Design, synthesis, and structure - Activity relationship, molecular modeling, and NMR studies of a series of phenyl alkyl ketones as highly potent and selective phosphodiesterase-4 inhibitors

J. Med. Chem. 2008, 51, 7673–7688

7673

Articles

Design, Synthesis, and Structure-Activity Relationship, Molecular Modeling, and NMR Studies

of a Series of Phenyl Alkyl Ketones as Highly Potent and Selective Phosphodiesterase-4

Inhibitors

Shilong Zheng,^†,¶Gurpreet Kaur,^†,¶Huanchen Wang,^‡Minyong Li,^†Megan Macnaughtan,^§Xiaochuan Yang,^†Suazette Reid,^†

James Prestegard,^§Binghe Wang,*^,†and Hengming Ke*^,‡

Department of Chemistry and Center for Biotechnology and Drug DiscoVery, Georgia State UniVersity, Atlanta, Georgia 30302-4098,

Department of Biochemistry and Biophysics, UniVersity of North Carolina, Chapel Hill, North Carolina, and Complex Carbohydrate Research

Center and Department of Chemistry, UniVersity of Georgia, Athens, Georgia

ReceiVed December 30, 2007

Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-

inﬂammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors.

Among them, 13 compounds were identiﬁed as having submicromolar IC₅₀values. The most potent

compounds have IC₅₀values of in the mid- to low-nanomolar range. Compound 5v also showed preference

for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za

into the binding pocket of the PDE4 catalytic domain revealed a similar binding proﬁle to PDE4 with

rolipram except that the ﬂuorine atoms of the diﬂuoromethyl groups of 5v, 5za, and 5zf are within a reasonable

range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears

additional van der Waals interactions with His 160, Asp 318, and Tyr 159.

Introduction

Phosphodiesterases (PDEs) are responsible for the hydrolysis

of second messengers cyclic adenosine and guanosine mono-

phosphates (cAMP and cGMP).^a,1Because of the important

roles that cAMP and cGMP play, PDEs are excellent targets

for the development of therapeutic agents. About 100 isoforms

of PDEs are coded by 21 human genes and differentially

expressed in various cell types.^2-7Such a large number of

isoforms presents a unique challenge to the design and synthesis

Figure 1. Structures of selected PDE4 inhibitors.

of PDE inhibitors that are speciﬁc for PDE isoforms of interest

studies because of side effects, which presumably arise from

for pharmaceutical applications. We are especially interested

nonspeciﬁc inhibition of other isoforms, while others including

in developing PDE4 inhibitors because of its implication in

roﬂumilast and cilomilast (Figure 1) are still in clinical

inﬂammatory diseases such as asthma and chronic obstructive

trials.^3,23,24Up until now no PDE4 inhibitors have been

pulmonary disease.^3,8-13PDE4 speciﬁcally catalyzes the hy-

approved for clinical use.

drolysis of cAMP¹⁴and has been found in inﬂammatory^15,16as

We are interested in the design, synthesis, and evaluation of

well in immune cells.¹⁷Several selective PDE4 inhibitors have

selective PDE4 inhibitors for potential pharmaceutical applica-

entered into clinical trials, the results from which have validated

tions. The design is based on published crystal structural

PDE4 as a pharmacological target for the development of

information.²⁵Forty-one potential PDE4 inhibitors have been

therapeutic agents for the treatment of inﬂammatory and chronic

designed, synthesized, and evaluated. Figure 2 shows the core

obstructive pulmonary diseases.^18-22Some PDE4 inhibitors,

structure and different substituents in general terms.

such as rolipram (Figure 1), have been dropped from clinical

Results and Discussion

* To whom correspondence should be addressed. For B.W.: phone, +1

404 413-5544; fax, +1 404 413-5543; e-mail, wang@gsu.edu. For H.K.:

Design. The design was based on published cocrystal

structures of PDE4D2 and rolipram.^25,26From the crystal

structure, it was clear that the side chain region of rolipram

still has plenty of space for structural optimization and explora-

tion of selectivity. Therefore, three series of compounds with

ketone, alcohol, and alkyl side chains as point of modiﬁcation

were designed with the ketone series looking especially promis-

ing because of the planar structure of the side chain moiety at

the aryl attachment point. However, the other compounds also

seemed like reasonable candidates (Figure 2).

phone, 1-919-966-2244; fax, 1-919-966-2852; e-mail, hke@med.unc.edu.

†

Georgia State University.

S. Zheng and G. Kaur made equal contributions to this manuscript.

University of North Carolina.

University of Georgia.

¶

‡

§

^aAbbreviations: PDE4, phosphodiesterase 4; cAMP, cyclic adenosine

monophosphate; cGMP, cyclic guanosine monophosphate; PCC, pydrinium

chlorochromate; Boc, di-tert-butyl dicarbonate; COPD, cardiovascular

obstructive pulmonary disease; PBMCs, peripheral blood mononuclear cells;

TNF, tumor necrosis factor; QSAR, quantitative structure-activity relation-

ship; CoMSIA, comparative molecular similarity index analysis; NOE,

nuclear Overhauser effect; STD, saturation transfer difference.

10.1021/jm701635j CCC: $40.75

2008 American Chemical Society

Published on Web 12/02/2008

7674 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Zheng et al.

Figure 2. General structures of potential inhibitors designed.

Scheme 1^a

^a(a) CClF₂COOMe, Cs₂CO₃, DMF; (b) (i) method A, R₁OH or R₂OH, PPh₃, t-BuO₂CNdNCO₂-t-Bu, THF; method B, R₁Br or R₂Br, CsCO₃, DMF; (c)

R₃Li or R₃MgBr, THF, -78 ° C; (d) PCC, DCM; (e) R₄Br, n-BuLi, THF, -78 ° C; (f) AcOH, H₂SO₄, 80 ° C; (g) H₂, Pd/C, room temp.

Chemical Synthesis. The synthesis of the designed analogues

started with catechol, which required differential alkylation of

the two hydroxyl groups of the catechol core. Therefore, the

synthesis started with the alkylation of 1 at either the 3- or

4-position (Scheme 1). In one series, a diﬂuoromethyl group

needed to be attached to the 4-position, which was achieved

through the alkylation of 3,4-dihydroxybenzaldehyde using

chlorodiﬂuoroacetate to give 4-diﬂuoromethoxy-3-hydroxyben-

zaldehyde 2a in 45% yield and 3,4-bis(diﬂuoromethoxy)ben-

zaldehyde 3n in 20% yield.^27,28For the series with methyl

substitution at either the 3- or 4-position of the catechol core,

commercially available 3-hydroxy-4-methoxybenzaldehyde 2b

or 4-hydroxy-3-methoxybenzaldehyde 2c was used as the

starting material. The second alkyl group on the catechol moiety

was attached by reacting 2a-c with racemic alcohols in THF

via the Mitsunobu reaction (method A) to give racemic

compounds 3a-j or by O-alkylation with bromides (method

B) to give compounds 3k-m. Treatment of aldehydes 3a-m

with n-butyllithium, tert-butyllithium, or a Grignard reagent gave

the corresponding diastereomeric mixtures of alcohols 4a-w

and 4za-zn. Oxidation of the alcohol with pyridium chloro-

chromate (PCC) afforded the corresponding ketones 5a-v and

5za-zm. Reaction of 5g,h with pyridinyllithium or quinolinyl-

lithium gave the respective alcohols 6a,b. Dehydration of 6a

afforded oleﬁns 7a. Hydrogenation of 7a on Pd/C afforded 8.

Compounds 4h and 4i were converted to their respective

chlorides 9a and 9b upon reaction with thionyl chloride (Scheme

2). Reaction of 9a,b with the sodium salt of methyl acetoacetate

afforded a diastereomeric mixture of esters 10a,b. Saponiﬁcation

followed by acidiﬁcation led to spontaneous decarboxylation

to give derivatives 11a,b (Scheme 2).

SAR of Potential PDE4D Inhibitors. The enzyme inhibitory

activities of the synthesized compounds were evaluated against

PDE4 using human PDE4D2 (79-438) expressed in E. coli

strain BL21 (Codonplus) as a model.²⁵The results are sum-

marized in Tables 1-3.

The alcohol series of compounds (entries 1-5, Table 1) only

exhibited weak inhibition activities with IC₅₀values in the range

Phenyl Alkyl Ketones as Inhibitors

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7675

Scheme 2^a

^a(a) SOCl₂, DCM; (b) ethyl acetoacetate, CH₃ONa, THF; (c) LiOH, THF/MeOH/ H₂O.

Table 1. IC₅₀(µM) Values of Phenyl Alkyl Alcohol PDE4 Inhibitors^a

the corresponding 3-methoxy substituted compounds (entries

7-12, Table 2). Such results are consistent with literature reports

as well.¹⁹

With the initial indication that the 4-methoxy ketones are

more active, the subsequent effort was focused on optimizing

this series of compounds. One approach adopted was to use a

4-diﬂuoromethoxy group in place of the methoxy group with

the idea of improved metabolic stability (entries 24-28 and

33-35, Table 2).^27,28It turned out that these 4-diﬂuoromethoxy

compounds were also 2- to 14-fold more potent than the

corresponding 4-methoxy substituted compounds (entries 14,

16, 18-20, and 37, Table 2). Within this series, the substituent

effect at the 3-position was also studied. The tetrahydrofuran-

3-yloxy substituted phenyl compounds (entries 16, 17) have 3-

to 8.5-fold higher potencies than the corresponding tetrahydro-

pyran-3-yloxy substituted phenyl compounds (entries 14, 15).

The replacement of the tetrahydrofuran ring by a cyclopentyl

ring (entry 25) gave a compound (entry 32) with comparable

potency (IC₅₀) 28 nM). The tetrahydrofuran-3-yloxy substi-

tuted phenyl compound (entry 28) also seems to be more active

than the corresponding Boc protected piperidi-4-nyl substituted

compound (entry 33) by more than 20- to 30-fold, and the 3,4-

bis(diﬂuoromethoxy)phenyl compounds (entry 31) are also less

active than the corresponding 4-diﬂuoromethyl-3- tetrahydro-

furan-3-yloxy substituted phenyl compounds (entries 27, 28, 34,

and 35) by 2.7- to 60-fold. Similarly, replacing the tetrahydro-

furan ring with a deprotected tetrahydropyrrol ring (entries 25,

28) also decreased the potency of IC₅₀by over 100 µM (entry

22) from 26 and 61 nM.

In the series of the 4-methoxy-3-tetrahydrofuran-3-yloxy

phenyl ketones (entries 16-21, 37, 38) and the series of the

4-diﬂuoromethoxy-3-tetrahydrofuran-3-yloxy phenyl ketones

(entries 25-28 and 34-36), both ketones (entries 25, 37) with

an isobutyl side chain have the highest potency (IC₅₀of 26 and

176 nM, respectively) and the ketones (entries 28 and 16) with

a butyl side chain have the second highest potency (IC₅₀of 61

and 220 nM, respectively). The ketones with the bulky cyclo-

hexyl (entries 21 and 26) and phenylalkyl (entries 20 and 18)

side chains (R₃) constantly showed the lowest potency.

We have also tested the compounds with further transforma-

tions of the ketone group into a sp³carbon (entries 39-41, Table

3). None of these transformations led to improved potency.

Some representatives of the PDE4 inhibitors were tested for

their PDE4 selectivity using human PDE7A1, 9A2, 2A3, and

5A1 subtypes, which were cloned and expressed in E. coli strain

BL21 (Codonplus) (Table 4).²⁵Most of the compounds that we

have synthesized showed high PDE4 selectivity. For example,

5v showed preference for PDE4 with selectivity of at least about

2000-fold over PDE7A1, PDE9A2, PDE2A3, and PDE5A1,

respectively; 5k had selectivity at least 14-fold over PDE7A1,

PDE9A2, PDE2A3, and PDE5A1.

^aAll potent compounds (low nanomolar) were assayed 2-3 times, and

their inhibition results are expressed with standard deviations. All other

results were from single runs.

from 10 µM to over 100 µM, which were many fold less potent

than the corresponding phenyl alkyl ketones (entries 9-12, 16,

Table 2). Such results indicate that a planar geometry is desirable

at this position for compounds with the catechol core. The

inhibition results with the disubsituted alcohol (entry 6, Table

1) further suggested that the planar geometry was required. With

the additional group on 6b the inhibition potency did not

improve signiﬁcantly compared to the ketone series. Within the

alcohol series, there are two substitution patterns: one with a

bulky alkyl group on the 3-position and the other with a bulky

alkyl group on the 4-position of the catechol core. It is very

clear that the compound (entry 5, IC₅₀) 10 µM) with a small

methyl group on the 4-position and the bulky substitution on

the 3-position has much higher potency than the analogues with

a reverse substitution pattern (entries 1-4, IC₅₀> 100 µM).

The same trend is reﬂected in the phenyl alkyl ketone series.

For example, the 4-methoxy substituted phenyl compounds

(entries 14-21, Table 2) are 20- to 500-fold more potent than

7676 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Table 2. IC₅₀(µM) Values of Phenyl Alkyl Ketone PDE4 Inhibitors^a

Zheng et al.

Table 3. IC₅₀(µM) Values of Phenylalkyl PDE4 Inhibitors^a

entry compd R₁

R₂

R₃

R₄

IC₅₀(µM)

39

40

41

11a

11b

8

2-py -CH₃3-quninolinyl -CH₂COCH₃

6

80

10

H

-CH₃3-py

-CH₂COCH₃

n-Bu

2-py -CH₃3-py

^aAll potent compounds (low nanomolar) were assayed 2-3 times, and

their inhibition results are expressed with standard deviations. All other

results were from single runs.

Table 4. IC₅₀Values (µM) of Selected Lead Inhibitors on Various

PDEs

compd

PDE4D2

PDE7A1

PDE9A2

PDE2A3

PDE5A1

5v

0.026

6

3.5

6

>50

17

>50

40

11a

5k

6b

Figure 3. Inhibitory effect of 5v (2) and 5zf (9) against LPS-mediated

TNF-R production, compared with rolipram (b).

stimulation with LPS, activated monocytes express and secrete

TNF-R for up to 8 h and plasma levels remain stable for 24 h.

Published studies have shown that inhibition of TNF-R produc-

tion by increasing intracellular cAMP via PDE4 inhibition and/

or enhanced adenylyl cyclase activity occurs at the transcrip-

tional level. Therefore, we selected the two most active

compounds and studied their ability to inhibit TNF-R production.

Speciﬁcally, the effect of 5v and 5zf for their ability to inhibit

LPS-mediated TNF-R production by human peripheral blood

mononuclear cells (PBMCs) was studied (Figure 3). Rolipram

(IC₅₀) 60 nM) was included as a reference. The results show

that both 5v and 5zf were able to inhibit LPS-mediated TNF-R

production with IC₅₀values of 40 and 100 nM, respectively.

IC₅₀values for TNF-R release from the literature may not be

directly comparable because of variations of assay systems and

conditions. However, if roliprarn is taken as a relative reference,

the potency of our 5v is higher than that of rolipram,³⁰

a

compound that went into clinical trials for treatment of COPD.

Molecular Modeling. In an effort to gain an understanding

of the structural basis for the empirical structure-activity

relationships observed, we also studied the binding of the

synthesized inhibitors with PDE4D2 through computer model-

ing. The crystal structure of PDE4D2-rolipram complex^25,26

was used as the starting point.

Molecular Docking. In this investigation, the 3D structure

of PDE4D was taken from a Protein Data Bank entry (PDB

entry 1OYN) having the ligand rolipram in place.²⁶The new

inhibitors were built and optimized at the Hartree-Fock level

^aAll potent compounds (low nanomolar) were assayed 2-3 times, and

their inhibition results are expressed with standard deviations. All other

results were from single runs.

The inhibition of TNF-R production induced by lipopolysac-

charide is an essential assay for evaluation of the pharmacologi-

cal effect of PDE4 inhibitors in anti-inﬂammation and the

treatment of COPD and asthma.^29,30Normal and nonstimulated

human blood does not contain detectable levels of TNF-R. Upon

Phenyl Alkyl Ketones as Inhibitors

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7677

333 N-H, which could engage in hydrogen bond interactions,

and the additional van der Waals interactions of the long alkyl

chain with His 160, Asp 318, and Tyr 159. In the case of

hydrogen bond interactions, the F-O distance is 2.68 Å but

with a nonideal C-F-H angle of 34.7°.

The computer modeling results are also consistent with the

empirically observed structure-activity relationship. From the

modeling results it is clear that the 4-methyl/diﬂuoromethyl

group occupies a small pocket. Anything larger at this position

would result in steric hindrance and therefore unfavorable

interactions (Figure 6). Such a ﬁnding is consistent with earlier

studies with rolipram²⁶and the fact that 4-position substitution

with a bulkier group leads to compounds with diminished

potency (entries 1-6, Table 1; entries 7-12, Table 2). Figure

6 shows the unfavorable interactions of an inhibitor with large

substituents at the 4-position. For 5za, the diﬂuoromethyl group

has an additional hydrogen bond with Thr 333; meanwhile, the

long alkyl chain also bears additional van der Waals interactions

with His 160, Asp 318, and Tyr 159. This difference could be

the reason that these diﬂuoremethyl compounds have higher

potencies than others (Figures 5 and 7). The 3-position has a

fairly large hydrophobic pocket, allowing favorable interactions

with bulkier groups such as tetrahydropyran and tetrahydrofuran

(entries 13-28, 32-38, Table 2). At this site, there is Lys 367,

which under normal physiological conditions should be posi-

tively charged. This helps to explain why the deprotected amino

group in compound 5i (entry 22, Table 2), which introduces a

positively charged protonated amine, leads to reduced potency.

Within the ketone series (entries 7-38, Table 2), it seems

that compounds with a four-carbon side chain have the highest

potency. This is consistent with the existence of a hydrophobic

binding pocket accommodating the side chain, which is

somewhat narrow but deep. Bulkier groups such as the phenyl

and cyclohexyl side chains protrude away from this hydrophobic

pocket, resulting in unfavorable interactions (Figures 4 and 7).

The planar sp²-hybridized ketone group seems to have the

ﬂexibility to put the hydrophobic side chain in the right position

and orientation for favorable hydrophobic interactions. In

contrast, a tetrahedral sp³carbon would ﬁx the side chain in a

position for less favorable hydrophobic contact with PDE4,

which explains why the compounds with a sp³carbon at the

benzylic position showed low potency (Figure 8).

Figure 4. Key residues in the binding site of rolipram (white), 5za

(yellow), 5v (blue), and 5zf (red) to PDE4.

with the 6-311 G basis set in the Gaussian 03 program.³¹The

optimized ligands were then embedded with Gastiger-Hu¨ckel

partial charges using the SYBYL 7.1 package.³⁰DOCK 5.2³²

was employed to dock these ligands into the PDE4D active site.

The resulting structures were then analyzed using HBPLUS

3.06³³and Ligplot 4.22³⁴programs to identify speciﬁc contacts

between ligands and receptor.

Initially, we selected the most potent compounds 5v, 5za,

and 5zf for the docking experiments. These three compounds

adopt the same alignments as rolipram in the active site. Such

alignments have also been conﬁrmed by a preliminary crystal-

lographic study, the details of which will be published elsewhere.

Figure 4 presents the docking conformations of rolipram (white),

5za (yellow), 5v (blue), and 5zf (red) in the active site of PDE4.

Figure 5 depicts a schematic binding proﬁle of 5za. Similar to

the binding of rolipram (Figure 5), 5za, 5v, and 5zf have a

hydrogen bond with Gln 369 and hydrophobic contact with Ile

336, Met 357, Phe 340, Ser 368, Met 337, Phe 372, and Tyr 3.

Different from rolipram binding are the possible interactions

of the diﬂuoromethyl group of 5za, 5v, and 5zf with the Thr

Figure 5. Binding proﬁle of 5za and rolipram with PDE4D2 obtained from Ligplot analysis.

7678 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Zheng et al.

Figure 6. Negative effect observed for a bulky substitution at

4-position: blue stick, 5f; gray stick, 5m.

Figure 8. Comparison of sp²-hybridized ketone (blue stick, 5m) and

sp³alcohol (gray stick, 4l).

Figure 9. Docking conformations of synthesized inhibitors in the

PDE4D active site.

Figure 7. Docking conformation of 5za in the PDE4D active site.

Molecular Similarity Index Analysis (CoMSIA). In order

to achieve some semiquantitative understanding of the contribu-

tion of various parameters to binding afﬁnity, we have also

conducted a structure-based comparative molecular similarity

index analysis (CoMSIA) implemented in SYBYL 7.1.³⁰

CoMSIA is an extension of the CoMFA (comparative molecular

ﬁeld analysis) methodology.^35,36Both are forms of 3D-QSAR

and are based on the assumption that changes in ligand binding

afﬁnities are related to changes in molecular properties,

represented by ﬁelds. They differ only in the implementation

of the ﬁelds.^35,36In this study the docking conformations of all

compounds synthesized were used as the input of molecular

alignments (Figure 9).

The CoMSIA model analysis indicates that the contribution

of steric, electrostatic, hydrophobic, hydrogen bond donor, and

hydrogen bond acceptor of this series of PDE4 inhibitors to

binding afﬁnity is 5.8%, 26.4%, 25.4%, 23.7%, and 18.7%,

respectively. In PLS analysis, the standard error of estimate of

0.312, non-cross-validated correlation coefﬁcient r²of 0.939,

cross-validated coefﬁcient q²of 0.832, and F value of 584.051

show that our CoMSIA model has good prediction. In order to

validate this CoMSIA model again, we introduced an external

test set consisting of rolipram plus nine compounds (s1-s9)

from literature (Figure 10).¹⁹After prediction by the CoMSIA

model, an r²of 0.803 and q²of 0.706 were obtained. This

external validation again suggests a reliable CoMSIA model

we harvested. Table 5 shows a comparison of the calculated

pIC₅₀and experimentally determined pIC₅₀values using the

CoMSIA model developed, and Figure 11 shows the schematic

correlation of such data. Such results will help future optimiza-

tion efforts.

NMR Studies of the Interactions of 5i with PDE4D2

Protein. In order to achieve some experimental veriﬁcation of

the modeled binding modes of the inhibitors synthesized, NMR

experiments were conducted in solution. We initially selected

two compounds, 5i (IC₅₀) 102 µM) and 5zi (IC₅₀) 40 µM),

for the studies. These two compounds have moderate afﬁnities,

which allow high sensitivity detection of transferred effects

Phenyl Alkyl Ketones as Inhibitors

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7679

Figure 10. Chemical structures for test set validation.

Figure 11. Actual versus predicted pIC₅₀for CoMSIA 3D-QSAR

model.

through observation of spectra from ligands in 10- to 100-fold

excess over protein.³⁷Under the conditions of rapid exchange,

normally associated with low to moderate binding afﬁnities,

effects such as nuclear Overhauser effects (NOEs) and saturation

transfer differences (STDs) originating with ligands bound to

PDE4 are carried into solution. Because of enhanced efﬁciencies

in magnetization transfer in large complexes, the bound-state

properties dominate the average effects observed through the

narrow lines and high intensities of the free ligand resonances.

Unfortunately, 5zi had solubility and nonspeciﬁc binding

problems that prevented the collection of meaningful data.

Therefore, only 5i was used for the NMR studies. Both STD

and transferred NOEs (trNOE) experiments were performed to

study the inhibitor. STD provides information on the proximity

of protons on the bound ligand to protons on the protein. The

relative signal intensities in an STD spectrum are interpreted

to produce an epitope map with protons giving the strongest

signal closest to the protein surface.³⁷The trNOE experiment

provides distance information between protons within the ligand,

which can be used to determine the compound’s bound state

conformation.³⁷The solubility of 5i (up to 800 µM in D₂O)

was conﬁrmed by NMR. A reference ¹H spectrum allowed

assignment of resonances as indicated in Figure 12a.

1

Figure 12. (a) Reference 1D H NMR spectrum of 400 µM 5i with

assignments indicated by letters on the chemical structure. The peak

for the proton in the 4-position of the piperidinyl group (labeled “h”

on the chemical structure) is buried under the water peak. Peak “i”

was not assigned and is believed to be a contaminant. (b) STD spectrum

of 800 µM 5i with 10 µM PDE4D2 using a 50 Hz Gaussian saturation

pulse train of 250 ms centered at 0.5 ppm. The protein background

was not subtracted or suppressed. The normalized STD percentages

calculated from the STD and reference spectra of 5i are superimposed

on the chemical structure. Both spectra were collected using a Varian

INOVA 800 MHz NMR instrument equipped with a cryogenic probe.

The water peaks in the center of the spectra were removed for clarity.

epitope map. For 5i, peak “i” was not observed in the STD

spectrum, indicating that it does not bind PDE4D2 providing

evidence that it is a contaminant. The n-butanyl, methyl, and

catechol protons show stronger STD contacts than the piperidi-

nyl protons. While it is possible to check these intensities for

consistencies with speciﬁc models when available,³⁸it is also

useful to seek a more qualitative interpretation. The results as

presented are consistent with computer modeling studies

The STD spectrum of 5i in the presence of PDE4D2 is

presented in Figure 12b. In an effort to map the binding epitope,

the peak integrals from the reference and STD spectra were

compared and normalized to give a STD percentage for each

proton. The STD percentages are shown on the chemical

structure in Figure 12b. The STD percentages give an indication

of which protons of bound 5i are close to the protein, i.e., an

7680 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Zheng et al.

Table 5. Actual pIC₅₀, Estimated pIC₅₀, and Residual Values of

Molecules Used for CoMSIA

compd

4b

4c

4d

4e

5i

5f

5a

11b

5d

5c

5j

5zj

5zi

5b

5e

4l

8

11a

5zm

5k

5q

5r

5o

5zg

5p

5zb

5l

5zc

5ze

5zl

5s

actual pIC₅₀

estimated pIC₅₀

residual

2.82

3.27

3.28

3.40

3.99

4.00

4.03

4.10

4.15

4.22

4.35

4.36

4.40

4.54

4.62

5.00

5.22

5.28

5.46

5.59

5.64

5.66

5.72

5.96

6.14

6.18

6.20

6.30

6.39

6.40

6.42

6.46

6.7

3.15

3.39

3.23

3.85

3.92

4.15

4.02

4.10

4.30

4.09

4.49

4.14

4.27

4.45

5.35

4.99

5.24

5.60

5.77

6.08

5.78

5.98

5.51

5.54

6.34

5.88

6.37

6.43

6.07

6.90

6.25

6.21

6.39

6.06

6.31

6.99

7.20

6.80

7.48

-0.33

0.12

-0.11

0.17

0.14

0.08

-0.12

0.08

0.05

-0.08

0.26

0.13

0.26

0.27

0.17

Figure 13. The 2D NOESY spectrum of 800 µM 5i and 10 µM

PDE4D2 with a 50 ms mixing time is shown. The cross peaks have

positive intensities (i.e., negative NOEs), which indicate that 5i binds

PDE4D2.

-0.35

0.01

-0.02

-0.32

-0.31

-0.49

-0.19

-0.34

0.11

0.18

-0.38

0.26

-0.19

-0.23

0.23

-0.01

0.15

0.21

0.07

0.14

0.43

and qualitative information on a structure can readily be

determined by comparing the cross peak intensities in Figure

13. Structurally restraining NOEs include contacts between the

catechol protons and the methyl, piperidinyl, and n-butanyl

protons. The catechol proton in the 6-position (peak “a”) has

an NOE to the n-butanyl protons (peak “g”), and the catechol

proton in the 5-position (peak “c”) has an NOE to the methyl

protons (peak “d”). This NOE would suggest a conformation

different from the structure used to illustrate the NMR spectrum

(Figure 12) with the keto chain rotated 180° about the chain to

catechol bond. This geometry is in fact consistent with the

geometries shown for 5v, 5za, and 5zf (Table 2). NOEs are

also seen from the catechol 2-position to the piperidinyl protons

in the 4-position (peak “h”) and the NMR equivalent methylene

protons in the 3- and 5-positions (peaks “j” and “k”). This NOE

restrains the relative orientation of the piperidinyl and catechol

rings and is consistent with the docking models of 5za in Figure

7.

5n

5u

5zh

5m

5zd

5t

5za

5zf

5v

6.74

6.75

7.21

7.66

7.74

-0.24

0.01

-0.25

0.26

Test set

rolipram

s1

s2

s3

s4

s5

s6

s7

6.26

4.97

5.51

7.55

4.43

6.40

7.15

6.19

5.80

6.70

6.87

4.56

6.12

7.93

4.82

7.01

6.54

7.01

5.82

7.1

-0.61

0.41

-0.61

-0.38

-0.39

-0.61

0.61

-0.82

-0.02

-0.40

Conclusions

A new series of phenyl alkyl ketones with variable side chains

was investigated as potential PDE4D inhibitors. Thirteen alkyl

ketones were identiﬁed to have submicromolar IC₅₀values.

Among them, the most potent compounds 5v, 5zf, and 5za have

IC₅₀values of 26, 28, and 61 nM, respectively. Compound 5v

also showed a preference for PDE4D with selectivity of >2000

fold over PDE7A1, PDE9A2, PDE2A3, and PDE5A1, respec-

tively. Docking of 5v, 5zf, and 5za into the binding pocket of

the PDE4 catalytic domain revealed a similar binding proﬁle

with PDE4 as rolipram. trNOEsy and STD NMR experiments

on 5i provided experimental support for many of the modeling

projections. Compound 5i appears to adopt the same overall

conformation in the free and enzyme bound form and to dock

in a similar manner as 5v, 5za, and 5zf.

s8

s9

indicating strong hydrophobic interactions of the alkyl chain

and adjacent parts of the catechol ring. Close approach combined

with the higher density of nonexchangeable protons on hydro-

phobic groups would lead to the observed effects.

A trNOEsy spectrum of 5i in the presence of PDE4D2 is

presented in Figure 13. A short mixing time of 50 ms was used

to avoid spin diffusion artifacts and provide a more accurate

interpretation. The cross peaks show the same sign as the

diagonal peaks indicating negative NOEs originating from the

bound form of 5i. The reference NOESY spectrum of 5i (not

shown) has positive NOEs typical of small molecules free in

solution and conﬁrms that the NOEs in the trNOEsy spectrum

reﬂect the bound state structure. The appearance of a set of cross

peaks similar to those seen in the reference NOESY spectrum

is indicative of some similarity in the bound form compared to

the solution form of the drug. Under an initial rate assumption,

the relative intensities of the NOESY cross peaks are inversely

related to the sixth power of the distance between proton pairs

Experimental Section

General Chemistry. All reagents were purchased from Acros

and Aldrich. N-(tert-Butoxycarbonyl)-4-piperidinol was synthesized

according to literature procedures.¹Microwave heating was per-

formed in the single-mode microwave cavity of a Discover

Synthesis System (CEM Co.), and all microwave reactions were

conducted in a heavy-walled glass vials sealed with Teﬂon septa.

¹H NMR, ¹³C NMR, and DEPT spectra were recorded at 400 and

100 MHz, respectively, on a Bruker 400 NMR spectrometer.

Phenyl Alkyl Ketones as Inhibitors

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7681

Combustion analyses and mass spectra were performed by the

analytical and the mass spectrometry facilities at Georgia State

University.

4-(4-Formyl-2-methoxyphenoxy)piperidine-1-carboxylic Acid

tert-Butyl Ester (3f). Yield: 76%. H NMR (CDCl₃): 9.85 (1H,

1

s), 7.44-7.41 (2H, m), 7.03 (1H, m), 4.61 (1H, m), 3.91 (3H, s),

3.77 (2H, m), 3.32 (2H, m), 1.97 (1H, m), 1.82 (1H, m), 1.46 (9H,

s). ¹³C NMR (CDCl₃): 190.7 (d), 154.6 (s), 152.1 (s), 150.7 (s),

130.3 (s), 126.1 (d), 114.1 (d), 110.0 (d), 79.5 (s), 73.7 (d), 56.0

(q), 40.5 (multiple, t), 30.3 (t), 28.3 (q).

4-Methoxy-3-(tetrahydropyran-4-yloxy)benzaldehyde (3g).

Yield: 52%. ¹H NMR (400 MHz, CDCl₃): 1.84-1.86 (2H, q, J )

4.4, 4.4 Hz), 2.06 (2H, d, J ) 8.8 Hz), 3.57 (2H, t, J ) 9.2 Hz),

3.95 (3H, s), 4.05 (2H, m), 4.51 (1H, m), 7.01 (1H, d, J ) 8.4 Hz),

7.44 (1H, s), 7.47-7.49 (1H, q, J ) 1.6, 6.4 Hz) 9.84 (1H, s) ppm.

¹³C NMR (100 MHz, CDCl₃): 31.86, 56.16, 65.31, 73.49, 111.25,

113.92, 127.15, 1.99, 147.09, 156.06, 190.80 ppm. HRMS (ESI+):

calcd for C₁₃H₁₆O₄, 237.1127; found, 237.1121.

4-Diﬂuoromethoxy-3-hydroxybenzaldehyde (2a) and 3,4-

Bisdiﬂuoromethoxybenzaldehyde (3n). A mixture of 3,4-dihy-

droxybenzaldehyde (1.38 g, 0.01 mol), methyl chloroﬂuoroacetate

(1.87 g, 0.013 mol), and cesium carbonate (4.24 g, 0.013 mol) in

DMF (20 mL) was stirred at 65 °C for 3 h under nitrogen

atmosphere. Then DMF was removed in vacuo and the residue was

partitioned between aqueous 3 N HCl and ether. The aqueous layer

was extracted three times with ether. The combined organic solution

was washed with water and brine, dried over MgSO₄, ﬁltered, and

evaporated. The residue was puriﬁed by ﬂash chromatography to

afford 2a as a white solid (0.85 g, 45%) and 3n as a yellowish

liquid (0.48 g, 20%).

1

4-Methyoxy-3-(tetrahydrofuran-3-yloxy)benzaldehye (3h).

2a. H NMR (CDCl₃): 9.92 (1H, s), 7.55 (1H, d, J ) 4.0 Hz),

1

Yield: 40%. H NMR (400 MHz, CDCl₃): 2.25 (2H, q, J ) 6.0,

7.45 (1H, dd, J ) 4.0 and 8.4 Hz), 7.28 (1H, d, J ) 8.4 Hz), 6.67

(1H, t, J ) 72.8 Hz), 6.17 (1H, s, br). ¹³C NMR (CDCl₃): 191.1

(d), 147.8 (s), 143.0 (s), 134.5 (s), 123.2 (d), 119.3 (d), 117.1 (d),

115.6 (triplet, J ) 262 Hz, d). MS-EI: 188 (M⁺).

8.0 Hz), 3.94 (4H, d, J ) 12 Hz), 4.04 (3H, d, J ) 2.4 Hz), 5.02

(1H, s), 7.00 (1H, d, J ) 8.0 Hz), 7.35 (1H, s), 7.48 (1H, q, J )

2.0, 6.4 Hz), 9.84 (1H, s) ppm. ¹³C NMR (100 MHz, CDCl₃): 32.98,

56.16, 67.72, 72.91, 78.67, 111.07, 112.18, 127.21, 1.96, 147.58,

155.56, 190.73 ppm. HRMS (ESI+): calcd for C₁₂H₁₄O₄, 223.0970;

found, 223.0965.

1

3n. H NMR (CDCl₃): 9.95 (1H, s), 7.79-7.77 (2H, m), 7.43

(1H, dd, J ) 8.8 Hz), 6.68 (1H, t, J ) 72.4 Hz), 6.63 (1H, t, J )

72.8 Hz). ¹³C NMR (CDCl₃): 190.1 (d), 147.1 (s), 142.3 (s), 134.1

(s), 128.7 (d), 122.1 (d), 121.4 (d), 115.5 (triplet, J ) 263 Hz, d),

115.3 (triplet, J ) 262 Hz, d). MS-EI: 238 (M⁺).

4-(5-Formyl-2-methoxyphenoxy)piperidine-1-carboxylic Acid

1

tert-Butyl Ester (3i). Yield: 53%. H NMR (400 MHz, CDCl₃):

1.47 (9H, s), 1.80 (2H, q, J ) 3.2, 3.6 Hz), 1.95 (2H, q, J ) 4.0,

4.8 Hz), 3.30 (2H, m), 3.80 (2H, s), 3.94 (3H, s), 4.52 (1H, s),

7.01 (1H, d, J ) 8.0 Hz), 7.44 (1H, s), 7.49 (1H, d, J ) 8.0 Hz),

9.84 (1H, s) ppm. ¹³C NMR (100 MHz, CDCl₃): 28.45, 30.61,

56.17, 74.20, 79.62, 111.26, 114.11, 127.21, 130.04, 147.16, 154.78,

156.13, 190.79 ppm. HRMS (ESI+): calcd for C₁₈H₂₅NO₅, 336.1811;

found, 336.1814.

General Procedure for the Synthesis of 3 by Mitsunobu

Reaction of 2a and 2c with R₂OH. To the mixture of compound

2 (1 mmol), R₂OH (1.1 mmol), and di-tert-butyl azodicarboxylate

(1.2 mmol) in THF (5 mL) was added dropwise triphenylphosphine

(1.2 mmol) in THF (5 mL) at 0 °C. The resulting solution was

stirred until compound 2 was consumed completely (usually within

24 h). Solvent was removed in vacuo and the residue was puriﬁed

by ﬂash chromatography to afford 3.

4-Diﬂuoromethoxy-3-(tetrahydropyran-4-yloxy)benzalde-

hyde (3a). Yield: 28%. ¹H NMR (CDCl₃): 9.93 (1H, s), 7.52 (1H,

d, J ) 2.0 Hz), 7.48 (1H, dd, J ) 2.0 and 8.0 Hz), 7.33 (1H, d, J

) 8.0 Hz), 6.70 (1H, t, J ) 74.0 Hz), 4.65 (1H, m), 3.98 (2H, m),

3.61 (2H, m), 2.06 (2H, m), 1.85 (2H, m). ¹³C NMR (CDCl₃): 190.6

(d), 149.2 (s), 146.0 (s), 134.4 (s), 125.0 (d), 122.3 (d), 115.6 (triplet,

J ) 259 Hz, d), 114.1 (d), 73.3 (d), 64.7 (t), 31.4 (t). MS-EI: 272

(M⁺)

4-Diﬂuoromethoxy-3-(tetrahydrofuran-3-yloxy)benzalde-

hyde (3b). Yield: 84%. ¹H NMR (CDCl₃): 9.93 (1H, s), 7.48 (1H,

dd, J ) 1.6 and 8.4 Hz), 7.44 (1H, d, J ) 1.6 Hz), 7.33 (1H, d, J

) 8.4 Hz), 6.67 (1H, t, J ) 74.4 Hz), 5.07 (1H, m), 4.06-3.91

(4H, m), 2.30 (1H, m), 2.19 (1H, m). ¹³C NMR (CDCl₃): 190.5

(d), 149.4 (s), 145.6 (s), 134.3 (s), 125.2 (d), 122.2 (d), 115.5 (triplet,

J ) 260 Hz, d), 112.9 (d), 78.8 (d), 72.5 (t), 67.0 (t), 32.7 (t).

MS-EI: 258 (M⁺).

4-(2-Diﬂuoromethoxy-5-formylphenoxy)piperidine-1-

carboxylic Acid tert-Butyl Ester (3c). Yield: 54%. ¹H NMR

(CDCl₃): 9.93 (1H, s), 7.52 (1H, s), 7.48 (1H, dd, J ) 1.2 and 8.4

Hz), 7.33 (1H, d, J ) 8.4 Hz), 6.66 (1H, t, J ) 74.0 Hz), 4.63 (1H,

m), 3.69 (2H, m), 3.41 (2H, m), 1.96 (2H, m), 1.81 (2H, m), 1.48

(9H, s). ¹³C NMR (CDCl₃): 190.6 (d), 154.6 (s), 149.3 (s), 146.0

(triplet, J ) 3 Hz, s), 134.5 (s), 125.2 (d), 122.3 (d), 115.6 (triplet,

J ) 260 Hz, d), 114.1 (d), 79.7 (s), 74.0 (d), 40.4 (multiple, t),

30.2 (t), 28.3 (q).

tert-Butyl 3-(2-(Diﬂuromethoxy)-5-formylphenoxy)pyrroli-

dine-1-carboxylate (3j). Yield: 26%. ¹H NMR (400 MHz, CDCl₃):

1.46 (9H, s), 2.20 (2H, d, J ) 7.6 Hz), 3.65-3.49 (4H, m), 5.01

(1H, s), 6.59 (1H, (d) t, J ) 74 Hz), 7.32 (1H, s), 7.45 (1H, s),

7.49 (1H, d, J ) 8.4 Hz), 9.26 (1H, s) ppm. ¹³C NMR (100 MHz,

CDCl₃): 28.46, 31.53 (d), 44.00 (d), 51.47 (d), 79.72 (d), 113.54

(d), 122.53 (d), 125.64, 154.54, 190.55 ppm. HRMS (ESI+): calcd

for C₁₃H₁₃F₂NO₅(M⁺- tert-butyl), 302.0840; found, 302.0823.

3-Cyclopentyloxy-4-diﬂuoromethoxybenzaldehyde (3k). A

mixture of 4-diﬂuoromethoxy-3-hydroxybenzaldehyde 2a (0.38 g,

2.0 mmol), cyclopentyl bromide (0.45 g, 3.0 mmol), and potassium

carbonate (0.41 g, 3.0 mmol) in DMF (10 mL) was stirred overnight

at 65 °C. After the mixture was ﬁltered, solvent was removed in

vacuo and the residue was puriﬁed by ﬂash chromatography to

afford 3-cyclopentyloxy-4-diﬂuoromethoxybenzaldehyde (0.18 g,

1

35%). H NMR (CDCl₃): 9.93 (1H, s), 7.48 (1H, d, J ) 1.6 Hz),

7.43 (1H, dd, J ) 1.6 and 8.0 Hz), 7.00 (1H, d, J ) 8.0 Hz), 6.65

(1H, t, J ) 74.8 Hz), 4.90 (1H, m), 1.98-1.80 (6H, m), 1.67 (2H,

m). ¹³C NMR (CDCl₃): 190.9 (d), 150.1 (s), 145.7 (s), 134.5 (s),

124.4 (d), 122.4 (d), 115.7 (triplet, J ) 259 Hz, d), 113.3 (d), 80.9

(d), 32.7 (t), 23.9 (t).

General Procedure for the Preparation of 3- or

4-(Pyridine-2-yloxy)benzaldehydes (3l or 3m). A mixture of

4-diﬂuoromethoxy-3-hydroxybenzaldehyde 2a (2.0 mmol) or 2c,

2-bromopyridine (0.95 g, 6.0 mmol), and potassium carbonate (0.41

g, 3.0 mmol) in DMSO (1 mL) was heated under microwave

irradiation for 10 min. After the solvent was removed in vacuo,

the residue was puriﬁed by ﬂash chromatography to afford the

3-(pyridine-2-yloxy)benzaldehyde 3l or 3m.

3-Methoxy-4-(tetrahydropyran-4-yloxy)benzaldehyde (3d).

1

Yield: 65%. H NMR (CDCl₃): 9.85 (1H, s), 7.43-7.42 (2H, m),

7.01 (1H, d, J ) 8.8 Hz), 4.62 (1H, m), 4.03 (2H, m), 3.93 (3H, s),

3.59 (2H, m), 2.07 (2H, m), 1.89 (2H, m). ¹³C NMR (CDCl₃): 190.7

(d), 152.2 (s), 150.7 (s), 130.4 (s), 126.1 (d), 114.0 (d), 110.0 (d),

73.2 (d), 65.1 (t), 56.0 (q), 31.7 (t). MS-EI: 236 (M⁺).

4-Diﬂuoromethoxy-3-(pyridine-2-yloxy)benzaldehyde (3l).

Yield: 11%. ¹H NMR (CDCl₃): 9.94 (1H, s), 8.09 (1H, m),

7.78-7.72 (3H, m), 7.41 (1H, d, J ) 8.8 Hz), 7.06-7.02 (2H, m),

6.52 (1H, t, J ) 74.0 Hz). ¹³C NMR (CDCl₃): 190.1 (d), 162.6 (s),

148.3 (s), 147.2 (d), 145.5 (s), 139.8 (d), 134.5 (s), 127.7 (d), 124.4

(d), 121.3 (d), 119.2 (d), 118.3 (d), 115.7 (triplet, J ) 260 Hz, d),

117.4 (d). MS-EI: 264 (M⁺).

3-Methoxy-4-(pyridine-2-yloxy)benzaldehyde (3m). Yield: 85%.

¹H NMR (CDCl₃): 9.95 (1H, s), 8.13 (1H, m), 7.71 (1H, m),

7.54-7.50 (2H, m), 7.00 (1H, d, J ) 8.0 Hz), 7.02-6.99 (2H, m),

3-Methoxy-4-(tetrahydrofuran-3-yloxy)benzaldehyde (3e).

1

Yield: 71%. H NMR (CDCl₃): 9.84 (1H, s), 7.44-7.41 (2H, m),

6.93 (1H, d, J ) 8.4 Hz), 5.06 (1H, m), 4.02 (4H, m), 3.90 (3H, s),

2.06 (2H, m). ¹³C NMR (CDCl₃): 190.4 (d), 152.1 (s), 150.0 (s),

130.0 (s), 125.8 (d), 112.8 (d), 109.5 (d), 78.4 (d), 72.4 (t), 66.8

(t), 55.5 (q), 32.6 (t). MS-EI: 222 (M⁺).

7682 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Zheng et al.

3.83 (3H, s). ¹³C NMR (CDCl₃): 191.0 (d), 162.9 (s), 152.3 (s),

148.2 (s), 147.4 (d), 139.4 (d), 134.1 (s), 125.1 (d), 122.9 (d), 118.7

(d), 111.3 (d), 111.1 (d), 55.9 (q). MS-EI: 198 (M⁺).

(d), 110.3 (d), 74.0 (d), 55.8 (q), 41.1 (t), 19.0 (t), 13.9 (q). HRMS-

ESI (+): calcd for C₁₆H₂₀NO₃, 274.1443; found, 274.1431 [M +

H]⁺.

General Procedure for the Synthesis of 4 by Nucleophilic

Addition to Aldehydes 3. To aldehyde 3 (1 mmol) in THF (5 mL)

was added dropwise n-butyllithium or Grignard reagent at -78 °C.

The resulting mixture was stirred overnight, allowing the temper-

ature too gradually warm from -78 °C to room temperature, and

then quenched with water. The aqueous layer was extracted three

times with ethyl acetate. The combined organic solution was dried

over MgSO₄, ﬁltered, and evaporated. The residue was puriﬁed by

ﬂash chromatography to afford 4.

4-[4-(1-Hydroxypentyl)-2-methoxyphenoxy]piperidine-1-car-

boxylic Acid tert-Butyl Ester (4a). Yield: 42%. ¹H NMR

(CDCl₃): 6.91 (1H, d, J ) 2.0 Hz), 6.87 (1H, d, J ) 8.0 Hz), 6.81

(1H, dd, J ) 2.0 and 8.0 Hz), 4.59 (1H, t, J ) 6.8 Hz), 4.37 (1H,

m), 3.84 (3H, s), 3.76 (2H, m), 3.23 (2H, m), 2.25 (1H, s, br), 1.89

(2H, m), 1.79-1.73 (4H, m), 1.46 (9H, s), 1.43-1.24 (4H, m),

0.89 (3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 154.7 (s), 150.9 (s),

145.6 (s), 139.3 (s), 118.1 (d), 117.5 (d), 109.9 (d), 79.4 (s), 74.5

(d), 74.3 (d), 55.8 (q), 40.6 (t), 38.7 (t), 30.7 (t), 28.3 (q), 27.8(t),

22.5 (t), 13.9 (q). MS-EI: 393 (M⁺).

[3-Methoxy-4-(pyridin-2-yloxy)phenyl]quinolin-3-ylmeth-

anol (4h). Yield: 68%. H NMR (CDCl₃): 8.75 (1H, d, J ) 1.2

1

Hz), 8.16 (1H, s), 8.03-8.00 (2H, m), 7.74 (1H, d, J ) 8.0 Hz),

7.65-7.59 (2H, m), 7.48 (1H, m), 7.09 (1H, d, J ) 1.6 Hz), 7.04

(1H, d, J ) 8.0 Hz), 6.94-6.84 (3H, m), 5.95 (1H, s), 5.76 (1H, s,

br), 3.63 (3H, s). ¹³C NMR (CDCl₃): 163.4, 151.7, 149.9, 147.2,

146.8, 141.8, 141.2, 139.3, 137.0, 133.1, 1.3, 128.5, 127.9, 127.7,

126.7, 122.7, 119.3, 118.1, 111.0, 110.6, 73.4, 55.7. MS-ESI (+):

359.58 [M + H]⁺.

[3-Methoxy-4-(pyridin-2-yloxy)phenyl]pyridin-3-ylmethanol

(4i). Yellow oil. Yield: 40%. ¹H NMR (CDCl₃): 8.51 (1H, s), 8.33

(1H, d, J ) 3.6 Hz), 8.03 (1H, m), 7.72 (1H, m), 7.62 (1H, m),

7.22 (1H, m), 7.07-7.05 (2H, m), 6.93-6.85 (3H, m), 5.78 (1H,

s), 5.26 (1H, s, br), 3.67 (3H, s). ¹³C NMR (CDCl₃): 163.4 (s),

151.7 (s), 147.9 (d), 147.8 (d), 147.1 (d), 141.7 (s), 141.4 (s), 139.9

(s), 139.2 (d), 134.5 (d), 123.4 (d), 122.6 (d), 119.0 (d), 118.0 (d),

110.9 (d), 110.6 (d), 73.1 (d), 55.7 (q).

1-[4-Methoxy-3-(tetrahydropyran-4-yloxy)phenyl]butan-

1

1-ol (4j). Yellow oil. Yield: 60%. H NMR (400 MHz, CDCl₃):

1-[3-Methoxy-4-(tetrahydropyran-4-yloxy)phenyl]butan-1-ol

(4b). Yield: 70%. H NMR (CDCl₃): 6.91 (1H, s), 6.87 (1H, d, J

0.92 (3H, t, J ) 7.6 Hz), 1.44 (3H, m), 1.68 (1H, m), 1.87 (4H,

m), 2.01 (2H, m), 3.56-3.51 (2H, dd, J ) 2.4, 8.8 Hz), 3.84 (3H,

s), 4.03 (2H, m), 4.44 (1H, m), 4.59 (1H, s), 6.86 (1H, d, J ) 8.4

Hz), 6.92 (1H, d, J ) 8.4 Hz), 6.95(1H, s) ppm. ¹³C NMR (100

MHz, CDCl₃): 13.97, 19.10, 32.12, 41.24, 56.05, 65.38, 73.80,

73.96, 112.10, 115.34, 119.66, 137.75, 146.40, 150.28 ppm. HRMS

(ESI+): calcd for C₁₆H₂₂O₃-H₂O, 263.1647; found, 263.1645.

1-[4-Methoxy-3-(tetrahydropyran-4-yloxy)phenyl]pentan-1

1

) 8.0 Hz), 6.81 (1H, d, J ) 7.6 Hz), 4.59 (1H, m), 4.36 (1H, m),

3.98 (1H, m), 3.84 (3H, s), 3.50 (2H, m), 2.32 (1H, s, br), 1.97

(2H, m), 1.82-1.76 (3H, m), 1.64 (1H, m), 1.42 (1H, m), 1.31

(1H, m), 0.93 (3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 150.9 (s),

145.5 (s), 139.3 (s), 118.0 (d), 117.4 (d), 109.9 (d), 74.0 (d), 73.8

(d), 65.3 (t), 55.8 (q), 41.1 (t), 32.0 (t), 19.0 (t), 13.9 (q). MS-EI:

280 (M⁺).

1

-ol (4k). Yellow oil. Yield: 72%. H NMR (400 MHz, CDCl₃):

1-[3-Methoxy-4-(tetrahydropyran-4-yloxy)phenyl]pentan-

1-ol (4c). Yield: 68%. ¹H NMR(CDCl₃): 6.92 (1H, s), 6.88 (1H, d,

J ) 8.0 Hz), 6.82 (1H, d, J ) 8.0 Hz), 4.59 (1H, m), 4.38 (1H, m),

4.00 (2H, m), 3.86 (3H, s), 3.53 (2H, m), 1.99 (3H, m), 1.83-1.67

(4H, m), 1.36-1.25 (4H, m), 0.89 (3H, t, J ) 6.8 Hz). ¹³C NMR

(CDCl₃): 151.0 (s), 145.7 (s), 139.2 (s), 118.1 (d), 117.4 (d), 110.0

(d), 74.4 (d), 73.9 (d), 65.4 (t), 55.9 (q), 38.7 (t), 32.1 (t), 28.1 (t),

22.6 (t), 13.9 (q). MS-EI: 4 (M⁺).

0.88 (3H, t, J ) 6.8 Hz), 1.25 (1.32 (3H, m), 1.65 (1H, m), 1.85

(4H, m), 2.01 (2H, s), 3.53 (2H, t, J ) 8.8 Hz), 3.84 (3H, s), 4.01

(2H, t, J ) 5.6 Hz), 4.43 (1H, d, J ) 4.0 Hz), 4.57 (1H, s), 6.86

(1H, d, J ) 8.4 Hz), 6.92 (1H, d, J ) 8.4 Hz), 6.95 (1H, s) ppm.

¹³C NMR (100 MHz, CDCl₃): 14.03, 22.58, 28.05, 32.10, 38.81,

56.02, 65.34, 73.76, 74.14, 112.09, 115.40, 119.69, 137.83, 146.35,

150.24 ppm. HRMS (ESI+): calcd for C₁₇H₂₇O₄- H₂O, 277.1804;

found, 277.1795.

1-[3-Methoxy-4-(tetrahydrofuran-3-yloxy)phenyl]butan-

1-ol (4d). Yield: 77%. H NMR (CDCl₃): 6.90 (1H, s), 6.80 (1H,

1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]pentan-1-

ol (4l). Yellow oil. Yield: 41%. ¹H NMR (400 MHz, CDCl₃): 0.88

(3H, t, J ) 6.4 Hz), 1.22-1.35 (4H, m), 1.65-1.77 (2H, m), 1.86

(1H, s), 2.18 (2H, d, J ) 5.6 Hz), 3.84 (2H, s), 3.89-3.92 (1H,

m), 4.00 (3H, s), 4.58 (1H, s), 4.96 (1H, s), 6.84-6.91 (3H, m)

ppm. ¹³C NMR (100 MHz, CDCl₃): 14.03, 22.59, 28.03, 33.04,

38.80, 56.05, 67.19, 72.98, 74.26, 78.83, 112.02, 113.65, 119.35,

137.76, 146.83, 149.62 ppm. HRMS (ESI+): calcd for C₁₆H₂₅O₄

- H₂O, 263.1647; found, 263.1643.

1

d, J ) 8.0 Hz), 6.75 (1H, d, J ) 8.0 Hz), 4.90 (1H, m), 4.57 (1H,

m), 3.99-3.82 (7H, m), 2.66 (1H, s, br), 2.14 (2H, m), 1.74 (1H,

m), 1.63 (1H, m), 1.41 (1H, m), 1.00 (1H, m), 0.92 (3H, t, J ) 7.2

Hz). ¹³C NMR (CDCl₃): 150.6 (s), 145.8 (s), 139.0 (s), 117.9 (d),

115.4 (d), 109.8 (d), 78.7 (d), 73.8 (d), 72.7 (t), 66.9 (t), 55.7 (q),

41.1 (t), 32.8 (t), 18.9 (t), 13.8 (q). MS-EI: 266 (M⁺).

1-[3-Methoxy-4-(tetrahydrofuran-3-yloxy)phenyl]pentan-1-

1

ol (4e). Yield: 66%. H NMR (CDCl₃): 6.90 (1H, s), 6.81 (1H, d,

1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]butan-1-ol

1

J ) 8.0 Hz), 6.76 (1H, d, J ) 8.0 Hz), 4.90 (1H, m), 4.56 (1H, m),

4.00-3.83 (7H, m), 2.54 (1H, s, br), 2.14 (2H, m), 1.76 (1H, m),

1.67 (1H, m), 1.35-1.23 (4H, m), 0.88 (3H, t, J ) 6.8 Hz). ¹³C

NMR (CDCl₃): 150.1 (s), 145.8 (s), 139.0 (s), 118.0 (d), 115.4 (d),

109.8 (d), 78.7 (d), 74.1 (d), 72.8 (t), 67.0 (t), 55.7 (q), 38.7 (t),

32.9 (t), 27.9 (t), 22.4 (t), 13.9 (q). MS-EI: 280 (M⁺).

(4m). Yield: 40%. H NMR (400 MHz, CDCl₃): 0.92 (3H, t, J )

7.2 Hz), 1.30 (1H, dd, J ) 6.4, 9.6 Hz), 1.42 (1H, d, J ) 7.2 Hz),

1.63 (1H, s), 1.81 (2H, bs), 2.19 (2H, m), 3.84 (2H, s), 3.90 (2H,

s), 4.00 (3H, s), 4.60 (1H, s), 4.97 (1H, s), 6.89 (3H, m) ppm. ¹³

C

NMR (100 MHz, CDCl₃): 13.97, 19.08, 33.07, 41.24, 56.08, 67.22,

73.01, 74.07, 78.88, 112.05, 113.66, 119.33, 137.68, 146.89, 149.70

ppm. HRMS (ESI+): calcd for C₁₅H₂₃O₄- H₂O, 249.1491; found,

249.1480.

1-[3-Methoxy-4-(pyridin-2-yloxy)phenyl]pentan-1-ol

(4f).

Yield: 45%. ¹H NMR (CDCl₃): 8.06 (1H, dd, J ) 1.2 and 4.8 Hz),

7.57 (1H, m), 7.03 (1H, d, J ) 8.0 Hz), 7.01 (1H, d, J ) 2.0 Hz),

6.90-6.85 (2H, m), 6.81 (1H, d, J ) 8.0 Hz), 4.60 (1H, m), 3.69

(3H, s), 2.89 (1H, s, br), 1.76 (2H, m), 1.43-1.31 (4H, m), 0.88

(3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 163.6 (s), 151.5 (s), 147.2

(d), 143.1 (s), 141.7 (s), 138.8 (d), 122.4 (d), 118.3 (d), 117.7 (d),

110.8 (d), 110.3 (d), 73.9 (d), 55.7 (q), 38.6 (t), 27.8 (t), 22.3 (t),

13.7 (q).

1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-

4-phenylbutan-1-ol (4n). Yield: 20%. ¹H NMR (400 MHz, CDCl₃):

1.60 (1H, m), 1.74 (2H, m), 1.85 (2H, m), 2.18 (2H, m), 2.64 (2H,t,

J ) 6.4 Hz), 3.83 (3H, s), 3.90 (2H, m), 4.04 (3H, s), 4.60 (1H,

m), 4.95 (1H, m), 6.83 (1H, d, J ) 2 Hz), 6.84 (1H, s), 6.87-6.89

(1H, dd, J ) 1.6, 1.6 Hz), 7.15 (3H, m), 7.25 (2H, d, J ) 6.8 Hz)

ppm. ¹³C NMR (100 MHz, CDCl₃): 27.61, 33.07, 35.72, 38.51,

56.06, 67.22, 73.02, 74.17, 78.84, 112.01, 113.49, 119.36, 125.77,

128.30, 128.42, 137.39, 142.22, 146.92,149.73 ppm. HRMS (ESI+):

calcd for C₂₁H₂₇O₄- H₂O, 325.1804; found, 325.1792.

3-Cyclohexyl-1-[4-methoxy-3-(tetrahydrofuran-3-yloxy)phe-

1-[3-Methoxy-4-(pyridin-2-yloxy)phenyl]butan-1-ol

(4g).

Yield: 80%. ¹H NMR (CDCl₃): 8.11 (1H, dd, J ) 2.0 and 5.2 Hz),

7.63 (1H, m), 7.07 (1H, d, J ) 8.0 Hz), 7.03 (1H, s), 6.94-6.87

(3H, m), 4.65 (1H, t, J ) 6.0 Hz), 3.75 (3H, s), 2.40 (1H, s, br),

1.78 (1H, m), 1.69 (1H, m), 1.46 (1H, m), 1.36 (1H, m), 0.94 (3H,

t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 163.6 (s), 151.6 (s), 147.4 (d),

143.0 (s), 141.5 (s), 139.1 (d), 122.6 (d), 118.4 (d), 117.9 (d), 110.5

1

nyl]propan-1-ol (4o). Yield: 70%. H NMR (400 MHz, CDCl₃):

0.86 (2H, t, J ) 12 Hz), 1.09-1.30 (7H, m), 1.61-1.69 (6H, m),

1.74-1.77 (2H, m), 2.16-2.20 (2H, m), 3.84 (3H, d, J ) 2.8 Hz),

Phenyl Alkyl Ketones as Inhibitors

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7683

3.88-3.91 (1H, m), 4.54 (1H, d, J ) 6.8 Hz), 4.96 (1H, s),

6.83-6.85 (2H, dd, J ) 2.8,5.2 Hz), 6.70 (1H, d, J ) 7.6 Hz)

ppm. ¹³C NMR (100 MHz, CDCl₃): 26.36, 26.65, 33.06, 33.35,

33.53, 36.43, 37.64, 56.06, 67.22, 73.01, 74.67, 78.84, 112.00,

113.60, 119.37, 137.67, 146.85, 149.66 ppm. HRMS (ESI+): calcd

for C₂₀H₃₁O₄- H₂O, 317.2117; found, 317.2112. Anal. Calcd for

C₂₀H₃₀O₄: C, 71.82; H, 9.04. Found: C, 71.92; H, 9.10.

1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-

-phenylpropan-1-ol (4p). Yield: 99%. ¹H NMR (400 MHz,

CDCl₃): 1.96-2.00 (1H, m), 2.09 (1H, s), 2.11-2.18 (2H, m),

2.63-2.72 (2H, m), 3.83 (3H, s), 3.82 (3H, m), 3.85-3.90 (1H,

m), 3.94-4.03 (3H, m), 4.59 (1H, t, J ) 7.2 Hz), 4.93-4.95 (1H,

m), 6.83 (1H, s), 6.85 (1H,s), 6.91 (1H, d, J ) 8.4 Hz), 7.17 (3H,

t, J ) 4.4 Hz), 7.25-7.00 (2H, dd, J ) 7.2, 7.6 Hz) ppm. ¹³C

NMR (100 MHz, CDCl₃): 32.14, 33.07, 40.49, 56.07, 67.22, 73.00,

73.49, 78.86, 112.08, 113.63, 119.41, 125.89, 128.42, 128.44,

137.35, 141.79, 146.92, 149.76 ppm. HRMS (ESI+): calcd for

C₂₀H₂₅O₄- H₂O, 311.1647; found, 311.1639. Anal. Calcd for

C₂₀H₂₄O₄, C, 73.15; H, 7.37; found, C, 73.25; H, 7.56.

4-[5-(1-Hydroxypentyl)-2-methoxyphenoxy]piperidine-1-car-

boxylic Acid tert-Butyl Ester (4v). Yield: 84%. H NMR (400

1

MHz, CDCl₃): 0.95 (3H, t, J ) 7.2 Hz), 1.44 (2H, q, J ) 7.2, 7.6

Hz), 1.47 (9H, s), 1.69 (4H, m), 1.73 (2H, s), 1.92-1.96 (2H, m),

2.91 (2H, t, J ) 7.2 Hz), 3.23-3.00 (2H, m), 3.80 (2H, m), 4.63

(1H, s), 3.91 (3H, s), 4.50-4.51 (1H, m), 4.70-4.72 (1H, s), 6.92

(1H, d, J ) 8.4 Hz), 7.57 (1H, d, J ) 2 Hz), 7.60-7.63 (1H, dd,

J ) 2, 6.4 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): 14.03, 22.59,

28.06, 28.45, 30.83, 38.79, 56.04, 74.28, 74.53, 79.52, 112.13,

115.49, 119.75, 137.72, 146.47, 150.37, 154.84 ppm. HRMS

(ESI+): calcd for C₁₈H₂₅NO₄- (H₂O + tert-butyl): 320.1862;

found, 320.1882.

1-[4-Diﬂuoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-

3-methylbutan-1-ol (4w). Yield: 15%. ¹H NMR (CDCl₃): 7.13 (1H,

d, J ) 8.4 Hz), 6.95 (1H, s), 6.90 (1H, d, J ) 8.4 Hz), 6.51 (1H,

t, J ) 75.2 Hz), 5.00 (1H, m), 4.72 (1H, m), 4.03-3.90 (4H, m),

2.20 (2H, m), 1.94 (1H, s, br), 1.70 (2H, m), 1.47 (1H, m), 0.96

(6H, d, J ) 6.0 Hz). ¹³C NMR (CDCl₃): 149.0, 144.3, 140.1, 122.9,

118.9, 116.3 (triplet, J ) 258 Hz), 112.8, 78.8, 72.8, 72.2, 67.1,

48.5, 33.0, 24.8, 23.1, 22.2. MS-EI: 316 (M⁺).

2-Cyclohexyl-1-[4-methoxy-3-(tetrahydrofuran-3-yloxy)phe-

1

1-[4-Diﬂuoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-

nyl]ethanol (4q). Yield: 55%. H NMR (400 MHz, CDCl₃): 0.94

1

pentan-1-ol (4za). Yield: %. H NMR (CDCl₃): 7.13 (1H, d, J )

(2H, m), 1.20 (2H, m), 1.36 (1H, m), 1.48 (1H, m), 1.69 (7H, m),

2.18 (2H, m), 3.84 (3H, s), 3.90 (1H, m), 4.00 (2H, m), 4.71 (1H,

s), 4.96 (1H, s), 6.83 (1H, s), 6.85 (1H, s), 6.92-6.89 (1H, q, J )

2.0, 6.0 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): 26.17, 26., 26.56,

33.03, 33.07, 33.91, 34., 46.97, 56.07, 67.23, 71.79, 73.01, 78.86,

112.06, 113.59, 113.63, 119.27, 138.03, 146.88, 149.68 ppm.

HRMS (ESI+): calcd for C₁₉H₂₈O₄- H₂O, 303.1960; found,

303.1975.

1-[4-Diﬂuoromethoxy-3-(tetrahydrofuran-3-ylxoy)phenyl]-

2,2-dimethylpropan-1-ol (4r). Yield: 8.6%. ¹H NMR (400 MHz,

CDCl₃): 0.92 (9H, d, J ) 0.8 Hz), 1.95 (1H, s), 2.16-2.20 (2H,

m), 3.90-3.92 (1H, m), 3.98-4.00 (3H, m), 4.36 (1H, s), 4.96

(1H, d, J ) 2.0 Hz), 6.52 (1H, (d) t, J ) 75.2 Hz), 6.85-6.87 (1H,

dd, J ) 2.0, 6.0 Hz), 6.89-6.91 (1H, dd, J ) 2.0, 2.4 Hz), 7.11

(1H, d, J ) 8.0 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): 25.88,

0.71, 32.98, 33.02, 35.71, 67.16, 72.80, 72.83, 78.72, 81.73, 114.69

(t, J ) 160 Hz), 120.96, 121.93, 140.05, 140.88, 148.17 ppm. MS

(EI+): calcd for C₁₆H₂₂F₂O₄, 316; found, 316.

1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-3-methyl-

butan-1-ol (4s). Yield: 34%. ¹H NMR (400 MHz, CDCl₃):

0.91-0.94 (6H, q, J ) 4.4, 2.0 Hz), 1.24 (1H, s), 1.44-1.49 (1H,

m), 1.64-1.72 (2H, m), 1.92 (1H, bs, O-H), 2.16-2.19 (2H, m),

3.83 (3H, s), 3.86-3.91 (1H, m), 3.97-4.02 (3H, m), 4.64-4.67

(1H, q, J ) 5.6, 2.0 Hz), 4.94-4.97 (1H, m), 6.84 (1H, d, J ) 8.4

Hz), 6.86 (1H, J ) 2 Hz), 6.91-6.89 (1H, dd, J ) 2, 6.4 Hz) ppm.

¹³C NMR (100 MHz, CDCl₃): 22.34, 23.09, 24.84, 33.04, 48.28,

56.06, 67.21, 72.41, 72.99, 78.85, 112.04, 113.62, 119.32, 137.96,

146.89, 149.68 ppm. HRMS (ESI+): calcd for C₁₆H₂₂O₃- H₂O,

263.1647; found, 263.1648.

3-[2-Diﬂuoromethoxy-5-(1-hydroxypentyl)phenoxy]pyrrolidine-1-

carboxylic Acid tert-Butyl Ester (4t). Yield: 25%. ¹H NMR

(400 MHz, CDCl₃): 0.89 (3H, t, J ) 6.8 Hz), 1.36 (4H, m), 1.46

(9H, s), 1.73 (2H, m), 1.95 (1H, d, J ) 2.8 Hz), 2.20 (2H, m), 3.67

(4H, m), 4.63 (1H, s), 4.93 (1H, s), 6.65 (1H, t, J ) 75.2 Hz), 6.91

(1H, s), 6.96 (1H, d, J ) 1.6 Hz), 7.12 (1H, d, J ) 6.8 Hz) ppm.

¹³C NMR (100 MHz, CDCl₃): 14.0, 22.55, 27.9, 28.47, 0.72, 30.82,

31.67, 39.02, 44.07, 51.08, 51.57, 74.02, 78.11, 79.61, 113.4, 119.4,

122.89 ppm. HRMS (ESI+): calcd for C₂₁H₃₁F₂NO₅, 416.2248;

found, 416.2247.

8.0 Hz), 6.94 (1H, s), 6.90 (1H, dd, J ) 2.0 and 8.4 Hz), 6.52 (1H,

t, J ) 75.2 Hz), 5.00 (1H, m), 4.64 (1H, m), 4.03-3.91 (4H, m),

2.18 (2H, m), 1.98 (1H, s, br), 1.75 (1H, m), 1.67 (1H, m),

1.42-1.24 (4H, m), 0.90 (3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃):

149.0 (s), 143.8 (s), 140.1 (s), 122.9 (d), 119.0 (d), 116.3 (triplet,

J ) 258 Hz, d), 112.8 (d), 78.7 (d), 74.0 (d), 72.8 (t), 67.1 (t), 39.0

(t), 33.0 (t), 27.8 (t), 22.5 (t), 14.0 (q). MS-EI: 316 (M⁺).

3-Cyclohexyl-1-[4-diﬂuoromethoxy-3-(tetrahydrofuran-3-

yloxy)phenyl]propan-1-ol (4zb). Yield: 51%. ¹H NMR (CDCl₃):

7.11 (1H, d, J ) 8.0 Hz), 6.94 (1H, s), 6.89 (1H, d, J ) 8.4 Hz),

6.50 (1H, t, J ) 74.8 Hz), 4.97 (1H, m), 4.59 (1H, m), 4.01-3.87

(4H, m), 2.18 (2H, m), 1.94 (1H, s, br), 1.80-1.67 (7H, m),

1.34-1.12 (6H, m), 0.88 (2H, m). ¹³C NMR (CDCl₃): 149.1, 143.9,

140.4, 122.8, 119.2, 116.4 (triplet, J ) 258 Hz), 113.4, 79.1, 74.4,

72.8, 67.1, 37.7, 36.7, 33.4, 33.3, 33.1, 26.6, 26.3.

2-Cyclohexyl-1-[4-diﬂuoromethoxy-3-(tetrahydrofuran-3-

yloxy)phenyl]ethanol (4zc). Yield: 35%. ¹H NMR (CDCl₃): 7.14

(1H, d, J ) 8.4 Hz), 6.95 (1H, d, J ) 2.0 Hz), 6.91 (1H, dd, J )

2.0 and 8.0 Hz), 6.53 (1H, t, J ) 75.2 Hz), 5.01 (1H, m), 4.77

(1H, m), 4.03-3.91 (4H, m), 2.20 (2H, m), 2.00 (1H, s, br),

1.83-1.66 (6H, m), 1.52-1.39 (2H, m), 1.31-1.15 (3H, m), 0.98

(2H, m). ¹³C NMR (CDCl₃): 149.0 (s), 144.3 (s), 140.0 (s), 122.9

(d), 118.91 (d), 118.89 (d), 116.3 (triplet, J ) 258 Hz, d), 112.8

(d), 78.7 (d), 72.8 (t), 71.5 (d), 67.1 (t), 47.2 (t), 34.2 (d), 33.9 (t),

33.0 (t), 32.8 (t), 26.5 (t), 26.2 (t), 26.1 (t).

1-[4-Diﬂuoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-3-

phenylpropan-1-ol (4zd). Yield: 46%. ¹H NMR (CDCl₃): 7.30-7.25

(2H, m), 7.20-7.11 (4H, m), 6.92-6.88 (2H, m), 6.50 (1H, t, J )

74.8 Hz), 4.96 (1H, m), 4.64 (1H, m), 3.99-3.89 (4H, m), 2.72

(2H, m), 2.18-1.97 (5H, m). ¹³C NMR (CDCl₃): 149.0 (s), 143.5

(s), 141.4 (s), 140.1 (s), 128.42 (d), 128.36 (d), 126.0 (d), 122.9

(d), 119.0 (d), 116.2 (triplet, J ) 258 Hz, d), 112.81 (d), 112.78

(d), 78.7 (d), 73.2 (d), 72.7 (t), 67.1 (t), 40.6 (t), 32.9 (t), 31.9 (t).

1-[4-Diﬂuoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-

4-phenylbutan-1-ol (4ze). Yield: 56%. ¹H NMR (CDCl₃): 7.28-7.25

(2H, m), 7.19-7.10 (4H, m), 6.89-6.85 (2H, m), 6.50 (1H, t, J )

75.2 Hz), 4.95 (1H, m), 4.64 (1H, m), 3.99-3.89 (4H, m), 2.63

(2H, t, J ) 6.8 Hz), 2.15 (2H, m), 2.01 (1H, s, br), 1.78-1.61 (4H,

m). ¹³C NMR (CDCl₃): 149.0 (s), 143.6 (s), 142.0 (s), 140.1 (s),

128.37 (d), 128.31 (d), 125.8(d), 122.9 (d), 119.0 (d), 116.2 (triplet,

J ) 258 Hz, d), 112.7 (d), 78.7 (d), 73.8 (d), 72.8 (t), 67.1 (t), 38.6

(t), 35.6 (t), 33.0 (t), 27.4 (t).

3[2-Diﬂuoromethoxy-5-(1-hydroxy-3-methylbutyl)phenoxy]-

pyrrolidine-1-carboxylic Acid tert-Butyl Ester (4u). Yield: 14%.

¹H NMR (400 MHz, CDCl₃): 0.96 (6H, d, J ) 6.4 Hz), 1.46 (9H,

s), 1.69 (2H, m), 1.90 (1H, d, J ) 2.8 Hz), 2.20 (2H, m), 3.57 (4H,

m), 4.71 (1H, s), 4.94 (1H, s), 6.65 (1H, d (t), J ) 75.2 Hz), 6.92

(1H, d, J ) 6.8 Hz), 6.97 (1H, d, J ) 1.2 Hz), 7.12 (1H, d, J ) 6.4

Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): 14.1 (d), 22.6, 24.7, 28.4,

31.5, 43.6 (d), 48.5, 51.5 (d), 60.3, 72.1, 79.60, 113.5 (d, J ) 14

Hz), 119.4, 122.9, 140.3 ppm. HRMS (ESI+): calcd for

C₁₇H₂₁F₂NO₄- (H₂O + tert-butyl), 342.1515; found, 342.1159.

1-(3-Cyclopentyloxy-4-diﬂuoromethoxyphenyl)-3-methyl-

butan-1-ol (4zf). Yield: 34%. ¹H NMR (CDCl₃): 7.09 (1H, d, J )

8.4 Hz), 6.97 (1H, d, J ) 1.6 Hz), 6.83 (1H, dd, J ) 1.6 and 8.4

Hz), 6.51 (1H, t, J ) 75.6 Hz), 4.82 (1H, m), 4.70 (1H, m),

1.92-1.79 (7H, m), 1.72-1.62 (4H, m), 1.46 (1H, m), 0.95 (6H,

d, J ) 6.0 Hz). ¹³C NMR (CDCl₃): 149.6 (s), 144.0 (s), 140.0

(triplet, J ) 3.0 Hz, s), 122.7 (d), 117.9 (d), 116.4 (triplet, J ) 257

7684 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Zheng et al.

Hz, d), 112.6 (d), 80.5 (d), 72.4 (d), 48.4 (t), 32.74 (t), 32.73 (t),

24.8 (d), 23.8 (t), 23.1 (q), 22.2 (q).

(d), 111.2 (d), 79.6 (s), 73.9 (d), 56.0 (q), 40.6 (t), 37.8 (t), 30.5

(t), 28.4 (q), 26.8(t), 22.5 (t), 14.0 (q). MS-EI: 391 (M⁺).

4-[2-Diﬂuoromethoxy-5-(1-hydroxypentyl)phenoxy]piperi-

dine-1-carboxylic Acid tert-Butyl Ester (4zg). Yield: 57%. ¹H

NMR (CDCl₃): 7.12 (1H, d, J ) 8.0 Hz), 7.02 (1H, d, J ) 1.2

Hz), 6.90 (1H, dd, J ) 1.6 and 8.0 Hz), 6.51 (1H, t, J ) 74.8 Hz),

4.63 (1H, m), 4.52 (1H, m), 3.67 (2H, m), 3.41 (2H, m), 2.11 (1H,

s, br), 1.90 (2H, m), 1.80-1.63 (4H, m), 1.47 (9H, s), 1.42-1.28

(4H, m), 0.88 (3H, t, J ) 7.2 Hz).

4-(4-Butyryl-2-methoxyphenoxy)piperidine-1-carboxylic Acid

tert-Butyl Ester (5b). Yield: 40%. H NMR (CDCl₃): 7.55-7.53

1

(2H, m), 6.93 (1H, d, J ) 8.8 Hz), 4.56 (1H, m), 3.90 (3H, s), 3.77

(2H, m), 3.30 (2H, m), 2.92 (2H, t, J ) 7.6 Hz), 1.94 (2H, m),

1.85-1.74 (4H, m), 1.47 (9H, s), 1.00 (3H, t, J ) 7.2 Hz). ¹³C

NMR (CDCl₃): 198.8 (s), 154.6 (s), 150.7 (s), 150.3 (s), 130.9 (s),

122.2 (d), 114.4 (d), 111.1 (d), 79.5 (s), 73.8 (d), 55.9 (q), 40.6 (t),

39.9 (t), 30.4 (t), 28.3 (q), 17.9 (t), 13.8 (q). MS-EI: 377 (M⁺).

1-[4-Diﬂuoromethoxy-3-(tetrahydropyran-4-yloxy)phenyl]-

1

butan-1-ol (4zh). Yield: 35%. H NMR (CDCl₃): 7.13 (1H, d, J

1-[3-Methoxy-4-(tetrahydropyran-4-yloxy)phenyl]butan-1-

one (5c). Yellow solid, mp 60-62 °C. Yield: 93%. ¹H NMR

(CDCl₃): 7.55-7.53 (2H, m), 6.93 (1H, d, J ) 8.0 Hz), 4.57 (1H,

m), 4.02 (2H, m), 3.92 (3H, s), 3.58 (2H, m), 2.90 (2H, t, J ) 7.2

Hz), 2.04 (2H, m), 1.88 (2H, m), 1.77 (2H, m), 1.00 (3H, t, J )

7.2 Hz). ¹³C NMR (CDCl₃): 199.0 (s), 150.7 (s), 150.3 (s), 130.8

(s), 122.2 (d), 114.2 (d), 111.2 (d), 73.2 (d), 65.1 (t), 56.0 (q), 40.0

(t), 31.9 (t), 18.0 (t), 13.9 (q). MS-EI: 278 (M⁺).

) 8.4 Hz), 7.02 (1H, s), 6.90 (1H, d, J ) 8.0 Hz), 6.54 (1H, t, J

) 75.2 Hz), 4.64 (1H, m), 4.52 (1H, m), 3.97 (2H, m), 3.56 (2H,

m), 2.02 (3H, m), 1.82-1.61 (4H, m), 1.44 (1H, m), 1.33 (1H, m),

0.94 (3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 148.8 (s), 143.9 (s),

140.7 (s), 122.8 (d), 119.2 (d), 116.4 (triplet, J ) 258 Hz, d), 114.2

(d), 73.8 (d), 73.3 (d), 64.8 (t), 41.4 (t), 31.7 (t), 18.9 (t), 13.9 (q).

MS-EI: 316 (M⁺).

1-[4-Diﬂuoromethoxy-3-(pyridin-2-yloxy)phenyl]>butan-1-

1-[3-Methoxy-4-(tetrahydropyran-4-yloxy)phenyl]pentan-1-

one (5d). Yield: 99%. ¹H NMR (CDCl₃): 7.55-7.54 (2H, m), 6.93

(1H, d, J ) 8.0 Hz), 4.58 (1H, m), 4.02 (2H, m), 3.91 (3H, s), 3.57

(2H, m), 2.92 (2H, t, J ) 7.2 Hz), 2.05 (2H, m), 1.87 (2H, m),

1.71 (2H, m), 1.42 (2H, m), 0.95 (3H, t, J ) 7.2 Hz). ¹³C NMR

(CDCl₃): 199.0 (s), 150.7 (s), 150.2 (s), 130.8 (s), 122.2 (d), 114.2

(d), 111.1 (d), 73.2 (d), 65.1 (t), 55.9 (q), 37.8 (t), 31.7 (t), 26.7

(t), 22.4 (t), 13.8 (q). MS-EI: 2 (M⁺).

1

ol (4zi). Yield: 52%. H NMR (CDCl₃): 8.07 (1H, m), 7.70 (1H,

m), 7.26-7.15 (3H, m), 7.00-6.96 (2H, m), 6.40 (1H, t, J ) 74.4

Hz), 4.64 (1H, m), 2.33 (1H, s, br), 1.70-1.60 (2H, m), 1.48-1.26

(2H, m), 0.92 (3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 163.0 (s),

147.3 (d), 145.0 (s), 144.1 (s), 142.4 (s), 139.6 (d), 123.2 (d), 121.9

(d), 121.3 (d), 118.7 (d), 116.3 (triplet, J ) 258 Hz, d), 111.2 (d),

73.3 (d), 41.1 (t), 18.9 (t), 13.9 (q).

1-(3,4-Bisdiﬂuoromethoxyphenyl]-4-phenylbutan-1-ol (4zj).

Yield: 43%. ¹H NMR (CDCl₃): 7.00-7.14 (8H, m), 6.52 (1H, t, J

) 73.6 Hz), 6.50 (1H, t, J ) 73.6 Hz), 4.68 (1H, m), 2.64 (2H, t,

J ) 7.2 Hz), 2.11 (1H, s, br), 1.92-1.58 (4H, m).

1-(3,4-Bisdiﬂuoromethoxyphenyl]pentan-1-ol (4zk). Yield:

25%. ¹H NMR (CDCl₃): 7.24-7.18 (3H, m), 6.53 (1H, t, J ) 73.6

Hz), 6.51 (1H, t, J ) 73.6 Hz), 4.67 (1H, m), 1.92 (1H, s, br),

1.77-1.67 (2H, m), 1.40-1.23 (4H, m), 0.89 (3H, t, J ) 7.2 Hz).

¹³C NMR (CDCl₃): 144.1 (s), 142.3 (s), 141.2 (s), 123.9 (d), 122.3

(d), 119.8 (d), 115.8 (triplet, J ) 261 Hz, d), 73.5 (d), 38.9 (t),

27.8 (t), 22.5 (t), 13.9 (q).

1-(3,4-Bisdiﬂuoromethoxyphenyl]butan-1-ol (4zl). Yield: 80%.

¹H NMR (CDCl₃): 7.24-7.17 (3H, m), 6.53 (1H, t, J ) 73.6 Hz),

6.51 (1H, t, J ) 73.6 Hz), 4.66 (1H, t, J ) 6.4 Hz), 2.19 (1H, s,

br), 1.74-1.60 (2H, m), 1.43-1.30 (2H, m), 0.93 (3H, t, J ) 7.2

Hz). ¹³C NMR (CDCl₃): 144.1 (s), 142.3 (s), 141.2 (s), 123.9 (d),

122.2 (d), 119.7 (d), 115.8 (triplet, J ) 260 Hz, d), 73.2 (d), 41.3

(t), 18.8 (t), 13.7 (q). MS-EI: 282 (M⁺).

1-(3,4-Bisdiﬂuoromethoxyphenyl]-3-phenylpropan-1-ol (4zm).

Yield: 73%. ¹H NMR (CDCl₃): 7.30-7.17 (8H, m), 6.51 (1H, t, J

) 74.0 Hz), 6.50 (1H, t, J ) 73.6 Hz), 4.67 (1H, m), 2.71 (2H, m),

2.18-1.98 (3H, m). ¹³C NMR (CDCl₃): 143.8, 142.3, 141.2, 128.9,

128.5, 128.4, 126.0, 123.9, 122.3, 119.8, 115.8 (triplet, J ) 260

Hz), 72.6, 40.5, 31.8.

1-(3,4-Bisdiﬂuoromethoxyphenyl]-2-cyclohexylethanol (4zn).

¹H NMR (CDCl₃): 7.24-7.17 (3H, m), 6.53 (1H, triplet, J ) 74.0

Hz), 6.51 (1H, triplet, J ) 74.0 Hz), 4.76 (1H, m), 2.01 (1H, s,

br), 1.82-1.62 (6H, m), 1.44 (2H, m), 1.26-1.14 (3H, m), 0.94

(2H, m). ¹³C NMR (CDCl₃): 144.6, 142.3, 141.2, 123.8, 122.3,

119.7, 115.8 (triplet, J ) 260 Hz), 71.0, 47.2, 34.1, 33.9, 32.7,

26.5, 26.2, 26.1.

General Procedure for the Synthesis of 5 by Oxidization

of the Alcohols with PCC. To a solution of the alcohol 4 (1 mmol)

in dichloromethane (5 mL) was added PCC in portions. The

resulting mixture was stirred at room temperature for 2 h. The

solvent was removed in vacuo and the residue was puriﬁed by ﬂash

chromatography to afford 5.

4-(2-Methoxy-4-pentanoylphenoxy)piperidine-1-carboxylic Acid

tert-Butyl Ester (5a). Yellow solid, mp 41-43 °C. Yield: 18%.

¹H NMR (CDCl₃): 7.55-7.53 (2H, m), 6.92 (1H, d, J ) 8.8 Hz),

4.56 (1H, m), 3.90 (3H, s), 3.78 (2H, m), 3.30 (2H, m), 2.92 (2H,

t, J ) 7.2 Hz), 1.95 (2H, m), 1.81 (2H, m), 1.70 (2H, m), 1.47

(9H, s), 1.40 (2H, m), 0.95 (3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃):

199.2 (s), 154.7 (s), 150.8 (s), 150.4 (s), 130.9 (s), 122.2 (d), 114.4

1-[3-Methoxy-4-(tetrahydrofuran-3-yloxy)phenyl]butan-1-

one (5e). Yield: 75%. ¹H NMR (CDCl₃): 7.56-7.54 (2H, m), 6.83

(1H, d, J ) 8.0 Hz), 5.02 (1H, m), 4.03-3.90 (7H, m), 2.90 (2H,

t, J ) 7.2 Hz), 2.22 (2H, m), 1.76 (2H, m), 1.00 (3H, t, J ) 7.2

Hz). ¹³C NMR (CDCl₃): 198.7 (s), 150.9 (s), 149.6 (s), 130.6 (s),

122.1 (d), 112.9 (d), 110.7 (d), 78.4 (d), 72.6 (t), 66.9 (t), 55.7 (q),

39.8 (t), 32.8 (t), 17.8 (t), 13.7 (q). MS-EI: 264 (M⁺).

1-[3-Methoxy-4-(tetrahydrofuran-3-yloxy)phenyl]pentan-1-

one (5f). Yield: 55%. ¹H NMR (CDCl₃): 7.56-7.54 (2H, m), 6.83

(1H, d, J ) 8.8 Hz), 5.02 (1H, m), 4.03-3.90 (7H, m), 2.92 (2H,

t, J ) 7.2 Hz), 2.22 (2H, m), 1.71 (2H, m), 1.41 (2H, m), 0.95

(3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 199.1 (s), 151.0 (s), 149.8

(s), 130.7 (s), 122.2 (d), 113.0 (d), 111.0 (d), 78.5 (d), 72.8 (t),

67.1 (t), 55.9 (q), 37.8 (t), 33.0 (t), 26.7 (t), 22.4 (t), 13.8 (q). MS-

EI: 278 (M⁺).

1-[3-Methoxy-4-(pyridine-2-yloxy)phenyl]pentan-1-one (5g).

Yield: 60%. ¹H NMR (CDCl₃): 8.13 (1H, dd, J ) 2.0 and 5.2 Hz),

7.70 (1H, m), 7.66 (1H, d, J ) 2.0 Hz), 7.61 (1H, dd, J ) 2.0 and

8.0 Hz), 7.20 (1H, d, J ) 8.0 Hz), 7.00-6.98 (2H, m), 3.82 (3H,

s), 2.96 (2H, t, J ) 7.2 Hz), 1.77 (2H, m), 1.42 (2H, m), 0.96 (3H,

t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 199.3 (s), 163.1 (s), 151.8 (s),

147.4 (d), 146.7 (s), 139.4 (d), 134.7 (s), 122.4 (d), 121.8 (d), 118.5

(d), 111.8 (d), 111.1 (d), 55.9 (q), 38.1 (t), 26.5 (t), 22.4 (t), 13.9

(q). MS-ESI (+): 286.24 [M + H]⁺.

1-[3-Methoxy-4-(pyridine-2-yloxy)phenyl]butan-1-one (5h).

Yield: 88%. ¹H NMR (CDCl₃): 8.13 (1H, dd, J ) 2.0 and 5.2 Hz),

7.70 (1H, m), 7.66 (1H, d, J ) 2.0 Hz), 7.61 (1H, dd, J ) 2.0 and

8.0 Hz), 7.20 (1H, d, J ) 8.0 Hz), 7.00-6.98 (2H, m), 3.82 (3H,

s), 2.94 (2H, t, J ) 7.2 Hz), 1.78 (2H, m), 1.01 (3H, t, J ) 7.2

Hz). ¹³C NMR (CDCl₃): 199.1 (s), 163.1 (s), 151.8 (s), 147.4 (d),

146.7 (s), 139.4 (d), 134.7 (s), 122.4 (d), 121.8 (d), 118.5 (d), 111.8

(d), 111.1 (d), 55.9 (q), 40.3 (t), 17.8 (t), 13.9 (q). HRMS-ESI (+):

calcd for C₁₆H₁₈NO₃, 272.1287; found, 272.1282 (M⁺).

1-[4-Methoxy-3-(piperidin-4-yloxy)phenyl]pentan-1-one (5i).

Yellow oil. Yield: 96%. ¹H NMR (400 MHz, CDCl₃): 0.93 (3H, t,

J ) 7.2 Hz), 1.36-1.43 (2H, m), 2.15 (4H, d, J ) 3.6 Hz), 2.91

(2H, t, J ) 7.6 Hz), 3.33 (2H, d, J ) 12 Hz), 3.53 (2H, s), 3.91

(3H, s), 4.66 (1H, t, J ) 3.2 Hz), 6.95 (1H, d, J ) 8.4 Hz), 7.56

(1H, d, J ) 2 Hz), 7.66-7.69 (1H, dd, J ) 2, 6.4 Hz) ppm. ¹³C

NMR (100 MHz, CDCl₃): 13.82, 22.43, 26.97 (d), 37.96, 40.48,

55.91, 70.00, 111.28, 113.98, 116.83, 117.24, 125.08, 1.99, 145.59,

155.60, 161.00 (d), 200.65 ppm. HRMS (ESI+): calcd for

C₁₇H₂₆NO₃, 2.1913; found, 2.1900.

Phenyl Alkyl Ketones as Inhibitors

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7685

4-Methoxy-3-(tetrahydropyran-4-yloxyphenyl]quinolin-3-

ylmethanone (5j). White solid, mp 72-74 °C. Yield: 88%. ¹H

NMR (400 MHz, CDCl₃): 1.85-1.92 (2H, m), 2.04-2.10 (2H, m),

3.53-3.59 (2H, m), 3.97 (3H, s), 4.02 (2H, t, J ) 6.0 Hz),

4.00-4.05 (2H, m), 4.56 (1H, m), 6.97 (2H, d, J ) 8.4 Hz),

7.45-7.47 (1H, dd, J ) 2.0, 6.4 Hz), 7.58 (1H, d, J ) 1.6 Hz),

7.65 (1H, t, J ) 7.2 Hz), 7.86 (1H, t, J ) 6.8 Hz), 8.21 (1H, d, J

) 8.4 Hz), 8.54 (1H, d, J ) 2.0 Hz), 9.27 (1H, d, J ) 2.0 Hz)

ppm. ¹³C NMR (100 MHz, CDCl₃): 0.72, 31.95, 56.19, 65.34,

73.75, 110.89, 117.15, 126.71, 127.60, 1.02, 1.51, 131.65, 138.27,

146.75, 150.27 ppm. MS (ESI+): calcd for C₂₂H₂₁NO₄, 363.1;

found, 363.

1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-3-phenyl-

propan-1-one (5q). Yield: 98%.¹H NMR (400 MHz, CDCl₃): 2.21

(2H, s), 3.06 (2H, s), 3.25 (2H, s), 3.91 (4H, s), 4.02 (3H, s), 5.01

(1H, s), 6.89 (1H, d, J ) 7.6 Hz), 7.21-7.30 (5H, m), 7.48 (1H,

s), 7.60 (1H, d, J ) 6.8 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃):

30.42, 33.00, 39.99, 56.08, 67.24, 72.96, 78.73, 110.74, 113.80,

123.27, 126.14, 128.45, 128.54, 1.98, 141.41, 146.93, 154.40,

197.72 ppm. HRMS (ESI+): calcd for C₂₀H₂₃O₄, 327.1596; found,

327.1609. Anal. Calcd for C₂₀H₂₂O₄: C, 73.60; H, 6.79. Found: C,

73.57; H, 7.09.

2-Cyclohexyl-1-[4-methoxy-3-(tetrahydrofuran-3-yloxy)phe-

1

nyl]ethanone (5r). Yellow oil. Yield: 78%. H NMR (400 MHz,

1-[4-Methoxy-3-(tetrahydropyran-4-yloxy)phenyl]butan-1-

one (5k). Yellow oil. Yield: 63%. H NMR (400 MHz, CDCl₃):

CDCl₃): 1.02 (2H, m), 1. (3H, m), 1.76 (5H, m), 1.96 (1H, m),

2.22 (2H, m), 2.76 (2H, d, J ) 6.8 Hz), 3.91 (1H, s), 4.03 (3H, s),

5.02 (1H, s), 6.90 (1H, d, J ) 8.4 Hz), 7.47 (1H, d, J ) 2.0 Hz),

7.60 (1H, q, J ) 2.0, 6.4 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃):

26.18, 26.27, 33.01, 33.50, 34.96, 45.73, 56.08, 67.24, 72.99, 78.72,

110.68, 113.89, 123.45, 130.62, 146.88, 154.24, 198.76 ppm.

HRMS (ESI+): calcd for C₁₉H₂₆O₄, 319.1909; found, 319.1911

1-[4-Diﬂuoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-

2,2-dimethylpropan-1-one (5s). Yellow oil. Yield: 81%. ¹H NMR

(400 MHz, CDCl₃): 1.36 (9H, s), 2.19-2.25 (2H, m), 3.91-3.95

(1H, m), 3.99-4.03 (3H, m), 5.00 (1H, s), 6.59 (1H, t, J ) 74.8

Hz), 7.18 (1H, d, J ) 8.4 Hz), 7.30 (1H, d, J ) 2.0 Hz), 7.40-7.42

(1H, dd, J ) 2.0, 1.6 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃):

28.15, 28.71, 32.96, 44.22, 67.16, 72.81, 78.94, 115.84 (d, J ) 36

Hz), 121.77 (d), 136.04, 148.72, 206.85 ppm. MS (EI+): calcd for

C₁₆H₂₀F₂O₄, 314; found, 314.

1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-3-methyl-

butan-1-one (5t). Yield: 93%. ¹H NMR (400 MHz, CDCl₃): 0.99

(6H, d, J ) 6.4 Hz), 2.19-2.28 (3H, m), 2.77 (3H, d, J ) 6.8 Hz),

3.90 (4H, d, J ) 4.8 Hz), 4.02 (3H, t, J ) 3.6 Hz), 5.02 (1H, d, J

) 3.2 Hz), 6.89 (1H, d, J ) 8.4 Hz), 7.47 (1H, d, J ) 1.6 Hz),

7.57-7.59 (1H, dd, J ) 2.0, 1.6 Hz) ppm. ¹³C NMR (100 MHz,

CDCl₃): 22.82, 25.48, 0.70, 33.00, 47.01, 56.05, 67.23, 72.97, 78.72,

110.67, 113.87, 123.39, 130.54, 146.90, 154.24, 198.73 ppm. MS

(EI+): calcd for C₁₆H₂₂O₄, 278; found, 278.

1

1.02 (3H, t, J ) 7.2 Hz), 1.78-1.73 (2H, q, J ) 7.6, 6.4 Hz), 1.85

(2H, m), 2.05 (2H, d, J ) 10.8 Hz), 2.89 (2H, t, J ) 7.2 Hz), 3.55

(2H, t, J ) 10 Hz), 3.92 (3H, s), 4.02 (2H, t, J ) 6.0 Hz), 4.51

(1H, s), 6.91 (1H, d, J ) 8.0 Hz), 7.57 (1H, s), 7.62 (1H, d, J )

8.4 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): 13.95, 18.10, 32.00,

40.08, 56.07, 65.41, 73.70, 110.87, 115.63, 123.46, 130.33, 146.44,

154.84, 199.14 ppm. HRMS (ESI+): calcd for C₁₆H₂₂O₄, 279.1596;

found, 279.1606.

1-[4-Methoxy-3-(tetrahydropyran-4-yloxy)phenyl]pentan-1-

one (5l). Yield: 75%. ¹H NMR (400 MHz, CDCl₃): 0.95 (3H, t, J

) 7.2 Hz), 1.41 (2H, q, J ) 7.2, 7.2 Hz), 1.72 (2H, q, J ) 7.2, 7.2

Hz), 1.84 (2H, t, J ) 4.4 Hz), 2.05 (2H, d, J ) 10.0 Hz), 2.90 (2H,

t, J ) 7.2 Hz), 3.55 (2H, t, J ) 9.2 Hz), 3.92 (3H, s), 4.03 (2H, d,

J ) 11.2 Hz), 4.52 (1H, s), 6.91 (1H, d, J ) 8.0 Hz), 7.57 (1H, s),

7.62 (1H, d, J ) 8.4 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): 13.95,

22.52, 26.83, 31.99, 37.86, 56.04, 65.37, 73.68, 110.87, 115.67,

123.48, 130.27, 146.42, 154.83, 199.14 ppm. HRMS (ESI+): calcd

for C₁₇H₂₅O₄, 3.1753; found, 3.1754. Anal. Calcd for C₁₇H₂₄O₄·¹/

₈H₂O: C, 69.24; H, 8.23. Found: C, 69.27; H, 8.61.

1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]pentan-1-

1

one (5m). Yield: 92%. H NMR (400 MHz, CDCl₃): 0.95 (3H, t,

J ) 7.2 Hz), 1.43 (2H, q, J ) 6.8, 7.2 Hz), 1.72 (2H, t, J ) 6.8

Hz), 2.24 (2H, m), 2.91 (2H, t, J ) 6.8 Hz), 3.92 (4H, s), 4.03

(3H, s), 5.03 (1H, s), 6.90 (1H, d, J ) 7.6 Hz), 7.48 (1H, s), 7.61

(1H, d, J ) 8 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): 13.96, 22.54,

26.84, 33.01, 37.86, 56.07, 67.23, 72.97, 78.74, 110.72, 113.90,

123.30, 130.22, 146.90, 154.24, 199.10 ppm. HRMS (ESI+): calcd

for C₁₆H₂₃O₄, 279.1596; found, 279.1598.

1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]butan-1-

one (5n). Yield: 64%. ¹H NMR (400 MHz, CDCl₃): 1.00 (3H, t, J

) 7.2 Hz), 1.75 (2H, m), 2.24 (2H, m), 2.91 (2H, t, J ) 7.2 Hz),

3.91 (4H, s), 4.06 (3H, s), 5.02 (1H, s), 6.91 (1H, d, J ) 8.4 Hz),

7.48 (1H, s), 7.61 (1H, d, J ) 8.4 Hz) ppm. ¹³C NMR (100 MHz,

CDCl₃): 13.98, 18.12, 33.03 (d), 40.08, 56.07, 67.25 (d), 72.99 (d),

78.77, 110.76 (d), 113.92, 123.31, 130.27 (d), 146.92, 154.28 (d),

198.95 ppm. HRMS (ESI+): calcd for C₁₅H₂₁O₄, 265.1440; found,

265.1436.

1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-4-phenyl-

butan-1-one (5o). Yield: 80%. ¹H NMR (400 MHz, CDCl₃):

2.11(2H, d, J ) 7.6 Hz), 2.24 (2H, d, J ) 5.2 Hz), 2.76 (2H, t, J

) 7.6 Hz), 2.96 (2H, t, J ) 7.6 Hz), 3.94 (4H, s), 4.06 (3H, s),

6.92 (1H, d, J ) 8.4 Hz), 7.26 (3H, d, J ) 7.2 Hz), 7.30-7.35

(2H, q, J ) 7.6, 4.8 Hz), 7.50 (1H, s), 7.60 (1H, d, J ) 8 Hz) ppm.

¹³C NMR (100 MHz, CDCl₃): 26.08, 33.00, 35.27, 37.22, 56.08,

67.24, 72.97, 78.71, 110.72, 113.77, 123.27, 125.95, 128.40, 128.54,

130.11, 141.75, 146.90, 154.30, 198.63 ppm. HRMS (ESI+): calcd

for C₂₁H₂₅O₄, 341.1753; found, 341.1748.

3-Cyclohexyl-1-[4-methoxy-3-(tetrahydrofuran-3-yloxy)phe-

nyl]propan-1-one (5p). Yield: 95%. ¹H NMR (400 MHz, CDCl₃):

0.88-0.97 (2H, q, J ) 11.6, 10 Hz), 1.31 (4H, m), 1.76 (7H, m),

2.20 (2H, m), 2.90 (2H, t, J ) 7.6 Hz), 3.90 (4H, s), 4.02 (3H, s),

5.01 (1H, s), 6.89 (1H, d, J ) 8.4 Hz), 7.47 (1H, s), 7.60 (1H, d,

J ) 7.6 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): 26., 26.58, 32.18,

33.01, 33.23, 35.69, 37.48, 56.07, 67.24, 72.98, 78.72, 110.71,

113.89, 123., 130.16, 146.89, 154.22, 199.38 ppm. HRMS (ESI+):

calcd for C₂₀HO₄, 333.2066; found, 333.2067. Anal. Calcd for

C₂₀H₂₈O₄: C, 72.26; H, 8.49. Found: C, 71.95; H, 8.76.

1-[4-Methoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-4-methyl-

pentan-1-one (5u). Yield: 93%. ¹H NMR (400 MHz, CDCl₃): 0.95

(6H, d, J ) 6.0 Hz), 1.59-1.64 (3H, m), 2.19-2.25 (2H, m), 2.90

(2H, t, J ) 7.6 Hz), 3.88-3.94 (4H, m), 4.02-4.06 (3H, m),

5.01-5.03 (1H, q, J ) 2.4, 2.8 Hz), 6.91 (1H, d, J ) 8.4 Hz), 7.48

(1H, d, J ) 1.6 Hz), 7.59-7.62 (1H, dd, J ) 6.8, 1.6 Hz) ppm.

¹³C NMR (100 MHz, CDCl₃): 22.46, 27.90, 29.70, 33.00, 33.64,

36.16, 56.05, 67.22, 72.97, 78.72, 110.71, 113.88, 123., 130.15,

146.90, 154.23, 199.28 ppm. MS (EI+): calcd for C₁₇H₂₄O₄, 292;

found, 292.

1-[4-Diﬂuoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-

3-methylbutan-1-one (5v). Yield: 65%. ¹H NMR (CDCl₃):

7.56-7.53 (2H, m), 7.23 (1H, d, J ) 8.8 Hz), 6.62 (1H, t, J )

74.4 Hz), 5.06 (1H, m), 4.06-3.93 (4H, m), 2.80 (2H, d, J ) 6.8

Hz), 2.32-2.18 (3H, m), 1.01 (6H, d, J ) 6.8 Hz). ¹³C NMR

(CDCl₃): 198.6 (s), 149.0 (s), 144.5 (s), 135.5 (s), 122.2 (d), 122.0

(d), 115.7 (triplet, J ) 259 Hz, d), 114.0 (d), 78.9 (d), 72.8 (t),

67.1 (t), 47.3 (t), 32.9 (t), 25.2 (s), 22.7 (q). MS-EI: 314 (M⁺).

1-[4-Diﬂuoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-

3-pentan-1-one (5za). Yield: 43%. ¹H NMR (CDCl₃): 7.57-7.55

(2H, m), 7.23 (1H, d, J ) 8.0 Hz), 6.62 (1H, t, J ) 74.4 Hz), 5.06

(1H, m), 4.03-3.92 (4H, m), 2.93 (2H, t, J ) 7.2 Hz), 2.32-2.15

(2H, m), 1.71 (2H, m), 1.41 (2H, m), 0.96 (3H, t, J ) 7.2 Hz). ¹³

C

NMR (CDCl₃): 199.0 (s), 149.0 (s), 144.5 (s), 135.2 (s), 122.08

(d), 122.05 (d), 115.7 (triplet, J ) 260 Hz, d), 114.0 (d), 78.9 (d),

72.7 (t), 67.1 (t), 38.2 (t), 32.9 (t), 26.5 (t), 22.4 (t), 13.9 (q). MS-

EI: 314 (M⁺).

Cyclohexyl-1-[4-diﬂuoromethoxy-3-(tetrahydrofuran-3-

yloxy)phenyl]propan-1-one (5zb). Yield: 83%. ¹H NMR (CDCl₃):

7.57-7.54 (2H, m), 7.23 (1H, d, J ) 8.0 Hz), 6.62 (1H, t, J )

74.4 Hz), 5.06 (1H, m), 4.03-3.92 (4H, m), 2.94 (2H, t, J ) 7.6

Hz), 2.28-2.18 (2H, m), 1.76-1.59 (7H, m), 1.31-1.16 (4H, m),

0.97 (2H, m). ¹³C NMR (CDCl₃): 199.3 (s), 149.0 (s), 144.5 (s),

135.2 (s), 122.1 (d), 115.7 (triplet, J ) 258 Hz, d), 114.0 (d), 78.9

7686 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Zheng et al.

(d), 72.7 (t), 67.1 (t), 37.4 (d), 36.0 (t), 33.2 (t), 32.9 (t), 31.8 (t),

26.5 (t), 26.3 (t). MS-EI: 368 (M⁺).

1-(3,4-Bisdiﬂuoromethoxyphenyl)-4-phenylbutan-1-one (5zj).

Yield: 63%. ¹H NMR (CDCl₃): 7.81 (1H, s), 7.77 (1H, dd, J ) 2.0

and 8.4 Hz), 7.32-7.27 (3H, m), 7.22-7.19 (3H, m), 6.59 (1H, t,

J ) 72.8 Hz), 6.56 (1H, t, J ) 73.2 Hz), 2.93 (2H, t, J ) 7.2 Hz),

2.72 (2H, t, J ) 7.2 Hz), 2.08 (2H, m). ¹³C NMR (CDCl₃): 197.6

(s), 145.9 (s), 141.9 (s), 141.4 (s), 135.1 (s), 128.48 (d), 128.45

(d), 126.5 (d), 126.1 (d), 121.9 (d), 121.2 (d), 115.52 (triplet, J )

262 Hz, d), 115.33 (triplet, J ) 263 Hz, d), 37.5 (t), 35.0 (t), 25.5

(t). MS-EI: 356 (M⁺).

2-Cyclohexyl-1-[4-diﬂuoromethoxy-3-(tetrahydrofuran-3-

yloxy)phenyl]ethanone (5zc). Yield: 89%. ¹H NMR (CDCl₃):

7.56-7.53 (2H, m), 7.23 (1H, d, J ) 8.8 Hz), 6.62 (1H, t, J )

74.4 Hz), 5.06 (1H, m), 4.06-3.90 (4H, m), 2.79 (2H, d, J ) 6.8

Hz), 2.30-2.18 (2H, m), 1.96 (1H, m), 1.77-1.65 (5H, m),

1.31-1.15 (4H, m), 1.03 (2H, m). ¹³C NMR (CDCl₃): 198.7 (s),

149.0 (s), 144.5 (s), 135.6 (s), 122.2 (d), 122.0 (d), 115.7 (triplet,

J ) 260 Hz, d), 114.0 (d), 78.9 (d), 72.8 (t), 67.1 (t), 46.0 (t), 34.7

(d), 33.4 (t), 32.9 (t), 26.2 (t), 26.1 (t). MS-EI: 354 (M⁺).

1-(3,4-Bisdiﬂuoromethoxyphenyl)butan-1-one (5zk). Yield:

72%. ¹H NMR (CDCl₃): 7.85-7.82 (2H, m), 7.33 (1H, d, J ) 8.0

Hz), 6.63 (1H, t, J ) 72.8 Hz), 6.60 (1H, t, J ) 73.2 Hz), 2.92

(2H, t, J ) 7.2 Hz), 1.76 (2H, m), 1.01 (3H, t, J ) 7.2 Hz). ¹³C

NMR (CDCl₃): 197.9 (s), 145.8 (s), 141.9 (s), 135.1 (s), 126.5 (d),

121.8 (d), 121.1 (d), 115.6 (triplet, J ) 261 Hz, d), 115.4 (triplet,

J ) 263 Hz, d), 40.3 (t), 17.5 (t), 13.6 (q). MS-EI: 280 (M⁺).

1-(3,4-Bisdiﬂuoromethoxyphenyl)-3-phenylpropan-1-on (5zl).

Yield: 46%. ¹H NMR (CDCl₃): 7.83-7.80 (2H, m), 7.30-7.24 (6H,

m), 6.59 (1H, t, J ) 74.4 Hz), 6.55 (1H, t, J ) 72.8 Hz), 3.26 (2H,

s), 3.06 (2H, s). ¹³C NMR (CDCl₃): 196.8, 146.0, 141.9, 140.8,

134.9, 128.6, 128.4, 126.5, 126.3, 121.3, 121.2, 115.5 (triplet, J )

262 Hz), 115.3 (triplet, J ) 263 Hz), 40.3, 0.9. MS-EI: 342 (M⁺).

1-(3,4-Bisdiﬂuoromethoxyphenyl)-2-cyclohexylethanone (5zm).

Yield: 92%. ¹H NMR (CDCl₃): 7.84-7.81 (2H, m), 7.33 (1H, d, J

) 7.6 Hz), 6.62 (1H, triplet, J ) 72.8 Hz), 6.60 (1H, triplet, J )

72.8 Hz), 2.79 (2H, d, J ) 5.2 Hz), 1.96 (1H, m), 1.76-1.68 (5H,

m), 1.31-1.15 (3H, m), 1.03 (2H, m). ¹³C NMR (CDCl₃): 197.7

(s), 145.8 (s), 141.9 (s), 135.5 (s), 126.6 (d), 121.9 (d), 121.1 (d),

115.6 (triplet, J ) 262 Hz, d), 115.4 (triplet, J ) 263 Hz, d), 46.0

(t), 34.4 (d), 33.3 (t), 26.1(t), 26.0 (t). MS-EI: 334 (M⁺).

General Procedure for the Synthesis of 6 by Nucleophilic

Addition to the Ketones 5. To ketones 5g or 5h (1 mmol) in THF

(5 mL) was added dropwise 3-pyridyllithium or 3-quinolyllithium

at -78 °C. The resulting mixture was stirred overnight, during

which time the mixture was allowed to gradually warm from -78

°C to room temperature and quenched with water. The aqueous

layer was extracted three times with ethyl acetate. The combined

organic solution was dried over MgSO₄, ﬁltered, and evaporated.

The residue was puriﬁed by ﬂash chromatography to afford 6.

1-[3-Methoxy-4-(pyridin-2-yloxy)phenyl]-1-pyridin-3-yl-

pentan-1-ol (6a). Yield: 36%. ¹H NMR (CDCl₃): 8.61 (1H, s), 8.32

(1H, s), 8.08 (1H, dd, J ) 1.6 and 5.2 Hz), 7.79 (1H, d, J ) 8.0

Hz), 7.63 (1H, m), 7.21 (1H, m), 7.15 (1H, d, J ) 1.6 Hz), 7.05

(1H, d, J ) 8.4 Hz), 6.98-6.91 (2H, m), 6.86 (1H, d, J ) 8.0 Hz),

4.27 (1H, s, br), 3.67 (3H, s), 2.27 (2H, t, J ) 7.2 Hz), 1.40-1.21

(4H, m), 0.86 (3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 163.4 (s),

151.4 (s), 147.31 (d), 147.26 (d), 144.4 (s), 142.8 (s), 141.4 (s),

139.1 (d), 134.1 (d), 122.9 (d), 122.2 (d), 118.5 (d), 118.0 (d), 111.2

(d), 110.6 (d), 76.5 (s), 55.8 (q), 41.6 (t), 25.7 (t), 22.9 (t), 13.9

(q). MS-EI: 364 (M⁺).

1-[4-Diﬂuoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-

1

3-phenylpropan-1-one (5zd). Yellow oil. Yield: 88%. H NMR

(CDCl₃): 7.55-7.52 (2H, m), 7.31-7.19 (6H, m), 6.61 (1H, t, J )

74.4 Hz), 5.03 (1H, m), 4.03-3.89 (4H, m), 3.27 (2H, t, J ) 7.6

Hz), 3.05 (2H, t, J ) 7.6 Hz), 2.27-2.14 (2H, m). ¹³C NMR

(CDCl₃): 197.6 (s), 149.0 (s), 144.6 (s), 141.0 (s), 134.9 (s), 128.51

(d), 128.35 (d), 126.2 (d), 122.00 (d), 121.99 (d), 115.7 (triplet, J

) 260 Hz, d), 113.9 (d), 78.8 (d), 72.7 (t), 67.1 (t), 40.2 (t), 32.9

(t), 30.1 (t). MS-EI: 362 (M⁺).

1-[4-Diﬂuoromethoxy-3-(tetrahydrofuran-3-yloxy)phenyl]-

4-phenylbutan-1-one (5ze). Yellow oil. Yield: 91%. ¹H NMR

(CDCl₃): 7.51-7.47 (2H, m), 7.31-7.26 (2H, m), 7.21-7.19 (4H,

m), 6.61 (1H, t, J ) 74.4 Hz), 5.03 (1H, m), 4.04-3.90 (4H, m),

2.94 (2H, t, J ) 7.2 Hz), 2.72 (2H, t, J ) 7.2 Hz), 2.28-2.14 (2H,

m), 2.08 (2H, m). ¹³C NMR (CDCl₃): 198.5 (s), 149.0 (s), 144.6

(s), 141.5 (s), 135.1 (s), 128.48 (d), 128.42 (d), 126.0 (d), 122.05

(d), 122.04 (d), 115.7 (triplet, J ) 259 Hz, d), 113.9 (d), 78.8 (d),

72.7 (t), 67.1 (t), 37.5 (t), 35.1 (t), 32.9 (t), 25.7 (t). MS-EI: 376

(M⁺).

1-(3-Cyclopentyloxy-4-diﬂuoromethoxyphenyl]-3-methyl-

butan-1-one (5zf). Yield: 74%. ¹H NMR (CDCl₃): 7.58 (1H, d, J

) 4.0 Hz), 7.49 (1H, dd, J ) 4.0 and 8.4 Hz), 7.19 (1H, d, J ) 8.4

Hz), 6.63 (1H, t, J ) 75.2 Hz), 4.90 (1H, m), 2.80 (2H, d, J ) 6.8

Hz), 2.28 (1H, m), 1.97-1.79 (7H, m), 1.69-1.64 (2H, m), 1.00

(6H, d, J ) 6.8 Hz). ¹³C NMR (CDCl₃): 198.9 (s), 149.6 (s), 144.4

(s), 135.5 (s), 122.0 (d), 121.3 (d), 115.8 (triplet, J ) 259 Hz, d),

114.1 (d), 80.8 (d), 47.3 (t), 32.7 (t), 25.3 (d), 23.7 (t), 22.7 (q).

MS-EI: 312 (M⁺).

4-(2-Diﬂuoromethoxy-5-pentanoylphenoxy)piperidine-1-car-

boxylic Acid tert-Butyl Ester (5zg). Yield: 10%. ¹H NMR (CDCl₃):

7.62 (1H, d, J ) 1.6 Hz), 7.55 (1H, dd, J ) 1.6 and 8.4 Hz), 7.23

(1H, d, J ) 8.4 Hz), 6.61 (1H, t, J ) 74.4 Hz), 4.60 (1H, m), 3.67

(2H, m), 3.40 (2H, m), 2.93 (2H, t, J ) 6.8 Hz), 1.93 (2H, m),

1.80 (2H, m), 1.71 (2H, m), 1.47 (9H, s), 1.40 (2H, m), 0.96 (3H,

t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 199.1 (s), 154.7 (s), 148.9 (s),

145.0 (s), 135.3 (s), 122.1 (d), 122.0 (d), 115.8 (triplet, J ) 259

Hz, d), 115.2 (d), 79.7 (s), 74.1 (d), 40.5 (t), 38.2 (t), 30.4 (t), 28.4

(q), 26.5 (t), 22.4 (t), 13.9 (q). MS-EI: 371 [M - C₄H₉(t-Bu) +

1-[3-Methoxy-4-(pyridin-2-yloxy)phenyl]-1-quinolin-3-ylbutan-

H]⁺, 354 [M - C₄H₉O (t-BuO)]⁺327 [M - C₅H₉O₂(Boc) +

,

1

1-ol (6b). Yield: 53%. H NMR (CDCl₃): 8.90 (1H, d, J ) 1.6

H]⁺.

Hz), 8.27 (1H, d, J ) 1.6 Hz), 8.13 (1H, dd, J ) 1.2 and 4.4 Hz),

8.07 (1H, d, J ) 8.0 Hz), 7.83 (1H, d, J ) 8.0 Hz), 7.71-7.62

(2H, m), 7.55 (1H, m), 7.16 (1H, s), 7.10-7.03 (2H, m), 6.94 (1H,

m), 7.89 (1H, d, J ) 8.4 Hz), 3.70 (3H, s), 2.53 (1H, s, br), 2.38

1-[4-Diﬂuoromethoxy-3-(tetrahydropyran-4-yloxy)phenyl]-

1

butan-1-one (5zh). Colorless oil. Yield: 59%. H NMR (CDCl₃):

7.62 (1H, s), 7.55 (1H, d, J ) 8.4 Hz), 7.23 (1H, d, J ) 8.4 Hz),

6.64 (1H, t, J ) 74.4 Hz), 4.62 (1H, m), 3.98 (2H, m), 3.60 (2H,

m), 2.92 (1H, t, J ) 7.2 Hz), 2.03 (2H, m), 1.84-1.74 (4H, m),

1.01 (3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 198.9 (s), 148.8 (s),

145.0 (s), 135.4 (s), 122.14 (d), 122.07 (d), 115.9 (triplet, J ) 259

Hz, d), 115.3 (d), 73.5 (d), 64.9 (t), 40.4 (t), 31.6 (t), 17.8 (t), 13.8

(q). MS-EI: 314 (M⁺).

(2H, m), 1.47 (1H, m), 1.00 (1H, m), 0.97 (3H, t, J ) 7.2 Hz). ¹³

C

NMR (CDCl₃): 163.5 (s), 151.7 (s), 149.9 (d), 147.5 (d), 146.8 (s),

144.0 (s), 141.9 (s), 139.3 (s), 139.2 (d), 132.1 (d), 1.3 (d), 1.0 (d),

128.1 (d), 127.5 (s), 126.8 (d), 122.5 (d), 121.8 (d), 118.7 (d), 118.1

(d), 111.3 (d), 110.8 (d), 77.3 (s), 56.0 (q), 44.2 (t), 17.1 (t), 14.4

(q). HRMS-ESI (+): calcd for C₂₅H₂₅N₂O₃, 401.1865; found,

401.1853 [M + H]⁺.

1-[4-Diﬂuoromethoxy-3-(pyridin-2-yloxy)phenyl]butan-1-

one (5zi). Yield: 99%. ¹H NMR (CDCl₃): 8.08 (1H, m), 7.85-7.83

(2H, m), 7.71 (1H, m), 7.32 (1H, d, J ) 8.8 Hz), 7.03-6.99 (2H,

m), 6.48 (1H, t, J ) 73.6 Hz), 2.91 (2H, t, J ) 7.2 Hz), 1.76 (2H,

m), 0.99 (3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 198.1 (s), 162.7

(s), 147.2 (d), 144.8 (s), 139.7 (d), 135.3 (s), 125.9 (d), 123.7 (d),

120.8 (d), 118.9 (d), 115.8 (triplet, J ) 260 Hz, d), 111.2 (d), 40.4

(t), 17.6 (t), 13.8 (q). HRMS-ESI (+): calcd for C₁₉H₁₅NO₂F,

308.1087; found, 308.1085.

Synthesis of 3-{1-[3-Methoxy-4-(pyridin-2-yloxy)phenyl]-

but-1-enyl}quinoline (7a). To a solution of 6a (0.33 g, 0.8 mmol)

in acetic acid (5 mL) was added dropwise concentrated H₂SO₄(0.3

mL). The mixture was heated at 80 °C for 1 h and then cooled and

neutralized with saturated NaHCO₃. The aqueous solution was

extracted with ethyl acetate three times. The combined organics

were washed with brine, dried over MgSO₄, ﬁltered, concentrated.

The residue was puriﬁed by ﬂash chromatography to afford 0.12 g

Phenyl Alkyl Ketones as Inhibitors

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7687

(37%) of 7a as a mixture of Z- and E-isomers. ¹H NMR (CDCl₃):

8.97 and 8.79 (1H, s), 8.20-7.49 (6H, m), 7.19-6.82 (5H, m),

6.00-6.25 (1H, m), 3.71 and 3.68 (3H, s), 2.30 (1H, m), 2.17 (1H,

m), 1.11 (3H, m). ¹³C NMR (CDCl₃): 163.6 (s), 163.5 (s), 150.1

(d0, 151.6 (s), 151.45 (s), 150.0 (d), 147.53 (d), 147.46 9d), 147.1

(s), 147.0 (s), 142.0 (s), 139.9 (s), 139.24 (d), 139.15 (d), 137.9

(s), 137.2 (s), 136.6 (s), 136.3 (d), 135.4 (s), 134.3 (d), 133.9 (d),

133.5 (d), 133.1 (s), 1.4 (d), 1.2 (d), 128.99 (d), 128.96 (d), 127.9

(d), 127.8 (d), 127.8 (s), 126.8 (d), 126.7 (d), 122.63 (d), 122.60

(d), 120.3 (d), 118.2 (d), 118.1 (d), 114.4 (d), 111.8 (d), 110.9 (d),

110.7 (d), 55.9 (q), 23.5 (t), 23.3 (t), 14.4 (q). HRMS-ESI (+):

calcd for C₂₅H₂₃N₂O₂, 383.1760; found, 383.1742 [M + H]⁺.

Synthesis of 8. To a solution of 6a (0.30 g, 0.80 mmol) in acetic

acid (5 mL) was added dropwise concentrated H₂SO₄(0.3 mL).

The mixture was heated at 80 °C for 1 h. After 6a was converted

to 7a completely, without workup the product was hydrogenated

at room temperature overnight using 10% Pd/C (0.03 g) as catalyst.

The reaction mixture was neutralized with saturated NaHCO₃. The

aqueous solution was extracted with ethyl acetate three times. The

combined organic solution was washed with brine, dried over

MgSO₄, ﬁltered, and concentrated. The residue was puriﬁed by ﬂash

chromatography to afford 0.11 g (38%) of 8 as a white solid, mp

(d), 147.7 (d), 146.8 (s), 144.6 (s), 139.7 (s), 135.3 (d), 134.5 (s),

123.5 (d), 119.8 (d), 114.6 (d), 110.7 (d), 55.9 (q), 49.4 (t), 43.2

(d), 30.6 (q).

PDE Inhibition Assays. The enzymatic activities of PDEs were

assayed using ³H-cAMP and ³H-cGMP as substrates.^39,40The

expression and puriﬁcation of PDE has been described earlier.⁴¹

First, PDEs were incubated with the reaction mixture of 50 mM

Tris-HCl, pH 7.8, 10 mM MgCl₂, and ³H-cAMP or ³H-cGMP

(40 000 cpm/assay) at 24 °C for 30 min. Then the reaction was

terminated by addition of ZnSO₄and Ba(OH)₂. The reaction product

³H-AMP or ³H-GMP was precipitated by BaSO₄, while unreacted

³H-cAMP or ³H-cGMP remained in the supernatant. Radioactivity

in the supernatant was measured by liquid scintillation. The activity

was measured at eight concentrations of cAMP and cGMP, and

each measurement was repeated three times. V_maxand K_mvalues

were calculated by linear plots of Lineweaver-Burk (1/V vs 1/[S])

and Eadie-Hofstee (V/[S] vs V)⁴²and also by nonlinear regression

analysis as implemented in the program DynaFit.⁴³For measure-

ment of IC₅₀, 10 concentrations of inhibitors were used under the

substrate concentration of one-tenth of K_Mand the suitable enzyme

concentration. For the potent inhibitors, a double or triple measure-

ment was performed, while a single measurement was carried out

for the poor inhibitors

1

56-58 °C. H NMR (CDCl₃): 8.57 (1H, s), 8.44 (1H, d, J ) 4.4

Hz), 8.11 (1H, dd, J ) 2.0 and 5.2 Hz), 7.62-7.54 (2H, m), 7.20

(1H, m), 7.70 (1H, d, J ) 8.0 Hz), 6.91-6.84 (4H, m), 3.91 (1H,

t, J ) 8.0 Hz), 3.70 (3H, s), 2.06 (2H, m), 1.38-1.24 (4H, m),

0.87 (3H, t, J ) 7.2 Hz). ¹³C NMR (CDCl₃): 163.4 (s), 151.4 (s),

149.34 (d), 147.37 (d), 147.20 (d), 141.6 (s), 140.8 (s), 140.1 (s),

138.9 (d), 134.9 (d), 123.2 (d), 122.6 (d), 119.8 (d), 117.8 (d), 111.4

(d), 110.4 (d), 55.7 (q), 48.5 (d), 35.0 (t), 0.8 (t), 22.3 (t), 13.7 (q).

NMR Study of the Interaction of Inhibitors with PDE4D2

Protein. A reference ¹H spectrum and a 2D NOESY (mixing time

of 500 ms) spectrum were taken on a Varian 800 MHz NMR using

a 400 µM sample in 20 mM potassium phosphate (pH 7.1) D₂O

buffer. A sample with a 1:80 molar ratio of the inhibitor to protein

was made in 20 mM potassium phosphate (pH 7.1) D₂O buffer

with concentrations of 800 µM 5i and 10 µM PDE4D2. STD and

trNOEsy (mixing time of 50 ms) experiments were performed. The

sample was subsequently diluted, and another STD spectrum was

collected to test for nonspeciﬁc binding.

Synthesis of 4-[3-Methoxy-4-(pyridin-2-yloxy)phenyl]-4-

quinolin-3-ylbutan-2-one (11a) and 4-(4-Hydroxy-3-methoxy-

phenyl]-4-pyridin-3-ylbutan-2-one (11b). To compound 4h or 4i

(0.50 mmol) in CH₂Cl₂(20 mL) at room temperature was added

SOCl₂(0.75 mmol). After 45 min, the mixture was carefully poured

into saturated NaHCO₃(5 mL). The layers were separated, and the

aqueous phase was extracted with CH₂Cl₂. The combined organic

solution was washed with saturated NaHCO₃and brine, dried over

MgSO₄, ﬁltered, and concentrated. The thick yellow oil (9a or 9b)

was used immediately in the next reaction without further puriﬁca-

tion. To a solution of ethyl acetoacetate (0.60 mmol) in THF at 0

°C was added sodium methoxide in portions. After the mixture was

stirred for 30 min, a solution of 9a or 9b in THF was added

dropwise. The mixture was stirred at room temperature overnight

and then poured into saturated NH₄Cl. The layers were separated,

and the aqueous phase was extracted twice with ethyl acetate. The

combined organic solution was washed with 25% NH₄OAc buffer

and brine, dried over MgSO₄, ﬁltered, and concentrated to provide

crude 10a or 10b. 10a or 10b was dissolved in a mixture of THF/

MeOH/H₂O (3:1:1, 10 mL), and then 2 N LiOH (1 mL, 2 mmol)

was added. The mixture was heated at 70 °C for 2 h. Volatile

components were removed on the rotovap, and the residue was

partitioned between saturated NaHCO₃and ethyl acetate. The

aqueous phase was extracted twice with ethyl acetate. The combined

organic solution was washed with brine, dried over MgSO₄, ﬁltered,

and concentrated. The residue was puriﬁed by ﬂash chromatography

to afford 11a or 11b.

Acknowledgment. We gratefully acknowledge the ﬁnancial

support by the Georgia Research Alliance, Georgia Cancer

Coalition, and the Molecular Basis of Disease Program at

Georgia State University. We also thank Dr. Lupei Du for

technical assistance.

Supporting Information Available: Purity and NMR results

for ﬁnal compounds. This material is available free of charge via

the Internet at http://pubs.acs.org.

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JM701635J

Article Doi

Design, synthesis, and structure - Activity relationship, molecular modeling, and NMR studies of a series of phenyl alkyl ketones as highly potent and selective phosphodiesterase-4 inhibitors

DOI: 10.1021/jm701635j

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Article abstract of DOI:10.1021/jm701635j

Full text of DOI:10.1021/jm701635j

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