and 32) show
the similarities in binding mode (Fig. 4). A similar binding mode
was also observed for compound 32 (results not shown). Thus,
inversion of the amide bond led to the intended binding mode,
but surprisingly the different binding modes gave similar PDE10A
affinity with only about twofold higher affinity of the ‘correctly’
binding N-methylanilides compared to the N-methylbenzamides.
Of the compounds made in development of this series, 15, 21
and 32 were of particular interest in that they show high potency
combined with a good MPO score or high ligand efficiency and
good selectivity for PDE10A compared to other PDEs (Table 6).
A closer look at their respective metabolic stability in human li-
ver microsomes indicates that as ligand efficiency increases, the
corresponding human metabolic stability decreases. This decrease
in human metabolic stability predicted from the decreasing MPO
scores which reflects their increase in MW and lipophilicity
(cLogD). Consequently, the observed decrease in human metabolic
The affinity and SAR of the relatively similar potencies between
N-methylanilides (8, 11 and 15) and the N-methylbenzamides (26,
29 and 32) appeared to be similar (Table 5). However, an X-ray
co-crystal structure of 32 bound to PDE10A (Fig. 4) revealed an

J. P. Kilburn et al. / Bioorg. Med. Chem. 21 (2013) 6053–6062
6057
Figure 3. X-ray crystal structures of PDE10A in complex with 8 and 19 showing the binding mode. Divalent metals zinc and magnesium are shown in magenta and purple,
respectively. Structure determined by H. Lundbeck A/S (Not published).
O
O
columns. Eluent systems are given in volume/volume concentra-
tions. 1H NMR-spectra were recorded on a 500 MHz Bruker Avance
AV500 instrument or on a 600 MHz Bruker Avance Ultrashield 600
plus instrument. The samples were prepared as CDCl3 solutions
using TMS/CDCl3 as internal standards, or DMSO-d6 solutions.
Chemical shifts (d) are given in parts per million (ppm), and cou-
pling constants (J) are given in Hertz (Hz). The following abbrevia-
tions are used: br = broad, s = singlet, d = doublet, dd = doublet of
doublet, t = triplet, dt = doublet of triplet, tt = triplet of triplet,
q = quartet, dq = doublet of quartet, m = multiplet.
R1
N
OH
a or b
N
N
O
O
26-32
Scheme 2. Synthesis of N-substituted benzamides. Procedures: (a) R1NHMe, HBTU,
DIPEA or (b) R1NH2, HBTU, DIPEA then MeI, NaH, DMF.
stability and lack of potency (cf. MP10) of compound 15, 21 and 32
meant the compounds did not meet the overall desired profile
(HLM Cl, int <1.4 L/min and PDE10A IC50 <10 nM) which prevented
the compounds from being further profiled in vivo (Table 7).
In summary, we have discovered substituted N-methylanilides
and N-methylbenzamides as a novel class of PDE10A inhibitors.
Employing structure–activity based drug design the initial potency
was improved by 20-fold, the structure–activity observations were
rationalized using X-ray crystal structure studies. Literature re-
ports on the conformation of N-methylamides assisted in identify-
ing a structural isostere for the pyrazole ring in MP-10. Although
the initial aim of increasing potency was achieved, the resulting
high microsomal intrinsic clearance of the compounds described
and the inability to circumvent this issue resulted in none of the
compounds being pursued further.
A.2. General procedure for the preparation of intermediates 5
exemplified by N-(4-Hydroxy-phenyl)-isonicotinamide
A solution of isonicotinoyl chloride (64 g, 0.46 mol) in dry THF
(450 mL) was added dropwise into a solution of 4-aminophenol
(50 g, 0.46 mol) and Et3N (47 g, 0.46 mol) in dry THF (500 mL)
cooled to 0 °C under an atmosphere of nitrogen. After the addition
was complete, the mixture was stirred at rt for 8 h. The volatiles
were removed under vacuum, and the residue was diluted with
water (500 mL) and ether (500 mL). The organics was separated,
washed with brine, dried over Na2SO4, filtered, and concentrated
under vacuum to give the title compound (66% yield) as a brown
solid. 1H NMR (DMSO-d6 500 MHz TMS): d 10.26 (s, 1H), 9.32 (s,
1H), 8.73 (dd, J = 4.4, 1.6 Hz, 2H), 7.81 (dd, J = 4.4, 1.6 Hz, 2H),
7.50 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H).
A. Experimental protocols
A.1. General
A.3. General procedure for the preparation of intermediates 6
exemplified by N-[4-(Quinolin-2-ylmethoxy)-phenyl]-
isonicotinamide (7)
Unless otherwise stated, all solvents and reagents were ob-
tained from commercial suppliers and used without further purifi-
cation unless otherwise stated. All reactions involving dry solvents
or air-sensitive agents were performed under a nitrogen or argon
atmosphere and glassware was dried prior to use. Solvents were
dried according to standard procedures. Reactions were monitored
by analytical thin-layer chromatography (TLC) analysis and analyt-
ical LC–MS. TLC was carried out using Merck silica gel 60 F254 alu-
minium sheets. The compounds were detected as single spots on
TLC plates and visualised using UV light (254 nm) and different
spraying reagents such as KMnO4, ninhydrin, and bromocresol
green, respectively. Flash chromatography was performed using
either a CombiFlash Rf System (Teledyne Isco, Inc.) on RediSep
columns or a Flashmaster II (Argonaut) on ISOLUTE Flash Si II
A
slurry of N-(4-hydroxy-phenyl)-isonicotinamide (1.61 g,
0.75 mmol) and K2CO3 (3.10 g, 2.25 mmol) in dry CH3CN
(100 mL) was stirred at room temperature for 20 min, then 2-chlo-
romethyl-quinoline (1.55 g, 0.75 mmol) was added. After addition
was complete, the mixture was stirred at reflux overnight. After
being cooled to room temperature, the reaction mixture was fil-
tered, and the filtrate was concentrated under vacuum. The residue
was crystallized from methanol to give the title compound as yel-
low solid (41% yield). 1H NMR (DMSO-d6 500 MHz TMS): d 8.39 (d,
J = 8.4 Hz, 1H), 8.01–7.96 (m, 2H), 7.92–7.89 (m, 2H), 7.78–7.74 (m,
1H), 7.67–7.64 (m, 3H), 7.61–7.57 (m, 1H), 7.53–7.45 (m, 3H),
7.05–7.01 (m, 2H), 5.33 (s, 2H). [M+H+]: 356.2.

6058
J. P. Kilburn et al. / Bioorg. Med. Chem. 21 (2013) 6053–6062
Table 5
SAR investigations on N-methylbenzamides
Compound
Structure
PDE10A inhibition at 2
94
lM (%)
PDE10A IC50 (nM)
950
MPO score
4.31
LE
N
26
0.30
N
O
O
O
N
N
N
N
27
100
400
5.34
0.28
N
O
N
N
N
N
N
28
29
30
101
101
105
240
140
130
5.34
5.56
4.65
0.29
0.34
0.30
N
O
O
O
N
N
O
N
N
N
N
N
N
N
N
O
O
O
O
O
31
32
105
109
93
16
4.63
3.94
0.31
0.34
N
O
S
N
O
Figure 4. X-ray crystal structures of PDE10A in complex with 32 and an overlay of the two co-crystal structures of 32 (green) together with MP10 (white) showing very
similar binding modes. Divalent metals zinc and magnesium are shown in magenta and purple, respectively. Structure determined by H. Lundbeck A/S (Not published).

J. P. Kilburn et al. / Bioorg. Med. Chem. 21 (2013) 6053–6062
6059
Table 6
7.80 (m, 1H), 7.79–7.70 (m, 1H), 7.63–7.59 (m, 1H), 7.59–7.51 (m,
1H), 7.45-6.80 (m, 10H), 5.30 (s, 2H), 3.46 (s, 3H). [M+H+]: 369.1.
Selectivity of compounds 8, 15, 21 and 32 for PDE10A compared to other PDEs
8
15
21
32
A.8. N-Methyl-N-(4-(quinolin-2-yloxy)phenyl)nicotinamide (12)
PDE10A
PDE2
PDE3A
PDE4D
PDE9
80
14
16
4
101
1
ND
ND
5
106
12
0
0
0
105
15
12
13
7
Prepared as described for compound 8 exchanging N-(4-hydro-
xy-phenyl)-isonicotinamide for N-(4-hydroxy-phenyl)-nicotin-
amide to yield the title compound as a yellow oil (22% yield). 1H
NMR (600 MHz, CDCl3): d 8.50 (s, 1H), 8.45–8.40 (m, 1H), 8.20–
8.18 (m, 1H), 8.10–8.05 (m, 1H), 7.82–7.80 (m, 1H), 7.77–7.70
(m, 1H), 7.61–7.52 (m, 2H), 7.19-6.80 (m, 5H), 5.40 (s, 2H), 3.46
(s, 3H). [M+H+]: 370.1.
22
a
ND is not determined. Results are given as% inhibition at 2 lM.
Table 7
Comparison of ligand efficiencies, MPO scores and metabolic stability (HLM Cl, int and
RLM Cl, int) of compounds 8, 15, 21 and 32
A.9. N-Methyl-N-(4-(quinolin-2-yloxy)phenyl)picolinamide (13)
8
15
21
32
MP10
Prepared as described for compound 8 exchanging N-(4-hydro-
PDE10A IC50 (nM)
LE
MW
cLogD
250
0.32
369
2.84
5.51
1.1
31
12
16
2.6
0.33
425
4.16
3.95
2.2
0.33
435
3.56
4.43
2.4
0.34
425
4.19
3.94
6.1
0.40
392
3.83
4.43
2.2
xy-phenyl)-isonicotinamide
for
N-(4-(quinolin-2-yloxy)
phenyl)picolinamide to yield the title compound as a yellow oil
(12% yield).
MPO
1H NMR (500 MHz, methanol-d4): d 8.96 (d, J = 8.8 Hz, 1H), 9.38
(d, J = 7.2 Hz, 1H), 8.26 (t, J = 8.8 Hz, 2H), 8.09 (t, J = 7.6 Hz, 1H),
7.99 (t, J = 8.4 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.79 (t, J = 7.6 Hz,
1H), 7.41 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 5.6 Hz, 1H), 7.17 (d,
J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 5.56 (s, 2H), 3.47 (s, 3H).
[M+H+]: 370.1.
HLM Cl, int (L/min)
RLM Cl, int (L/min)
23
18
90
150
58
A.4. General procedure for the alkylation of intermediates (6) as
exemplified by N-ethyl-N-(4-(quinolin-2-
ylmethoxy)phenyl)isonicotinamide (8)
A.10. Benzothiazole-6-carboxylic acid methyl-[4-(quinolin-2-
ylmethoxy)-phenyl]-amide (14)
A mixture of N-[4-(quinolin-2-ylmethoxy)-phenyl]-isonicotina-
mide (100 mg, 0.29 mmol) and NaH (53 mg, 1.32 mmol) in dry
DMF (3 mL) was stirred at room temperature for 15 min, then
CH3I (62 mg, 0.44 mmol) was added, the mixture was stirred an
additional 2 h at rt, 2 drops of ice-water was added to quench
the excess NaH. After evaporation, the residue was purified by pre-
parative HPLC to give the tile compound as a yellow oil (26% yield)
1H NMR (600 MHz, CD3CN) d 8.39 (s, 2H), 8.29 (d, J = 11.6 Hz, 1H),
8.00 (d, J = 11.6 Hz, 1H), 7.93 (d, J = 11.2 Hz, 1H), 7.76 (m, 1H), 7.59
(m, 2H), 7.08 (m, 4H), 6.92 (d, J = 9.2 Hz, 2H), 5.28 (s, 2H), 3.41 (s,
3H). [M+H+]: 370.1.
Benzothiazole-6-carboxylic acid (0.0717 g, 0.582 mmol) and 1-
hydroxybenzotriazole (118 mg, 0.874 mmol) were dissolved in
N,N-dimethylformamide (8 mL, 100 mmol). N-(3-dimethylamino-
propyl)-N0-ethylcarbodiimide hydrochloride (0.168 g, 0.874 mmol)
was added and the reaction was stirred at rt for 20 min. Methyl-[4-
(quinolin-2-ylmethoxy)-phenyl]-amine (0.153 g, 0.582 mmol) was
added followed by triethylamine (0.244 mL, 1.75 mmol). The reac-
tion was stirred at room temperature for 20 h. H2O (20 mL) was
added to the reaction and the mixture was extracted with ethyl
acetate (40 mL ꢁ 3). The combined organic phases were washed
with satd aq NaHCO3 (40 mL), dried with magnesium sulfate, fil-
tered and evaporated. The crude product was purified using col-
umn chromatography. The product fractions were combined and
evaporated and the residue crystallised from ethyl acetate/heptane
to yield the title compound as an off white solid (20% yield). 1H
NMR: (600 MHz, CDCl3) d 9.00 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H),
8.05 (d, J = 8.7 Hz, 1H), 8.01 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.83
(d, J = 8.2 Hz, 1H), 7.73 (dt, J = 1.4 Hz, J = 7.4 Hz, 1H), 7.59–7.53
(m, 2H), 7.35 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.86 (d,
J = 8.8 Hz, 2H), 5.29 (s, 2H), 3.49 (s, 3H). [M+H+]: 426.1.
A.5. N-Ethyl-N-(4-(quinolin-2-
ylmethoxy)phenyl)isonicotinamide (9)
Prepared as described for compound 8 exchanging CH3I for
C2H5I to yield the title compound as a yellow oil (14% yield). 1H
NMR: (600 MHz, DMSO-d6) d 8.53–8.52 (m, 2H), 8.42–8.40 (m,
1H), 8.03–7.99 (m, 2H), 7.80–7.78 (m, 1H), 7.68–7.61 (m, 2H),
7.21–7.18 (m, 2H), 6.94–6.89 (m, 2H), 6.68–6.60 (m, 2H), 5.27 (s,
1H), 4.39–4.30 (m, 2H), 1.39–1.33 (m, 3H). [M+H+]: 384.1.
A.6. N-Butyl-N-(4-(quinolin-2-ylmethoxy)phenyl)isonicotina
mide (10)
A.11. 4-(1H-Imidazol-1-yl)-N-methyl-N-(4-(quinolin-2-
ylmethoxy)phenyl)benzamide (15)
Prepared as described for compound 8 exchanging CH3I for n-
C4H9I to yield the title compound as a yellow oil (12% yield). 1H
NMR (500 MHz, methanol-d4): d 8.80 (d, J = 8.4 Hz, 1H), 8.62 (d,
J = 5.6 Hz, 2H), 8.21–8.16 (m, 2H), 8.01 (t, J = 7.6 Hz, 1H), 7.91 (d,
J = 8.4 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.75 (d, J = 6.4 Hz, 2H), 7.22 (d,
J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 5.49 (s, 2H), 3.94 (t, J = 7.2 Hz,
2H), 1.48–1.35 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). [M+H+]: 412.2.
This compound was synthesized according to compound 14 but
employing 4-(1H-imidazol-1-yl)benzoic acid instead of benzothia-
zole-6-carboxylic acid to yield the title compound as an off white
solid (27% yield). 1H NMR (600 MHz, CDCl3): d 8.20–8.12 (m, 1H),
8.10–8.00 (m, 1H), 7.87–7.77 (m, 2H), 7.77–7.70 (m, 1H), 7.66–
7.59 (m, 1H), 7.59–7.50 (m, 1H), 7.49-6.80 (m, 10H), 5.31 (s, 2H),
3.47 (s, 3H). [M+H+]: 435.1.
A.7. N-Methyl-N-(4-(quinolin-2-yloxy)phenyl)benzamide (11)
A.12. N-Methyl-4-(pyridin-4-yl)-N-(4-(quinolin-2-
Prepared as described for compound 8 exchanging N-(4-hydro-
xy-phenyl)-isonicotinamide for N-(4-hydroxy-phenyl)-benzamide
to yield the title compound as a yellow oil (14% yield). 1H NMR:
(600 MHz, CDCl3) d 8.21–8.17 (m, 1H), 8.10–8.02 (m, 1H), 7.87–
yloxy)phenyl)thiazole-2-carboxamide (16)
This compound was synthesized according to compound 14 but
employing 4-(pyridin-4-yl)thiazole-2-carboxylic acid instead of

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J. P. Kilburn et al. / Bioorg. Med. Chem. 21 (2013) 6053–6062
benzothiazole-6-carboxylic acid to yield the title compound as an
off white solid (60% yield). 1H NMR: (500 MHz, DMSO-d6) d 8.69–
8.60 (m, 2H), 8.34–8.27 (m, 1H), 8.02–7.95 (m, 3H), 7.82–7.74
(m, 1H), 7.67–7.52 (m, 4H), 7.21–7.15 (m, 2H), 7.05-6.99 (m, 2H),
5.43 (s, 2H), 3.47 (s, 3H). ([M+H+]: 453.3).
1H), 7.81 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.71–7.63 (m,
3H), 7.55 (t, J = 7.7 Hz, 1H), 7.24–7.7.03 (m, 5H), 5.76 (br s, 1H),
5.42 (s, 2H), 3.44 (s, 3H). [M+H+]: 436.2.
A.18. N-(4-(Imidazo[1,2-a]pyridin-2-yloxy)phenyl)-N-
methylisonicotinamide (22)
A.13. N-Methyl-4-(pyridin-3-yl)-N-(4-(quinolin-2-
yloxy)phenyl)thiazole-2-carboxamide (17)
Intermediate N-[4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-phe-
nyl]-isonicotinamide was synthesized according to compound 7
but employing 2-chloromethyl-imidazo[1,2-a]pyridine instead of
2-chloromethyl-quinoline. The title compound was prepared as
described for compound 8 exchanging N-(4-hydroxy-phenyl)-iso-
nicotinamide for N-[4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-phe-
nyl]-isonicotinamide to yield 22 as a yellow oil (26% yield). 1H
NMR (400 MHz, methanol-d4): d 8.79 (d, J = 6.8 Hz, 1H), 8.69 (d,
J = 5.6 Hz, 2H), 8.30 (s, 1H), 8.00–7.96 (m, 2H), 7.92 (d, J = 8.8 Hz,
2H), 7.50–7.46 (m, 1H), 7.26–7.23 (t, 2H), 7.04–7.01 (t, 2H), 5.35
(s, 2H), 3.48 (s, 3H). [M+H+]: 359.1.
This compound was synthesized according to compound 14
but employing 4-(pyridin-3-yl)thiazole-2-carboxylic acid instead
of benzothiazole-6-carboxylic acid to yield the title compound
as an off white solid (51% yield). 1H NMR: (500 MHz, DMSO-d6)
d 8.88–8.73 (br s, 1H), 8.68–8.59 (m, 1H), 8.36–8.26 (m, 1H),
8.04–7.93 (m, 4H), 7.80–7.75 (m, 1H), 7.49–7.45 (m, 1H), 7.20–
7.15 (m, 2H), 7.04-6.97 (m, 2H), 5.33 (s, 2H), 3.47 (s, 3H).
[M+H+]: 453.2.
A.14. N-Methyl-5-phenyl-N-(4-(quinolin-2-yloxy)phenyl)-1H-
pyrazole-3-carboxamide (18)
A.19. Intermediate N-(4-hydroxyphenyl)-N-
methylbenzo[d]thiazole-6-carboxamide
This compound was synthesized according to compound 14 but
employing 5-phenyl-2H-pyrazole-3-carboxylic acid instead of ben-
zothiazole-6-carboxylic acid to yield the title compound as an off
white solid (50% yield). 1H NMR: (500 MHz, CDCl3) d 11.16 (s,
1H), 8.15 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.81 (d,
J = 8.2 Hz, 1H), 7.75 (dt, J = 7.5 Hz, J = 1.4 Hz, 1H), 7.67 (d,
J = 8.9 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.52 (d, J = 7.5 Hz, 2H), 7.34
(t, J = 7.5 Hz, 2H), 7.31–7.26 (m, 1H), 7.21 (d, J = 8.8 Hz, 2H), 7.12
(d, J = 8.8 Hz, 2H), 5.46 (s, 2H), 5.26 (br s, 1H), 3.43 (s, 3H).
[M+H+]: 434.9.
Benzothiazole-6-carboxylic acid (6.00 g, 33.5 mmol) and 1-
hydroxybenzotriazole (6.79 g, 50.2 mmol) were dissolved in N,N-
dimethylformamide (500 mL, 6000 mmol). Then N-(3-dimethyl-
aminopropyl)-N0-ethylcarbodiimide
hydrochloride
(9.63 g,
50.2 mmol) was added and the reaction was stirred at room tem-
perature for 20 min. 4-(Methylamino)phenol sulphate (5.76 g,
16.7 mmol) was added followed by triethylamine (14.0 mL,
1.00E2 mmol). The reaction was stirred at room temperature for
5 days. The reaction mixture was evaporated and the residue was
suspended in H2O (300 mL) and extracted with ethyl acetate
(400 mL ꢁ 3). The combined organic phases were washed with
sat. aq. NaHCO3 (300 mL), dried with magnesium sulfate, filtered
and evaporated. The crude product was purified using Combiflash
(Silica, Column Size 220 g, Eluent: heptane:ethyl acetate). Fractions
containing the product were combined and evaporated to yield the
intermediate N-(4-hydroxyphenyl)-N-methylbenzo[d]thiazole-6-
carboxamide (26%) as light brown crystals. 1H NMR: (600 MHz,
DMSO) d 9.50 (s, 1H), 9.42 (s, 1H), 8.13 (br s, 1H), 7.89 (d,
J = 8.2 Hz, 1H), 7.35 (br s, 1H), 7.00 (d, J = 8.2 Hz, 2H), 6.60 (d,
J = 8.6 Hz, 2H), 3.34 (s, 3H). [M+H+]: 284.9.
A.15. N-Methyl-5-(pyridin-4-yl)-N-(4-(quinolin-2-
yloxy)phenyl)-1H-pyrazole-3-carboxamide (19)
This compound was synthesized according to compound 14 but
employing 5-pyridin-4-yl-2H-pyrazole-3-carboxylic acid instead
of benzothiazole-6-carboxylic acid to yield the title compound as
an off white solid (52% yield). 1H NMR: (500 MHz, CDCl3) d
11.80–11.50 (br s, 1H), 8.62–8.55 (m, 2H), 8.27–8.19 (m, 1H),
8.15–8.08 (m, 1H), 7.90–7.83 (m, 1H), 7.83–7.74 (m, 1H), 7.74–
7.68 (m, 1H), 7.63–7.55 (m, 1H), 7.97–7.88 (m, 2H), 7.30–7.12
(m, 5H), 5.49 (s, 2H), 5.30 (s, 1H), 3.46 (s, 3H). [M+H+]: 436.3.
A.20. N-Methyl-N-(4-((6-methylpyridin-2-
A.16. N-Methyl-5-(pyridin-3-yl)-N-(4-(quinolin-2-
yloxy)phenyl)-1H-pyrazole-3-carboxamide (20)
yl)methoxy)phenyl)isonicotinamide (23)
N-(4-Hydroxyphenyl)-N-methylbenzo[d]thiazole-6-carboxam-
ide (200 mg, 0.77 mmol), 2-(chloromethyl)-6-methylpyridine
(98.23 mg, 0.77 mmol), cesium carbonate (460 mg, 1.4 mmol)
and potassium iodide (230 mg, 1.4 mmol) were stirred in acetone
(30 mL) and heated to reflux for 21 h. The cooled reaction was
mixed with 100 mL water and extracted with EtOAc (3 ꢁ 75 mL).
The combined organic extracts were washed with brine, dried
(MgSO4), filtered and purified by flash chromatography (gradient,
heptane to EtOAc), yielding the product as a white solid (40%).
1H NMR: (500 MHz, DMSO-d6) d 9.41 (s, 1H), 8.14 (s, 1H), 7.89
(d, J = 8.4 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H),
7.22–7.17 (m, 1H), 7.14 (d, J = 8.5, 1H), 6.88 (d, J = 8.5 Hz, 1H),
5.02 (s, 2H), 3.36 (s, 3H), 2.44 (s, 3H). [M+H+]: 390.1.
This compound was synthesized according to compound 14 but
employing 5-pyridin-3-yl-2H-pyrazole-3-carboxylic acid instead
of benzothiazole-6-carboxylic acid to yield the title compound as
an off white solid (39% yield). 1H NMR: (500 MHz, CDCl3) d 11.78
(s, 1H), 8.68 (s, 1H), 8.53 (dd, J = 4.8 Hz, J = 1.4 Hz, 1H), 8.27 (d,
J = 8.2 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H),
7.83 (d, J = 7.9 Hz, 1H), 7.74 (t, J = 7.4 Hz, 1H), 7.70 (d, J = 8.3 Hz,
1H), 7.55 (t, J = 7.4 Hz, 1H), 7.27 (dd, J = 8.1 Hz, J = 5.0 Hz, 1H),
7.21 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 5.47 (s, 2H), 5.23
(br s, 1H), 3.44 (s, 3H). [M+H+]: 436.2.
A.17. N-Methyl-5-(pyridin-2-yl)-N-(4-(quinolin-2-
yloxy)phenyl)-1H-pyrazole-3-carboxamide (21)
A.21. N-(4-(Benzo[d]oxazol-2-ylmethoxy)phenyl)-N-
This compound was synthesized according to compound 14 but
employing 5-pyridin-2-yl-2H-pyrazole-3-carboxylic acid instead
of benzothiazole-6-carboxylic acid to yield the title compound as
an off white solid (39% yield). 1H NMR: (500 MHz, CDCl3) d 11.58
(s, 1H), 8.54 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 8.2 Hz,
methylisonicotinamide (24)
This compound was synthesized according to compound 23 but
employing 2-(chloromethyl)benzo[d]oxazole instead of 2-(chloro-
methyl)-6-methylpyridine to yield the title compound as an off

J. P. Kilburn et al. / Bioorg. Med. Chem. 21 (2013) 6053–6062
6061
white solid (90% yield). 1H NMR: (500 MHz, DMSO-d6) d 9.40 (s,
A.26. N-Methyl-N-(pyridin-4-yl)-4-(quinolin-2-
1H), 8.13 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.74 (m, 2H), 7.40 (m,
3H), 7.17 (d, J = 8.6, 2H), 6.96 (d, J = 8.6, 2H), 5.38 (s, 2H), 3.36 (s,
3H). [M+H+]: 416.1.
ylmethoxy)benzamide (29)
This compound was synthesized according to compound 26 but
employing N-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine instead
of N-methylaniline to yield the title compound (7% yield). 1H NMR
(500 MHz, CDCl3): d 8.44 (s, 2H), 8.18 (d, J = 8.4 Hz, 1H), 8.06 (d,
J = 8.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.74 (m, 1H), 7.59 (d,
J = 8.8 Hz, 1H), 7.56 (m, 1H), 7.31 (m, 2H), 6.93 (d, J = 5.2 Hz, 2H),
6.88 (m, 2H), 5.35 (s, 2H), 3.50 (s, 3H). [M+H+]: 370.1.
A.22. N-Methyl-N-(4-((1-methyl-1H-benzo[d]imidazol-2-
yl)methoxy)phenyl)isonicotinamide (25)
This compound was synthesized according to compound 23 but
employing 2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole in-
stead of 2-(chloromethyl)-6-methylpyridine to yield the title com-
pound as a white solid (96%). 1H NMR: (500 MHz, DMSO-d6) d 9.41
(s, 1H), 8.15 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H),
7.56 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.1, 1H), 7.29 (t, J = 7.6, 1H), 7.22
(t, J = 7.6 Hz 1H), 7.17 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H),
5.33 (s, 2H), 3.79 (s, 3H), 3.36 (s, 3H). [M+H+]: 429.1.
A.27. N-(Imidazo[1,2-a]pyridin-6-yl)-N-methyl-4-(quinolin-2-
ylmethoxy)benzamide (30)
The intermediate N-imidazo[1,2-a]pyridin-6-yl-4-(quinolin-2-
ylmethoxy)-benzamide was synthesized according to compound
26 but employing imidazo[1,2-a]pyridin-6-ylamine instead of N-
methylaniline. Methylation of the intermediate N-imidazo[1,2-
a]pyridin-6-yl-4-(quinolin-2-ylmethoxy)-benzamide was per-
formed as described for compound 28 to yield the title compound
as a yellow oil (9% yield). 1H NMR (500 MHz, CDCl3): d 8.17–8.14
(m, 1H), 8.06–8.04 (m, 1H), 7.83–7.75 (m, 2H), 7.73–7.71 (m,
1H), 7.62–7.57 (m, 4H), 7.45 (s, 1H), 7.34–7.32 (m, 2H), 7.07–7.04
(m, 1H), 6.85–6.83 (m, 2H), 5.31 (s, 2H), 3.47 (s, 3H). [M+H+]: 409.1.
A.23. N-Methyl-N-phenyl-4-(quinolin-2-ylmethoxy)benzamide
(26)
HBTU (147 mg, 0.39 mmol) and DIPEA (0.13 g, 1.0 mmol) were
added to
a solution of 4-(quinolin-2-ylmethoxy)benzoic acid
(100 mg, 0.35 mmol) in DMF (5 mL), and the mixture was stirred
at room temperature for 30 min N-methylaniline (38 mg,
0.35 mmol) was added, and the resulting mixture was stirred at
room temperature for 12 h. Water (15 mL) was added, the resul-
tant mixture was extracted with EtOAc (15 mL). The organic layer
was separated, dried over Na2SO4, filtered, and concentrated under
vacuum. The residue was purified by preparative HPLC to afford
the title compound as an off white solid (11% yield). 1H NMR
(500 MHz, CDCl3): d 8.25–8.21 (m, 1H), 8.06–8.13 (m, 1H), 7.96–
7.84 (m, 1H), 7.76–7.58 (m, 3H), 7.29–7.23 (m, 4H), 7.17–7.15
(m, 1H), 7.06–7.04 (m, 2H), 6.81 (d, J = 9.2 Hz, 2H), 5.35 (s, 2H),
3.50 (s, 3H). [M+H+]: 369.1.
A.28. N-(Benzo[d]oxazol-6-yl)-N-methyl-4-(quinolin-2-
ylmethoxy)benzamide (31)
The intermediate N-benzooxazol-6-yl-4-(quinolin-2-ylmeth-
oxy)-benzamide was synthesized according to compound 26 but
employing benzooxazol-6-ylamine instead of N-methylaniline.
Methylation of the intermediate N-benzooxazol-6-yl-4-(quinolin-
2-ylmethoxy)-benzamide was performed as described for com-
pound 28 to yield the title compound as a yellow oil (20% yield).
1H NMR (500 MHz, CD3CN): d 8.31–8.29 (m, 2H), 7.99–7.97 (m,
1H), 7.92–7.91 (m, 1H), 7.78–7.74 (m, 1H), 7.62–7.56 (m, 3H),
7.47–7.46 (m, 1H), 7.26–7.19 (m, 3H), 6.84–6.82 (m, 2H), 5.26 (s,
2H), 3.42 (s, 3H). [M+H+]: 410.1.
A.24. N-([1,2,4]Triazolo[1,5-a]pyridin-7-yl)-N-methyl-4-
(quinolin-2-ylmethoxy)benzamide (27)
This compound was synthesized according to compound 26 but
employing N-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine instead
of N-methylaniline to yield the title compound as an off white solid
(5% yield). 1H NMR (500 MHz, CDCl3): d 8.31 (d, J = 7.2 Hz, 1 H),
8.23 (s, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 7.75
(d, J = 8.0 Hz, 1 H), 7.67 (t, J = 8.4 Hz, 1 H), 7.52–7.49 (m, 2 H),
7.35–7.29 (m, 3 H), 6.81 (d, J = 8.8 Hz, 1 H), 6.66–6.61 (m, 1 H),
5.27 (s, 2 H), 3.49 (s, 3 H). [M+H+]: 410.0.
A.29. N-(Benzo[d]thiazol-6-yl)-N-methyl-4-(quinolin-2-
ylmethoxy)benzamide (32)
The intermediate N-benzothiazol-6-yl-4-(quinolin-2-ylmeth-
oxy)-benzamide was synthesized according to compound 26 but
employing benzothiazol-6-ylamine instead of N-methylaniline.
Methylation of the intermediate N-benzothiazol-6-yl-4-(quinolin-
2-ylmethoxy)-benzamide was performed as described for com-
pound 28 to yield the title compound as a yellow oil (69% yield).
1H NMR (500 MHz, methanol-d4): d 9.21 (s, 1H), 8.73–8.70 (m,
1H), 8.14–8.10 (2H), 7.98–7.93 (m, 2H), 7.82–7.76 (m, 3H), 7.32–
7.29 (m, 3 H), 6.92–6.89 (m, 2H), 5.43 (s, 2H), 3.52 (s, 3H).
[M+H+]: 426.0.
A.25. N-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-N-methyl-4-
(quinolin-2-ylmethoxy)benzamide (28)
The intermediate 4-(quinolin-2-ylmethoxy)-N-[1,2,4]triazol-
o[1,5-a]pyridin-7-yl-benzamide was synthesized according to
compound 26 but employing [1,2,4]triazolo[1,5-a]pyridin-7-yla-
mine instead of N-methylaniline. To a solution of 4-(quinolin-2-
ylmethoxy)-N-[1,2,4]triazolo[1,5-a]pyridin-7-yl-benzamide (0.1 g,
0.25 mmol) in dry DMF (2 mL) was added NaH (12 mg, 0.5 mmol)
at 0 °C, after 15 min, 36 mg of CH3I was added into, the reaction
mixture was stirred at room temperature for 30 min. 10 mL of
water was poured into the mixture, and extacted with EtOAc, the
combined organic layer was concentrated and the residue was
purified by preparative HPLC to give yield the title compound
(yield: 26%). 1H NMR (500 MHz, CDCl3): d 8.35–8.32 (m, 2H),
8.17–8.15 (m, 1H), 8.05–8.03 (m, 1H), 7.83–7.81 (m, 1H), 7.75–
7.71 (m, 1H), 7.68–7.66 (m, 1H), 7.56–7.54 (m, 2H), 7.37–7.32
(m, 3H), 6.86–8.84 (m, 2H), 5.31 (s, 2H), 3.51 (s, 3H). [M+H+]: 410.0.
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