Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3- yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia

Article abstract of DOI:10.1021/jm900521k

By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.

Full text of DOI:10.1021/jm900521k

5188 J. Med. Chem. 2009, 52, 5188–5196
DOI: 10.1021/jm900521k
Discovery of a Novel Class of Phosphodiesterase 10A Inhibitors and Identification of Clinical
Candidate 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920)
for the Treatment of Schizophrenia†
Patrick R. Verhoest,* Douglas S. Chapin, Michael Corman, Kari Fonseca, John F. Harms, Xinjun Hou, Eric S. Marr,
Frank S. Menniti, Frederick Nelson, Rebecca O’Connor, Jayvardhan Pandit, Caroline Proulx-LaFrance, Anne W. Schmidt,
Christopher J. Schmidt, Judith A. Suiciak, and Spiros Liras
Neuroscience, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340
Received April 23, 2009
By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE)
10A inhibitors was identified. The structure-based drug design efforts identified a unique “selectivity
pocket” for PDE10A inhibitors, and interactions within this pocket allowed the design of highly
selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like
properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism
in the treatment of schizophrenia.
Introduction
mine, and for the dual substrate PDEs, this residue can rotate
to form donor-acceptor hydrogen bonds to both cGMP and
cAMP. There is a common hydrophobic clamp that is made
up of lipophilic amino acids that form a stacking interaction
with the purine-like heterocyclic core of both cGMP and
cAMP. In addition, there is a common bimetal ion binding
center that binds the phosphates of the cyclic nucleotides.6
PDE inhibitors have potential therapeutic utility but also
have potential unwanted safety risks due to off-target PDE
inhibition. Some examples that have been reported in the
literature are with PDE6 inhibition and visual disturbances7
and PDE3 inhibitors with cardiovascular changes.8 A previous
publication has highlighted the quinazoline series of PDE10A
inhibitors, which were challenged with PDE3 selectivity issues.9
The phosphodiesterase (PDEa) gene family has led to the
identification of drugable targets and treatments for various
disease states. With the success of the PDE5 inhibitor sildenafil,1
Pfizer initiated a gene family initiative to identify potential
therapeutic utility for the 21 different human PDE genes.2 Out
of this effort, PDE10A was identified as a potential target for the
treatment of central nervous system (CNS) disorders. PDE10A
is highly expressed in the medium spiny neurons of the striatum3
andhasbeenshowntoregulatebothcGMP(Km =7.2μM) and
cAMP (Km = 0.26 μΜ).4 It is believed that inhibitors of
PDE10A will regulate cyclic nucleotide signaling in the corticos-
triatothalamic circuit. It has previously been shown that
PDE10A inhibitors are active in a variety of preclinical models
that may predict efficacy in the treatment of schizophrenia.5
Although compounds with high PDE affinity have been
readily identified, achieving high selectivity is still a key
challenge. There are distinct differences in the full length
structure of the PDEs, but it is not surprising that the catalytic
domains that share a common function have a much more
conserved structure. All the PDEs possess a common gluta-
Results and Discussion
In an effort to identify a more selective class of PDE10A
inhibitors, a diverse set of compounds from our internal
compound collection were screened for PDE10A affinity.
This effort identified triarylimidazole 1 (Figure 1), which
has a PDE10A IC50 of 35 nM and displays >100ꢀ fold
selectivity against the other PDEs.10 Examination of its
cocrystal structure with the PDE10A catalytic domain
(Figure 2) revealed the basis for this extraordinary selectivity.
It showed a binding interaction that is markedly different, not
just from other PDE10A inhibitors but from PDE inhibitors
in general. Unlike previously known PDE inhibitors, this
inhibitor does not make a hydrogen bond with the conserved
glutamine Gln-726.2 Instead, the side chain amino nitrogen of
Gln-726 is positioned directly above the center of one the
methoxyphenyl groups, thus making a favorable amino-π
interaction.11 Most importantly for selectivity, the thiophene
occupies a lipophilic pocket near the entrance of the hydro-
phobic cleft that defines the common PDE substrate binding
site. Additionally, the imidazole accepts a hydrogen bond at
†Coordinates of the PDE10A crystal structures have been deposited
in the Protein Data Bank for compound 1 (3HQW), 2 (3HQY), 3
(3HQW) and 9 (3HR1).
*To whom correspondence should be addressed. Phone: 860-686-
2288. Fax: 860-686-0013. E-mail: patrick.r.verhoest@pfizer.com.
a Abbreviations: PDE, phosphodiesterase; SBDD, structure-based
drug design; CNS, central nervous system; cGMP, cyclic guanosine
monophosphate; cAMP, cyclic adenosine monophosphate; Tyr, tyro-
sine; Gln, glutamine; Leu, leucine; PDB, protein data bank; Mw,
molecular weight; TPSA, topological polar surface area; HTS, high-
throughput screen; LDA, lithium diisopropyl amine; THF, tetrahydro-
furan; CYP, cytochrome P450; PgP, P-glycoprotein; SC, subcutaneous;
LE, ligand efficiency; LLE, lipophilic ligand efficiency; CAR, condi-
tioned avoidance response; MED, minimal effective dose; ADME,
absorption distribution metabolism and excretion; HBE, hydrogen
bond energy.
r
pubs.acs.org/jmc
Published on Web 07/24/2009
2009 American Chemical Society

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 16 5189
the top of the pocket from the OH of Tyr-693, which accepts a
hydrogen bond from the carbonyl of conserved Gln-726.
A comparison of the known PDE crystal structures and
profiling the inhibitor binding site led us to determine that the
lipophilic pocket occupied by the thiophene group is unique to
PDE10A in the PDE family for the following reasons. First,
among all the 21 PDE family proteins, only PDE10A has a
glycine residue at position 725, next to the conserved gluta-
mine.2 The presence of a larger side chain in all other PDEs
blocks access to this lipophilic pocket. In addition, the resi-
dues that form the back of this lipophilic pocket are from the
M-loop, which connects helix 14 and 15. Because of an
insertion, this loop is longer in PDE10A than all the other
PDEs except PDE5 and PDE6, which results in this pocket
being deeper in PDE10A than all other PDEs. Finally,
PDE10A has Tyr-693 to form a hydrogen bond interaction
withwhich toanchoraninhibitor in this pocket. Inadditionto
PDE10A, this potential hydrogen bonding group is only
found in PDE2, where access to this pocket is blocked by a
leucine residue of PDE2.
Figure 1. Structure of triaryl imidazole 1.
Utilizing the structural knowledge of how to obtain selec-
tivity for PDE10A, we implemented a strategy to develop
multiple chemical series to address attrition risks. We had
been focusing on multiple chemical series, but none of these
bound in the selectivity pocket and possessed the desired
physiochemical properties.12 After the biological confidence
in rationale was built through the quinazoline and triaryl
imidazole series, we undertook a full file high-throughput
screen (HTS). To identify lead series with built in selectivity,
we only pursued diverse hits from this screen that had
potential to bind in the PDE10A selectivity pocket and to
form a hydrogen bond with Tyr-693. To confirm our hypoth-
esis, we subjected promising hits to X-ray crystallography to
unambiguously identify their binding modes. In addition, we
focused on identifying lead structures with drug-like physio-
chemical properties. We targeted leads that had a molecular
weight less than 400, were only moderately lipophilic with a
ClogP e4, and contained a minimum number of hydrogen
bond donors to increase our probability of achieving brain
penetration. These physicochemical targets are a major
change from the PDE5 inhibitors that are on the market.13
Compounds like sildenafil (Figure 3) have difficulty accessing
the CNS compartment due to their size (Mw = 475) and
polarity (TPSA=113).
Figure 2. Compound 1 (PDB 3HQW) bound in PDE10A selectiv-
ity pocket.
Out of this high-throughput screen, we found multiple
chemical series that met our desired criteria. One that was
rapidly prosecuted is exemplified by novel pyrazole com-
pound 2 (Figure 4). In this case, the X-ray crystal structure
of 2 confirmed the quinoline formed a hydrogen bond to the
desired tyrosine and occupied the “selectivity” pocket
(Figure 5). Pyrazole 2 was a fairly efficient inhibitor (ligand
efficiency=0.37)14 of PDE10A with an IC50 of 11.5 nM and
possessed reasonable physicochemical properties with a mo-
lecular weight of 392 and a ClogP of 4. Further screening
guided by SBDD led us to identify compound 3, where the
Figure 3. Structure of sildenafil.
Figure 4. Identification of HTS hit 2 and lead pyrazole 3.

5190 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 16
Verhoest et al.
Table 1. PDE10A Potency for Core Heterocycles
Figure 5. Cocrystal structure of 2 (yellow, PDB code 3HQY)
bound to the PDE10A catalytic site. Cocrystal structure of 3
(blue, PDB code 3HQZ) is overlaid.
a PDE10A IC50 Potency reported in nM.
methylene has been excised. Pyrazole 3 is a subnanomolar
PDE10A inhibitor with an IC50 of 0.42 nM and exhibits
>1000ꢀ selectivity over the other PDEs.
of 5 mg/kg (SC) but required a high free plasma concentration
in mice (15 nM) in relation to the PDE10A potency (0.42 nM)
to achieve activity. The high ratio of free plasma exposure
relative to the enzyme IC50 (36ꢀ) to produce the desired
biochemical and behavioral effect was the result of modest
brain penetration (brain/plasma = 0.21). These higher free
and total drug levels could lead to an increase in safety risks
and led to a higher dose projection to sustain efficacy in
humans. These liabilities directed us to identify compounds
with improved CNS penetration.
This series of pyrazoles represents a nonclassical binding
mode for a PDE inhibitor. They do not form a hydrogen bond
interaction with the conserved glutamine as most PDE5 and
PDE4 inhibitors do. Pyrazole 3 maintains the hydrogen bond
to the tyrosine and occupies the PDE10A selectivity pocket
but goes deeper into a pocket behind the conserved glutamine
than HTS hit 2. The pyridyl nitrogen also forms a hydrogen
˚
bond to a water molecule (2.6 A) that is hydrogen bound to
the PDE10A backbone. This deeper penetration of an addi-
tional binding pocket and the hydrogen bond to the water
molecule may help explain the significant increase in potency
that is seen with compound 3.
Our strategy to improve brain penetration was to maintain
molecular weight and remove the hydrogen bond donor
present in pyrazole 3. The enaminone 8 (Scheme 2) afforded
a versatile intermediate to rapidly synthesize compounds with
this desired profile. Treatment with small hydrazines afforded
substituted pyrazoles and addition of hydroxyl amine pro-
vided an isoxazole. In addition, treatment with amidines
delivered pyrimidines, which allowed us to determine the
optimal ring size of the core heterocycle.
The SAR for the pyrazole and pyrazole replacements that
remove the hydrogen bond donor was very promising
(Table 1). Substitution of the pyrazole with simple alkyl groups
retained potency while adding minimal molecular weight. The
simple methyl substituted pyrazole 9 (PF-2545920)18 proved to
be 0.37 nM and in an in vitro P-glycoprotein (PgP) over-
expressing cell line had improved the efflux ratio from 2.3 to
1.0.19 We expected that this reduced PgP liability would
improve our brain penetration and in vivo efficacy. The
pyrazole heterocycle was the most potent of the five-membered
heterocycles prepared, with isoxazole 14 displaying a signifi-
cant loss in potency. The pyrimidine analogues were also
significantly less active than 3, potentially due to the decreased
bond angle between the phenyl and pyridine rings. This may
prohibit the pyridine ring from making a key hydrogen bond
to a tightly bound water molecule.
Synthesis of 3 was completed starting with 4-hydroxyl
benzoic acid methyl ester 4 and alkylating with 2-chloro-
methyl quinoline followed by hydrolysis to afford the desired
acid 5. Activation of the acid with thionyl chloride and
Weinreb amide formation provides the coupling partner 6 in
good yield.15 The anion of 4-picoline (2 equiv) was formed
with lithium diisopropyl amide (LDA) and added to a tetra-
hydrofuran (THF) solution of the Weinreb amide coupling
partner. Two equivalents of the anion were necessary to
achieve an acceptable yield of 7 (80%). Following treatment
with dimethoxymethyl-dimethyl amine to form the enami-
none 8, hydrazine was added to form the desired pyrazole
compound 3.
Compound 3 is an excellent lead structure with improved
potency over compound 2. It also shows a reduced drug-drug
interaction liability with less CYP3A4 inhibition (IC50 >
10 μΜ vs 450 nM compound 2) due to the sterics around
the pyridyl nitrogen and the deactivation of the pyridine by
conjugation to the pyrazole.16 While this lead compound had
the requisite potency and selectivity, it fell short of a drug
candidate in terms of its in vivo efficacy. It raised cGMP levels
in the striatum 350% at 10 mg/kg and was active in the
conditioned avoidance response task (CAR)17 with an ED50
To test the hypothesis that the pyridyl hydrogen bond
to the water molecule was crucial for PDE10A affinity,

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 16 5191
Table 2. PDE10A Potency of Aryl Pyridyl Replacements and Calculated Hydrogen Bond Energy
a PDE10A IC50 potency in nM. b ΔG = RT ln(Kd) ≈ 1.36 log (IC50), at T = 298 K.
Scheme 1. Synthesis of Lead 3a
a Reagents and conditions: (a) 2-chloromethyl quinoline, K2CO3, acetone, reflux, 16 h, then MeOH, 1 N NaOH 16 h (60% 2 steps); (b) thionyl
chloride 3 h, then THF, triethylamine, NHMeOMe, 18 h (87%), (c) 4-picoline, LDA, -78 to rt (80%); (d) dimethoxymethyl-dimethyl amine, reflux, 1 h;
(e) MeOH, hydrazine, reflux 1 h (82%, 2 steps).
aromatic and heteroaromatic replacements for the pyridine
ring were designed. Compounds 16-20 (Table 2) were synthe-
sized from the Weinreb intermediate 6 (Scheme 1) utilizing the
anion chemistry that has previously been described. As pre-
dicted by the X-ray crystal structure, compounds 18 and 19
that could not accept a hydrogen bond to the water were
significantly less active. The two heterocyclic analogues that
could form a hydrogen bond, pyrimidine 16 and pyridazine
17, retained good affinity but were significantly less potent
than 3.
multiple components such as ligand and protein interactions,
conformational strain, and desolvation. For a closely related
congeneric series of compounds, we assumed similar contri-
butions from one or more of these binding components. In
particular, if we assume most of the energetic terms are similar
for compounds 3, 16, and 17 except for the ability of each
heterocycle to make a hydrogen bond to the water molecule in
the active site, we could computationally test this hypothesis
by calculating their hydrogen bond strength. The hydrogen
bond energy was computed by applying pseudospectral local
second-order Moller-Plesset or the PS-LMP2 method.20 The
model system was built by using the crystal water bound to the
pyridyl nitrogen and the corresponding heterocycle deriva-
tives. The structures were optimized with X3LYP/6-31G**,
To further understand the SAR discrepancy of 16 and 17,
the nitrogen hydrogen bond strengths of the heterocycles were
computationally estimated. Ligand binding is a complex
process, and binding energy contains contributions from

5192 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 16
Table 3. PDE10A Potency of Quinoline Replacements
Verhoest et al.
Figure 6. Subcutaneous dose response of 9 in the condition avoid-
ance response assay (statistical analysis comparing drug to vehicle:
p = 0.012 at 1.78 mg/kg, p = <0.01 at 3.2 mg/kg).
Scheme 3. Synthesis of Quinoline Replacement Analogues
a PDE10A IC50 potency in nM.
Scheme 2. Heterocycle Synthesis
Reagents and conditions: (a) thionyl chloride 3 h, then THF, triethy-
lamine, NHMeOMe, 18 h (99%), 4-picoline, LDA, -78 to rt (73%);
(b) dimethoxymethyl-dimethyl amine, reflux, 1 h, then MeOH, methyl
hydrazine, reflux 1 h (45%, 2-steps, major isomer); (c) H2, Pd(OH)2,
ethanol/EtOAc (91%); (d) AR-OH, ditertbutyldiazocarboxylate, PPh3
(67-96%).
metabolic liability. In addition, these compounds maintained
or improved their lipophilic ligand efficiency (LLE), which is a
measure of potency for lipophilicity (LLE=-logKi - ClogP)
(Table 3).22 Although there was an improvement in intrinsic
clearance and LLE, none of the compounds provided a sig-
nificant improvement over compound 9.
Our extensive SAR efforts confirmed that 9 possessed the
most attractiveattributes. Thus, compound9 was put through
a battery of in vivo behavioral models and shown to be
efficacious. As designed by removing the hydrogen bond
donor in compound 3 and replacing it with a methyl, 9
demonstrated improvements in CNS penetration. The brain
to plasma ratio in a mouse increased from 0.21 to 0.86. In the
conditioned avoidance response assay (CAR), 9 was active
with an ED50 of 1 mg/kg (Figure 6) at a significantly lower
total plasma exposure (115 nM) than compound 3. It is highly
protein bound, showing efficacy at a free plasma exposure of
0.3 nM. It was also inactive in the PDE10A knockout mice,
providing evidence that the efficacy is mediated through
PDE10A inhibition.
The effects on cyclic nucleotide signaling in the striatum
were measured with subcutaneous dosing of 9 in mice. The
striatum section of the brain was chosen as the tissue due to the
high expression levels of PDE10A. Administration of 9 to mice
caused a dose dependent increase in striatal cGMP (Figure 7).
The minimal effective dose (MED) was ∼1 mg/kg, which
elevated cGMP ∼3 fold. The elevation in cGMP appears
to plateau and displays a maximal elevation of approximately
a 5-fold increase at 3.2 mg/kg.
and the binding energies were calculated using two correla-
tion-consistent basis sets (cc-pVTZ(-f) and cc-pVQZ(-g)) and
LMP2 theory, including corrections for the basis set super-
position error.21 As expected, pyridyl 3 calculates to have a
stronger interaction with the crystal water (Table 2) by more
than 0.5 kcal/mol of energy. It is interesting to note that this
calculation correctly predicts the rank order of the com-
pounds in terms of potency but does not predict the absolute
potency difference seen between 3 and 16/17.
In an effort to understand how lipophilicity affected human
liver microsomal intrinsic clearance in this series, compounds
25-28 (Table 3) were designed that replaced the quinoline
ring with a more polar bicyclic aromatic group.19 To rapidly
prepare these desired targets compound 24 was synthesized
(Scheme 3) utilizing similar chemistry that has been described
in Scheme 2. From the phenol, coupling with the heteroaro-
matic benzyl alcohols utilizing Mitsonobu chemistry afforded
compounds 25-28.
Out of this effort, potent compounds with both 9- and 10-
membered bicyclic aromatic groups with lower ClogP were
identified. As intended, some of these analogues showed
reduced human liver microsomal intrinsic clearance compared
to the parent. Compound 28 was not metabolized by human
liver microsomes, and compound 25 displayed significantly less

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 16 5193
In summary, structure-based drug design efforts utilized a
novel binding pocket to identify a selective class of PDE10A
inhibitors (Figure 9). This class possessed distinct physico-
chemical properties from the marketed PDE5 inhibitors, and
this series was optimized for potency, selectivity, in vivo
efficacy, CNS penetration, and pharmacokinetics to yield 9.
It is a highly potent and selective PDE10A inhibitor with
excellent in vivo efficacy in neurochemical elevation of cyclic
nucleotides and in models predictive of antipsychotic activity.
The preclinical pharmacokinetic properties were very promis-
ing. With the entry of 9 into clinical trials, we plan to
determine if PDE10A inhibition can improve schizophrenic
patient outcomes.
Figure 7. Subcutaneous dose response of 9 in the striatal cGMP
assay.
Experimental Section
All reagents and solvents were used as purchased from com-
mercial sources. Reactions were carried out under a blanket of
nitrogen. Silica gel chromatography was done using the appro-
priatesizeBiotage prepacked silicafilled cartridges. Massspectral
data was collected on a Micromass ADM atmospheric pressure
chemical ionization instrument (LRMS APCI). NMR spectra
were generated on a Varian 400 MHz instrument. Chemical shifts
were recorded in ppm relative to tetramethylsilane (TMS) with
multiplicities given as s (singlet), bs (broad singlet), d (doublet), t
(triplet), dt (double of triplets), and m (multiplet). Compound
purity is determined by combustion analysis (Quantitative Tech-
nologies inc.) or high pressure liquid chromatography (HPLC).
HPLC conditions utilized are as follows. Gradient: 0-0.25 min
5%A:95%B, 0.25-6.25 min 5%A:95%B => 90%A:10%B,
6.25-6.75 min 90%A:10%B, 6.75-6.85 min 90%A:10%B =>
5%A:95%B, 6.85-9.5 min 95%A:5%B; column temp: 45 °C.
UV detector: 210 nM. Retention times (RT) are in minutes and
purity is calculated as % total area. (Column 1: Waters BEH C8
2.1 mm ꢀ 100 mm 1.7 um; mobile phase A: acetonitrile, B: 0.1%
(v/v) H3PO4 þ 50 mM NaClO4. Column 2: Waters BEH C8
2.1 mm ꢀ 100 mm 1.7 um; mobile phase A; acetonitrile, B: 20 mM
ammonium bicarbonate pH 6.8. Column 3: Waters BEH RP C18
2.1 mm ꢀ 100 mm 1.7 um; mobile phase A: acetonitrile, B: 0.1%
methanesulfonic acid. Column4:WatersHSST3 2.1μm ꢀ 100 1.8
μm; mobile phase A: acetonitrile, B: 0.1% methanesulfonic acid.
Column 5: Waters BEH C8 2.1 mm ꢀ 100 mm 1.7 μm; mobile
phase A; acetonitrile, B: 20 mM ammonium bicarbonate pH 8.0.
All final compounds either met combustion analysis within
(0.4% or were >95% purity by HPLC.
Figure 8. In vivo pharmacokinetic properties of 9.
4-(Quinolin-2-ylmethoxy)-benzoic Acid Methyl Ester. To a
solution of 2-chloromethyl quinoline (2 g, 9.3 mmol) in acetone
(47 mL, 0.2M) was added 4-hydroxy benzoic acid methyl ester
4 (1.42 g, 1.0 equiv) and potassium carbonate (3.86 g, 3 equiv).
The reaction mixture was heated at 60 °C for 16 h under N2
atmosphere, cooled to ambient temperature, and poured into
1 N sodium hydroxide (50 mL)/ethyl acetate (100 mL). The
layers were separated and the organic layer dried with magne-
sium sulfate, filtered, and concentrated. Biotage MPLC was run
using a 5-30% ethyl acetate/hexane gradient on a 40 M column
to provide the title compound as a white solid (1.66 g, 61%). 1H
NMR (400 MHz, CDCl3) δ 8.18 (d, J=8.7 Hz, 1 H), 8.07 (d, J=
8.3 Hz, 1 H), 7.95 (m, 2H), 7.82 (d, J=7.9 Hz, 1 H), 7.74 (dt, J=
7.1, 1.7 Hz, 1 H), 7.62 (d, J=8.3 Hz, 1 H), 7.55 (dt, J=7.9,
1.2 Hz, 1 H), 7.03 (d, J=9.1, 2 H), 5.41 (s, 2 H), 3.84 (s, 3 H); MS:
(MþH m/z=294.2).
4-(Quinolin-2-ylmethoxy)-benzoic Acid (5). To a solution of
4-(quinolin-2-ylmethoxy)-benzoic acid methyl ester (500 mg,
1.7 mmol) in tetrahydrofuran (8.5 mL) and methanol (3 mL)
was added 1 N NaOH (3.4 mL, 2 equiv). The reaction mixture
was stirred at ambient temperature for 16 h. To the reaction
mixture was added 50 mL of brine and the pH was adjusted
to 3 with 1 N HCl to provide a white precipitate, which was
filtered and dried to provide the title compound as a white solid
Figure 9. Compound 9 bound in PDE10A pocket (PDB 3HR1).
With 9 displaying efficacy in vivo, a high degree of PDE
selectivity (>1000ꢀ) and selectivity in the CEREP panel
(>100ꢀ), we explored its pharmacokinetic properties in
multiple preclinical species (Figure 8). Overall, it displays
low to moderate in vivo clearance with a moderate volume
of distribution. Absorption of 9 following oral administration
of a single dose was variable in preclinical species, with an
absolute bioavailability of 30% in rats to 68-100% in dogs.
This encouraging preclinical data together with the human in
vitro ADME properties suggested that 9 would possess desir-
able drug-like human pharmacokinetic properties.
Conclusion
On the basis of the exciting preclinical data, 9 has entered
clinical trials for the treatment of schizophrenia.23 It is the
first reported clinical entry for this exciting new mechanism.

5194 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 16
Verhoest et al.
1
(463 mg, 98%). H NMR (400 MHz, DMSO) δ 8.39 (d, J=
stirred 1 h at ambient temperature and solvent evaporated. The
reaction mixture was partitioned between methylene chloride and
saturated sodium bicarbonate. The layers were separated and the
organic layer dried with magnesium sulfate, filtered, and concen-
trated. Preparative HPLC chromatography provided the title
compound (major isomer) as a clear oil (0.97 g, 56%). 1H NMR
(400 MHz, CDCl3) δ 8.44 (d, J=5.0 Hz, 2 H), 8.17 (d, J=8.7 Hz,
1 H), 8.05 (d, J=8.3 Hz, 1H), 7.81 (d, J=7.9 Hz, 1 H), 7.70 (m,
1 H), 7.66 (d, J=8.7 Hz, 1H), 7.54 (s, 1H), 7.53 (m, 1H), 7.37 (d, J=
8.7 Hz, 2H) 7.15 (d, J=5.0, 2H), 7.00 (d, J=8.7 Hz, 2H), 5.38
(s, 2H), 3.93 (s, 3H). MS: (MþH m/z=393.3). The free base was
dilute in ethyl acetate, and a suspension of succinic acid (1 equiv) in
ethyl acetate was added. The mixture was stirred overnight,
then filtered and washed with ether to provide the succinate salt.
1H NMR (500 MHz, methanol-d4) δ ppm 2.57 (s, 4 H) 3.96 (s, 3 H)
5.41 (s, 2 H) 7.11 (d, J=8.79 Hz, 2 H) 7.30 (d, J=6.35 Hz, 2 H) 7.36
(d, J=8.79 Hz, 2 H) 7.59-7.65 (m, 1 H) 7.75 (d, J=8.54 Hz, 1 H)
7.80 (ddd, J=8.48, 6.89, 1.46 Hz, 1 H) 7.95 (d, J=1.22 Hz, 1 H)
8.02 (s, 1 H) 8.06 (d, J=8.54 Hz, 1 H) 8.36 (dd, J=4.76, 1.59 Hz,
2H) 8.40(d, J=8.54 Hz, 1 H) MS: (MþHm/z=510.6). Anal. Calcd
8.3 Hz, 1 H), 7.99 (m, 2 H), 7.81 (m, 2H), 7.76 (dt, J=8.3, 1.7 Hz,
1 H), 7.64 (d, J=8.3 Hz, 1 H), 7.60 (dt, J=7.9, 1.3 Hz, 1 H), 7.12
(M, 2 H), 5.41 (s, 2 H). MS: (MþH m/z=280.2).
N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide (6).
To a solution of 4-(quinolin-2-ylmethoxy)-benzoic acid 5 (25.98 g,
93 mmol) was added 250 mL of thionyl chloride under N2. The
reaction mixture stirred 3 h, and the excess thionyl chloride was
removed under vacuum. The acid chloride was dissolved in
tetrahydrofuran (450 mL), and triethylamine (50 mL, 4 equiv)
was slowly added. O,N-Dimethyl hydroxyl amine hydrochloride
(27 g, 3 equiv) was added and the reaction stirred for 18 h. The
reaction mixture was placed on a rotovap to remove the solvent,
partitioned between 1 N NaOH and methylene chloride, sepa-
rated, dried with magnesium sulfate, filtered, and concentrated.
The crude product was filtered through silica gel eluting with 30-
70% ethyl acetate/hexane to proved the title compound as a
1
brown oil (26.26 g, 87%). H NMR (400 MHz, CDCl3) δ 8.17
(d, J=8.7 Hz, 1 H), 8.06 (d, J=8.3 Hz, 1 H), 7.81 (d, J=8.3 Hz,
1H), 7.67 (m, 3 H), 7.63 (d, J=8.3 Hz, 1 H), 7.52 (m, 1 H), 7.01 (M,
2 H), 5.39 (s, 2 H), 3.52 (s, 3 H) 3.31 (s, 2H). MS: (MþH m/z=
323.2).
for C24H18N4O C4H6O4: C, 68.22%; H, 5.13%; N, 10.97%.
Found: C, 68.05%; H, 4.99%; N, 10.87%.
3
2-Pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone (7).
To a solution of lithium diisopropyl amide (1.0M) in tetrahydro-
furan was added 4-picoline dropwise (7.55 mL, 5 equiv) at 0 °C
under N2. After 30 min, the anion was cooled to -78 °C. In a
separate round-bottom flask, N-methoxy-N-methyl-4-(quinolin-
2-ylmethoxy)-benzamide 6 (5.0, 15.5 mmol) was dissolved in
tetrahydrofuran (77 mL, 0.2M) and cooled to -78 °C under N2.
Then 1.2 equiv of the 4-picoline anion was added dropwise to the
amide solution. After 45 min, 1 equiv more of the 4-picoline anion
was added. After an additional 30 min, acetic acid (40 mL) was
added dropwise and the reaction was slowly warmed to ambient
temperature. The solid product (acetate salt) was filtered and
partitioned between saturated sodium bicarbonate and dichloro-
methane. The layers were separated, dried with magnesium sulfate,
filtered, and concentrated to provide the title compound as a tan
solid (4.41 g, 80%). 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=
5.8 Hz, 2 H), 8.19 (d, J=8.7 Hz, 1 H), 8.07 (d, J=8.7 Hz, 1H), 7.93
(m,2 H), 7.82 (d, J=8.3 Hz, 1 H), 7.75 (m, 1 H), 7.61 (d, J=8.3 Hz,
1 H), 7.54 (dt, J=7.9, 1.0 Hz, 1 H), 7.23 (m, 2 H) 7.07 (m, 2H), 5.42
(s, 2H), 4.19 (s, 2H). MS: (MþH m/z=355.2).
2-[4-(2-Methyl-4-pyridn-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-
quinoline (10). To a solution of 3-dimethylamino-2-pyridin-4-
yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenone 8 (1.72 g) in
ethanol (20 mL) was added methyl hydrazine (3.5 mL, 1.5 equiv)
and concentrated sulfuric acid (0.1 mL). The reaction mixture was
stirred 1 h at ambient temperature followed by solvent evapora-
tion. The reaction mixture was partitioned between methylene
chloride and saturated sodium bicarbonate. The layers were
separated and the organic layer dried with magnesium sulfate,
filtered, and concentrated. Preparative HPLC chromatography
provided the title compound (minor isomer) as a white solid
(0.30 g, 17%). 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J =
5.4 Hz, 2 H), 8.21 (d, J=8.7 Hz, 1 H), 7.80 (d, J=8.3 Hz, 1H),
7.77 (s, 1 H), 7.66 (m, 3 H), 7.53 (m, 1H), 7.19 (d, J=8.7 Hz, 2 H),
7.11 (d, J=8.7 Hz, 2 H), 7.01 (d, J=6.2 Hz, 2H) 5.40 (s, 2H), 3.69
(s, 3H). MS: (MþH m/z=393.3). HPLC purity, column 4: RT
2.764, 96.76%.
2-[4-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
quinoline (11). Following the procedure for the preparation of
2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
quinoline 9 but substituting ethyl hydrazine provided the title
compound (37%). 1H NMR (400 MHz, CDCl3) δ 8.35 (bs, 2H),
8.19 (d, J=8.3 Hz, 1 H), 8.07 (d, J=9.1 Hz, 1 H), 7.82 (d, J=
7.9 Hz, 1H), 7.73 (t, J=8.3 Hz, 1H), 7.67 (d, J=8.3 Hz, 2 H), 7.62
(s, 1H), 7.55 (t, J=7.9 Hz, 1 H), 7.37 (d, J=9.1 Hz, 2H), 7.21 (bs,
2 H), 7.01 (d, J=8.7 Hz, 2H) 5.39 (s, 2H), 4.24 (q, J=7.5 Hz, 2H),
1.56 (t, J=7.5 Hz, 3H). MS: (MþH m/z=407.3). HPLC purity,
column 4: RT 3.007, 95.73%.
3-Dimethylamino-2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-
phenyl]-propenone (8). To 2-pyridin-4-yl-1-[4-(quinolin-2-
ylmethoxy)-phenyl]-ethanone 7 (4.0 g, 11.3 mmol) was added
dimethoxymethyl-dimethyl amine (10 mL) and the reaction
mixture was heated at reflux for 1 h. The reaction mixture was
concentrated to give a quantitative yield of the title compound,
which was used without purification in the next step. LC/MS:
RT=1.4 min. MS: (MþH m/z=410.2).
2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline
(3). To a solution of 3-dimethylamino-2-pyridin-4-yl-1-[4-(qui-
nolin-2-ylmethoxy)-phenyl]-propenone 8 (9.57 g, 27 mmol) in
methanol was added hydrazine hydrate (3.33 g, 40.5 mmol) and
the reaction mixture was heated at reflux for 1 h. The solvent was
evaporated to yield a white solid. The solid was washed with
water and ethyl ether. The solid was recrystallized from hot
ethanol/ethylacetate (10 mL/g) to give 8.34 g of the title com-
pound (82%). 1H NMR (400 MHz, DMSO) δ 8.41 (m, 3 H), 8.16
(s, 1 H), 7.97 (m, 2H), 7.86 (s, 1 H), 7.75 (t, J=7.9 Hz, 1 H), 7.68
(d, J=8.3 Hz, 1 H), 7.60 (t, J=7.5 Hz, 1 H), 7.33 (m, 2 H), 7.18
(m, 2 H) 7.15 (d, J=8.3 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 5.38 (s,
2H). MS: (MþH m/z=379.2). Anal. Calcd for C24H18N4O: C,
76.17%; H, 4.79%; N, 14.81%. Found: C, 75.82%; H, 4.73%;
N, 14.71%.
2-[4-(2-Ethyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-
quinoline (12). Following the procedure for the preparation of
2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
quinoline 9 but substituting ethyl hydrazine provided the title
compound (33%). 1H NMR (400 MHz, CDCl3) δ 8.35 (bs, 2H),
8.23 (d, J=8.3 Hz, 1 H), 8.08 (d, J=8.3 Hz, 1 H), 7.85 (d, J=
7.4 Hz, 1H), 7.83 (s, 1 H), 7.74 (m, 2 H), 7.57 (t, J=7.9 Hz, 1H),
7.21(d, J=8.7 Hz, 2 H), 7.14 (d, J=9.1 Hz, 2 H), 7.04 (m, 2H) 5.42
(s, 2H), 4.03 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.5 Hz, 3H). MS:
(MþH m/z=407.3). HPLC purity, column 4: RT 2.977, 99.00%.
2-{4-[-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-
phenoxymethyl}-quinoline (13). Following the procedure for the
preparation of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-
phenoxymethyl]-quinoline 9 but substituting (2,2,2-trifluoro-
ethyl)-hydrazine provided the title compound (58%). MS:
(MþH m/z=461.2). The free base was diluted in ethyl acetate,
and a suspension of succinic acid (1 equiv) in ethyl acetate was
added. The mixture was stirred overnight, then filtered to
provide the hemisalt. 1H NMR (500 MHz, methanol-d4)
δ ppm 2.57 (s, 2 H) 5.01 (q, J = 8.54 Hz, 3 F) 5.40 (s, 2 H)
2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
quinoline (9). To a solution of 3-dimethylamino-2-pyridin-4-
yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-propenone 8 (1.72 g) in
ethanol (20 mL) was added methyl hydrazine (3.5 mL, 1.5 equiv)
and concentrated sulfuric acid (0.1 mL). The reaction mixture was

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 16 5195
7.11 (d, J=9.03 Hz, 2 H) 7.31 (d, J=6.10 Hz, 2 H) 7.38 (d, J=
9.03 Hz, 2 H) 7.60-7.64 (m, 1 H) 7.75 (d, J=8.54 Hz, 1 H) 7.79
(ddd, J=8.42, 6.96, 1.46 Hz, 1 H) 7.96 (dd, J=8.30, 1.22 Hz, 1 H)
8.05 (d, J=8.54 Hz, 1 H) 8.17 (s, 1 H) 8.40 (d, J=1.46 Hz, 2 H)
8.39 (t, J=2.44 Hz, 2 H). MS: (MþH m/z=519.51). Anal. Calcd
(4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline 3 and
substituting 2-methyl pyridine for 4-picoline provided the title
compound (53%). 1H NMR (400 MHz, methanol-d4) d ppm
5.37 (br s, 2 H) 7.08 (br s, 2 H) 7.20 (ddd, J = 7.46, 5.03,
0.98 Hz, 2 H) 7.35 (d, J = 8.78 Hz, 2 H) 7.55-7.65 (m, 2 H)
7.68-7.81 (m, 2 H) 7.71 (d, J=8.39 Hz, 1 H) 7.92 (dd, J=8.20, 1.17
Hz, 1 H) 8.01 (d, J=8.59 Hz, 1 H) 8.36 (d, J=8.39 Hz, 1 H) 8.45
(ddd, J=4.98, 1.85, 0.98 Hz, 1 H). MS (LC/MS)=379.1 (M þ H).
HPLC purity, column 2: RT 4.040, 99.28%.
for C26H19N4OF3 C4H6O4: C, 64.74%; H, 4.27%; N, 10.78%;
F, 10.97%. Found: C, 64.63%; H, 4.12%; N, 10.72%; F,
11.00%.
3
2-[4-(4-Pyridin-4yl-isoxazol-5-yl)-phenoxymethyl]-quinoline (14).
2-Pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone 7
(200 mg, 0.56 mmol) was heated at reflux in dimethoxymethyl-
dimethyl amine (1 mL) for 1 h and concentrated. The crude
product was dissolved in methanol/water (3:1, 4 mL), and
hydroxyl amine hydrochloride (43 mg, 1.1 equiv) was added.
After 1 h, acetic acid was added (0.016 mL) and the reaction was
heated at reflux for 1 h, cooled to ambient temperature, poured
into saturated sodium bicarbonate, extracted with methylene
chloride, dried with magnesium sulfate, filtered, and concen-
trated. Biotage MPLC was run on a 25S column elution with 3%
methanol/1%ammonium hydroxide/ethyl acetate 50% in hex-
anes to provide the title compound as a tan solid (94 mg, 45%).
1H NMR (400 MHz, CDCl3) δ 8.59 (dd, J=6.2, 1.7 Hz, 2 H),
8.36 (s, 1H), 8.20 (d, J=8.3 Hz, 1H), 8.07 (d, J=8.7 Hz, 1 H),
7.82 (d, J=9.1 Hz, 1 H), 7.73 (dt, J=7.1, 1.7 Hz, 1H), 7.64 (d, J=
8.3 Hz, 1H), 7.54 (m, 3H), 7.28 (d, J=4.2 Hz, 2H) 7.05 (d, J=9.1,
2H), 5.40 (s, 2H). MS: (MþH m/z = 380.2). HPLC purity,
column 5: RT 4.467, 99.08%.
2-[4-(2-Methyl-5-pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-
quinoline (15). Following the procedure for the preparation
of 2-[4-(5-pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline
but substituting acetamidine hydrochloride provide the title com-
pound (58%). 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.63 (S,
1H), 8.58(m, 2 H), 8.17 (d, J=8.7 Hz, 1H), 8.04 (d, J=8.7Hz, 1H),
7.81 (d, J=8.3Hz, 1H), 7.70(m, 1H), 7.60(d, J=8.3 Hz, 1H), 7.52
(m, 1H), 7.37 (m, 2H) 7.15 (d, J=6.2, 2H), 6.93 (d, J=9.1 Hz, 2H),
5.35 (s, 2H). MS: (MþH m/z=405.2). HPLC purity, column 1: RT
3.050, 97.98%.
2-{4-[4-(3-Methyl-isoxazol-5-yl)-2H-pyrazol-3-yl]-phenoxy-
methyl}-quinoline (20). Following the procedure for the pre-
paration of 2-[-4-(4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxy-
methyl]-quinoline 3 and substituting 3,5-dimethyl isoxazole
1
for 4-picoline provided the title compound (43%). H NMR
(400 MHz, CDCl3) δ 8.23 (d, J=8.7 Hz, 1H), 8.12 (d, J=8.7 Hz,
1H), 7.94(s, 1 H), 7.84 (d, J=7.1 Hz, 1H), 7.74 (m, 1H), 7.69 (d,
J=8.3 Hz, 1 H), 7.57 (t, J=6.6 Hz, 2 H), 7.46 (d, J=8.7 Hz, 2H),
7.08 (d, J=8.7 Hz, 2H), 5.88 (s, 1H), 5.42 (s, 2H), 2.23 (s, 3H).
MS: (MþH m/z=383.2). HPLC purity, column 1: RT 3.660,
96.23%.
4-Benzyloxy-N-methoxy-N-methyl-benzamide. Following the
procedure for the preparation of N-methoxy-N-methyl-
4-(quinolin-2-ylmethoxy)-benzamide 6 but substituting 4-ben-
zyloxy benzoic acid 21 provided the title compound as a waxy
solid (99%). 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 2H), 7.65 (d,
J=9.1 Hz, 1H), 7.33 (m, 5H), 6.93 (d, J=9.1 Hz, 1H), 5.05 (s,
2H), 3.52 (s, 3H), 3.30 (s, 3H). MS: (MþH m/z=272.3).
1-(4-Benzyloxy-phenyl)-2-pyridin-4-yl-ethanone (22). Follow-
ing the procedure for the preparation of 2-pyridin-4-yl-
1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone 7 but substitut-
ing 4-benzyloxy-N-methoxy-N-methyl-benzamide provided the
title compound (73%). 1H NMR (400 MHz, CDCl3) δ 8.53 (d,
J=5.8 Hz, 2H), 7.95 (d, J=9.1 Hz, 2H), 7.36 (m, 5H), 7.17 (d, J=
6.2 Hz, 2H) 7.01 (d, 9.1 Hz, 2H), 5.12 (s, 2H), 4.21 (s, 2H). MS:
(MþH m/z=304.2).
4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyridine
(23). Following the procedure for the preparation of 2-[4-(1-
methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quino-
line 9 but substituting 1-(4-benzyloxy-phenyl)-2-pyridin-4-yl-
ethanone 22 provided the title compound (45%). 1H NMR
(400 MHz, CDCl3) δ 8.45 (d, J = 6.2 Hz, 2H), 7.36 (m, 8H),
7.15 (d, J=6.2 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 5.06 (s, 2H), 3.96
(s, 3H). MS: (MþH m/z=342.2).
2-[-4-(4-Pyrimidin-4yl-2H-pyrazol-3-yl)-phenoxymethyl]-qui-
noline (16). Following the procedure for the preparation of 2-
[-4-(4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline 3
and substituting 4-methylpyrimidine for 4-picoline provided the
1
title compound as a white solid (75%). H NMR (400 MHz,
methanol-d4) d ppm 5.41 (s, 2 H) 7.16 (br s, 4 H) 7.43 (br s, 2 H)
7.59 (s, 1 H) 7.68-7.83 (m, 2 H) 7.92 (s, 1 H) 8.02 (s, 1 H) 8.36 (s,
1 H) 8.44 (s, 1 H) 8.96 (d, J=1.17 Hz, 1 H). LC/MS: RT=1.8 min.
MS: (MþH m/z = 380.2). HPLC purity, column 4: RT 2.790,
99.52%.
4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol (24). To a
solution of 4-[3-(4-benzyloxy-phenyl)-1-methyl-1H-pyrazol-4-yl]-
pyridine 23 (1.28 g) in ethanol (50 mL)/ethyl acetate (50 mL) in a
parr bottle was added palladium hydroxide (500 mg). The parr
bottle was charged to 40 psi on a shaker for 6 h. The reaction
mixture was filtered and concentrated. MPLC biotage chroma-
tography eluting with methanol (1-7%)/chloroform provided the
2-[4-(4-Pyridazin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-qui-
noline (17). Following the procedure for the preparation of 2-
[-4-(4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline 3
but substituting 4-methyl pyridazine for 4-picoline provided the
1
title compound (860 mg, 91%). H NMR (400 MHz, DMSO)
1
title compound as a white solid (32%). H NMR (400 MHz,
δ 9.53 (s, 1H), 8.39 (d, J=5.8 Hz, 2 H), 7.15 (m, 4H), 6.72 (d, J=
CDCl3) δ 9.11 (s, 1H), 9.01 (d, J=5.0 Hz, 1H), 8.34(d, J=8.7 Hz,
1 H), 8.25(d, J=8.7 Hz, 1H), 7.89 (m 2H), 7.81 (d, J=8.3 Hz, 1 H),
7.79 (m, 2 H), 7.61 (t, J=7.6 Hz, 1H), 7.34 (m, 1H), 7.31 (d, J=
8.7 Hz, 2H), 7.05 (d, J=8.7, 2H), 5.49 (s, 2H). MS: (MþH m/z=
380.2). HPLC purity, column 5: RT 3.433, 95.51%.
8.7 Hz, 1H), 3.84 (s, 3H). MS: (MþH m/z=252.2).
2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
quinoxaline (25). To a solution of 4-(1-methyl-4-pyridin-4-yl-1H-
pyrazol-3-yl)-phenol 24 (50 mg) in dioxane (2 mL) was added
triphenylphosphine (84 mg), quinoxaline-2-yl-methanol (48 mg),
and di-t-butyl-aza-dicarboxylate (73 mg) and the reaction mixture
was heated at 60 °C for 18 h. The reaction mixture was poured into
1 N NaOH, extracted 3ꢀ methylene chloride, dried with magne-
sium sulfate, filtered, and concentrated. Purification via MPLC
biotage chromatography provided the title compound (54 mg,
2-((4-(4-phenyl-1H-pyrazol-5-yl)phenoxy)methyl)quinoline (18).
Following the procedure for the preparation of 2-[-4-(4-pyridin-4-
yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline 3 and substituting
1
toluene for 4-picoline provided the title compound (38%). H
NMR (400 MHz, methanol-d4) δ ppm 5.34 (s, 2 H) 7.02 (d, J=
8.78 Hz, 2 H) 7.22 (d, J=4.49 Hz, 4 H) 7.12-7.25 (m, 2 H) 7.32 (d,
J=8.98 Hz, 2 H) 7.58 (ddd, J=8.15, 6.98, 1.07 Hz, 1 H) 7.69 (d, J=
8.39 Hz, 2 H) 7.75 (ddd, J=8.44, 6.98, 1.56 Hz, 1 H) 7.91 (dd, J=
8.20, 1.37 Hz, 1 H) 8.01 (dd, J=8.59, 0.98 Hz, 1 H) 8.34 (d, J=8.39
Hz, 1 H). MS (LC/MS)=378.1 (M þ H). HPLC purity, column 4:
RT 4.156, 97.77%.
1
67%). H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.45 (d, J=
6.2 Hz, 2H), 8.10 (m, 2 H), 7.77 (m, 2H), 7.55 (s, 1H), 7.37 (d, J=
9.1 Hz, 2H), 7.10 (d, J=6.9 Hz, 2 H), 7.01 (d, J=8.7, 2H), 5.41 (s,
2 H), 3.94 (s, 3H). MS: (MþH m/z=394.4)). HPLC purity, column
5: RT 3.660, 98.64%.
1-Methyl-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxy-
methyl]-1H-benzoimidazole (26). To a solution of 4-(1-methyl-4-
pyridin-4-yl-1H-pyrazol-3-yl)-phenol (50 mg) in dioxane (1 mL)
2-((4-(4-(pyridin-2-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quino-
line (19). Following the procedure for the preparation of 2-[-4-

5196 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 16
Verhoest et al.
was added triphenyl phosphine (83 mg), (1-methyl-1H-benzoimida-
zol-2-yl)-methanol (48 mg) and di-t-butyl azodicarboxylate (73 mg).
The reaction mixture was heated at 60 °C for 18, poured into 1 N
NaOH, extracted 3ꢀ with chloroform, dried with magnesium
sulfate, filtered, and concentrated. Purification via biotage MPLC
eluting with 80% ethyl acetate/hexane provided the title compound
(75 mg, 96%). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=6.2 Hz,
2 H), 7.76 (dd, J=7.1, 1.7 Hz, 1 H), 7.55 (s, 1H), 7.37-7.28 (m, 5 H),
7.15 (dd, J=4.6, 1.7 Hz, 2H), 7.05 (d, J=9.1 Hz, 2H), 5.38 (s, 2H),
3.94 (s, 3H) 3.88 (s, 3H). MS: (MþH m/z=396.2). The free base was
dilute in ethyl acetate and a suspension of succinic acid (1 equiv) in
ethyl acetate was added. The mixture was stirred overnight, and the
filtrates were washed with ether to provide the succinic acid salt.
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Anal. Calcd for C24H21N5O C4H6O4: C, 65.49%; H, 5.30%; N,
13.64%. Found: C, 65.49%; H, 5.30%; N, 13.45%.
3
2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
imidazo[1,2-a]pyridine (27). Following the procedure for the
preparation of 1-methyl-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyra-
zol-3-yl)-phenoxymethyl]-1H-benzoimidazole 26 but substituting
imidazo[1,2-a]pyridin-2-yl-methanol provided the title compound
(74%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=6.2, 2 H), 7.87
(d, J=7.1 Hz, 1H), 7.60 (d, J=9.1 Hz, 1H), 7.57 (s, 1H), 7.38 (t, J=
8.7 Hz, 2 H), 7.18 (d, J=6.2 Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 6.86
(d, J=6.6 Hz, 1H), 5.28 (s, 2H), 3.97 (s, 3H) 2.52 (s, 3H). MS:
(MþH m/z=382.1). HPLC purity, column 1: RT 3.660, 99.20%.
2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-
[1,2,4]triazolo[1,5-a]-pyridine (28). Following the procedure for
the preparation of 1-methyl-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyr-
azol-3-yl)-phenoxymethyl]-1H-benzoimidazole 26 but substituting
[1,2,4]triazolo[1,5-a]pyridin-2-yl-methanol provided the title com-
pound (91%). 8.57 (d, J=6.6 Hz, 1 H), 8.44 (d, J=5.8 Hz, 2H), 7.73
(d, J=9.1 Hz, 1H), 7.55 (s, 1H), 7.54 (dd, J=6.6, 1.3 Hz, 1 H), 7.38
(d, J=8.7 Hz, 2H), 7.14 (d, J=5.8 Hz, 2H), 7.05 (m, 3H), 5.36
(s, 2H), 3.94 (s, 3H). MS: (MþH m/z = 383.1). HPLC purity,
column 2: RT 3.143, 99.01%.
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Acknowledgment. We thank S. Simons, K. Fennell, and T.
Subashi forcloningandexpressionoftherecombinantprotein
used in the crystallography experiments.
Supporting Information Available: Crystal structure data, in
vitro biology data with statistics, biological experimentals, and
pharmacokinetic experimentals are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
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