Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor δ agonists

J. Med. Chem. 2010, 53, 77–105 77

DOI: 10.1021/jm9007399

Novel Bisaryl Substituted Thiazoles and Oxazoles as Highly Potent and Selective Peroxisome

Proliferator-Activated Receptor δ Agonists

Robert Epple,*^,†Christopher Cow,^†Yongping Xie,^†Mihai Azimioara,^†Ross Russo,^†Xing Wang,^†

†

‡

^

^~

^

John Wityak, Donald S. Karanewsky, Tove Tuntland, Van T. B. Nguyen-Tran, Cara Cuc Ngo, David Huang,

Enrique Saez,^{^}Tracy Spalding,^{^}Andrea Gerken,^{^}Maya Iskandar,^{^}H. Martin Seidel,^{^}and Shin-Shay Tian^{^}

†

Deparments of Chemistry, ^‡Pharmacology, and ^{^}Biology, The Genomics Institute of the Novartis Research Foundation,

10675 John Jay Hopkins Drive, San Diego, California 92121

Received May 28, 2009

The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to

highly potent and selective peroxisome proliferator-activated receptor δ (PPARδ) agonists are reported.

The synthesis and structure-activity relationship in this series are described in detail. On the basis of

a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and

tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays.

A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic

center ring with two hydrophobic aryl substituents were required for efficient and selective PPARδ

activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective

compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in

vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate

dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved

in energy homeostasis and regulated by PPARδ in skeletal muscle.

Introduction

to the nuclear receptor superfamily and comprise three

distinct subtypes: PPARR, PPARγ, and PPARδ(β). PPARR

is highly expressed in tissues with high fatty acid oxidation

and upon stimulation increases high-density lipoprotein

cholesterol (HDL-C) synthesis, promotes reverse cholesterol

transport, induces cellular uptake of fatty acids, and reduces

triglycerides.^12,13The fibrate class of hypolipidemic drugs

are synthetic PPARR ligands.^14,15PPARγ plays a critical

role in the differentiation of preadipocytes to adipocytes,

promotes lipid storage, and enhances glucose disposal

into peripheral tissues.^16,17A group of marketed insulin

sensitizers called the thiazolidinediones (TZDs) are agonists

for PPARγ.^18,19

The physiological role of the third isoform PPARδ re-

mained elusive mainly because of the lack of selective ligands.

There are currently no PPARδ drugs on the market. The

emergence of fairly selective synthetic agonists such as

GW501516 and their utilization in appropriate in vitro and

in vivo models have revealed that PPARδ may also play

an important role in lipid absorption, transport, and meta-

bolism.^20-24GW501516, when dosed once a day orally at

0.1-3 mg/kg in male obese rhesus monkeys, increased

HDL-C up to 80% while reducing triglyceride levels by

50% in a dose dependent manner. Low-density lipoprotein

cholesterol (LDL-C) (-30%) and insulin (-50%) were also

affected without any change in fasting glucose levels.²⁵

PPARδ is ubiquitously expressed and is activated by long-

chain fatty acids and by prostacyclin.²⁶Increased intake of

long-chain fatty acids leads to an increase in circulating fatty

acids and fat accumulation in several tissues, resulting in an

imbalance of metabolic parameters and onset of insulin

Lack of physical exercise and caloric imbalance are two

hallmarks of the sedentary lifestyle common in Western

societies. This has led to a rise in metabolic diseases of nearly

epidemic proportions. According to the World Health Orga-

nization, the incidence of type 2 diabetes will likely exceed an

alarming 200 million cases by year 2010.^1,2The metabolic

syndrome encompasses type 2 diabetes and has emerged as a

term that generally defines the presence of conditions asso-

ciated with the imbalance of lipid and/or glucose homeostasis,

such as obesity, insulin resistance, dyslipidemia, and hyper-

tension.³Themetabolic syndromehas also been identified as a

strong predictor ofcardiovascular diseaseand atherosclerosis,

which in turn may lead to myocardial infarction and cerebral

stroke, events that rank among the leading causes of mortality

in Western societies.

The peroxisome proliferator-activated receptors (PPARs^a)

are key regulators of genes involved in energy homeostasis

and as such provide excellent targets for the potential treat-

ment of diseases associated with the metabolic syndrome.^4-11

ThePPARs arelipid-activatedtranscriptionfactorsbelonging

*To whom correspondence should be addressed. Phone: 858-812-

1720. Fax: 858-812-1648. E-mail: repple@gnf.org.

^aAbbreviations: PPAR, peroxisome proliferator-activated receptor;

SAR, structure-activity relationship; PDK4, pyruvate dehydrogenase

kinase-4; UCP3, uncoupling protein-3; HDL-C, high-density lipo-

protein cholesterol; LDL-C, low-density lipoprotein cholesterol; TZD,

thiazolidinedione; HTS, high throughput screen; DBD, DNA-binding

domain; LBD, ligand binding domain; RXR, retinoid X receptor; HG,

headgroup; TA, transactivation; FRET, fluorescence resonance energy

transfer; PCR, polymerase chain reaction; PK, pharmacokinetics.

r

2009 American Chemical Society

Published on Web 11/20/2009

pubs.acs.org/jmc

78 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Epple et al.

Figure 1. PPARδ agonists with reported EC₅₀values in the transactivation assay of the three PPAR subtypes (in μM).

Figure 2. Initial hit compound 1 derived from HTS (left) and the general schematic structural features of PPAR agonists (right).

resistance. PPARδ may act as a sensor for these fatty acids

and may help to normalize these parameters by regulating

fatty acid uptake, β-oxidation, energy uncoupling, and the

number of oxidative myofibers.^27-29PPARδ has also been

implicated in several developmental aspects, which is reflected

in the high mortality and phenotype of knockout animals.³⁰

The role of PPARδ in the development of intestinal tumors is

still a matter of debate.^31,32

depth analysis of the compounds.^37,38Therefore, novel

PPARδ agonists with an improved selectivity profile and

with improved physicochemical properties leading to an

adequate in vivo profile are needed to further elucidate the

pharmacology of this receptor.

Inan effort toidentifynovelstructureswithPPARδ agonist

activity, we performed a high throughput screen (HTS) of

approximately 1 million compounds using a cell-based trans-

activation assay. Hits were defined as compounds that in-

duced luciferase activity in cells transiently transfected with a

luciferase reporter gene plasmid containing the GAL4 binding

element and a chimeric plasmid consisting of the yeast GAL4

DNA-binding domain (DBD) fused to the ligand binding

domain (LBD) of PPARδ (GAL4-PPARδ). Approximately

1000 compounds were selected that displayed luciferase acti-

vities at least half the levels of that induced by GW501516.

These primary hits were evaluated for selectivity against

GAL4-PPARR, GAL4-PPARγ, and GAL4-RXR. On the

basis of their relative potency, their lack of activity on RXR,

and their chemical structure, a set of ∼100 molecules were

selected and reconfirmed. Compound 1 (Figure 2) was among

the identified and reconfirmed hits. The molecule could be

divided into a headgroup, linker, and a tailgroup, a general

structural feature that is frequently observed for PPAR

agonists.

In addition to GW501516, a number of small-molecule

agonists for PPARδ have been identified and reported,³³

including L-165461, as part of a benzisoxazole series disclosed

by a research group at Merck displaying moderate selectivity

(Figure 1).³⁴Compounds from both series have been exten-

sively used by several research laboratories in various in

vitro and in vivo studies, but the results from these studies

cannot be exclusively attributed to effects on the PPARδ

subtype due to their significant cross-activity to PPARR

and PPARγ. During the course of our efforts reported in

this publication, researchers at Bayer and Novo-Nordisk

published PPARδ agonists without any detectable cross-

reactivity to the other subtypes.^35,36However, to date there

are no in vivo studies reported with these compounds, and in

the case of the Bayer compound the authors noted extensive

metabolism of the cyclohexyl moiety that limits the use of this

compound in in vivo studies. We recently reported two novel

scaffolds as PPARδ selective agonists, but despite reasonable

exposure in rodents at low doses, the overall poor physico-

chemical properties proved to be an impediment to further in

As a nonselective PPAR agonist, compound 1 showed

moderate activity on all three PPAR subtypes. Although

not nearly as potent, the hit stood out in displaying

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 79

a comparable efficacy (∼80%) for PPARδ activation when

compared to GW501516 (100%), which was used as the

PPARδ standard in this assay. This indicates that compound

1 has the potential to act as a full agonist of the PPARδ

subtype, one of the main criteria for our lead compounds.

Compound 1 also possesses a novel bisarylthiazole tailgroup,

making it a promising starting point for medicinal chemistry

optimization.

mercaptothiazole intermediate 4. The ammonium dithio-

carbamate was freshly prepared by passing ammonia

through a solution of carbon disulfide.⁴³The headgroup

intermediates 50 and 51 were alkylated with excess alkyl

dibromide⁴⁴to give the corresponding bromides 5a-c and

6a-c, respectively. These and the methylene chlorides 54 and

55 were then reacted with intermediate 4 under basic condi-

tions. The intermediate esters were hydrolyzed to give final

compounds 7a-c, 8a-c, 9, and 10.

Results and Discussion

Different synthetic routes, depicted in Scheme 2, were

employed in order to obtain hybrid compounds with shorter

linkers. The first route started by reacting bromoketone 3

with potassium rhodanide. The intermediate thiocyanate

was closed to the 2-chlorothiazole 11 by treatment with

HCl (g).⁴⁵High temperature condensation with headgroups

52 and 53 under basic conditions followed by saponification

yielded sulfur-linked compounds 12 and 13. Alternatively,

bromoketone 3 was reacted with ethyl thiooxamate in a

Hantsch type cyclization.^46,47Then the carboxylate was

reduced with LiAlH₄to give the thiazole alcohol 14. The

corresponding oxazole alcohol 15 was synthesized by esteri-

fication of commercially available p-methoxybenzoin with

bromoacetic acid in the presence of dicyclohexylcarbodii-

mide (DCC) and N-dimethylaminopyridine (DMAP), follo-

wed by ring closure to the oxazole using ammonium acetate

and hydrolysis under basic conditions.⁴⁸Both alcohols 14

and 15 could be converted to the final products 16-22 by

Mitsunobu coupling with the headgroups 50-53 and sub-

sequent saponification of the ester intermediates.

Chemistry and SAR. Research groups at Merck and GSK

have previously reported PPARδ-selective agonists that

display optimized headgroups for this subtype.^39,40Our

initial strategy was to enhance the potency and selectivity

of compound 1 for the PPARδ subtype by linking the

reported headgroups with our novel tail piece. Thus, inter-

mediate headgroups 50-55 were synthesized according to

the literature (Figure 3),^33,39,41,42and were connected to the

bisarylthiazole portion of compound 1 through a variety of

different linkers to create a series of hybrid structures

(Scheme 1).

The commercially available ketone 2 was brominated to

give bromoketone 3. Compound 3 was cyclized with ammo-

nium dithiocarbamate at elevated temperatures to yield the

All analogues were assessed for their PPAR modu-

lator activities using the standard Gal4 chimera cell-based

reporter assays as described above. The experimental data

shown in Table 1 indicate the importance of linker type and

linker length for both potency and selectivity of PPAR

activation. For compounds containing longer linkers,

such as in compounds 7a-c and 8a-c, marginal PPARR

and PPARγ activity but no PPARδ activity was observed.

Figure 3. Intermediate headgroups 50-55 used to enhance potency

and selectivity for PPARδ.

Scheme 1. Synthetic Scheme for Thiothiazoles 7-10^a

^aReagents: (a) THF, 10 ꢀC, 2 h, 94%; (b) Br₂, CHCl₃, room temp, 0.5 h, 88%; (c) EtOH, 60 ꢀC, 3 h, 96%; (d) Br(CH₂)_nBr (n = 2-4), Cs₂CO₃, acetone,

50 ꢀC, 8 h, 66-82%; (e) 4, NaOEt, EtOH, room temp, 12 h; (f) LiOH, THF, H₂O, 60 ꢀC, 12 h, 57-83% over two steps.

80 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Scheme 2. Synthesis of Thiazoles and Oxazoles 12-22^a

Epple et al.

^aReagents: (a) KSCN, acetone, reflux, 8 h, 94%; (b) HCl (gas), EtOAc, room temp, 6 h, 50%; (c) NaOEt, EtOH, reflux 5 h; (d) LiOH, H₂O, THF,

room temp, 24 h, 60-72% over two steps; (e) (i) ethyl thiooxamate, EtOH, reflux, 12 h, 81%; (ii) LiAlH₄, THF, room temp, 1 h, 79%; (f) (i) bromoacetic

acid, DCC, DMAP, DCM, room temp, 18 h, 74%, (ii) NH₄OAc, AcOH, reflux, 2 h, 76%, (iii) K₂CO₃, MeCN, reflux, 2 h, 80%; (g) 50-53, PPh₃, DEAD,

DCM, room temp, 12 h, 50-63% over two steps.

Table 1. Cell-Based Transactivation Activity of PPAR Subtypes for Compounds with Various Headgroups and Linkers

for above-left structure

PPAR EC₅₀(μM) (% efficacy^a)

for above-right structure

PPAR EC₅₀(μM) (% efficacy^a)

compd

linker L

X

R

γ

δ

compd

linker L

X

R

γ

δ

7c

7b

7a

9

-O-(CH₂)₄-S-

-O-(CH₂)₃-S-

-O-(CH₂)₂-S-

-CH₂-S-

S

O

2.37 (89)

5.25 (62)

5.35 (64)

>10

6.36 (39)

6.89 (47)

5.66 (26)

>10

8c

8b

8a

10

13

17

19

21

-O-(CH₂)₄-S-

-O-(CH₂)₃-S-

-O-(CH₂)₂-S-

-CH₂-S-

S

O

0.80 (65)

0.84 (66)

1.06 (61)

>10

2.56 (57)

4.61 (52)

5.87 (41)

>10

5.67 (28)

1.41 (56)

0.10 (75)

0.47 (59)

0.12 (73)

0.66 (69)

3.30 (58)

6.36 (22)

0.81 (47)

0.03 (55)

0.25 (54)

12

16

18

20

22

-S-

-O-CH₂-

-S-CH₂-

>10

-S-

>10

-O-CH₂-

-S-CH₂-

>10

-O-CH₂-

-S-CH₂-

>10

^aThe % efficacy is calculated relative to response to reference compounds (100%). Reference compounds used for % efficacy calculation: PPARR,

KRP297; PPARγ, rosiglitazone; PPARδ, GW501516.

Shorter linkers as in compounds 9-22 led to the desired

selective PPARδ activity. In the hydroquinone headgroup

series (Table 1, left), the optimal linker was oxomethylene

(compound 16). A sulfur linked compound (compound 12)

as in the initial hit resembles a similar linker length, but this

compound was markedly less potent and efficacious pro-

bably because of its reduced flexibility. The analysis of a

recently solved cocrystal structure suggests that a flexible

linker is crucial for efficient PPAR activation.²⁶A simple

reversal of the thio-methylene linker (compound 18) to the

methylene-thio linker (entry 9) resulted in a significant loss

of activity. This observation suggests that not only linker

length but also changes in the electronic properties of

the adjacent aromatic systems play a major role in influen-

cing PPAR activity. When the shorter phenyl acetate

headgroup was used (Table 1, right), the optimal linker

was thio-methylene (compound 19), which leads to an

overall similar distance between the carboxylate and the

hydrophobic tail piece when compared to compound 16.

In this series, the disadvantage of having a sulfur atom next

to the heterocycle seems to be even more pronounced

(compounds 10, 13). When the tailgroup heterocycle was

changed from a thiazole to an oxazole ring, the activity of the

derived compounds followed a similar trend (compounds

20-22). Because of its repeated display of significantly

higher efficacy, the hydroquinone series was chosen over

the phenylacetate series for further optimization. It is worth

noting that a series of imidazole analogues (X = NR) were

also prepared (synthesis not shown), all of which failed to

show any PPAR activity.

After the initial optimization of headgroup and linker

in our hybrid molecules, we turned our attention to the

heteroaromatic tail moiety. In order to quickly access thia-

zole analogues bearing various substituents, we first trans-

formed headgroup 50 to the thioamide intermediate 23

via sulfurization of a nitrile intermediate (Scheme 3).⁴⁹

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Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 81

Scheme 3. Initial Exploration of Thiazole Tail via Hantsch Condensation^a

^aReagents: (a) chloroacetonitrile, MeCN, Cs₂CO₃, 2 h, room temp, 94%; (b) thioacetamide, HCl, dioxane, DMF, 100 ꢀC, 12 h, 62%; (c) KCN, EtOH,

refux, 7 h, 65-90%; (d) DDQ, PPh₃, n-Bu₄NBr, DCM, room temp, 2 h, 30-40%; (e) TMSCN, ZnI₂, DCM, 0 ꢀC, 2 h, then room temp 12 h, 85-95%;

(f) LDA, ArCH₂Br, THF, -78 ꢀC, 2 h, then room temp 15 h, 40-60%; (g) pyridinium tribromide, DCM, room temp, 2 h, 75-92%; (h) EtOH, 180 ꢀC,

microwave, 5 min; (i) LiOH, H₂O, THF, room temp, 2 h, 53-90% over two steps.

Thioacetamide was used as the sulfur source, as it was found

to be easier to handle and afforded higher yields than

the more commonly used hydrogen sulfide or diethyl dithio-

phosphate procedures.⁵⁰The thioamide 23 was condensed

with a wide range of R-bromoketones 24 and saponified to

give thiazoles of general formula 25. Some R-bromoketones

or their nonbrominated ethanone precursors were commer-

cially available. When both R¹and R²were aryl groups, we

employed an Umpolung type synthesis route similar to the

benzoin synthesis.⁵¹Condensation of two arylaldehyde

molecules in the presence of cyanide gave the “symmetric”

(R¹= R²) R-hydroxyketone. Transformation of alcohol to

bromide using tetrabutylammonium bromide and DDQ

gave R-bromoketones 24. For R¹¼ R², the arylaldehyde

was first reacted with trimethylsilyl cyanide in the presence of

zinc iodide. The stable silanyloxy-acetonitrile interme-

diate was isolated, then deprotonated with lithium diiso-

propylamide (LDA) and quenched with a benzyl bromide.⁵²

The resulting unsymmetric (R¹¼ R²) 1,2-diarylethanone

was brominated using pyridinium tribromide to yield

R-bromoketones 24.⁵³

More than 150 analogues were synthesized according

to Scheme 3. The activities of selected representatives

are depicted in Table 2. The amide analogues 25b were

prepared by bromination and subsequent condensation of

β-ketoamides, and ethers such as 25m were prepared by

condensation of the corresponding R-bromomethylacetates

with intermediates 24 followed by alkylation of the hydroxy

group (syntheses not shown). Any combination of unsub-

stituted phenyl as R¹or R²with hydrogen, alkylamides, or

ethers (compounds 25a,b,l,m) resulted in inactive com-

pounds. The same result was obtained when both R¹and

R²were unsubstituted phenyls (25r). Once the phenyl rings

were substituted on either R¹or R², moderate activity was

observed on the PPAR receptors. Only compounds with

para-substitution showed significant activity. Any ortho,

meta, or multiple substituents on the phenyl rings obliterated

activity (data not shown). Any charged or highly polar

substituents were not tolerated, in agreement with the overall

hydrophobic nature of the binding pocket.^26,54By compa-

ring series 25c-e to series 25n-p, one can observe a divergent

preference for the nature of the substituents on the phenyl

rings of both R¹and R². This finding is further supported by

comparing the activities of the compound pairs 25j,u and

25k,v. Generally, the activities of this scaffold for PPARδ

activation are optimal when both R¹and R²are aryl rings.

Each series experiences more than a 10-fold increase in

activity when substituting sterically similar but electronically

different groups on the phenyl ring of R¹or R². Evidently,

the aryl ring of R¹strongly preferred an electron-donating

substituent such as a methoxy group, and the aryl ring of

R²preferred an electron-withdrawing substituent such as a

chloride. Electron-withdrawing groups on both aryl rings

were tolerated (compounds 25i,t) but were not as active as

the unsymmetric analogues.

In addition to the electronic effects, there also was a strong

steric component to the SAR. Even extended aromatic

systems such as biphenyls (25f) or naphthyls (data not

shown) were tolerated. The retention of activity of com-

pound 25s, which bears a biphenyl substituent on both R¹

2

3

˚

and R , is consistent with the substantial size (>1000 A ) of

the PPAR ligand binding pocket seen in the reported crystal

structures.⁵⁴

One interesting observation from this survey was that the

thiazole positions 4 and 5 of these analogues were not

equivalent as might be expected if the thiazole ring was

merely holding the aryl groups in the right geometry to fit

the receptor binding pocket, despite the difference in size of

the sulfur versus the nitrogen atom. Another surprising

observation was the high activity of 25q which has a

3-pyridyl substituent at R¹. Combining these results with

the earlier finding that a methoxy group on the substituent at

this side of the molecule (R¹) was preferred, we hypothesized

that one or more of the heteroatoms in and around the

thiazole ring are likely involved in the binding event.

In general, most compounds were selective for PPARδ

with only a few showing limited cross-activity to PPARR

(compounds 25d,f). These results were supportive of our

strategy to optimize the linker length and tail substituents in

combination with previously described headgroups for the

generation of highly PPARδ-selective compounds.

The methodologies described in Scheme 3 were crucial

to get a first impression of the characteristics and SAR

within the thiazole unit of our scaffold. There are only a

limited number of diphenylethanones commercially avail-

able, and the formation of R-bromoketones through the non-

symmetric benzoin condensation route lacked the scope and

seviceability to quickly generate a wide range of diverse

82 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Table 2. Selected SAR Results of the Initial Tailgroup Survey

Epple et al.

^aThe % efficacy is calculated relative to response to reference compounds (100%). Reference compounds used for % efficacy calculation: PPARR,

KRP297; PPARγ, rosiglitazone; PPARδ, GW501516.

analogues. Alternative strategies had to be explored that

allowed us to specifically address either position 4 or position

5 on the heteroaromatic ring and to utilize a general and

robust diversifying step late in the synthetic route. Scheme 4

shows an efficient route for the rapid exploration of position

5 in the thiazole (oxazole) ring. After bromination of the aryl

acetate with pyridinium tribromide, the heterocycle was

formed by condensation with either thioamide or acetamide

to give thiazoles or oxazoles of the general structure 26.

Position 5 of the heterocycle was then brominated using

bromine in acidic media, followed by radical bromination of

the methyl group in position 2 using N-bromosuccinimide to

yield dibromide 27.⁵⁵Alternatively, position 5 of the ester

precursor to compound 25 (R²= H, Scheme 3) could also

be brominated as long as R₁did not contain electron-

withdrawing or extended aromatic substituents. In the latter

cases, bromination was observed in the aryl ring of the

headgroup. After substitution of dibromide 27 with head-

group 50, intermediate 28 was subjected to microwave-

mediated Suzuki coupling conditions in the presence

of various arylboronic acids.^56,57Final products 29 were

obtained by saponification of the ester precursors.

The wide scope of the Suzuki coupling gave us the

opportunity for a detailed investigation and optimization

of position 5 in the heteroaromatic ring. The results for

Ar¹= p-methoxyphenyl are summarized in Table 3. Con-

sistent with the findings of Table 2, thiazoles (X = S) with

aryl groups bearing electron-withdrawing substituents in

position 5 (compounds 29a,b,e) generally showed increased

potency over electron-donating substituents (compound 18).

A more in depth survey of hydrophobic substituents led to

several interesting findings. The unusually high efficacy of

compound 29i having a n-propyl substitution was remark-

able, whereas a tert-butyl group (compound 29j) proved

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 83

Scheme 4. Synthesis of Diaryl Thiazoles and Oxazoles Allowing Rapid Exploration of Position 5^a

^aReagents: (a) pyridinium tribromide, DCM, room temp, 1 h, 50-90%; (b) thioamide, EtOH, reflux, 2 h, 37-75%; (c) acetamide, 150 ꢀC, 2 h,

55-70%; (d) Br₂, HOAc, DCM, room temp, 2 h, 70-85%; (e) NBS, AIBN, CCl₄, 55 ꢀC, 24 h, 35-70%; (f) Cs₂CO₃, MeCN, room temp, 2 h, 41-60%;

(g) Pd(PPh₃)₄, DME, EtOH, Na₂CO₃(aq), 170 ꢀC, 5 min; (h) 1 N LiOH, THF, room temp, 6 h, 67-90% over two steps.

to be too bulky even for the large hydrophobic PPAR

ligand binding pocket. Extended aromatic systems as Ar²

(compounds 29k,m-p) were among the most potent com-

pounds in this series with the exception of compound 29l,

which most likely led to a steric clash with the ligand binding

pocket. Heterocycles such as pyridines and pyrimidines

or five-membered heterocycles were not well tolerated

(exemplified by compound 29g) with the exception of the

3-quinolyl substituent in compound 29n. Any attempt to

decorate Ar²with two or more substituents led to a signifi-

cant loss of activity (e.g., compounds 29h,q). The substitu-

tion pattern clearly showed a preference in the order of para

(compound 29b) > meta (compound 29c) . ortho (com-

pound 29d). In general the oxazole analogues (X = O,

compounds 29aa-ah) followed the trends observed for the

thiazoles (X = S). Remarkably, none of the analogues in this

series had any detectable cross-activity to the other PPAR

subtypes.

Switching the diversifying step from position 5 to posi-

tion 4 proved to be more challenging (Scheme 5). Gaining

access to the common intermediate 30 (analogous to inter-

mediate 26 in Scheme 4) required simultaneous exploration

of several synthetic routes. The first route employed hy-

droboration of ethyl ethynyl ether followed by in situ

palladium mediated cross-coupling with an aryl halide.⁵⁸

The resulting ethoxyethene was brominated in EtOH to

give intermediate 31, which can be viewed as a stable

equivalent to the bromoketone intermediates used in

Schemes 3 and 4 but with switched bromide and keto

functionalities. Hantsch cyclization of the in situ formed

R-bromoaldehyde of 31 led to heterocycle 30. Alterna-

tively, intermediate 30 (X = S) was obtained directly via

cross-coupling of 2-methylthiazole with aryl halides in the

presence of copper iodide using conditions previously

reported for imidazoles,⁵⁹although with rather modest

yields. In a third route, a diazo transfer reaction of aryl

acetates and freshly prepared methanesulfonylazide^60,61

led to intermediate 32, which was cyclized with acetonitrile

in a 1,3-dipolar cycloaddition to give intermediate 30

(X = O). The remainder of the synthetic route was accom-

plished similar to Scheme 4: double bromination of inter-

mediate 30 to dibromide 33, followed by substitution with

50 led to intermediate 34. Intermediate 34 was diversified

by Suzuki cross-coupling with various boronic acids and

saponified to yield final compounds 35.

The results obtained in Table 3 enabled us to focus on a few

optimal substituents at position 5 of the thiazole (oxazole)

such as substituents displaying electron-withdrawing and/

or hydrophobic properties. Table 4 lists examples that have

a fixed p-OCF₃-phenyl substitution in position 5. A similar

survey was performed for other substituents in position 5 such

as biphenyl or p-propylphenyl. The activities of these com-

pounds showed the same general trends as the ones observed

in Table 4. A hydrophobic and/or electron-withdrawing sub-

stituent in position 4 (compounds 35a,b) led to a 5- to 10-fold

decrease in activity. Consistent with earlier results, multiple

and/or meta substitution (compounds 35c,d) tended to be less

potent. Exceptions were the alkylenedioxobenzene substitu-

ents in compounds 35l-n which retained good potency and

showed excellent efficacy. A linear extension of the alkoxy

group from methoxy to butoxy (compounds 29e, 35e-g) was

tolerated but did not improve activity. On the other hand,

R-branched alkoxy groups (compounds 35h,i,k) significantly

enhanced potencies, compound 35h representing the first

single digit nanomolar compound in this series.

The generally high hydrophobicity of the analogues de-

scribed so far could potentially lead to cytotoxic liabilities or

bioavailability problems due to lack of solubility. To address

these potential issues, we continued to optimize position

5 with the goal to incorporate more hydrophilic substituents

to lower the clogP value (>7) of compounds in this series.

Highly solubilizing or polar groups such as charged species

or sulfones were not tolerated (data not shown), as already

mentioned, not surprising given the overall hydrophobic

nature of both the receptor ligand binding pocket and the

endogenous lipid ligands. Also, incorporation of sulfon-

amides or amides such as in compound 35s or benzoxazo-

lones (compound 35t) and related heterocycles led to a

substantial decrease in activity. It became apparent that we

had to optimize within a small window of hydrophilicity

tolerated by the ligand binding pocket. Anilines (compounds

35o-r) were mostly well tolerated but did not significantly

improve the physicochemical properties of the molecules. At

most, an aniline type morpholino group (compound 35r)

maintained the compound activity fairly well while decreas-

ing the clogP value of the compound (clogP = 6.3). A similar

84 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Epple et al.

Table 3. Optimization of Position 5 in the Thiazole/Oxazole Ring (Ar¹= p-OMe-phenyl)

^aThe % efficacy is calculated relative to response to reference compounds (100%). Reference compounds used for % efficacy calculation: PPARR,

KRP297; PPARγ, rosiglitazone; PPARδ, GW501516.

decrease in clogP was observed in the “reverse” amide series

35u-w. Unfortunately, the very potent representatives of

this series (compounds 35v,w) were also starting to show

cross-activity to the other PPAR subtypes.

The survey of thiazoles (X = S) presented in Table 4 was

repeated with the oxazole (X = O) analogues. In general,

the oxazoles followed the same trends as the thiazoles

(data not shown). A few subtle differences can be noted

and are represented in Table 4 by compounds 35aa-ad:

the oxazole analogues tended to be more potent but also

showed a higher degree of cross-activity within the PPAR

subtypes when compared to their thiazole counterparts.

The incorporation of heteroatoms into the aryl substituent

leads to a further decrease of hydrophobicity in the series.

Since compound 25q in Scheme 2 contained a pyridine as Ar¹

and showed good activity, a logical follow-up was to com-

bine this feature with the findings of Tables 3 and 4 to

generate compound series 38. When the corresponding

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 85

Scheme 5. Synthesis of Diaryl Thiazoles and Oxazoles Allowing Rapid Exploration of Position 4^a

^aReagents: (a) BH₃, THF, 2 h; (b) Pd(OAc)₂, PPh₃, NaOH, THF, reflux, 15 h, 40-60%; (c) N-bromosuccinimide, EtOH, room temp, 2 h, 70-80%;

(d) Ac₂O, AcCl, NaOAc, CHCl₃, 60 ꢀC, 5 h, 90-100%; (e) thioacetamide, EtOH, 180 ꢀC, microwave, 5 min, 50-60%; (f) acetamide, 150 ꢀC, 2 h,

65-80%; (g) 2-methylthiazole, Cs₂CO₃, CuI, Pd(OAc)₂, PPh₃, DMF, 140 ꢀC, 24 h, 15-25%; (h) LiHMDS, THF, -78 ꢀC, then CF₃CO₂CH₂CF₃,

20 min; (i) methanesulfonyl azide, NEt₃, H₂O, MeCN, room temp, 1 h, 43-93% over two steps; (j) AlCl₃, MeCN; (k) Br₂, DCM, room temp, 1 h,

65-80%; (l) NBS, AIBN, CCl₄, 75 ꢀC, 12 h, 66-79%; (m) Cs₂CO₃, MeCN, room temp, 2 h, 80-100%; (n) Pd(PPh₃)₄, DME, EtOH, Na₂CO₃(aq),

170 ꢀC, 5 min; (o) 1 N LiOH, THF, room temp, 6 h, 67-90% over two steps.

boronic acids were not commercially available, we synthe-

sized the building blocks according to Scheme 6. Aromatic

nucleophilic substitution to intermediate 36 was followed by

lithiation and quenching with triisopropyl borate^62,63to

yield compounds of the general formula 37. Indeed, the use

of pyridine-3-boronic acids and 5-pyrimidine-5-boronic

acids in the Suzuki coupling step of Scheme 5 led to com-

pounds with high potency and efficacy for PPAR activation.

The in vitro activities and a comparison of thiazoles versus

oxazoles are summarized in Table 5. Both series showed

outstanding ability for PPARδ activation, especially in con-

junction with additional substituents from the prior optimi-

zation efforts (compounds 38c-h, 38ac-ah). Having

nitrogens in any other position in the aryl ring than the one

displayed in Table 5 led to inactive compounds (data not

shown). The oxazoles again were more potent in the PPARδ

transactivation assay but also had considerably more cross-

activity to PPARR and PPARγ.

In parallel with the optimization of the bisarylthiazole

tailpiece, a survey of acidic headgroups was conducted.

The synthesis to their ester precursors was described pre-

viously.^42,64-69These esters were coupled with bromide 39

using Cs₂CO₃in acetonitrile and hydrolyzed to give final

products 40 (Scheme 7). Intermediate 39 was synthesized

following the general procedures described in Scheme 4, with

the exception that the Suzuki coupling with 4-trifluoro-

methylphenylboronic acid was done directly after bromina-

tion of the thiazole ring.

(compound 40e) as commonly seen with PPARR/γ dual

agonists⁶⁶led to activity across all PPAR subtypes, although

with quite low efficacies. An alkyl substitution (methyl,

propyl) within the phenyl ring (compounds 29b, 40f) as in

50 led to a dramatic >25-fold increase in activity over

compound 40a. Changing the position of the methyl group

in the phenyl ring (compound 40g) caused a ∼100-fold drop

in activity. The decrease in activity of analogue 40h can be

explained by the increase in linker length when incorporating

sulfur instead of oxygen (cf. compound 20, Table 1). The

substitution of the oxygen closer to the carboxylate warhead

with a methylene group (compound 40i) did not lead to any

improvements. Replacing the methyl group with a trifluoro-

methyl group (compound 40j) was fairly well tolerated.

Several attempts to enclose the methyl group into a bicyclic

system (compound 40k-o) gave compounds with lower

PPAR activity compared to compound 29b. The loss of

activity of compound 40n can be explained by the require-

ment of the acidic warhead to reach out of plane orthogon-

ally to the center phenyl ring in order to form the crucial

contacts with the AF-2 helix of the receptor.²⁶Phenylacetic

acid analogues (compounds 40p-s) were also tolerated and

gave good results when phenyl substituents and linker length

were reoptimized (compound 40s) as explained earlier

(cf. compound 17, Table 1). In summary, none of the various

headgroups employed in this survey was able to increase

PPARδ agonist activity when compared to 50.

Biology. Our optimization efforts described above gene-

rated a collection of approximately 100 PPARδ-selective

compounds with activities of <25 nM potency and >80%

efficacy. Representative examples can be found in Table 7.

The compounds displayed similar activities when comparing

their ability to bind and induce activation of the ligand

binding domain of PPARδ in a cell-based Gal4-DBD-based

A number of interesting results are listed in Table 6. The

bare p-phenoxyacetic acid was active (compound 40a),

whereas meta (compound 40b) and ortho (compound 40c)

orientations were not tolerated for PPAR activation.

Adding a geminal dimethyl group (compound 40d) had little

effect on PPARδ activity, while adding an ethoxy group

86 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Epple et al.

Table 4. Optimization of Position 4 in the Thiazole/Oxazole Ring (Ar²= p-OCF₃-phenyl)

^aThe % efficacy is calculated relative to response to reference compounds (100%). Reference compounds used for % efficacy calculation: PPARR,

KRP297; PPARγ, rosiglitazone; PPARδ, GW501516.

luciferase reporter gene assay [transactivation (TA) assay]

and their ability to induce a conformational change in the

LBD of PPARδ to recruit a coactivator peptide [fluorescence

resonance energy transfer (FRET) assay] in a cell-free

system. The ability of the compounds to activate a rodent

(mouse) PPARδ receptor was comparable to the human

PPARδ activities. In general, the compounds were well

tolerated in cellular assays up to 10 μM and were cytotoxic

only when tested at high concentrations (>30 μM),

as indicated by the reduction of TA activity at high com-

pound concentrations. This moderate cytotoxicity was also

observed in hepatocytes and bone marrow cells again only

at high compound concentrations (>50 μM) for some

compounds and appeared to decrease with decreasing

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 87

lipophilicity of the compounds. The same trend was ob-

served for their potential to nonselectively inhibit trans-

membrane receptors in a cell-free setting when tested against

a panel of GPCRs and ion channels (data not shown). These

observations led to the hypothesis that the highly lipo-

philic compounds in this series probably have membrane-

disruptive, detergent-like properties at critical micelle

concentrations.⁷⁰A subset of compounds was further char-

acterized for in vivo phamacokinetics, and compounds

showing reasonable oral exposure were evaluated in an

acute dosing in vivo model using C57BL/6 mice. The

compounds chosen for in vivo evaluation had >90%

parent remaining after 2 h of incubation with mouse liver

microsomes except compound 46 and were well tolerated in

both the pharmacokinetic and acute efficacy studies. The

solubility and oral exposure was clearly affected by the

nature of the substituents on the thiazole/oxazole core,

with the slight trend toward less hydrophobic substituents

accounting for better oral exposure. As reported pre-

viously,^21,27,71,72PPARδ regulates lipid metabolism by

increasing fatty acid metabolism in peripheral tissues,

particularly in skeletal muscle, and by promoting energy

uncoupling in fat and muscle. To assess the in vivo effects of

PPARδ-selective compounds, real-time PCR gene expres-

sion studies were performed on samples of relevant

metabolic tissues collected from mice dosed with our com-

pounds. Briefly, C57BL6 mice were treated with either

vehicle or compound once daily orally at 10 mg/kg for 3

days and skeletal muscle, liver, and adipose tissues were

Scheme 6. Synthesis of Heterocyclic Boronic Acid Building

Blocks^a

^aReagents: (a) NaH, ROH, reflux, 15 h, 75-80%; (b) R₂NH, K₂CO₃,

MeCN, reflux, 5 h, 75-80%; (c) n-BuLi, diethyl ether, -78 ꢀC, 2 h, then

B(OⁱPr)₃, 2 h, 60-77%.

Table 5. Optimization of Position 4 in the Thiazole/Oxazole Ring (Ar²= p-OCF₃-phenyl) Continued

^aThe % efficacy is calculated relative to response to reference compounds (100%). Reference compounds used for % efficacy calculation: PPARR,

KRP297; PPARγ, rosiglitazone; PPARδ, GW501516.

88 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Scheme 7. Exploration of Headgroup SAR^a

Epple et al.

Table 6. Selected SAR of the Headgroup Survey

^aThe % efficacy is calculated relative to response to reference compounds (100%). Reference compounds used for % efficacy calculation: PPARR,

KRP297; PPARγ, rosiglitazone; PPARδ, GW501516.

collected for quantitative real-time PCR analysis of

PPARδ-regulated genes. The fold induction of two

PPARδ-regulated genes, PDK4 (pyruvate dehydrogenase

kinase-4, a key enzyme in glucose metabolism) and UCP3

(uncoupling protein-3, involved in energy uncoupling), in

skeletal muscle is summarized in Table 7. As shown,

compounds in this series showed in vivo up-regulation of

the skeletal muscle PDK4 and UCP3 gene expression at the

RNA levels. Compounds in this series also regulated

expression of some additional PPARδ-regulated genes

involved in fatty acid oxidation and energy metabolism in

skeletal muscle, liver, and adipose tissues (data not shown).

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 89

Table 7. In Vitro Human and Mouse PPARδ Activities,^ain Vivo PK Properties, and Acute Dosing in Vivo Gene Induction Results of Representative

Examples

^aThe % efficacy is calculated relative to response to reference compounds (100%). Reference compounds used for % efficacy calculation: TA assay,

GW501516; FRET assay, L165041. ^bDetectable cross-activity to PPARR. ^cclogP values were calculated using the program cLogP 4.0 developed by BioByte,

Inc. of Claremont, CA. ^dGene expression data are reported as fold change ( SEM (n = 5-6 mice/group) relative to the vehicle control. Student’s t test was

used for the statistical analysis. The symbol / indicates p < 0.01 relative to vehicle control, and // indicates P < 0.05 relative to vehicle control.

90 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Epple et al.

Conclusions

The HPLC uses a Waters Atlantis dC18 50 mm ꢀ 2.1 mm, 5 μm

column, with mobile phases A (H₂O þ 0.05% TFA) and

B (ACN þ 0.035% TFA). The data were acquired in positive

mode with the ESI source probe at 4000 V, drying gas flow of

12 L/min, nebulizer pressure of 60 psig, and drying gas tem-

perature of 350 ꢀC.

In conclusion, we described the discovery and synthesis

of a novel series of selective PPARδ agonists. The structure-

activity relationships of the headgroup, linker, and tailgroup

moieties were thoroughly investigated. The compound series

was gradually optimized on the basis of transactivation

activities and resulted in several examples with an improved

PPAR subtype selectivity and an improved pharmacokinetic

profile compared to prior disclosed PPARδ agonists. The

requirement of a flexible linker in the series for improved

potency was in line with the general agonist model known in

the PPAR field, as was the overall hydrophobic character of

the heteroaromatic tailgroup. While thiazoles followed the

trend of being more selective over the other PPAR subtypes,

the oxazole analogues were generally more potent but less

selective for PPARδ activation. The five-membered hetero-

aromatic center ring required two aryl substituents for high

potency, efficacy, and selectivity for PPARδ activation. The

aryl substituents were not interchangable and had to be

optimized individually, suggesting that the center hetero-

aromatic ring is involved in the binding event. The aryl ring

in position 5 of the heterocycle was optimal when para-

substituted with an electron-withdrawing and/or hydropho-

bic substituent. The aryl ring in position 4 was amenable to

slightly more hydrophilic features. Within the series, optimal

physicochemical parameters were achieved when substituting

position 4 with pyridines or pyrimidines displaying p-alkoxy

or amino substituents. A survey of various headgroups was

conducted on the scaffold but did not lead to any improve-

ments over the initially selected (2-methylphenoxy)acetic

acid. Compounds with good to excellent pharmacokinetic

properties, such as compound 38c, demonstrated in vivo

regulation of genes involved in energy homeostasis in rele-

vant metabolic tissues when dosed acutely in C57Bl/6 mice.

Several compounds are currently undergoing additional

evaluation to further elucidate the role of PPARδ in glucose

and lipid metabolism and to assess the potential of develop-

ing this series for diseases associated with the metabolic

syndrome.

High resolution mass spectroscopy (HRMS) analysis was per-

formed using the following system: an eight-channel pipetter was

used to flush 10 μL of a solution of 80% MeCN/0.2% AcOH into

each well of the sample plate containing varying amounts of

compound in DMSO. After the liquid was mixed by aspirating

and dispensing 3ꢀ, an aliquot of 10 μL was taken and diluted into

100 μL of 80% MeCN/0.2% AcOH. Solutions were analyzed by

flow-injecting 3 μL of the diluted samples with an autosampler

(Agilent Technologies, Palo Alto, CA) into a 50 μL/min stream

of 80% MeCN/0.2% AcOH delivered by an HPLC pump

(Agilent Technologies, Palo Alto, CA) into the ESI source of an

LTQOrbitrap mass spectrometer (ThermoElectron, San Jose,

CA). Centroid data were recorded for 2 min at 30 000 resolution

on the Orbitrap analyzer. The signal was integrated for 30 s across

the “plug” profile of the eluting samples using the Xcalibur soft-

ware package (ThermoElectron, San Jose, CA) to obtain the

accurate mass values of the samples.

Reference compounds were obtained using previously dis-

closed synthetic procedures: 2-[2-methyl-4-([4-methyl-2-[4-(tri-

fluoromethyl)phenyl)-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]-

acetic acid (GW501516);⁴¹[4-[3-(4-acetyl-3-hydroxy-2-propyl-

phenoxy)propoxy]phenoxy]acetic acid (L165041);⁷³5-[2,4-di-

oxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)-

phenyl]methyl]benzamide (KRP297).⁷⁴(RS)-5-[4-(2-[Methyl-

(pyridin-2-yl)amino]ethoxy)benzyl]thiazolidine-2,4-dione (Rosi-

glitazone) was obtainedbyextraction (aqueous NaHCO₃, EtOH)

from commercially available Avandia tablets (Pharmaceutical

Buyers International Inc.).

2-Bromo-1,2-bis(4-methoxyphenyl)ethanone (3). To a solution

of desoxyanisoin 2 (10 g, 39.0 mmol) in anhydrous CHCl₃

(200 mL) was added bromine (2.4 mL, 46.8 mmol) dropwise.

After the addition was complete (indicated by a color change to

red), the solvent was removed in vacuo, the remainder was

triturated with diethyl ether, and the precipitated product was

filtered to give 3 (11.5 g, 88%) as a white solid: ¹H NMR

(400 MHz, CD₃OD) δ = 7.98 (d, J = 9.0 Hz, 2H), 7.35 (d,

J = 8.7 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 8.7 Hz,

2H), 5.72 (s, 1H), 3.83 (s, 3H), 3.75 (s, 3H). MS m/z 255.4

[M þ H]^þ.

Experimental Section

4,5-Bis(4-methoxyphenyl)-3H-thiazole-2-thione (4). 2-Bromo-

1,2-bis(4-methoxyphenyl)ethanone 3 (3.0 g, 8.9 mmol) and

ammonium dithiocarbamate (1.5 g, 13.4 mmol, prepared ac-

cording to WO 9837074) were dissolved in EtOH (50 mL) and

heated to 60 ꢀC for 3 h. The solvent was then partially removed

in vacuo and the precipitate filtered and recrystallized from

EtOH to yield 4 (2.8 g, 96%) as a white solid: ¹H NMR

(400 MHz, CD₃OD) δ = 7.26 (d, J = 8.8 Hz, 2H), 7.11 (d,

J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz,

2H), 3.81 (s, 3H), 3.77 (s, 3H). MS m/z 330.2 [M þ H]^þ.

[4-(2-Bromoethoxy)-2-methylphenoxy]acetic Acid Methyl Ester

(5a). (4-Hydroxy-2-methylphenoxy)acetic acid methyl ester

(50, 0.5 g, 2.8 mmol), 1,2-dibromoethane (2.4 mL, 27.7 mmol),

and Cs₂CO₃(4.5 g, 13.9 mmol) were suspended in dry acetone.

The mixture was heated to reflux overnight. The reaction mixture

was cooled to room temperature and filtered, and the solvent was

removed in vacuo. The remainder was purified by chromatography

(silica, DCM/MeOH gradient) to afford 5a (0.7 g, 82%) as a white

solid: ¹H NMR (400 MHz, CDCl₃) δ = 6.77 (s, 1H), 6.66 (m, 2H),

4.60 (s, 2H), 4.23 (t, J = 7.6 Hz, 2H), 3.80 (s, 3H), 3.60 (t, J =

7.6 Hz, 2H), 2.27 (s, 3H). MS m/z 303.2 [M þ H]^þ.

Chemistry. Nuclear magnetic resonance (¹H NMR) spectra

were obtained with a Bruker Avance spectrometer operating at

400 MHz with a QNP 5 mm probe. Chemical shifts are given in

parts per million (δ, ppm) and are referenced to the solvent in

which they were run. Microwave reactions were performed in an

Emrys optimizer (Biotage AB). Wattage was automatically

adjusted to maintain the desired temperature. Flash column

chromatography was performed using silica gel (Merck grade

˚

9385, 230-400 mesh, 60 A (Aldrich)) or on an ISCO Combiflash

system Sg100c using Redisep normal phase disposable columns

(Teledyne ISCO, Lincoln NE). For compound elution, a gra-

dient of either MeOH/DCM or EtOAc/hexanes was used as the

mobile phase. Preparative reverse phase high pressure liquid

chromatography (HPLC) was performed on an automated

Gilson HPLC system using an Ultro C18 Guard column,

50 mm ꢀ 50 mm i.d. (Peeke Scientific, Redwood City, CA)

and an XTerra Prep MS C18, 10 μm, 250 mm ꢀ 50 mm i.d., part

number 186001083 (Waters Corp., Milford, MA). A flow rate of

100 mL/min, λ = 220 nm, and a gradient of mobile phases

A (0.05% TFA in H₂O) and B (0.035% TFA in MeCN) were

used to purify selected compounds. The purity of final com-

pounds was assessed on the basis of analytical HPLC, and

the results were greater 95% unless specified otherwise

(Agilent 1100 HPLC stack and 1946 MSD mass spectrometer.

(4-{2-[4,5-Bis(4-methoxyphenyl)thiazol-2-ylsulfanyl]ethoxy}-

2-methylphenoxy)acetic Acid (7a). [4-(2-Bromoethoxy)-2-methyl-

phenoxy]acetic acidmethyl ester 5a (91 mg, 0.30 mmol) was added

dropwise to a solution of NaOMe (23 mg, 0.33 mmol) and

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 91

intermediate 4 in EtOH (5 mL). After the mixture was stirred at

room temperature for 24 h the solvent was removed in vacuo to

afford crude (4-{2-[4,5-bis(4-methoxyphenyl)thiazol-2-ylsulfanyl]-

ethoxy}-2-methylphenoxy)acetic acid methyl ester, which was

dissolved in THF (3 mL). A solution of 1 M LiOH in H₂O

(0.6 mL) was added, and the mixture was stirred overnight at

room temperature. Then the mixture was acidified with 1 M HCl,

EtOAc (10 mL) was added, and the organic layer was washed with

H₂O (3 ꢀ 5 mL). The organic layer was dried (MgSO₄), filtered,

concentrated, and purified on reverse phase HPLC to afford 7a

(115 mg, 77%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ=

7.34 (d, J = 8.9 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 6.88 (d, J =

8.9 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 6.73-6.64 (m, 3H), 4.56 (s,

2H), 4.29 (t, J = 6.4 Hz), 3.79 (s, 3H), 3.78 (s, 3H), 3.57 (t, J =

6.4 Hz, 2H), 2.18 (s, 3H). MS m/z 538.4 [M þ H]^þ. HRMS calcd

for C₂₈H₂₈NO₆S₂[M þ H]^þ538.1353; found 538.1344.

to reflux in acetone (20 mL) for 8 h. The mixture was cooled,

diluted with H₂O (50 mL), extracted with EtOAc (3 ꢀ 50 mL),

and washed with brine (30 mL). The organic layer was dried

(MgSO₄), filtered, and concentrated to give crude 1,2-bis-

(4-methoxyphenyl)-2-thiocyanatoethanone, which was dis-

solved in EtOAc (100 mL). Then HCl gas was bubbled through

the solution for 2 h. The mixture was neutralized with aqueous

NaOH to pH 6, extracted with EtOAc (3 ꢀ 50 mL), and washed

sequentially with H₂O (30 mL) and brine (30 mL). The organic

layer was dried (MgSO₄), filtered, concentrated, and purified

by flash column chromatography (silica, EtOAc/hexane

gradient) to afford 11 (230 mg, 50%) as a white solid: ¹H

NMR (400 MHz, CDCl₃) δ = 7.42 (d, J = 9.0 Hz, 2H), 7.25 (d,

J = 9.3 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 9.3 Hz,

2H), 3.83 (s, 3H), 3.80 (s, 3H). MS m/z 332.3 [M þ H]^þ.

{4-[4,5-Bis(4-methoxyphenyl)thiazol-2-ylsulfanyl]-2-methyl-

phenoxy}acetic Acid (12). 52 (28 mg, 0.131 mmol), intermediate

11 (40 mg, 0.131 mmol), and NaOEt (18 mg, 0.262 mmol) were

dissolved in EtOH (1 mL) and heated to reflux for 6 h. The

mixture was acidified with aqueous 1 N HCl (1 mL) and

extracted with EtOAc (2 ꢀ 4 mL). The organic layer was

separated, dried (MgSO₄), filtered, and concentrated to pro-

vide crude {4-[4,5-bis(4-methoxyphenyl)thiazol-2-ylsulfanyl]-

2-methylphenoxy}acetic acid ethyl ester, which was then dis-

solved in THF (1 mL) and 1 N LiOH (200 μL) and stirred at

room temperature for 2 h. The mixture was acidified with

aqueous HCl, extracted with EtOAc (2 ꢀ 4 mL), dried

(MgSO₄), filtered, concentrated, and purified on reverse phase

Compounds 7b-10 were prepared following the synthetic

procedure of 7a using the appropriate headgroups 50-55 and

dibromoalkanes.

2-(4-(3-(4,5-Bis(4-methoxyphenyl)thiazol-2-ylthio)propoxy)-

2-methylphenoxy)acetic Acid (7b). H NMR (400 MHz, CD₃-

1

OD) δ = 7.34 (d, J = 8.9 Hz, 2H), 7.14 (d, J = 8.9 Hz, 2H),

6.87 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 6.73-6.63

(m, 3H), 4.55 (s, 2H), 4.06 (t, J = 5.9 Hz, 2H), 3.79 (s, 3H), 3.78

(s, 3H), 3.42 (t, J = 7.0 Hz, 2H), 2.23 (m, 2H), 2.18 (s, 3H). MS

m/z 552.4 [M þ H]^þ. HRMS calcd for C₂₉H₃₀NO₆S₂[M þ H]^þ

552.1509; found 552.1508.

2-(4-(4-(4,5-Bis(4-methoxyphenyl)thiazol-2-ylthio)butoxy)-2-

methylphenoxy)acetic Acid (7c). ¹H NMR (400 MHz, CD₃OD)

δ = 7.34 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 6.87 (d,

J = 8.9 Hz, 2H), 6.80 (d, J = 8.9 Hz, 2H), 6.72-6.61 (m, 3H),

4.56 (s, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.79 (s, 3H), 3.77 (s, 3H),

3.31 (t, J = 7.2 Hz, 2H), 2.19 (s, 3H), 2.01-1.89 (m, 4H). MS

m/z 566.4 [M þ H]^þ. HRMS calcd for C₃₀H₃₂NO₆S₂[M þ H]^þ

566.1666; found 566.1669.

1

HPLC to afford 12 (12 mg, 18%) as a white solid: H NMR

(400 MHz, CDCl₃) δ = 7.45 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H),

7.33 (d, 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.70 (m, 5H), 4.65

(s, 2H), 3.71 (s, 3H), 3.69 (s, 3H), 2.22 (s, 3H). MS m/z 494.4

[M þ H]^þ. HRMS calcd for C₂₆H₂₄NO₅S₂[M þ H]^þ494.1091;

found 494.1089.

2-(4-(4,5-Bis(4-methoxyphenyl)thiazol-2-ylthio)-3-chlorophenyl)-

acetic Acid (13). The compound was prepared according to the

procedure for 12 starting with 53 instead of 52.¹H NMR (400 MHz,

CDCl₃) δ = 7.59 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.37 (d, J =

8.8 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.80

(d, J = 8.4 Hz, 4H), 3.77 (s, 6H), 3.64 (s, 2H). MS m/z 498.3

[M þ H]^þ. HRMS calcd for C₂₆H₂₄NO₅S₂[M þ H]^þ498.0595;

found 498.0595.

2-(4-(2-(4,5-Bis(4-methoxyphenyl)thiazol-2-ylthio)ethoxy)-3-

chlorophenyl)acetic Acid (8a). H NMR (400 MHz, CD₃OD)

1

δ = 7.37-6.82 (m, 11H), 4.42 (t, J = 6.4 Hz, 2H), 3.79 (s, 3H),

3.78 (s, 3H), 3.66 (t, J = 6.4 Hz, 2H), 3.50 (s, 2H). MS m/z

542.3 [M þ H]^þ. HRMS calcd for C₂₇H₂₅ClNO₅S₂[M þ H]^þ

542.0857; found 542.0855.

2-(4-(3-(4,5-Bis(4-methoxyphenyl)thiazol-2-ylthio)propoxy)-

3-chlorophenyl)acetic Acid (8b). ¹H NMR (400 MHz, CD₃OD)

δ = 7.35-6.80 (m, 11H), 4.19 (t, J = 5.8 Hz, 2H), 3.79 (s, 3H),

3.77 (s, 3H), 3.55 (s, 2H), 3.47 (t, J = 7.0 Hz, 2H), 2.30 (m, 2H).

MS m/z 556.4 [M þ H]^þ. HRMS calcd for C₂₈H₂₇ClNO₅S₂

[M þ H]^þ556.1014; found 556.1020.

[4,5-Bis(4-methoxyphenyl)thiazol-2-yl]methanol (14). A solu-

tion of 2-bromo-1,2-bis(4-methoxyphenyl)ethanone 3 (3.0 g, 9.0

mmol) and ethyl thiooxamate (1.2 g, 9.0 mmol) in anhydrous

EtOH (20 mL) was heated to reflux for 12 h. The solvent was

removed in vacuo and the remainder was purified by flash

column chromatography (silica, EtOAc/hexane gradient) to

afford 4,5-bis(4-methoxyphenyl)thiazole-2-carboxylic acid eth-

2-(4-(4-(4,5-Bis(4-methoxyphenyl)thiazol-2-ylthio)butoxy)-

3-chlorophenyl)acetic Acid (8c). ¹H NMR (400 MHz, CD₃-

OD) δ = 7.36-6.80 (m, 11H), 4.10 (t, J = 5.7 Hz, 2H), 3.80

(s, 3H), 3.78 (s, 3H), 3.51 (s, 2H), 3.36 (t, J = 7.1 Hz, 2H),

2.08-1.98 (m, 4H). MS m/z 570.4 [M þ H]^þ. HRMS calcd for

1

yl ester (2.7 g, 81%) as a colorless wax: H NMR (400 MHz,

CD₃OD) δ = 7.39 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H),

6.92 (d, J = 8.9 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.45 (q, J =

7.1, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). MS

m/z 370.4 [M þ H]^þ.

C

₂₉H₂₉ClNO₅S₂[M þ H]^þ570.1170; found 570.1182.

{4-[4,5-Bis(4-methoxyphenyl)thiazol-2-ylsulfanylmethyl]-2-

methylphenoxy}acetic Acid (9). ¹H NMR (400 MHz, CDCl₃)

δ = 7.44 (d, J = 8.8 Hz, 2H), 7.24-7.18 (m, 4H), 6.86-6.80

(m, 4H), 6.66 (d, J = 8.4 Hz, 1H), 5.30 (s, 2H), 4.67 (s, 2H),

3.81 (s, 3H), 3.80 (s, 3H), 2,27 (s, 3H). MS m/z 508.1 [M þ H]^þ.

HRMS calcd for C₂₇H₂₆NO₅S₂[M þ H]^þ508.1247; found

508.1249.

4,5-Bis(4-methoxyphenyl)thiazole-2-carboxylic acid ethyl es-

ter (1.0 g, 2.7 mmol) was dissolved in dry THF (20 mL) and

cooled to 0 ꢀC. A solution of 1 M lithium aluminum hydride in

THF (4 mL, 4.1 mmol) was added dropwise via cannula, and the

mixture was stirred at 0 ꢀC for 1 h. Sodium sulfate decahydrate

(1.3 g, 4.1 mmol) was added slowly, and the mixture was stirred

an additional 1 h at room temperature. The suspension was then

filtered over Celite, dried (MgSO₄), and concentrated. The

concentrate was purified by flash column chromatography

(silica, EtOAc/hexane gradient) to yield 14 (0.7 g, 79%) as a

yellow oil: ¹H NMR (400 MHz, CD₃OD) δ = 7.34 (d, J = 8.8

Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.84

(d, J = 8.8 Hz, 2H), 3.96 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H). MS

m/z 328.4 [M þ H]^þ.

2-(4-((4,5-Bis(4-methoxyphenyl)thiazol-2-ylthio)methyl)-3-

chlorophenyl)acetic Acid (10). H NMR (400 MHz, CDCl₃)

1

δ = 7.51-7.45 (m, 3H), 7.35 (d, J = 1.2 Hz, 1H), 7.22 (s, 1H),

7.20 (s, 1H), 7.13 (dd, J = 1.2 Hz, J = 8.0 Hz, 1H), 4.57

(s, 2H), 3.802 (s, 3H), 3.809 (s, 3H), 3.62 (s, 2H). MS m/z

512.0 [M þ H]^þ. HRMS calcd for C₂₆H₂₃ClNO₄S₂[M þ H]^þ

512.0752; found 512.0752.

2-Chloro-4,5-bis(4-methoxyphenyl)thiazole (11). 2-Bromo-

1,2-bis(4-methoxyphenyl)ethanone 3 (500 mg, 1.49 mmol)

and potassium rhodanide (145 mg, 1.49 mmol) were heated

2-Hydroxymethyl-4,5-bis(4-methoxyphenyl)oxazole (15). A

mixture of anisoin (1.00 g, 3.49 mmol), bromoacetic acid

92 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Epple et al.

(0.53 g, 3.84 mmol), 1,3-dicyclohexycarbodiimide (0.88 g,

4.23 mmol), DMAP (21.5 mg, 0.17 mmol), and DCM

(25 mL) was stirred for 16 h at room temperature under

nitrogen. Then the mixture was filtered, concentrated, and

purified by flash column chromatography (silica, EtOAc/

hexane gradient) to give bromoacetic acid 1,2-bis(4-methoxy-

phenyl)-2-oxoethyl ester (1.02 g, 74%) as a slightly yellow

solid: ¹H NMR (400 MHz, CDCl₃) δ = 7.89 (d, J = 8.4 Hz,

2H), 7.37 (d, J = 8.8 Hz, 2H), 6.90-6.84 (m, 5H), 4.03-3.96

(m, 2H), 3.82 (s, 3H), 3.77 (s, 3H). MS m/z 393.2 [M þ H]^þ.

A solution of the previously prepared ester (393 mg,

1.00 mmol) and NH₄OAc (384 mg, 5.0 mmol) in AcOH

(6 mL) was heated to reflux for 90 min. The mixture was poured

into H₂O (15 mL) and extracted with DCM (30 mL). The

organic layer was dried (MgSO₄), filtered, and purified by flash

chromatography (silica, EtOAc/hexane gradient) to afford

2-(bromomethyl)-4,5-bis(4-methoxyphenyl)oxazole (283 mg,

76%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ =

7.58-7.50 (m, 4H), 6.90 (d, J = 8.0 Hz, 4H), 5.22 (s, 2H),

3.83 (s, 6H). MS m/z 374.1 [M þ H]^þ.

MS m/z 476.1 [M þ H]^þ. HRMS calcd for C₂₇H₂₆NO₇

[M þ H]^þ476.1704; found 476.1701.

2-(4-((4,5-Bis(4-methoxyphenyl)oxazol-2-yl)methylthio)-3-

chlorophenyl)acetic acid (21). H NMR (400 MHz, CD₃OD)

1

δ = 7.47 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.30 (d,

J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 7.12 (dd, J =

2.0 Hz, J = 8.0 Hz, 1H), 6.79-6.85 (m, 4H), 4.21 (s, 2H), 3.72

(s, 6H), 3.52 (s, 2H). MS m/z 496.0 [M þ H]^þ. HRMS calcd for

C

₂₆H₂₃ClNO₅S [M þ H]^þ496.0980; found 496.0981.

2-(4-((4,5-Bis(4-methoxyphenyl)oxazol-2-yl)methylthio)-2-

1

methylphenoxy)acetic Acid (22). H NMR (400 MHz, CD₃-

OD) δ = 7.29 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H),

7.18 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 6.86-6.81 (m, 4H), 6.67

(d, J = 8.4 Hz, 1H), 4.58 (s, 2H), 4.01 (s, 2H), 3.73 (s, 6H),

2.01 (s, 3H). MS m/z 492.1 [M þ H]^þ. HRMS calcd for

C

₂₇H₂₆NO₆S [M þ H]^þ492.1476; found 492.1472.

(2-Methyl-4-thiocarbamoylmethoxyphenoxy)acetic Acid Methyl

Ester (23). 50 (1.64 g, 8.3 mmol) and chloroacetonitrile (0.55 mL,

8.7 mmol) were dissolved in MeCN (30 mL). Cs₂CO₃(5.4 g,

16.7 mmol) was added, and the mixture was stirred for 2 h at room

temperature. Insoluble salts were filtered and washed with EtOAc.

Then the filtrate was concentrated to give an oil which crystallized

under vacuum to give (4-cyanomethoxy-2-methylphenoxy)acetic

A mixture of the bromomethyl intermediate (75.0 mg,

0.20 mmol), K₂CO₃(110.4 mg, 0.80 mmol), and MeCN

(5 mL) was heated to reflux for 2 h. The mixture was diluted

with H₂O, then extracted with EtOAc (50 mL). The organic

layer was dried (MgSO₄), filtered, and concentrated to give 15

(50 mg, 80%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ =

7.49 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 6.84 (d, J =

5.2 Hz, 1H), 6.82 (d, J = 5.2 Hz, 2H), 4.72 (s, 2H), 3.77 (s, 6H).

MS m/z 312.1 [M þ H]^þ.

1

acid methyl ester (1.84 g, 94%) as a pale-yellow solid: H NMR

(400 MHz, CDCl₃) δ = 6.76 (s, 1H), 6.67 (s, 1H), 6.60 (d, J =

8.5 Hz, 1H), 4.62 (s, 2H), 4.54 (s, 2H), 3.73 (s, 3H), 2.21 (s, 3H).

MS m/z 236.3 [M þ H]^þ.

(4-Cyanomethoxy-2-methylphenoxy)acetic acid methyl ester

(1.75 g, 7.45 mmol) and thioacetamide (1.12 g, 14.9 mmol)

were dissolved in DMF (120 mL). A 4 M HCl solution and

1,4-dioxane (20 mL) was added, and the mixture was stirred at

100 ꢀC overnight. The mixture was diluted with saturated

NaHCO₃, extracted with EtOAc, and washed subsequently with

H₂O (4 ꢀ 100 mL) and brine (100 mL). The organic layer was

dried (MgSO₄), filtered, and concentrated. The residue was

triturated with DCM (5 mL) and hexanes (5 mL) and collected

by filtration to afford 23 (1.24 g, 62%) as a beige solid: ¹H NMR

(400 MHz, DMSO-d₆) δ = 6.84 (d, J = 2.9 Hz, 1H), 6.78 (d,

J = 8.9 Hz, 1H), 6.71 (dd, J = 3.0, 8.9 Hz, 1H), 4.75 (s, 2H), 4.67

(s, 2H), 4.04 (s, 1H), 3.69 (s, 3H), 2.18 (s, 3H). MS m/z 270.3

[M þ H]^þ.

{4-[4,5-Bis(4-methoxyphenyl)thiazol-2-ylmethoxy]-2-methyl-

phenoxy}acetic Acid (16). Intermediate 14 (25 mg, 0.08 mmol),

50 (18 mg, 0.09 mmol), and triphenylphosphine (30 mg,

0.11 mmol) were dissolved in dry DCM (1 mL) and cooled to

0 ꢀC. Diethyl azodicarboxylate (24 μL, 0.15 mmol) was added

slowly, and the solution was stirred at room temperature

overnight. The solvent was removed in vacuo, and the residue

was dissolved in THF (1 mL). Then a solution of 1 M LiOH in

H₂O (0.2 mL) was added and the mixture was stirred at room

temperature for 2 h. The mixture was acidified with 1 M HCl

and extracted with EtOAc (10 mL). The organic layer was

washed with H₂O (5 mL), dried (MgSO₄), filtered, concen-

trated, and purified on reverse phase HPLC to afford 16

(23 mg, 63%) as a colorless glass: ¹H NMR (400 MHz,

CD₃OD) δ = 7.36 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.8 Hz,

2H), 6.91-6.75 (m, 7H), 5.30 (s, 2H), 4.62 (s, 2H), 3.79 (s, 3H),

3.78 (s, 3H), 2.25 (s, 3H). MS m/z 492.4 [M þ H]^þ. HRMS calcd

for C₂₇H₂₆NO₆S [M þ H]^þ492.1476; found 492.1474.

Compounds 17-22 were prepared following the synthetic

procedure of 16 using the appropriate headgroups 50-55 and

intermediate 14 or 15.

General Procedures to Intermediate 24. Method A: From

Aldehyde (R¹= R²), Exemplified by 2-Bromo-1,2-bis(4-chloro-

phenyl)ethanone. 4-Chlorobenzaldehyde (0.57 g, 2.04 mmol)

was dissolved in EtOH (8 mL). A solution of KCN (18.0 mg,

0.27 mmol) in H₂O (4 mL) was added and the mixture was

heated at reflux for 7 h, then cooled, extracted with EtOAc

(50 mL), dried (MgSO₄), filtered, concentrated, and purified by

flash column chromatography (diethyl ether/hexane gradient)

to give 1,2-bis(4-chlorophenyl)-2-hydroxyethanone (0.57 g,

1

2-(4-((4,5-Bis(4-methoxyphenyl)thiazol-2-yl)methoxy)-3-chloro-

phenyl)acetic Acid (17). ¹H NMR (400 MHz, CDCl₃) δ =

7.74-6.80 (m, 11H), 5.43 (s, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.57

(s, 2H). MS m/z 496.3 [M þ H]^þ. HRMS calcd for C₂₆H₂₃ClNO₅S

[M þ H]^þ496.0980; found 496.0981.

81%): H NMR (400 MHz, CDCl₃) δ = 7.83 (m, 2H), 7.39

(m, 2H), 7.31 (m, 2H), 7.25 (m, 2H), 5.88 (s, 1H), 4.50 (bro. 1H).

MS m/z 262.9 [M - OH]^þ.

To a solution of 2,3-dichloro-5,6-dicyanobenzoquinone

(242 mg, 1.07 mmol) and triphenylphosphine (280 mg, 1.07 mmol)

in DCM (5 mL) was added tetrabutylammonium bromide (344 mg

(1.07 mmol) and 1,2-bis(4-chlorophenyl)-2-hydroxyethanone

(200 mg, 0.71 mmol). The solution was stirred for 1.5 h at room

temperature, then concentrated and purified by flash column

chromatography (silica, EtOAc/hexane gradient) to give 2-bromo-

1,2-bis(4-chlorophenyl)ethanone (85 mg, 0.25 mmol, 35%)

2-(4-((4,5-Bis(4-methoxyphenyl)thiazol-2-yl)methylthio)-2-

methylphenoxy)acetic Acid (18). ¹H NMR (400 MHz, CDCl₃)

δ = 7.74-6.63 (m, 11H), 4.62 (s, 2H), 4.35 (s, 2H), 3.80

(s, 3H), 3.77 (s, 3H), 2.23 (s, 3H). MS m/z 508.4 [M þ H]^þ.

HRMS calcd for C₂₇H₂₆NO₅S₂[M þ H]^þ508.1247; found

508.1241.

1

2-(4-((4,5-Bis(4-methoxyphenyl)thiazol-2-yl)methylthio)-3-

chlorophenyl)acetic Acid (19). H NMR (400 MHz, CDCl₃)

as a colorless oil: H NMR (400 MHz, CDCl₃) δ = 7.86 (d,

1

J = 8.8 Hz, 2H), 7.40-7.35 (m, 4H), 7.29 (d, J = 8.4 Hz, 2H),

δ = 7.74-6.78 (m, 11H), 4.51 (s, 2H), 3.79 (s, 3H), 3.79

6.17 (s, 1H). MS m/z 343.0 [M þ H]^þ.

(s, 3H), 3.58 (s, 2H). MS m/z 512.3 [M þ H]^þ. HRMS calcd for

Method B: From Aldehyde (R¹¼ R²), Exemplified by 2-Bromo-

1-(4-chlorophenyl)-2-phenylethanone. 4-Chlorobenzaldehyde (4.2 g,

30.4 mmol) and trimethylsilyl cyanide (3.0 g, 30.4 mmol) were

dissolved in DCM (50 mL). The solution was cooled to 0 ꢀC, and

then zinc iodide (43 mg, 1.13 mmol) was added. The reaction

mixture was warmed to room temperature and stirred for 16 h at

C

₂₆H₂₃ClNO₄S₂[M þ H]^þ512.0752; found 512.0756.

{4-[4,5-Bis(4-methoxyphenyl)oxazol-2-ylmethoxy]-2-methyl-

phenoxy}acetic Acid (20). ¹H NMR (400 MHz, CD₃OD) δ =

7.40-7.37 (m, 4H), 6.81-6.87 (m, 5H), 6.74-6.66 (m, 2H),

5.04 (s, 2H), 4.52 (s, 2H), 3.73 (s, 3H), 3.72 (s, 3H), 2.16 (s, 3H).

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 93

room temperature. Then it was concentrated, suspended in

diethyl ether, and filtered through activated charcoal. The

filtrate was dried (MgSO₄) and concentrated to give (4-chloro-

phenyl)trimethylsilanyloxyacetonitrile (6.6 g, 90%): MS m/z

214.1 [M - CN]^þ.

temperature for 1 h. The mixture was poured into H₂O (5 mL),

extracted with DCM (10 mL), dried (MgSO₄), concentrated, and

purified by flash column chromatography (silica, EtOAc/hexane

gradient) to give 2-bromo-3-oxo-3,N-diphenylpropionamide

1

(270 mg, 76%) as a white solid: H NMR (400 MHz, CDCl₃)

(4-Chlorophenyl)trimethylsilanyloxyacetonitrile (906 mg,

3.78 mmol) was dissolved in THF (8 mL) and added dropwise

into a solution of 2 M LDA (1.89 mL, 3.78 mmol) in THF (4 mL)

at -78 ꢀC. The reaction mixture was stirred for 30 min followed

by addition a solution of benzyl bromide (0.65 g, 3.78 mmol) in

THF (2 mL) at -78 ꢀC. The mixture was allowed to warm to

room temperature and stirred for 18 h. Then it was diluted with

H₂O (10 mL) and extracted with EtOAc (2 ꢀ 30 mL). The

combined organic layers were washed with brine, dried

(MgSO₄), and concentrated. The residue was dissolved in

MeOH (10 mL), 1 M H₂SO₄(4 mL) was added, and the mixture

was stirred at room temperature for 12 h. Then the pH of the

mixture was adjusted to 10 by adding 1 N NaOH, followed by

extraction with EtOAc (3 ꢀ 20 mL). The organic layers were

combined, washed with H₂O (10 mL) and brine (10 mL), dried

(MgSO₄), filtered, and concentrated to give 1-(4-chlorophenyl)-

δ =8.78 (s, 1H), 8.06 (d, J = 8.6 Hz, 2H), 7.67 (t, J =7.4Hz, 1H),

7.54 (m, 4H), 7.37 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H),

7.17 (t, J = 7.4 Hz, 1H), 5.70 (s, 1H). MS m/z 318.2 [M þ H]^þ.

(2-Methyl-4-thiocarbamoylmethoxyphenoxy)acetic acid methyl

ester 23 (63 mg, 0.234 mmol) and 2-bromo-3-oxo-3,N-diphenyl-

propionamide (78 mg, 0.245 mmol) were dissolved in a mixture of

EtOH (2 mL) and piperidine (4 μL). The reaction mixture was

subjected to microwave irradiation (180 ꢀC) for 3 min. The mixture

was diluted with H₂O (5 mL), extracted with EtOAc (8 mL), and

washed with brine (5 mL). The organic layer was dried (MgSO₄),

filtered, concentrated, and purified on reverse phase HPLC to give

the [2-methyl-4-(5-phenylbenzooxazol-2-ylmethoxy)phenoxy]acetic

acid methyl ester. The ester was dissolved in THF (1 mL). Then 1 N

LiOH (200 μL) was added and the mixture was stirred at room

temperature for 2 h. Then it was acidified with 1 M HCl, extracted

with EtOAc (10 mL), dried (MgSO₄), filtered, concentrated, and

purified on reverse phase HPLC to afford 25c (14 mg, 12%) as

1

2-phenylethanone. H NMR (400 MHz, CDCl₃) δ = 7.95 (d,

J = 8.8 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.33 (m, 2H), 7.25 (m,

1

a yellow solid: H NMR (400 MHz, DMSO) δ = 6.89 (s, 1H),

3H), 4.26 (s, 2H). MS m/z 231.1 [M þ H]^þ.

6.79 (d, J = 2.8 Hz, 1H), 6.68 (m, 4H), 5.70 (m, 6H), 5.51 (s, 2H),

5.21 (s, 2H), 4.56 (s, 2H), 4.54 (s, 2H), 2.11 (s, 3H), 2.09 (s, 3H). MS

m/z 475.3 [M þ H]^þ. HRMS calcd for C₂₆H₂₃N₂O₅S [M þ H]^þ

475.1322; found 475.1322.

1-(4-Chlorophenyl)-2-phenylethanone (100 mg, 0.4 mmol)

and pyridinium tribromide (126 mg, 0.4 mmol) were dissolved

in DCM (2 mL) and stirred at room temperature for 1 h. The

solution was concentrated to give 2-bromo-1-(4-chlorophenyl)-

[4-(4-Methoxy-5-phenylthiazol-2-ylmethoxy)-2-methylphenoxy]-

acetic Acid (25d, R = Me). (2-Methyl-4-thiocarbamoylmethoxy-

phenoxy)acetic acid methyl ester 23 (50 mg, 0.186 mmol) and

methyl R-bromophenyl acetate (44 μL, 0.278 mmol) were dissolved

in toluene (5 mL) and pyridine (60 μL, 0.742 mmol) and heated to

100 ꢀC for 12 h. The mixture was diluted with H₂O (10 mL),

extracted with EtOAc (10 mL), and washed with brine (10 mL).

The organic layer was dried (MgSO₄), filtered, concentrated, and

purified on reverse phase HPLC to afford [4-(4-hydroxy-5-phenyl-

thiazol-2-ylmethoxy)-2-methylphenoxy]acetic acid methyl ester

(27 mg, 40%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ =

7.66 (d, J = 7.6 Hz, 2H), 7.29 (m, 3H), 6.82 (d, J = 3.1 Hz, 1H),

6.71 (dd, J = 3.0, 8.6 Hz, 1H), 6.59 (d, J = 8.9 Hz, 1H), 5.16

(s, 2H), 4.52 (s, 2H), 3.71 (s, 3H), 2.21 (s, 3H). MS m/z 386.4

[M þ H]^þ.

1

2-phenylethanone. H NMR (400 MHz, CDCl₃) δ = 7.92 (d,

J = 8.4 Hz, 2H), 7.51 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.38 (s,

1H), 7.36 (m, 1H), 6.31 (s, 1H). MS m/z 308.0 [M þ H]^þ.

[2-Methyl-4-(4-phenylthiazol-2-ylmethoxy)phenoxy]acetic Acid

(25a, R²= H). 2-Bromo-1-phenylethanone (26 mg, 0.13 mmol)

and (2-methyl-4-thiocarbamoylmethoxyphenoxy)acetic acid

methyl ester 23 (34 mg, 0.13 mmol) were dissolved in EtOH

(1 mL) and subjectedto microwaveirradiation (180 ꢀC) for 5 min.

The mixture was concentrated, then dissolved in a mixture of

THF (1 mL) and H₂O (0.5 mL). LiOH H₂O (54 mg, 0.64 mmol)

3

was added. The mixture was stirred for 2 h at room temperature,

then acidified with 1 N HCl and extracted with EtOAc (5 mL).

The organic layer was dried (MgSO₄), filtered, concentrated, and

purified on reverse phase HPLC to afford [2-methyl-4-(4-phe-

nylthiazol-2-ylmethoxy)phenoxy]acetic acid 25a (35 mg, 76%):

¹H NMR (400 MHz, CDCl₃) δ = 7.81 (m, 2H), 7.45 (s, 1H), 7.38

(m, 2H), 7.30 (m, 1H), 6.83 (d, J = 2.9 Hz, 1H), 6.73 (dd, J = 3.1,

8.9 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 5.29 (s, 2H), 4.51 (s, 2H),

2.22 (s, 3H). MS m/z 356.4 [M þ H]^þ. HRMS calcd for

C₁₉H₁₈NO₄S [M þ H]^þ356.0951; found 356.0957.

[4-(4-Hydroxy-5-phenylthiazol-2-ylmethoxy)-2-methylphe-

noxy]acetic acid methyl ester (14 mg, 0.036 mmol), K₂CO₃

(15 mg, 0.109 mmol), and methyl iodide (5.7 μL, 0.091 mmol)

were stirred together in DMF (1 mL) at room temperature for

1 h. The mixture was diluted with H₂O (5 mL), extracted with

EtOAc (8 mL), and washed with H₂O (3 ꢀ 5 mL) and brine

(5 mL). The organic layer was dried (MgSO₄), filtered, and

concentrated to give crude [4-(4-methoxy-5-phenylthiazol-

2-ylmethoxy)-2-methylphenoxy]acetic acid methyl ester, which

was dissolved in THF (1 mL). Then 1 N LiOH (200 μL) was

added and the reaction mixture was stirred at room temperature

for 1 h. Then it was acidified with 1 M HCl, extracted with

EtOAc (10 mL), dried (MgSO₄), filtered, concentrated, and

purified on reverse phase HPLC to afford 25d (4 mg, 29%) as

[4-(4-Ethyl-5-phenylthiazol-2-ylmethoxy)-2-methylphenoxy]-

acetic Acid (25b, R¹= Ethyl). 1-Bromo-1-phenylbutan-2-one

(29 mg, 0.13 mmol) and (2-methyl-4-thiocarbamoylmethoxy-

phenoxy)acetic acid methyl ester 23 (34 mg, 0.13 mmol) were

dissolved in EtOH (1 mL) and subjected to microwave irradia-

tion (180 ꢀC) for 5 min. The mixture was concentrated, then

dissolved in a mixture of THF (1 mL) and H₂O (0.5 mL).

LiOH H₂O (54 mg, 0.64 mmol) was added. The mixture was

3

1

stirred for 2 h at room temperature, then acidified with 1 N HCl

and extracted with EtOAc (5 mL). The organic layer was dried

(MgSO₄), filtered, concentrated, and purified on reverse phase

HPLC to afford [4-(4-ethyl-5-phenylthiazol-2-ylmethoxy)-

2-methylphenoxy]acetic acid 25b (34 mg, 68%): ¹H NMR

(400 MHz, CD₃OD) δ = 7.27-7.23 (m, 2H), 7.18-7.14 (m,

3H), 6.83 (d, J = 2.4 Hz, 1H), 6.76-6.71 (m, 2H), 5.19 (s, 2H),

4.60 (s, 2H), 4.05 (s, 2H), 2.40 (s, 3H), 2.22 (s, 3H). MS m/z

384.1 [M þ H]^þ. HRMS calcd for C₂₁H₂₂NO₄S [M þ H]^þ

384.1264; found 384.1266.

a white solid: H NMR (400 MHz, DMSO) δ = 7.60 (d, J =

8.5 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 7.4 Hz, 1H),

6.82 (d, J = 2.8 Hz, 1H), 6.70 (dd, J = 3.0, 8.8 Hz, 1H), 6.63 (d,

J = 8.8 Hz, 1H), 5.14 (s, 2H), 4.57 (s, 2H), 4.03 (s, 3H), 2.22

(s, 3H). MS m/z 386.4 [M þ H]^þ. HRMS calcd for C₂₀H₂₀NO₅S

[M þ H]^þ386.1057; found 386.1060.

Compounds 25e-v were prepared following the synthetic

procedures of 25a,b using the appropriate intermediate 24.

[2-Methyl-4-(4-p-tolylthiazol-2-ylmethoxy)phenoxy]acetic Acid

(25e). ¹H NMR (600 MHz, (CD₃)₂SO) δ = 8.06 (d, J = 1.3 Hz,

1H), 7.85(d, J= 7.0 Hz, 2H), 7.26 (d, J= 7.0 Hz, 2H), 6.94 (s, 1H),

6.84 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.40 (s, 2H), 4.62

(s, 2H), 2.34 (s,3H), 2.18 (s, 3H). MS m/z 370.4 [M þ H]^þ. HRMS

calcd for C₂₀H₂₀NO₄S [M þ H]^þ370.1108; found 370.1114.

[2-Methyl-4-(4-phenyl-5-phenylcarbamoylthiazol-2-ylmethoxy)-

phenoxy]acetic Acid (25c, R = Ph). 2-Benzoylacetanilide (267 mg,

1.11 mmol) and N-bromosuccinimide (218 mg, 1.23 mmol) were

dissolved in carbon tetrachloride (5 mL) and stirred at room

94 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Epple et al.

2-(4-((4-(4-Methoxyphenyl)thiazol-2-yl)methoxy)-2-methyl-

phenoxy)acetic Acid (25f). H NMR (400 MHz, CDCl₃) δ =

6.91 (d, J = 3.2 Hz, 1H), 6.84-6.73 (m, 2H), 5.33 (s, 2H), 4.58

(s, 2H), 2.20 (s, 3H). MS m/z 584.2 [M þ H]^þ.

1

7.76 (d, J = 8.8 Hz, 2H), 7.32 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H),

6.84 (d, J = 2.9 Hz, 1H), 6.73 (dd, J = 3.0, 8.9 Hz, 1H), 6.65 (d,

J = 8.8 Hz, 1H), 5.30 (s, 2H), 4.53 (s, 2H), 3.81 (s, 3H), 2.24 (s,

3H). MS m/z 386.4 [M þ H]^þ. HRMS calcd for C₂₀H₂₀NO₅S

[M þ H]^þ386.1057; found 386.1063.

2-(4-((4,5-Bis(4-(trifluoromethyl)phenyl)thiazol-2-yl)methoxy)-

2-methylphenoxy)acetic Acid (25q). H NMR (400 MHz, CD₃-

1

OD) δ = 7.71 (d, J = 8.4 Hz, 2H), 7.65 (s, 4H), 7.56 (d, J =

8.4 Hz, 2H), 6.94 (d, J = 2.8 Hz, 1H), 6.87-6.77 (m, 2H), 5.39

(s, 2H), 4.63 (s, 2H), 2.27 (s, 3H). MS m/z 568.0 [M þ H]^þ. HRMS

calcd C₂₇H₂₀F₆NO₄S [M þ H]^þ568.1012; found 568.1011.

{4-[4,5-Bis(4-chlorophenyl)thiazol-2-ylmethoxy]-2-methylphe-

noxy}acetic Acid (25r). ¹H NMR (400 MHz, CD₃OD) δ = 7.45

(d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.34-7.30 (m, 4H),

6.91 (d, J = 2.8 Hz, 1H), 6.85-6.76 (m, 2H), 5.34 (s, 2H), 4.62

(s, 2H), 2.26 (s, 3H). MS m/z 501.0 [M þ H]^þ. HRMS calcd

C₂₅H₂₀Cl₂NO₄S [M þ H]^þ500.0485; found 500.0488.

{4-[4-(4-Chlorophenyl)thiazol-2-ylmethoxy]-2-methylphenoxy}-

acetic Acid (25g). ¹H NMR (600 MHz, (CD₃)₂SO) δ = 8.21 (s,

1H), 7.99 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 6.94 (d,

J = 3.0 Hz, 1H), 6.84 (dd, J = 3.0 Hz, J = 8.9 Hz, 1H), 6.77 (d,

J = 8.9 Hz, 1H), 5.41 (s, 2H), 4.62 (s, 2H), 2.18 (s, 3H). MS

m/z 390.3 [M þ H]^þ. HRMS calcd for C₁₉H₁₇ClNO₄S [M þ H]^þ

390.0562; found 390.0568.

[2-Methyl-4-(4-methyl-5-p-tolylthiazol-2-ylmethoxy)phenoxy]-

{4-[4-(4-Methoxyphenyl)-5-phenylthiazol-2-ylmethoxy]-2-

methylphenoxy}acetic Acid (25s). ¹H NMR (600 MHz, (CD₃)₂SO)

δ = 7.40-7.34 (m, 7H), 6.96 (d, J = 3.0 Hz, 1H), 6.87 (m, 3H),

6.78 (d, J = 8.9 Hz, 1H), 5.38 (s, 2H), 4.63 (s, 2H), 3.74 (s, 3H),

2.19 (s, 3H). MS m/z 462.4 [M þ H]^þ. HRMS calcd C₂₆H₂₄NO₅S

[M þ H]^þ462.1370; found 462.1372.

1

acetic Acid (25h). H NMR (400 MHz, DMSO-d₆) δ = 7.31-

7.20 (m, 4H), 6.85 (d, J = 2.8 Hz, 1H), 6.77-6.69 (m, 2H), 5.22

(s, 2H), 4.56 (s, 2H), 2.35 (s, 3H), 2.27 (s, 3H), 2.11 (s, 3H). MS

m/z 384.1 [M þ H]^þ. HRMS calcd for C₂₁H₂₂NO₄S [M þ H]^þ

384.1264; found 384.1267.

{4-[5-(4-Methoxyphenyl)-4-methylthiazol-2-ylmethoxy]-2-methyl-

{4-[5-(4-Methoxyphenyl)-4-phenylthiazol-2-ylmethoxy]-2-

methylphenoxy}acetic Acid (25t). ¹H NMR (600 MHz, (CD₃)₂SO)

δ = 7.47-7.26 (m, 7H), 6.95 (m, 3H), 6.87 (dd, J = 3.0 Hz, J =

8.9 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 5.38 (s, 2H), 4.63 (s, 2H),

3.77 (s, 3H), 2.19 (s, 3H). MS m/z 462.4 [M þ H]^þ. HRMS calcd

C₂₆H₂₄NO₅S [M þ H]^þ462.1370; found 462.1373.

1

phenoxy}acetic Acid (25i). H NMR (400 MHz, CDCl₃) δ =

7.35 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.43 (s,

1H), 3.82 (s, 3H), 2.31 (s, 3H). MS m/z 400.1 [M þ H]^þ.

HRMS calcd for C₂₁H₂₂NO₅S [M þ H]^þ400.1213; found

400.1217.

{4-[5-(4-Chlorophenyl)-4-methylthiazol-2-ylmethoxy]-2-methyl-

phenoxy}acetic Acid (25j). ¹H NMR (400 MHz, DMSO-d₆) δ =

7.48-7.43 (m, 4H), 6.86 (d, J = 2.8 Hz, 1H), 6.77-6.69 (m, 2H),

5.24 (s, 2H), 4.56 (s, 2H), 2.36 (s, 3H), 2.11 (s, 3H). MS m/z 404.0

[M þ H]^þ. HRMS calcd for C₂₀H₁₉ClNO₄S [M þ H]^þ404.0718;

found 404.0723.

{4-[4-(4-Chlorophenyl)-5-phenylthiazol-2-ylmethoxy]-2-methyl-

phenoxy}acetic Acid (25u). ¹H NMR (600 MHz, (CD₃)₂SO) δ =

7.46-7.31 (m, 9H), 6.96 (d, J = 3.0 Hz, 1H), 6.87 (dd, J = 3.0 Hz,

J = 8.9 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 5.40 (s, 2H), 4.63

(s, 2H), 2.19 (s, 3H). MS m/z 466.3 [M þ H]^þ. HRMS calcd

C₂₅H₂₁ClNO₄S [M þ H]^þ466.0875; found 466.0880.

[4-(4-Biphenyl-4-ylthiazol-2-ylmethoxy)-2-methylphenoxy]-

acetic Acid (25k). ¹H NMR (600 MHz, (CD₃)₂SO) δ = 8.20 (d,

J = 1.4 Hz, 1H), 7.99-8.07 (m, 2H), 7.78-7.72 (m. 4H),

7.50-7.48 (m, 2H), 7.40-7.38 (m, 1H), 6.96 (s, 1H), 6.86 (d,

J = 8.9 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 5.43 (s, 2H), 4.63 (s,

2H), 2.19 (s, 3H). MS m/z 432.4 [M þ H]^þ. HRMS calcd for

C₂₅H₂₂NO₄S [M þ H]^þ432.1264; found 432.1269.

{4-[5-(4-Chlorophenyl)-4-phenylthiazol-2-ylmethoxy]-2-methyl-

phenoxy}acetic Acid (25v). ¹H NMR (600 MHz, (CD₃)₂SO) δ =

7.47-7.30 (m, 9H), 6.96 (d, J = 3.0 Hz, 1H), 6.87 (dd, J = 3.0 Hz,

J = 8.9 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 5.40 (s, 2H), 4.64 (s,

2H), 2.19 (s, 3H). MS m/z 466.3 [M þ H]^þ. HRMS calcd

C₂₅H₂₁ClNO₄S [M þ H]^þ466.0875; found 466.0880.

General Procedures to Intermediate 26. Method A: X = S, Exem-

plified by 4-(4-Methoxyphenyl)-2-methylthiazole). 1-(4-Methoxy-

phenyl)ethanone (200 mg, 1.33 mmol) and pyridinium tribromide

(425 mg, 1.33 mmol) were dissolved in DCM (5 mL), and the

mixture was stirred for 1 h at room temperature. The mixture was

diluted with 1 N HCl (10 mL), extracted with DCM, and washed

with brine (10 mL). The organic layer was dried (MgSO₄), filtered,

and concentrated to give crude 2-bromo-1-(4-methoxyphenyl)-

{2-Methyl-4-[4-(4-trifluoromethylphenyl)thiazol-2-ylmethoxy]-

phenoxy}acetic Acid (25l). ¹H NMR (600 MHz, (CD₃)₂SO) δ =

8.37 (s, 1H), 8.18 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H),

6.94 (d, J = 3.0 Hz, 1H), 6.84 (dd, J = 3.0 Hz, J = 8.9 Hz, 1H),

6.76 (d, J = 8.9 Hz, 1H), 5.42 (s, 2H), 4.61 (s, 2H), 2.17 (s,

3H). MS m/z 424.3 [M þ H]^þ. HRMS calcd for C₂₀H₁₇F₃NO₄S

[M þ H]^þ424.0825; found 424.0829.

1

{2-Methyl-4-[5-methyl-4-(4-trifluoromethylphenyl)thiazol-2-

ylmethoxy]phenoxy}acetic Acid (25m). ¹H NMR (400 MHz,

DMSO-d₆) δ = 7.85 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz,

1H), 6.86 (d, J = 2.8 Hz, 1H), 6.76 (dd, J = 3.0, 8.9 Hz, 1H),

6.69 (d, J = 8.9 Hz, 1H), 5.27 (s, 2H), 4.56 (s, 2H), 2.95 (s, 3H),

2.11 (s, 3H). MS m/z 438.3 [M þ H]^þ. HRMS calcd for

C₂₁H₁₉F₃NO₄S [M þ H]^þ438.0982; found 438.0980.

[2-Methyl-4-(4-pyridin-3-yl-5-p-tolylthiazol-2-ylmethoxy)-

ethanone which was used without further purification. H NMR

(400 MHz, CDCl₃) δ = 7.97 (d, J = 9.2 Hz, 2H), 6.96 (d, J =

9.2 Hz, 2H), 4.40 (s, 2H), 3.89 (s, 3H). MS m/z 229.0 [M þ H]^þ.

2-Bromo-1-(4-methoxyphenyl)ethanone (25 g, 109 mmol)

and thioacetamide (9.0 g, 120 mmol) were dissolved in EtOH

(60 mL) and heated to reflux for 2 h. The solvent was removed in

vacuo to afford crude 4-(4-methoxyphenyl)-2-methylthiazole.

¹H NMR (400 MHz, CDCl₃) δ = 7.62 (d, J = 8.8 Hz, 2H), 6.99

(s, 1H), 6.76 (d, J = 8.8 Hz, 2H), 3.66 (s, 3H), 2.58 (s, 3H). MS

m/z 206.1 [M þ H]^þ.

1

phenoxy]acetic Acid (25n). H NMR (600 MHz, (CD₃)₂SO)

δ = 8.64 (d, J = 1.7 Hz, 1H), 8.54 (dd, J = 1.4 Hz, J = 4.8 Hz,

1H), 7.91 (d, J = 8.0 Hz), 7.47 (dd, J = 5.0 Hz, J = 7.9 Hz, 1H),

7.27 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.97 (d, J =

3.0 Hz, 1H), 6.87 (dd, J = 3.0 Hz, J = 8.9 Hz, 1H), 6.79 (d, J =

8.9 Hz, 1H), 5.41 (s, 2H), 4.64 (s, 2H), 2.34 (s, 3H), 2.19 (s, 3H).

MS m/z 447.4 [M þ H]^þ.

Method B: X = O, Exemplified by 4-(4-Methoxyphenyl)-2-

methyloxazole). 2-Bromo-1-(4-methoxyphenyl)ethanone (20.0 g,

87.3 mmol) and acetamide (15.5 g, 262.0 mmol) were heated to

150 ꢀC for 2 h. The mixture was cooled to room temperature,

diluted with EtOAc, and washed successively with saturated

NaHCO₃and brine. The organic layer was dried (MgSO₄), filtered,

concentrated, and purified by flash column chromatography

(silica, EtOAc/hexane gradient) to give 4-(4-methoxyphenyl)-2-

methyloxazole (10.3 g, 62%) as a white solid: ¹H NMR (400 MHz,

CDCl₃) δ = 7.65 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.85 (d, J =

8.8 Hz, 2H), 3.76 (s, 3H), 2.44 (s, 3H). MS m/z 190.1 [M þ H]^þ.

General Procedure to Intermediate 27 (X = S), Exemplified by

5-Bromo-2-(bromomethyl)-4-(4-methoxyphenyl)thiazole. 4-(4-

Methoxyphenyl)-2-methylthiazole (872 mg, 4.25 mmol) was

[4-(4,5-Diphenylthiazol-2-ylmethoxy)-2-methylphenoxy]acetic

Acid (25o). ¹H NMR (400 MHz, CDCl₃) δ = 7.40 (m, 2H), 7.23

(m, 8H), 6.82 (d, J = 2.9 Hz, 1H), 6.69 (dd, J = 3.0, 8.9 Hz, 1H),

6.61 (d, J = 8.9 Hz, 1H), 5.26 (s, 2H), 4.53 (s, 2H), 2.20 (s, 3H).

MS m/z 432.4 [M þ H]^þ. HRMS calcd C₂₅H₂₂NO₄S [M þ H]^þ

432.1264; found 432.1266.

2-(4-((4,5-Bis(4-biphenyl)thiazol-2-yl)methoxy)-2-methylphe-

noxy)acetic Acid (25p). ¹H NMR (400 MHz, CD₃OD) δ =

7.66-7.57 (m, 10H), 7.43-7.36 (m, 6H), 7.32-7.26 (m, 2H),

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 95

dissolved in DCM (10 mL). Then bromine (240 μL,

4.67 mmol) was added and the mixture was stirred at room

temperature for 2 h. The mixture was diluted with saturated

NaHCO₃, extracted with DCM, and washed with brine

(10 mL). The organic layer was dried (MgSO₄), filtered, and

concentrated to give 5-bromo-4-(4-methoxyphenyl)-2-methyl-

2-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (29b). ¹H

NMR (400 MHz, CDCl₃) δ = 7.48 (d, J = 8.2 Hz, 2H), 7.36

(d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 6.83 (d, J =

3.0 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.71 (dd, J = 3.0, 8.9

Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 5.26 (s, 2H), 4.56 (s, 2H),

3.74 (s, 3H), 2.21 (s, 3H). MS m/z 530.3 [M þ H]^þ. HRMS

calcd C₂₇H₂₃F₃NO₅S [M þ H]^þ530.1244; found 530.1244.

2-(4-((5-(3-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (29c).

¹H NMR (400 MHz, CDCl₃) δ = 7.61 (s, 1H), 7.56 (d, J =

7.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H),

7.38 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 2.8 Hz, 1H), 6.85 (d, J =

8.8 Hz, 2H), 6.78 (dd, J = 3.2, 8.8 Hz, 1H), 6.71 (d, J =

8.8 Hz, 1H), 5.37 (s, 2H), 4.64 (s, 2H), 3.82 (s, 3H), 2.29 (s,

3H). MS m/z 530.4 [M þ H]^þ. HRMS calcd C₂₇H₂₃F₃NO₅S

[M þ H]^þ530.1244; found 530.1241.

1

thiazole as a white solid (1.15 g, 96%): H NMR (400 MHz,

CDCl₃) δ = 7.89 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H),

3.85 (s, 3H), 3.26 (s, 3H). MS m/z 283.9 [M þ H]^þ.

N-Bromosuccinimide (69 mg, 0.39 mmol) was added to a

solution of 5-bromo-4-(4-methoxyphenyl)-2-methylthiazole

(100 mg, 0.35 mmol) in carbon tetrachloride (10 mL). The above

solution was stirred at room temperature for 15 h. Then the

mixture was washed successively with saturated aqueous

NaHCO₃and brine. The organic layer was dried (MgSO₄), filtered,

concentrated, and purified by flash column chromatography (silica,

EtOAc/hexane gradient) to give 5-bromo-2-(bromomethyl)-4-

(4-methoxyphenyl)thiazole (74 mg, 58%) as a white solid: ¹H

NMR (400 MHz, CDCl₃) δ = 7.78 (d, J = 8.8 Hz, 2H), 6.90 (d,

J = 8.8 Hz, 2H), 4.62 (s, 2H), 3.78 (s, 3H). MSm/z 361.8 [M þ H]^þ.

5-Bromo-2-(bromomethyl)-4-(4-methoxyphenyl)oxazole (27, X =

O). ¹H NMR (400 MHz, CDCl₃) δ = 7.87 (d, J = 8.8 Hz, 2H),

6.97 (d, J = 8.8 Hz, 2H), 4.46 (s, 2H), 3.85 (s, 3H). MS m/z 347.9

[M þ H]^þ.

2-(4-((5-(2-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (29d). ¹H

NMR (400 MHz, DMSO-d₆) δ = 7.93 (dd, J = 1.6, 8.8 Hz,

1H), 7.85 (m, 1H), 7.74 (m, 1H), 7.56 (dd, J = 1.6, 8.0 Hz,

1H), 7.27 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 2.8 Hz, 1H), 6.88

(dd, J = 3.2, 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.79 (d,

J = 8.8 Hz, 1H), 5.43 (s, 2H), 4.65 (s, 2H), 3.71 (s, 3H), 2.19 (s,

3H). MS m/z 530.2 [M þ H]^þ. HRMS calcd C₂₇H₂₃F₃NO₅S

[M þ H]^þ530.1244; found 530.1243.

General Procedure to Intermediate 28, Exemplified by Ethyl

2-(4-((5-Bromo-4-(4-methoxyphenyl)thiazol-2-yl)methoxy)-2-

methylphenoxy)acetate. A mixture of 5-bromo-2-bromo-

methyl-4-(4-methoxyphenyl)thiazole (2.87 g, 7.92 mmol), 50

(1.24 g of ethyl ester, 6.34 mmol), and Cs₂CO₃(3.01 g,

9.48 mmol) in MeCN (200 mL) was stirred at room tempera-

ture for 2 h. The mixture was filtered, then concentrated

and purified by flash column chromatography (silica,

EtOAc/hexane gradient) to give ethyl 2-(4-((5-bromo-4-(4-

methoxyphenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetate

(3.38 g, 86%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ =

7.80 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 6.92 (d, J =

8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 3.0 Hz, 1H),

6.67 (dd, J = 3.0, 8.9 Hz, 1H), 6.59 (d, J = 8.8 Hz, 1H), 5.20 (s,

2H), 4.51 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 2.22 (s,

3H), 1.20 (t, J = 7.2 Hz, 3H). MS m/z 492.2 [M þ H]^þ.

{4-[4-(4-Methoxyphenyl)-5-(4-trifluoromethoxyphenyl)thiazol-

2-ylmethoxy]-2-methylphenoxy}acetic Acid (29e). ¹H NMR

(400 MHz, CDCl₃) δ = 7.32 (d, J = 8.8 Hz, 2H), 7.28 (d, J =

8.7 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 6.82 (d, J = 2.9 Hz, 1H),

6.76 (d, J = 8.8 Hz, 2H), 6.71 (dd, J = 2.8, 8.8 Hz, 1H), 6.63 (d,

J = 8.9 Hz, 1H), 5.25 (s, 2H), 4.56 (s, 2H), 3.75 (s, 3H), 2.21

(s, 3H). MS m/z 530.2 [M þ H]^þ. HRMS calcd C₂₇H₂₃F₃NO₆S

[M þ H]^þ546.1193; found 546.1193.

2-(4-((4-(4-Methoxyphenyl)-5-(4-(trifluoromethylthio)phenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (29f). ¹H

NMR (400 MHz, CD₃OD) δ = 7.57 (d, J = 8.4 Hz, 2H), 7.36

(d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 2.4 Hz,

1H), 6.80 (d, J = 8.8 Hz, 2H), 6.76-6.54 (m, 2H), 5.25 (s, 2H),

4.53 (s, 2H), 3.70 (s, 3H), 2.16 (s, 3H). MS m/z 562.1 [M þ H]^þ.

HRMS calcd C₂₇H₂₃F₃NO₅S₂[M þ H]^þ562.0965; found

562.0963.

Methyl 2-(4-((5-Bromo-4-(4-methoxyphenyl)oxazol-2-yl)-

methoxy)-2-methylphenoxy)acetate (28, X = O). The com-

pound was prepared following the synthetic procedure to the

thiazole 28 (X = S). ¹H NMR (400 MHz, CDCl₃) δ = 7.81 (d,

J = 9.8 Hz, 2H), 6.90 (d, J = 9.8 Hz, 2H), 6.80 (d, J = 3.2 Hz,

1H), 6.71 (m, 1H), 6.58 (m, 1H), 4.99 (s, 2H), 4.52 (s, 2H), 3.78

(s, 3H), 3.72 (s, 3H), 2.20 (s, 3H). MS m/z 463.0 [M þ H]^þ.

2-(4-((5-(4-Chlorophenyl)-4-(4-methoxyphenyl)thiazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (29a). A mixture of

{4-[5-bromo-4-(4-methoxyphenyl)thiazol-2-ylmethoxy]-2-methyl-

phenoxy}acetic acid methyl ester (30.0 mg, 0.064 mmol), 4-chloro-

phenylboronic acid (20 mg, 0.13 mmol), tetrakis(triphenyl-

phosphine)palladium (8 mg, 0.006 mmol), K₂CO₃(36 mg,

0.26 mmol), 1,4-dioxane (1 mL), EtOH (0.4 mL), and H₂O

(0.2 mL) in a sealed vial was heated to 120 ꢀC and stirred at this

temperature overnight. The reaction mixture was cooled to room

temperature. Then THF (1 mL) and LiOH (200 μL of 1 N) were

added and the mixture was stirred at room temperature for 2 h. The

reaction mixture was acidified with 1 M HCl, extracted with

EtOAc (10 mL), dried (MgSO₄), filtered, concentrated, and puri-

fied on reverse phase HPLC to afford 29a (15 mg, 45%) as a white

solid: ¹H NMR (400 MHz, CDCl₃) δ = 7.40 (d, J = 8.8 Hz, 2H),

7.29 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 6.90 (d, J =

2.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.78 (dd, J = 3.2, 8.8 Hz,

1H), 6.70 (d, J = 8.8 Hz, 1H), 5.33 (s, 2H), 4.63 (s, 2H), 3.82 (s,

3H), 2.29 (s, 3H). MS m/z 496.3 [M þ H]^þ. HRMS calcd

C₂₆H₂₃ClNO₅S [M þ H]^þ496.0980; found 496.0984.

2-(4-((5-(6-Chloropyridin-3-yl)-4-(4-methoxyphenyl)thiazol-

2-yl)methoxy)-2-methylphenoxy)acetic Acid (29g). ¹H NMR

(400 MHz, CDCl₃) δ = 8.40 (d, J = 2.4 Hz, 1H), 7.57 (dd,

J = 2.4, 8.4 Hz, 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.28 (d, J =

8.4 Hz, 1H), 6.90 (d, J = 2.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H),

6.78 (dd, J = 2.8, 8.8 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 5.36

(s, 2H), 4.65 (s, 2H), 3.82 (s, 3H), 2.29 (s, 3H). MS m/z 497.0

[M þ H]^þ. HRMS calcd C₂₅H₂₂ClN₂O₅S [M þ H]^þ497.0933;

found 497.0933.

2-(4-((5-(3-Chloro-4-methoxyphenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (29h). H

1

NMR (400 MHz, CDCl₃) δ = 7.41 (d, J = 8.8 Hz, 2H), 7.36

(d, J = 2.4 Hz, 1H), 7.15 (dd, J = 2.0, 8.4 Hz, 1H), 6.89 (d, J =

2.8 Hz, 1H), 6.84 (m, 3H), 6.76 (dd, J = 2.8, 8.8 Hz, 1H), 6.70

(d, J = 8.8 Hz, 1H), 5.32 (s, 2H), 4.63 (s, 2H), 3.94 (s, 3H), 3.82

(s, 3H), 2.28 (s, 3H). MS m/z 526.3 [M þ H]^þ. HRMS calcd

C

₂₇H₂₅ClNO₆S [M þ H]^þ526.1086; found 526.1085.

2-(4-((4-(4-Methoxyphenyl)-5-(4-propylphenyl)thiazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (29i). ¹H NMR (400 MHz,

CDCl₃) δ = 7.28-7.05 (m, 6H), 6.82 (d, J = 2.8 Hz, 1H),

6.77-6.66 (m, 4H), 5.22 (s, 2H), 4.52 (s, 2H), 3.69 (s, 3H), 2.49

(t, J = 7.6 Hz, 2H), 2.16 (s, 3H), 1.58-1.52 (m, 2H), 0.85 (t, J =

7.4 Hz, 3H). MS m/z 504.2 [M þ H]^þ. HRMS calcd C₂₉H₃₀NO₅S

[M þ H]^þ504.1839; found 504.1839.

2-(4-((5-(4-tert-Butylphenyl)-4-(4-methoxyphenyl)thiazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (29j). ¹H NMR (400 MHz,

CDCl₃) δ = 7.40 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.4 Hz,

2H), 7.23 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 2.4 Hz, 1H), 6.86

Compounds 29b-ah were prepared following the synthetic

procedure of 29a using the appropriate bromothiazole or bro-

mooxazole intermediates and boronic acids.

96 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Epple et al.

(d, J = 8.8 Hz, 2H), 6.78 (dd, J = 2.8, 8.8 Hz, 1H), 6.70 (d, J =

8.8 Hz, 1H), 5.44 (s, 2H), 4.63 (s, 2H), 3.83 (s, 3H), 2.28 (s, 3H),

1.31 (s, 9H). MS m/z 518.4 [M þ H]^þ. HRMS calcd C₃₀H₃₂NO₅S

[M þ H]^þ518.1996; found 518.1996.

6.79-6.69 (m, 2H), 5.10 (s, 2H), 4.53 (s, 2H), 3.75 (s, 3H), 2.17

(s, 3H). MS m/z 514.1 [M þ H]^þ. HRMS calcd C₂₇H₂₃F₃NO₆

[M þ H]^þ514.1472; found 514.1470.

{4-[4-(4-Methoxyphenyl)-5-(3-trifluoromethylphenyl)oxazol-

2-ylmethoxy]-2-methylphenoxy}acetic Acid (29ac). ¹H NMR

(400 MHz, CDCl₃) δ = 7.74 (s, 1H), 7.72 (d, J = 7.6 Hz,

1H), 7.56 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (d,

J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 2.8, 1H),

6.78 (dd, J = 3.0 Hz, 9.0 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 5.09

(s, 2H), 4.52 (s, 2H), 3.74 (s, 3H), 2.16 (s, 3H). MS m/z 514.1

[M þ H]^þ. HRMS calcd C₂₇H₂₃F₃NO₆[M þ H]^þ514.1472;

found 514.1470.

2-(4-((5-(4-Biphenyl)-4-(4-methoxyphenyl)thiazol-2-yl)methoxy)-

2-methylphenoxy)acetic Acid (29k). ¹H NMR (400 MHz, CDCl₃)

δ = 7.60 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.41 (m,

7H), 6.91 (d, J = 2.8 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.79 (dd,

J = 2.4, 8.8 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 5.35 (s, 2H), 4.64 (s,

2H), 3.82 (s, 3H), 2.29 (s, 3H). MS m/z 538.4 [M þ H]^þ. HRMS

calcd C₃₂H₂₈NO₅S [M þ H]^þ538.1683; found 538.1684.

2-(4-((4-(4-Methoxyphenyl)-5-(naphthalen-1-yl)thiazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (29l). ¹H NMR (400 MHz,

CDCl₃) δ = 7.91 (m, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.48 (m, 3H),

7.40 (m, 1H), 7.33 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 2.8 Hz, 1H),

6.82 (dd, J = 2.8, 8.8 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.64 (d,

J= 8.9 Hz, 2H), 5.42 (s, 2H), 4.65 (s, 2H), 3.69 (s, 3H), 2.30 (s, 3H).

MS m/z 512.1 [M þ H]^þ. HRMS calcd C₃₀H₂₆NO₅S [M þ H]^þ

512.1527; found 512.1526.

2-(4-((4-(4-Methoxyphenyl)-5-(4-(trifluoromethoxy)phenyl)-

oxazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (29ad). H

1

NMR (400 MHz, CD₃OD) δ = 7.59 (d, J = 8.8 Hz, 2H), 7.43

(d, J = 9.2 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.8

Hz, 2H), 6.84 (d, J = 2.8 Hz, 1H), 6.79-6.68 (m, 2H), 5.08

(s, 2H), 4.53 (s, 2H), 3.75 (s, 3H), 2.17 (s, 3H). MS m/z 530.0

[M þ H]^þ. HRMS calcd C₂₇H₂₃F₃NO₇[M þ H]^þ530.1421;

found 530.1416.

2-(4-((4-(4-Methoxyphenyl)-5-(4-propylphenyl)oxazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (29ae). ¹HNMR(400 MHz,

CD₃OD) δ = 7.41-7.35 (m, 4H), 7.11 (d, J = 8.4 Hz, 2H), 6.87

(d, J = 8.8 Hz, 2H), 6.82 (d, J = 2.4 Hz, 1H), 6.76-6.65 (m, 2H),

5.03 (s, 2H), 4.51 (s, 2H), 3.72 (s, 3H), 2.50 (t, J = 7.6 Hz, 2H), 2.15

(s, 3H), 1.59-1.50 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). MS m/z 488.2

[M þ H]^þ. HRMS calcd C₂₉H₃₀NO₆[M þ H]^þ488.2068; found

488.2068.

2-(4-((4-(4-Methoxyphenyl)-5-(naphthalen-3-yl)thiazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (29m). ¹H NMR (400 MHz,

CDCl₃) δ = 7.88 (s, 1H), 7.76 (m, 3H), 7.49 (m, 2H), 7.45 (d, J =

8.8 Hz, 2H), 7.34 (dd, J = 1.6, 8.4 Hz, 1H), 6.92 (d, J = 2.8 Hz,

1H), 6.81 (d, J = 8.8 Hz, 2H), 6.80 (dd, J = 2.8, 8.8 Hz, 1H), 6.71

(d, J = 8.8 Hz, 1H), 5.39 (s, 2H), 4.64 (s, 2H), 3.80 (s, 3H), 2.29 (s,

3H). MS m/z512.1 [M þ H]^þ.HRMScalcdC₃₀H₂₆NO₅S[Mþ H]^þ

512.1527; found 512.1528.

2-(4-((4-(4-Methoxyphenyl)-5-(quinolin-3-yl)thiazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (29n). ¹HNMR(400MHz,

CDCl₃) δ = 8.86 (d, J = 2.0 Hz, 1H), 8.24 (s, 1H), 8.20 (d, J =

8.4 Hz, 1H), 7.77 (m, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.39 (d, J =

8.4 Hz, 2H), 6.85 (d, J= 2.8 Hz, 1H), 6.81 (d, J= 8.8 Hz, 2H), 6.79

(dd, J = 2.8, 8.8 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 5.36 (s, 2H),

4.63 (s, 2H), 3.77 (s, 3H), 2.27 (s, 3H). MS m/z 513.0 [M þ H]^þ.

HRMS calcd C₂₉H₂₅N₂O₅S [M þ H]^þ513.1479; found 513.1471.

2-(4-((5-(Benzofuran-2-yl)-4-(4-methoxyphenyl)thiazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (29o). ¹HNMR(400MHz,

DMSO-d₆) δ = 7.48 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H),

7.39 (d, J = 8.8 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 7.11 (d, J =

7.6 Hz, 1H), 6.88 (d, J= 8.8 Hz, 2H), 6.83 (d, J= 3.2 Hz, 1H), 6.73

(dd, J = 3.2, 8.8 Hz, 1H), 6.72 (s, 1H), 6.64 (d, J = 8.8 Hz, 1H),

5.28 (s, 2H), 4.48 (s, 2H), 3.71 (s, 3H), 2.10 (s, 3H). MS m/z 502.3

[M þ H]^þ. HRMS calcd C₂₈H₂₄NO₆S [M þ H]^þ502.1319; found

502.1313.

{4-[5-Biphenyl-4-yl-4-(4-methoxyphenyl)oxazol-2-ylmethoxy]-

2-methylphenoxy}acetic Acid (29af). ¹H NMR (400 MHz, CD₃-

OD) δ = 7.63-7.57 (m, 6H), 7.49-7.47 (m, 2H), 7.38 (t, J =

7.4 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 6.93-6.91 (m, 2H), 6.87 (d,

J = 2.8 Hz, 1H), 6.79-6.69 (m, 2H), 5.11 (s, 2H), 4.54 (s, 2H),

3.75 (s, 3H), 2.17 (s, 3H). MS m/z 522.2 [M þ H]^þ. HRMS calcd

C₃₂H₂₈NO₆[M þ H]^þ522.1911; found 522.1910.

2-(4-((4-(4-Methoxyphenyl)-5-(quinolin-3-yl)oxazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (29ag).¹H NMR (400 MHz,

CD₃OD) δ = 8.94(s, 1H), 8.61 (s, 1H), 8.01-7.95 (m, 2H),

7.80-7.63 (m, 2H), 7.53 (d, J = 8.8 Hz, 2H), 6.96 (d, J =

8.8 Hz, 1H), 6.89 (d, J = 3.2 Hz, 1H), 6.83-6.70 (m, 2H), 5.17

(s, 2H), 4.56 (s, 2H), 3.76 (s, 3H), 2.17 (s, 3H). MS m/z 497.2

[M þ H]^þ. HRMS calcd C₂₉H₂₅N₂O₆[M þ H]^þ497.1707; found

497.1703.

2-(4-((5-(3,4-Dichlorophenyl)-4-(4-methoxyphenyl)oxazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (29ah).¹H NMR (400 MHz,

CD₃OD) δ = 7.65 (d, J = 2.0 Hz, 1H), 7.52-7.40 (m, 4H), 6.95

(d, J = 8.4 Hz, 2H), 6.86 (d, J = 2.8 Hz, 1H), 6.80-6.69 (m, 2H),

5.11 (s, 2H), 4.54 (s, 2H), 3.76 (s, 3H), 2.16 (s, 3H). MS m/z 514.1

[M þ H]^þ. HRMS calcd C₂₆H₂₂Cl₂NO₆[M þ H]^þ514.0819; found

514.0820.

2-(4-((4-(4-Methoxyphenyl)-5-styrylthiazol-2-yl)methoxy)-2-

methylphenoxy)acetic Acid (29p). ¹H NMR (400 MHz, DMSO-

d₆) δ = 7.54 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 7.6 Hz, 2H), 7.24

(m, 2H), 7.20 (m, 2H), 7.02 (d, J = 8.8 Hz, 2H), 6.96 (d, J =

16.0 Hz, 1H), 6.88 (d, J = 2.8 Hz, 1H), 6.78 (dd, J = 2.8, 8.8 Hz,

1H), 6.71 (d, J = 8.8 Hz, 1H), 5.31 (s, 2H), 4.56 (s, 2H), 3.76

(s, 3H), 2.12 (s, 3H). MS m/z 488.4 [M þ H]^þ. HRMS calcd

C₂₈H₂₆NO₅S [M þ H]^þ488.1527; found 488.1521.

General Procedures to Intermediate 30. Method A: X = S,

Exemplified by 2-Methyl-5-(4-(trifluoromethoxy)phenyl)thiazole.

Ethyl ethynyl ether (6.0 g, 85.6 mmol) was dissolved in THF

(100mL) at0ꢀC. Then borane-tetrahydronfuran complex (1 M in

THF, 28.5 mL, 28.5 mmol) was added. The reaction mixture was

warmed to room temperature and stirred for 2 h at room tem-

perature. The resulting solution was added to a mixture of 1-iodo-

4-trifluoromethoxybenzene (20.5 g, 71.33 mmol), triphenylpho-

sphine (598 mg, 2.28 mmol), palladium(II) acetate (128 mg,

0.57 mmol), and sodium hydroxide (8.5 g, 214 mmol) in THF

(200 mL). The reaction mixture was heated to reflux for 15 h, then

cooled, diluted with EtOAc (1000 mL), washed with saturated

NaHCO₃, brine, and H₂O. The organic layer was dried (MgSO₄),

filtered, concentrated, and purified by flash column chromatogra-

phy (silica, EtOAc/hexane gradient) to give 1-(2-ethoxyvinyl)-4-

trifluoromethoxybenzene as a white solid (4.6 g, 28%): ¹H NMR

(400 MHz, CDCl₃) δ = 7.38 (d, J = 8.8 Hz, 2H), 7.26 (d, J =

8.4 Hz, 2H), 7.13 (d, J = 12.8 Hz, 1H), 5.98 (d, J = 13.2 Hz, 1H),

4.08 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H). MS m/z 233.1

[M þ H]^þ.

2-(4-((5-(4-Phenyl-3-(trifluoromethyl)phenyl)-4-(4-methoxy-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (29q).

¹H NMR (400 MHz, CD₃OD) δ = 7.59 (s, 1H), 7.50 (d, J =

8.0 Hz, 1H), 7.34-7.30 (m, 5H), 7.25-7.21 (m, 3H), 6.85-6.82 (m,

3H), 6.77-6.68 (m, 2H), 5.26 (s, 2H), 4.53 (s, 2H), 3.71 (s, 3H), 2.17

(s, 3H). MS m/z 606.1 [M þ H]^þ. HRMS calcd C₃₃H₂₇F₃NO₅S

[M þ H]^þ606.1557; found 606.1558.

2-(4-((5-(4-Chlorophenyl)-4-(4-methoxyphenyl)oxazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (29aa). ¹H NMR (400 MHz,

CD₃OD) δ = 7.49(d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H),

7.37 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.85 (d, J =

2.8 Hz, 1H), 6.79-6.69 (m, 2H), 5.09 (s, 2H), 4.55 (s, 2H), 3.75 (s,

3H), 2.16 (s, 3H). MS m/z 480.1 [M þ H]^þ. HRMS calcd C₂₆H₂₃-

ClNO₆[M þ H]^þ480.1209; found 480.1209.

2-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

oxazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (29ab).

¹H NMR (400 MHz, CD₃OD) δ = 7.67-7.59(m, 4H), 7.43 (d,

J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.85 (d, J= 2.8 Hz, 1H),

Article

1-(2-Ethoxyvinyl)-4-trifluoromethoxybenzene (4.6 g, 19.8 mmol)

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 97

The organic layer was dried (MgSO₄), filtered, concentrated, and

purified by flash column chromatography (silica, EtOAc/hexane

gradient) to give 2-diazo-4⁰-trifluoromethoxyacetophenone 32 (7.93

g, 70%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ = 7.82 (d,

J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 5.89 (s, 1H). MS m/z

203.0 [M þ H - N₂]^þ.

was dissolved in a mixture of EtOH/THF, 4:1 (150 mL). Then NBS

(3.52 g, 19.8 mmol) was added. The mixture was stirred at

room temperature for 2 h, then concentrated and purified by flash

column chromatography (silica, EtOAc/hexane gradient) to give

1-(1-bromo-2,2-diethoxyethyl)-4-trifluoromethoxybenzene 31 as a

white solid (5.9 g, 83%): ¹H NMR (400 MHz, CDCl₃) δ = 7.52 (d,

J = 8.8 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 4.95 (d, J = 6.4 Hz, 1H),

4.83 (d, J = 6.0 Hz, 1H), 3.84-3.77 (m, 1H), 3.71-3.61 (m, 2H),

3.50-3.43 (m, 1H), 1.29 (t, J = 7.0 Hz, 3H), 1.09 (t, J = 7.0 Hz,

3H). MS m/z 277.0 [M - Br]^þ.

Aluminum chloride (19.6 g, 146.8 mmol) was added in

portions into anhydrous MeCN (200 mL) under argon.

2-Diazo-4⁰-trifluoromethoxyacetophenone 32 (16.89 g, 73.4 mmol)

in MeCN (200 mL) was added dropwise over 30 min at room

temperature under nitrogen. The mixture was stirred for 45 min at

room temperature. Then it was poured into ditheyl ether (500 mL).

The solution was carefully quenched with 0.2 N HCl, then basified

with 1 N NaOH to pH 9-10 and extracted with diethyl ether

(3 ꢀ 200 mL). The combined organic layers were washed with H₂O

(100 mL) and brine (50 mL), dried (MgSO₄), filtered, concentrated,

and purified by flash column chromatography (silica, EtOAc/

hexane gradient) to give 2-methyl-5-(4-trifluoromethoxyphe-

nyl)oxazole (14.0 g, 78%) as an oil: ¹H NMR (400 MHz, CDCl₃)

δ = 7.56 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.13 (s, 1H),

2.46 (s, 3H). MS m/z 244.0 [M þ H]^þ.

1-(1-Bromo-2,2-diethoxyethyl)-4-trifluoromethoxybenzene 31

(1.00 g, 2.80 mmol) was dissolved in CHCl₃(3 mL). Then Ac₂O

(286 mg, 2.80 mmol), NaOAc 3H₂O (228 mg, 1.68 mmol), and

3

AcCl (153 mg, 1.97 mmol) were added successively and the

mixture was stirred at 50 ꢀC for 5 h. The mixture was diluted

with DCM (50 mL) and washed with saturated NaHCO₃and

brine. The organic layer was dried (MgSO₄), filtered, and con-

centrated to give crude bromo-(4-trifluoromethoxyphenyl)-

acetaldehyde(793mg, 100%). Thisaldehyde(793 mg, 2.80 mmol)

and thioacetamide (211 mg, 2.80 mmol) were dissolved in EtOH

(8 mL), and the mixture was stirred at 90 ꢀC for 15 h. The solution

was diluted with EtOAc (50 mL) and washed with saturated

NaHCO₃(30 mL) and brine (10 mL). The organic layer was

dried (MgSO₄), filtered, concentrated, and purified by flash

column chromatography (silica, EtOAc/hexane gradient) to

give 2-methyl-5-(4-trifluoromethoxyphenyl)thiazole as a white

General Procedure to Intermediate 33 (X = S), Exemplified by

4-Bromo-2-(bromomethyl)-5-(4-(trifluoromethoxy)phenyl)thiazole.

2-Methyl-5-(4-(trifluoromethoxy)phenyl)thiazole (1.0 g, 3.68 mmol)

was dissolved in CHCl₃(100 mL). Then bromine (245 μL,

4.77 mmol) was added and the mixture was stirred at room

temperature for 15 h. The solution was diluted with DCM

(100 mL) and washed with saturated NaHCO₃(50 mL) and brine

(30 mL). The organic layer was dried (MgSO₄), filtered, and

concentrated to give crude product, which was purified by flash

column chromatography (diethyl ether/hexane gradient) to give

1

solid (442 mg, 61%): H NMR (400 MHz, CDCl₃) δ = 7.71

(s, 1H), 7.46 (m, 2H), 7.18 (m, 2H), 2.68 (s, 3H). MS m/z 260.0

[M þ H]^þ.

Method B: X = S, Exemplified by 5-(4-Biphenyl)-2-methyl-

thiazole. 4-Iodobiphenyl (40.0 g, 171.6 mmol) was dissolved in

DMF (800 mL). Then 2-methylthiazole (8.50 g, 85.5 mmol),

triphenylphosphine (3.6 g, 13.73 mmol), cesium carbonate

(55.9 g, 171.6 mmol), and palladium(II) acetate (3.01 g, 13.7 mmol)

were added successively. The reaction mixture was stirred at 140 ꢀC

for 24 h, then filtered through Celite 545. The filter was washed

with saturated aqueous K₂CO₃and EtOAc. The filtrate was

diluted with EtOAc and washed with saturated NaHCO₃, H₂O,

and brine. The organic layer was dried (MgSO₄), filtered, concen-

trated, and purified by flash column chromatography (silica,

EtOAc/hexane gradient) to give 5-biphenyl-4-yl-2-methylthiazole

4-bromo-2-methyl-5-(4-(trifluoromethoxy)phenyl)thiazole as

a

1

colorless oil (730 mg, 56%): H NMR (400 MHz, CDCl₃) δ =

7.56 (m, 2H), 7.21 (m, 2H), 2.67 (s, 3H). MS m/z 337.90 [M þ H]^þ.

N-Bromosuccinimide (504 mg, 2.83 mmol) was added to a

solution of 4-bromo-2-methyl-5-(4-trifluoromethoxyphenyl)-

thiazole (730 mg, 2.16 mmol) in carbon tetrachloride (50 mL).

The above solution was stirred at 75 ꢀC for 18 h. The solution

was diluted with DCM (50 mL) and washed with saturated

NaHCO₃(50 mL) and brine (30 mL). The organic layer was

dried (MgSO₄), filtered, concentrated, and purified by flash

column chromatography (diethyl ether/hexane gradient) to give

4-bromo(2-bromomethyl)-5-(4-(trifluoromethoxy)phenyl)thiazole

1

(7.62 g, 18%): H NMR (400 MHz, CDCl₃) δ = 7.78 (s, 1H),

1

7.51-7.56 (m, 5H), 4.28-7.41 (m, 4H), 2.69 (s, 3H). MS m/z 252.0

(486 mg, 54%) as a yellow oil: H NMR (400 MHz, CDCl₃)

δ =7.59 (m, 2H), 7.23 (m, 2H), 4.63 (s, 2H). MS m/z 416.8

[M þ H]^þ.

Method C: X = O, Exemplified by 5-(4-trifluoromethoxyphenyl)-

2-methyloxazole. 1,1,1,3,3,3-Hexamethyldisilazane (8.93 g, 55.35

mmol) was dissolved in THF (50 mL) and cooled to 0 ꢀC.

n-Butyllithium (2.5 M in hexanes, 21.55 mL, 53.88 mmol) was

added dropwise, and the resulting solution was stirred for 10 min at

0ꢀC. Then it was cooled to -78 ꢀC. 4⁰-(Trifluoromethoxy)acetophe-

none (10.0 g, 48.98 mmol) in THF (64 mL) was added dropwise

over 30 min and stirred for another 45 min at -78 ꢀC. Then

2,2,2-trifluoroethyltrifluoroacetate (11.43 g, 58.78 mmol) was added

rapidly. The mixture was stirred for 20 min at -78 ꢀC. Then it was

poured into 5% HCl (200 mL) and extracted with diethyl ether (2 ꢀ

100 mL). The organic layers were combined, washed with brine

(50 mL), dried (MgSO₄), and concentrated. The residue was

dissolved in MeCN (50 mL), and then H₂O (0.88 mL, 48.98 mmol)

and triethylamine (7.43 g, 73.47 mmol) were added. Freshly

prepared methanesulfonyl azide (8.98 g, 73.47 mmol) in MeCN

(16 mL) was added over 30 min at room temperature.

[Methanesulfonyl azide was prepared from the following procedure:

Methanesulfonyl chloride (8.85 g, 73.47 mmol) was dissolved in

acetone (50 mL). Then sodium azide (7.56 g, 116.0 mmol) was added

over 30 min, and the mixture was stirred for 1.5 h at room

temperature. The solution was filtered, washed with acetone, and

concentrated.] The reaction mixture was stirred for 1 h and then

concentrated. The residue was diluted with diethyl ether (200 mL),

washed with 10% NaOH (3 ꢀ 50 mL), then with brine (50 mL).

[M þ H]^þ.

4-Bromo-2-bromomethyl-5-(4-trifluoromethoxyphenyl)oxazole

(33, X = O). The compound was prepared following the syn-

thetic procedure to thiazole 33 (X = S). H NMR (400 MHz,

1

CDCl₃) δ =7.91 (d, 2H, J = 8.6 Hz), 7.25 (d, 2H, J = 8.6 Hz),

4.41 (s, 3H). MS m/z 399.8 [M þ H]^þ.

General Procedure to Intermediate 34 (X = S), Exemplified by

Methyl 2-(4-((4-Bromo-5-(4-(trifluoromethoxy)phenyl)thiazol-2-

yl)methoxy)-2-methylphenoxy)acetate. A mixture of 4-bromo-

(2-bromomethyl)-5-(4-(trifluoromethoxy)phenyl)thiazole (486 mg,

1.16 mmol), 50 (227 mg, 1.16 mmol), and Cs₂CO₃(756 mg,

2.32 mmol) in MeCN (20 mL) was stirred at room temperature

for 2 h. The mixture was filtered, then concentrated and purified by

flash column chromatography (silica, EtOAc/hexane gradient) to

give methyl 2-(4-((4-bromo-5-(4-(trifluoromethoxy)phenyl)thiazol-

2-yl)methoxy)-2-methylphenoxy)acetate (586 mg, 95%) as a white

solid: ¹H NMR (400 MHz, CDCl₃) δ = 7.66 (m, 2H), 7.28 (m, 2H),

6.85 (d, J = 2.8 Hz, 1H), 6.74(dd, J = 3.2 Hz, J = 8.8 Hz, 1H), 6.67

(d, J = 8.8 Hz, 1H), 5.28 (s, 2H), 4.61 (s, 2H), 3.80 (s, 3H), 2.29

(s, 3H). MS m/z 532.0 [M þ H]^þ.

{4-[4-Bromo-5-(4-trifluoromethoxyphenyl)oxazol-2-ylmethoxy]-

2-methylphenoxy}acetic Acid Methyl Ester (34, X = O). The

compound was prepared following the synthetic procedure to

thiazole 34 (X = S). ¹H NMR (400 MHz, CDCl₃) δ = 7.89 (d,

J = 8.4 Hz, 2H), 7.23 (d, J= 8.4 Hz, 2H), 6.79 (d, J= 3.2 Hz, 1H),

98 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Epple et al.

6.70 (m, 1H), 6.59 (m, 1H), 5.03 (s, 2H), 4.53 (s, 2H), 3.72 (s, 3H),

3.72 (s, 3H), 2.21 (s, 3H). MS m/z 516.9 [M þ H]^þ.

[M þ H]^þ. HRMS calcd C₃₀H₂₉F₃NO₆S [M þ H]^þ588.1662;

found 588.1665.

2-(4-((4-(4-(Trifluoromethyl)phenyl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35a).

A mixture of methyl 2-(4-((4-bromo-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetate 34 (30.0

mg, 0.056 mmol), 4-trifluoromethylphenylboronic acid (20 mg,

0.10 mmol), tetrakis(triphenylphosphine)palladium (7.9 mg, 0.006

mmol), K₂CO₃(35.8 mg, 0.26 mmol), 1,4-dioxane (1 mL), EtOH

(0.4 mL), and H₂O (0.2 mL) in a sealed vial was heated to 120 ꢀC

and stirred at this temperature overnight. The reaction mixture was

cooled to room temperature. Then THF (1 mL) and LiOH (200 μL

of 1 N) were added and stirred at room temperature for 2 h. The

mixture was acidified with 1 M HCl, extracted with EtOAc

(10 mL), dried (MgSO₄), filtered, concentrated, and purified on

reverse phase HPLC to afford 35a (27.7 mg, 85%) as a white solid:

¹H NMR(400MHz, CDCl₃) δ=7.60(d, J= 8.8 Hz, 2H), 7.56 (d,

J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.20 (d, J= 8.8 Hz, 2H),

6.91 (d, J = 3.2 Hz, 1H), 6.79 (dd, J = 3.2, 8.8 Hz, 1H), 6.71 (d,

J = 8.8 Hz, 1H), 5.35 (s, 2H), 4.65 (s, 2H), 2.30 (s, 3H). MS m/z

584.0 [M þ H]^þ. HRMS calcd C₂₇H₂₀F₆NO₅S [M þ H]^þ

584.0961; found 584.0961.

{4-[4-(4-Isopropoxyphenyl)-5-(4-trifluoromethoxyphenyl)thiazol-

2-ylmethoxy]-2-methylphenoxy}acetic Acid (35h). ¹H NMR

(400 MHz, CD₃OD) δ = 7.34 (d, J = 8.8 Hz, 2H), 7.26 (d, J =

8.8 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 2.8 Hz, 1H),

6.78-6.67 (m, 4H), 5.24 (s, 2H), 4.53 (s, 2H), 4.51 (m, 1H), 2.16 (s,

3H), 1.22 (s, 3H), 1.20 (s, 3H). MS m/z 574.2 [M þ H]^þ. HRMS

calcd C₂₉H₂₇F₃NO₆S [M þ H]^þ574.1506; found 574.1505.

2-(4-((4-(4-sec-Butoxyphenyl)-5-(4-(trifluoromethoxy)phenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35i). ¹H

NMR (400 MHz, CD₃OD) δ = 7.34 (d, J = 8.8 Hz, 2H),

7.26 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.82 (d, J =

2.8 Hz, 1H), 6.77-6.67 (m, 4H), 5.24 (s, 2H), 4.52 (s, 2H),

4.30-4.25 (m, 1H), 2.16 (s, 3H), 1.62-1.52 (m, 2H), 1.18 (d,

J = 6.0 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). MS m/z 588.1

[M þ H]^þ. HRMS calcd C₃₀H₂₉F₃NO₆S [M þ H]^þ588.1662;

found 588.1664.

2-(4-((4-(4-Isobutoxyphenyl)-5-(4-(trifluoromethoxy)phenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35j). ¹H

NMR (400 MHz, CD₃OD) δ = 7.34 (d, J = 8.8 Hz, 2H),

7.27 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.82 (d, J =

2.8 Hz, 1H), 6.80-6.66 (m, 4H), 5.24 (s, 2H), 4.49 (s, 2H), 3.66

(d, J = 6.4 Hz, 2H), 2.19 (s, 3H), 2.01-1.91 (m, 1H), 0.94 (s,

3H), 0.93 (s, 3H). MS m/z 588.1 [M þ H]^þ. HRMS calcd

C₃₀H₂₉F₃NO₆S [M þ H]^þ588.1662; found 588.1663.

Compounds 35b-ad were prepared following the syn-

thetic procedure of 35a using the appropriate bromothiazole

or bromooxazole intermediates and boronic acids.

2-(4-((4-(4-Biphenyl)-5-(4-(trifluoromethoxy)phenyl)thiazol-

2-yl)methoxy)-2-methylphenoxy)acetic Acid (35b). ¹H NMR

(400 MHz, CDCl₃) δ = 7.61 (d, J = 7.2 Hz, 2H), 7.56 (s,

4H), 7.44 (t, J = 7.2 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.35 (t,

J = 7.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 2.8 Hz,

1H), 6.79 (dd, J = 2.8, 8.8 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H),

5.36 (s, 2H), 4.64 (s, 2H), 2.30 (s, 3H). MS m/z 592.4 [M þ H]^þ.

HRMS calcd C₃₂H₂₅F₃NO₅S [M þ H]^þ592.1401; found

592.1401.

2-(4-((4-(3-Fluoro-4-methoxyphenyl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35c).

¹H NMR (400 MHz, CDCl₃) δ = 7.35 (d, J = 8.4 Hz, 2H),

7.21 (m, 3H), 6.89 (m, 2H), 6.78 (dd, J = 2.8, 8.8 Hz, 1H), 6.70 (d,

J= 8.8 Hz, 1H), 5.34 (s, 2H), 4.65 (s, 2H), 3.90 (s, 3H), 2.29 (s, 3H).

MS m/z 564.3 [M þ H]^þ. HRMS calcd C₂₇H₂₂F₄NO₆S [M þ H]^þ

564.1099; found 564.1099.

2-(4-((4-(4-(Cyclopentyloxy)phenyl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35k).

¹H NMR (400 MHz, CD₃OD) δ = 7.38 (d, J = 8.8 Hz, 2H), 7.29

(d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 2.8 Hz,

1H), 6.79-6.69 (m, 4H), 5.27 (s, 2H), 4.73 (m, 1H), 4.54 (s, 2H),

2.16 (s, 3H), 1.86-1.54 (m, 8H). MS m/z 600.1 [M þ H]^þ. HRMS

calcd C₃₁H₂₉F₃NO₆S [M þ H]^þ600.1662; found 600.1664.

2-(4-((4-(Benzo[d][1,3]dioxol-5-yl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35l).

¹H NMR (400 MHz, CDCl₃) δ = 7.35 (d, J = 8.8 Hz, 2H), 7.17

(d, J = 8.4 Hz, 2H), 6.94 (m, 2H), 6.89 (d, J = 2.8 Hz, 1H), 6.77

(m, 2H), 6.70 (d, J = 8.8 Hz, 1H), 5.97 (s, 2H), 5.33 (s, 2H), 4.64

(s, 2H), 2.29 (s, 3H). MS m/z 560.3 [M þ H]^þ. HRMS calcd

C₂₇H₂₁F₃NO₇S [M þ H]^þ560.0985; found 560.0984.

2-(4-((4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5-(4-(trifluoro-

methoxy)phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic

2-(4-((4-(3-Methoxyphenyl)-5-(4-(trifluoromethoxy)phenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35d). ¹H

NMR (400 MHz, CD₃OD) δ = 7.34 (d, J = 8.8 Hz, 2H), 7.18-

7.11 (m, 3H), 6.93-6.88 (m, 2H), 6.82 (d, J = 2.8 Hz, 1H),

6.80-6.66 (m, 3H), 5.25 (s, 2H), 4.52 (s, 2H), 3.57 (s, 3H), 2.16

(s, 3H). MS m/z 546.1 [M þ H]^þ. HRMS calcd C₂₇H₂₃F₃NO₆S

[M þ H]^þ546.1193; found 546.1194.

1

Acid (35m). H NMR (400 MHz, CDCl₃) δ = 7.37 (d, J =

8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 2.0 Hz, 1H),

6.90 (m, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 8.8 Hz, 1H),

5.31 (s, 2H), 4.63 (s, 2H), 4.26 (m, 4H), 2.28 (s, 3H). MS

m/z 574.1 [M þ H]^þ. HRMS calcd C₂₈H₂₃F₃NO₇S [M þ H]^þ

574.1142; found 574.1138.

2-(4-((4-(4-Ethoxyphenyl)-5-(4-(trifluoromethoxy)phenyl)thia-

zol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35e). ¹H NMR

(400 MHz, CD₃OD) δ = 7.36-7.16 (m, 6H), 6.85 (d, J = 2.8 Hz,

1H), 6.79-6.68 (m, 4H), 5.26 (s, 2H), 4.54 (s, 2H), 3.97-3.91

(m, 2H), 2.16 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H). MS m/z 560.2

[M þ H]^þ. HRMS calcd C₂₈H₂₅F₃NO₆S [M þ H]^þ560.1349;

found 560.1348.

2-(4-((4-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-8-yl)-5-(4-(tri-

fluoromethoxy)phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)-

1

acetic Acid (35n). H NMR (400 MHz, CD₃OD) δ = 7.34 (d,

J = 8.8 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 8.97 (d, J = 2.0 Hz,

2H), 6.90-6.77 (m, 3H), 6.75-6.67 (m, 2H), 5.24 (s, 2H), 4.53

(s, 2H), 4.09-4.02 (q, 4H), 2.16 (s, 3H), 2.08-2.03 (m, 2H). MS

m/z 588.1 [M þ H]^þ. HRMS calcd C₂₉H₂₅F₃NO₇S [M þ H]^þ

588.1299; found 588.1299.

2-(4-((4-(4-(Diethylamino)phenyl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35o).

¹H NMR (400 MHz, CD₃OD) δ = 7.50 (d, J = 8.4 Hz, 2H), 7.38

(d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.14 (bs, 2H), 6.83

(d, J = 2.8 Hz, 1H), 6.76-6.67 (m, 2H), 5.26 (s, 2H), 4.53 (s, 2H),

3.51(q, J = 7.2Hz, 4H), 2.16 (s, 3H), 1.05 (t, J =7.0 Hz, 6H). MS

m/z 587.2 [M þ H]^þ. HRMS calcd C₃₀H₃₀F₃N₂O₅S [M þ H]^þ

587.1822; found 587.1820.

2-(4-((4-(4-(Pyrrolidin-1-yl)phenyl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35p).

¹H NMR (400 MHz, CD₃OD) δ = 7.33 (d, J = 8.8 Hz, 2H), 7.20

(d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 2.8 Hz,

1H), 6.74-6.65 (m, 2H), 6.50 (d, J = 8.8 Hz, 2H), 5.21 (s, 2H),

4.52 (s, 2H), 3.21 (t, J = 5.4 Hz, 4H), 2.15 (s, 3H), 1.95-1.90

2-(4-((4-(4-Propoxyphenyl)-5-(4-(trifluoromethoxy)phenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35f). ¹H

NMR (400 MHz, CD₃OD) δ = 7.34 (d, J = 8.8 Hz, 2H), 7.27

(d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 2.8

Hz, 1H), 6.79-6.67 (m, 4H), 5.24 (s, 2H), 4.53 (s, 2H), 3.84 (t,

J = 6.4 Hz, 2H), 2.16 (s, 3H), 1.72-1.67 (m, 2H), 0.94 (t, J =

7.4 Hz, 3H). MS m/z 574.1 [M þ H]^þ. HRMS calcd C₂₉H₂₇

F₃NO₆S [M þ H]^þ574.1506; found 574.1507.

-

2-(4-((4-(4-Butoxyphenyl)-5-(4-(trifluoromethoxy)phenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35g).

¹H NMR (400 MHz, CD₃OD) δ = 7.34 (d, J = 8.8 Hz,

2H), 7.27 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.82

(d, J = 2.8 Hz, 1H), 6.79-6.67 (m, 4H), 5.24 (s, 2H), 4.53 (s,

2H), 3.88 (t, J = 6.4 Hz, 2H), 2.16 (s, 3H), 1.68-1.64 (m, 2H),

1.44-1.38 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). MS m/z 588.1

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 99

(m, 4H). MS m/z 585.2 [M þ H]^þ. HRMS calcd C₃₀H₂₈F₃N₂O₅S

[M þ H]^þ585.1666; found 585.1663.

6.88-6.77 (m, 2H), 5.20 (s, 2H), 4.63 (s, 2H), 3.56-3.53 (m, 4H),

2.26 (s, 3H), 1.98-1.75 (m, 6H). MS m/z 583.2 [M þ H]^þ. HRMS

calcd C₃₁H₃₀F₃N₂O₆[M þ H]^þ583.2051; found 583.2047.

2-(4-((4-(4-(Cyclopentyloxy)phenyl)-5-(4-(trifluoromethoxy)-

phenyl)oxazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35ac).

¹H NMR (400 MHz, CD₃OD) δ = 7.59 (d, J = 8.8 Hz, 2H),

7.40 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.87 (d, J =

8.4 Hz, 2H), 6.83 (d, J = 2.8 Hz, 1H), 6.77-6.67 (m, 2H), 5.08 (s,

2H), 4.87-4.75 (m, 1H), 4.48 (s, 2H), 2.16 (s, 3H), 1.96-1.58

(m, 8H). MS m/z 584.1 [M þ H]^þ. HRMS calcd C₃₁H₂₉F₃NO₇

[M þ H]^þ584.1891; found 584.1887.

2-(4-((4-(4-(Piperidin-1-yl)phenyl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35q).

¹H NMR (400 MHz, CD₃OD) δ = 7.51 (d, J = 8.8 Hz, 2H), 7.37

(d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.0 Hz,

2H), 6.83 (d, J = 2.8 Hz, 1H), 6.76-6.67 (m, 2H), 5.27 (s, 2H),

4.54 (s, 2H), 3.42 (t, J = 5.4 Hz, 4H), 2.17 (s, 3H), 1.87-1.82 (m,

4H), 1.68-1.64 (m, 2H). MS m/z 599.2 [M þ H]^þ. HRMS calcd

C₃₁H₃₀F₃N₂O₅S [M þ H]^þ599.1822; found 599.1818.

2-(4-((4-(4-Morpholinophenyl)-5-(4-(trifluoromethoxy)phenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35r). ¹H

NMR (400 MHz, CDCl₃) δ = 7.42 (d, J = 8.8 Hz, 2H), 7.35

(d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.98 (d, J =

8.4 Hz, 2H), 6.89 (d, J = 2.8 Hz, 1H), 6.77 (dd, J = 2.8, 8.8 Hz,

1H), 6.69 (d, J = 8.8 Hz, 1H), 5.33 (s, 2H), 4.63 (s, 2H), 3.93

(m, 4H), 3.27 (m, 4H), 2.28 (s, 3H). MS m/z 601.2 [M þ H]^þ.

HRMS calcd C₃₀H₂₈F₃N₂O₆S [M þ H]^þ601.1615; found

601.1615.

2-(4-((4-(4-(N-Isopropyl-N-methyl)benzamide)-5-(4-(trifluoro-

methoxy)phenyl)oxazol-2-yl)methoxy)-2-methylphenoxy)acetic

Acid (35ad). ¹H NMR (400 MHz, CD₃OD) δ = 7.61-7.58 (m,

4H), 7.40-7.31 (m, 2H), 7.25 (d, J = 8.4 Hz, 2H), 6.83 (d, J =

3.2 Hz, 1H), 6.78-6.67 (m, 2H), 5.10 (s, 2H), 4.52 (s, 2H),

3.97-3.84 (m, 1H), 2.86-2.78 (m, 3H), 2.15 (s, 3H), 1.19-1.09

(m, 6H). MS m/z 599.2 [M þ H]^þ. HRMS calcd C₃₁H₃₀F₃N₂O₇

[M þ H]^þ599.1927; found 599.1928.

2-(4-((4-(4-(Methylsulfonamide)phenyl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35s).

¹H NMR (400 MHz, CD₃OD) δ = 7.36-7.32 (m, 4H), 7.20 (d,

J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 2.8 Hz, 1H),

6.76-6.67 (m, 2H), 5.25 (s, 2H), 4.52 (s, 2H), 2.89 (s, 3H), 2.16 (s,

3H). MS m/z 609.1 [M þ H]^þ. HRMS calcd C₂₇H₂₄F₃N₂O₇S₂

[M þ H]^þ609.0972; found 609.0972.

General Procedures to Intermediate 36. Method A: Nu =

ROH, Exemplified by 2-Isopropoxy-5-bromopyridine. NaH

(5.2 g, 130 mmol) was suspended in isopropanol (50 mL). The

reaction mixture was stirred for 30 min at 60 ꢀC. After the gas

evolution ceased, 2-chloro-5-bromopyridine (10.0 g, 52 mmol)

dissolved in isopropanol (100 mL) was added and the mixture

was heated to reflux for 24 h. Then the solvent was removed in

vacuo, and the residue was diluted with H₂O and extracted into

EtOAc (2 ꢀ 40 mL). The organic layer was separated, dried

(MgSO₄), filtered, and concentrated to afford 2-isopropoxy-

2-(4-((4-(6-Benzo[d]oxazol-2(3H)-one)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35t).

¹H NMR (400 MHz, DMSO-d₆) δ = 11.64 (s, 1H), 8.13 (m,

2H), 7.49 (m, 2H), 7.33 (br s, 3H), 7.26 (d, J = 8.4 Hz, 1H), 7.03

(dd, J = 4.0, 8.0 Hz, 1H), 6.95 (s, 1H), 6.88 (m, 1H), 6.79 (dd, J =

3.2, 8.8 Hz, 1H), 5.41 (s, 2H), 4.63 (s, 2H), 2.30 (s, 3H). MS

m/z 573.2 [M þ H]^þ. HRMS calcd C₂₇H₂₀F₃N₂O₇S [M þ H]^þ

573.0938; found 573.0936.

1

5-bromopyridine (8.4 g, 75%) as a light-brown oil: H NMR

(400 MHz, CDCl₃) δ = 8.10 (d, J = 2.5 Hz, 1H), 7.54 (dd, J =

2.5 Hz, J = 8.8 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 5.17 (m, 1H),

1.26 (d, J = 6.2 Hz, 6H). MS m/z 215.9 [M þ H]^þ.

Method B: Nu = R₂NH, Exemplified by 5-Bromo-2-morpho-

linopyrimidine. Morpholine (5.4 mL, 62.4 mmol) was dissolved

in MeCN (250 mL). K₂CO₃(8.6 g, 62.4 mmol) was added, and

the mixture was stirred at room temperature for 1 h. Then

2-chloro-5-bromopyrimidine (10.0 g, 52 mmol) was added, and

the mixture was heated to reflux for 5 h. The reaction mixture

was concentrated, and the residue was taken up in H₂O (100 mL)

and extracted with EtOAc (2 ꢀ 100 mL). The organic layers were

combined, dried (MgSO₄), filtered, and concentrated to afford

5-bromo-2-morpholinopyrimidine (10.1 g, 80%) as a light-

brown oil: ¹H NMR (400 MHz, CDCl₃) δ = 8.24 (s, 2H), 3.69

(m, 8H). MS m/z 243.9 [M þ H]^þ.

2-(4-((4-(4-(N,N-Dimethyl)benzamide)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35u).

¹H NMR (400 MHz, CD₃OD) δ = 7.48 (d, J = 8.4 Hz, 2H),

7.37-7.30 (m, 4H), 7.20 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 2.8 Hz,

1H), 6.77-6.68 (m, 2H), 5.28 (s, 2H), 4.53 (s, 2H), 3.01 (s, 3H),

2.92 (s, 3H), 2.17 (s, 3H). MS m/z 587.1 [M þ H]^þ. HRMS calcd

C₂₉H₂₆F₃N₂O₆S [M þ H]^þ587.1458; found 587.1457.

2-(4-((4-(4-(N-Isopropyl-N-methyl)benzamide)-5-(4-(trifluoro-

methoxy)phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic

1

Acid (35v). H NMR (400 MHz, CD₃OD) δ = 7.52 (d, J =

8.0 Hz, 2H), 7.41-7.28 (m, 4H), 7.24 (d, J = 8.8 Hz, 2H), 6.88

(d, J = 3.2 Hz, 1H), 6.82-6.73 (m, 2H), 5.32 (s, 2H), 4.58 (s,

2H), 3.95-3.86 (m, 1H), 2.89-2.88 (m, 3H), 2.22 (s, 3H), 1.25-

1.12 (m, 6H). MS m/z 615.2 [M þ H]^þ. HRMS calcd C₃₁H₃₀F₃-

N₂O₆S [M þ H]^þ615.1772; found 615.1772.

General Procedure to Intermediate 37, Exemplified by 2-Iso-

propoxy-5-pyridineboronic Acid. 2-Isopropoxy-5-bromopyri-

dine (0.65 g, 3 mmol) was dissolved in diethyl ether (10 mL)

and cooled to -78 ꢀC under argon. n-Butyllithium (1.6 M in

hexane, 2.81 mL, 4.5 mmol) was added dropwise, and the

mixture was stirred at -78 ꢀC for 2 h. Triisopropyl borate

(1.72 mL, 7.5 mmol) was added, and the mixture was stirred for

2 h at -78 ꢀC. The mixture was warmed to room temperature,

quenched with H₂O (20 mL), and stirred overnight at room

temperature. The diethyl ether was removed in vacuo, and the

aqueous layer was adjusted to pH 10 (with 2 M NaOH) and

washed with diethyl ether. Then the aqueous layer was adjusted

to pH 3 (with 48% aq. HBr) and extracted with EtOAc (3 ꢀ

10 mL). The organic layers were combined, dried (MgSO₄),

filtered, and concentrated to afford 2-isopropoxy-5-pyridine-

boronic acid (0.42 g, 77%) as a colorless glass. ¹H NMR could

not be obtained. MS m/z 182.1 [M þ H]^þ.

2-(4-((4-(4-((Piperidin-1-yl)methanone)phenyl)-5-(4-(trifluoro-

methoxy)phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic

1

Acid (35w). H NMR (400 MHz, CD₃OD) δ = 7.57 (d, J =

8.4 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H),

7.29 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 2.8 Hz, 1H), 6.86-6.77

(m, 2H), 5.37 (s, 2H), 4.63 (s, 2H), 3.70(bs, 2H), 3.39 (bs, 2H),

2.26 (s, 3H), 1.72-1.54 (m, 6H). MS m/z 627.1 [M þ H]^þ.

HRMS calcd C₃₂H₃₀F₃N₂O₆S [M þ H]^þ627.1772; found

627.1777.

2-(4-((4-(4-Isopropoxyphenyl)-5-(4-(trifluoromethoxy)phenyl)-

oxazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35aa). ¹H

NMR (400 MHz, CD₃OD) δ = 7.69 (d, J = 8.8 Hz, 2H), 7.50

(d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz,

2H), 6.93 (d, J = 3.2 Hz, 1H), 6.87-6.77 (m, 2H), 5.18 (s, 2H),

4.69 (m, 1H), 4.59 (s, 2H), 2.26 (s, 3H), 1.35 (d, J = 6.0 Hz, 6H).

MS m/z 558.2 [M þ H]^þ. HRMS calcd C₂₉H₂₇F₃NO₇[M þ H]^þ

558.1734; found 558.1733.

Compounds 38a-ah were prepared following the synthetic

procedure of 35a using the appropriate bromothiazole or bro-

mooxazole intermediates and boronic acids.

2-(4-((4-(Pyridin-3-yl)-5-(4-(trifluoromethoxy)phenyl)thiazol-

2-yl)methoxy)-2-methylphenoxy)acetic Acid (38a). ¹H NMR

(400 MHz, CD₃OD) δ = 8.68 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H),

8.11 (dd, J = 1.8 Hz, J = 8.2 Hz, 1H), 7.60-7.56 (m, 1H), 7.47 (d,

J = 8.8 Hz, 2H), 7.32 (d, J= 8.8 Hz, 2H), 6.88 (d, J= 2.8 Hz, 1H),

2-(4-((4-(4-(Piperidin-1-yl)phenyl)-5-(4-(trifluoromethoxy)-

phenyl)oxazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (35ab).

¹H NMR (400 MHz, CD₃OD) δ = 7.73-7.68 (m, 4H), 7.50 (d,

J = 8.8 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 6.93 (d, J= 2.8 Hz, 1H),

100 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Epple et al.

6.81-6.70 (m, 2H), 5.34 (s, 2H), 4.56 (s, 2H), 2.16 (s, 3H). MS

m/z 516.9 [M þ H]^þ. HRMS calcd C₂₅H₂₀F₃N₂O₅S [M þ H]^þ

517.1040; found 517.1036.

5.11 (s, 2H), 4.54 (s, 2H), 3.85 (s, 3H), 2.16 (s, 3H). MS m/z 531.1

[M þ H]^þ. HRMS calcd C₂₆H₂₂F₃N₂O₇[M þ H]^þ531.1374;

found 531.1373.

2-(4-((4-(Pyrimidin-5-yl)-

2-(4-((4-(2-Methoxypyrimidin-5-yl)-5-(4-(trifluoromethoxy)-

phenyl)oxazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (38ad).

¹H NMR (400 MHz, CD₃OD) δ = 8.66 (s, 2H), 7.62 (d, J =

8.8 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 2.8 Hz, 1H),

6.77-6.66 (m, 2H), 5.11 (s, 2H), 4.53 (s, 2H), 3.96 (s, 3H), 2.15

(s, 3H). MS m/z 532.1 [M þ H]^þ. HRMS calcd C₂₅H₂₁F₃N₃O₇

[M þ H]^þ532.1326; found 532.1322.

5-(4-(trifluoromethoxy)phenyl)thiazol-2-yl)methoxy)-2-methylphe-

noxy)acetic Acid (38b). ¹H NMR (400 MHz, CD₃OD) δ = 9.24 (s,

1H), 8.98 (s, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz,

2H), 7.08 (d, J = 2.8 Hz, 1H), 7.02-6.90 (m, 2H), 5.56 (s, 2H),

4.67 (s, 2H), 2.39 (s, 3H). MS m/z 518.1 [M þ H]^þ. HRMS calcd

C₂₄H₁₉F₃N₃O₅S [M þ H]^þ518.0992; found 518.0987.

{4-[4-(6-Methoxypyridin-3-yl)-5-(4-trifluoromethoxyphenyl)-

thiazol-2-ylmethoxy]-2-methylphenoxy}acetic Acid (38c). ¹H

NMR (400 MHz, CD₃OD) δ = 8.13 (d, J = 2.0 Hz, 1H),

7.72 (dd, J = 2.4 Hz, J = 8.4 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H),

7.24 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 2.8 Hz, 1H), 6.77-6.68

(m, 3H), 5.27 (s, 2H), 4.54 (s, 2H), 3.83 (s, 3H), 2.17 (s, 3H). MS

m/z 547.1 [M þ H]^þ. HRMS calcd C₂₆H₂₂F₃N₂O₆S [M þ H]^þ

547.1145; found 547.1142.

{4-[4-(6-Isopropoxypyridin-3-yl)-5-(4-trifluoromethoxyphenyl)-

oxazol-2-ylmethoxy]-2-methylphenoxy}acetic Acid (38ae). ¹H

NMR (400 MHz, CD₃OD) δ = 8.36 (d, J = 2.4 Hz, 1H), 7.90

(dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 2H),

7.38 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 3.2 Hz, 1H), 6.88-6.77

(m, 3H), 5.28 (m, 1H), 5.20 (s, 2H), 4.63 (s, 2H), 2.26 (s, 3H),

1.38 (d, J = 6.0 Hz, 6H). MS m/z 558.9 [M þ H]^þ. HRMS

calcd C₂₈H₂₆F₃N₂O₇[M þ H]^þ559.1687; found 559.1681.

2-(4-((4-(2-Isopropoxypyrimidin-5-yl)-5-(4-(trifluoromethoxy)-

phenyl)oxazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (38af).

¹H NMR (400 MHz, CDCl₃) δ=8.75(s,2H), 7.96(d, J =8.7 Hz,

1H), 7.60 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.25 (d,

J = 8.6 Hz, 1H), 6.90-6.68 (m, 3H), 5.32 (m, 1H), 5.16 (s, 2H),

4.64 (s, 2H), 2.28 (s, 3H), 1.42 (d, J = 6.2 Hz, 6H). MS m/z 560.2

[M þ H]^þ. HRMS calcd C₂₇H₂₅F₃N₃O₇[M þ H]^þ560.1639;

found 560.1635.

2-(4-((4-(2-Methoxypyrimidin-5-yl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (38d).

¹H NMR (400 MHz, CD₃OD) δ = 8.53 (s, 2H), 7.44 (d, J = 8.8

Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 2.8 Hz, 1H),

6.77-6.68 (m, 2H), 5.29 (s, 2H), 4.54 (s, 2H), 3.93 (s, 3H), 2.17 (s,

3H). MS m/z 548.1 [M þ H]^þ. HRMS calcd C₂₅H₂₁F₃N₃O₆S

[M þ H]^þ548.1098; found 548.1093.

2-(4-((4-(6-Isopropoxypyridin-3-yl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (38e).

¹H NMR (400 MHz, CDCl₃) δ = 8.48 (m, 1H), 7.77 (m, 1H),

7.32-7.16 (m, 5H), 6.80-6.64 (m, 3H), 5.31 (m, 2H), 5.25 (s,

2H), 4.58 (s, 2H), 3.77 (m, 4H), 2.21 (s, 3H), 1.38 (d, J = 6.1 Hz,

6H). MS m/z 575.1 [M þ H]^þ. HRMS calcd C₂₈H₂₆F₃N₂O₆S

[M þ H]^þ575.1458; found 575.1452.

2-(4-((4-(6-Morpholinopyridin-3-yl)-5-(4-(trifluoromethoxy)-

phenyl)oxazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (38ag).

¹H NMR (400 MHz, CDCl₃) δ = 8.36 (s, 1H), 7.37 (dd, J =

2.2 Hz, J = 9.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.27 (d, J =

8.5 Hz, 2H), 6.91-6.68 (m, 3H), 5.15 (s, 2H), 4.64 (s, 2H), 3.89 (m,

4H), 3.72 (m, 4H), 2.26 (s, 3H). MS m/z 586.3 [M þ H]^þ. HRMS

calcd C₂₉H₂₇F₃N₃O₇[M þ H]^þ586.1796; found 586.1791.

2-(4-((4-(2-Morpholinopyrimidin-5-yl)-5-(4-(trifluoromethoxy)-

phenyl)oxazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (38ah).

¹H NMR (400 MHz, CDCl₃) δ=8.33(s,2H), 7.37(d, J =8.3 Hz,

2H), 7.00 (d, J = 8.3 Hz, 2H), 6.64-6.43 (m, 3H), 4.90 (s, 2H),

4.38 (s, 2H), 3.61 (m, 4H), 3.55 (m, 4H), 2.02 (s, 3H). MS m/z 587.2

[M þ H]^þ. HRMS calcd C₂₈H₂₆F₃N₄O₇[M þ H]^þ587.1748;

found 587.1747.

2-(4-((4-(2-Isopropoxypyrimidin-5-yl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (38f).

MS m/z 576.1 [M þ H]^þ. HRMS calcd C₂₇H₂₅F₃N₃O₆S [M þ H]^þ

576.1411; found 576.1408.

2-(4-((4-(6-Morpholinopyridin-3-yl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (38g).

¹H NMR (400 MHz, CDCl₃) δ = 8.39 (d, J = 2.1 Hz, 1H), 7.83

(m, 1H), 7.51-7.35 (m, 4H), 6.99-6.82 (m, 4H), 5.41 (s, 2H), 4.77

(s, 2H), 3.98 (m, 4H), 3.79 (m, 4H), 2.40 (s, 3H). MS m/z 602.2

[M þ H]^þ. HRMS calcd C₂₉H₂₆F₃N₃O₆S [M þ H]^þ602.1567;

found 602.1564.

2-(4-((4-(2-Morpholinopyrimidin-5-yl)-5-(4-(trifluoromethoxy)-

phenyl)thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (38h).

¹H NMR (400 MHz, CDCl₃) δ = 8.48 (s, 2H), 7.40 (d, J =

8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.89 (s, 1H), 6.79 (d, J =

7.3 Hz, 1H), 6.71 (d, J = 7.3 Hz, 1H), 5.32 (s, 2H), 4.64 (s, 2H),

3.82 (m, 4H), 3.78 (m, 4H), 2.29 (s, 3H). MS m/z 603.3 [M þ H]^þ.

HRMS calcd C₂₈H₂₆F₃N₄O₆S [M þ H]^þ603.1520; found

603.1517.

2-(4-((4-(Pyridin-3-yl)-5-(4-(trifluoromethoxy)phenyl)oxazol-

2-yl)methoxy)-2-methylphenoxy)acetic Acid (38aa). ¹H NMR

(400 MHz, CD₃OD) δ = 8.89 (bs, 1H), 8.69 (bs, 1H), 8.13 (d,

J = 7.6 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.61-7.52 (m, 3H),

7.05 (d, J = 2.0 Hz, 1H), 6.99-6.88 (m, 2H), 5.33 (s, 2H), 4.73 (s,

2H), 2.33 (s, 3H). MS m/z 501.1 [M þ H]^þ. HRMS calcd

C₂₅H₂₀F₃N₂O₆[M þ H]^þ501.1268; found 501.1270.

2-(4-((4-(Pyrimidin-5-yl)-5-(4-(trifluoromethoxy)phenyl)oxazol-

2-yl)methoxy)-2-methylphenoxy)acetic Acid (38ab). ¹H NMR

(400 MHz, CD₃OD) δ = 9.09 (s, 1H), 8.92 (s, 2H), 7.67 (d, J =

8.8 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 2.4 Hz, 1H),

6.81-6.70 (m, 2H), 5.17 (s, 2H), 4.55 (s, 2H), 2.16 (s, 3H). MS

m/z 502.1 [M þ H]^þ. HRMS calcd C₂₄H₁₉F₃N₃O₆[M þ H]^þ

502.1221; found 502.1212.

2-Bromomethyl-4-(4-methoxyphenyl)-5-(4-trifluoromethyl-

phenyl)thiazole (39). 2-Bromo-1-(4-methoxyphenyl)ethanone

(25.0 g, 109 mmol) and thioacetamide (9.0 g, 120 mmol) were

dissolved in EtOH (60 mL) and heated to reflux for 2 h. The

mixture was concentrated to give crude 4-(4-methoxyphenyl)-

2-methylthiazole, which was dissolved in DCM (300 mL).

Bromine (6.20 mL, 120 mmol) was added, and the mixture

was heated at 40 ꢀC for 3 h. The mixture was diluted

with saturated NaHCO₃(100 mL), extracted into DCM,

and washed with brine (50 mL). The organic layer was

dried (MgSO₄), filtered, and concentrated to give 5-bromo-

4-(4-methoxyphenyl)-2-methylthiazole (31.0 g, quant). ¹H

NMR (400 MHz, CDCl₃) δ = 7.89 (d, J = 8.8 Hz, 2H),

7.04 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.26 (s, 3H). MS m/z

283.9 [M þ H]^þ.

5-Bromo-4-(4-methoxyphenyl)-2-methylthiazole (4 g, 14.1

mmol), 4-trifluoromethylphenylboronic acid (3.2 g, 16.9 mmol),

and sodium carbonate (4.5 g, 42.3 mmol) were dissolved in a

mixture of H₂O (12.6 mL), EtOH (9.3 mL), and 1,2-dimethoxy-

ethane (37.8 mL) in a sealed tube. Pd(PPh₃)₄(490 mg,

0.42 mmol) was added, and the mixture was subjected to micro-

wave irradiation (170 ꢀC, 10 min). Then the mixture was diluted

with H₂O (50 mL), extracted into EtOAc (200 mL), and washed

withbrine (50mL). The organic layer was dried (MgSO₄), filtered,

concentrated, and purified by flash column chromatography

(silica, EtOAc/hexane gradient) to afford 4-(4-methoxyphenyl)-

2-(4-((4-(6-Methoxypyridin-3-yl)-5-(4-(trifluoromethoxy)-

phenyl)oxazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (38ac).

¹H NMR (400 MHz, CD₃OD) δ = 8.28 (d, J = 2.4 Hz, 1H), 7.79

(dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.30

(d, J = 8.4 Hz, 2H), 6.85 (d, J = 2.8 Hz, 1H), 6.81-6.68 (m, 3H),

1

2-methyl-5-(4-trifluoromethylphenyl)thiazole (3.66 g, 74%): H

NMR (400 MHz, CDCl₃) δ = 7.54 (d, J = 8.0 Hz, 2H), 7.42 (d,

J = 8.0 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz,

2H), 3.81 (s, 3H), 2.77 (s, 3H). MS m/z 350.0 [M þ H]^þ.

Article

4-(4-Methoxyphenyl)-2-methyl-5-(4-trifluoromethylphenyl)-

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 101

[M þ H]^þ. HRMS calcd C₂₉H₂₇F₃NO₅S [M þ H]^þ558.1557;

found 558.1555.

thiazole (3.66 g, 10.5 mmol) and N-bromosuccinimide (2.05 g,

11.5 mmol) were dissolved in carbon tetrachloride (60 mL) and

heated to 50 ꢀC. Azo-bis-isobutyronitrile (172 mg, 1.0 mmol)

was dissolved in carbon tetrachloride (10 mL) and added

dropwise to the reaction mixture. Then it was heated to 60 ꢀC

for 16 h. The reaction mixture was diluted with saturated

NaHCO₃, extracted into DCM, and washed with brine

(50 mL). The organic layer was dried (MgSO₄), filtered, con-

centrated, and purified by flash chromatography (silica, EtOAc/

hexane gradient) to afford 39 (2.6 g, 58%). ¹H NMR (400 MHz,

CDCl₃) δ = 7.50 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H),

7.32 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 4.69 (s, 2H),

3.74 (s, 3H). MS m/z 428.0 [M þ H]^þ.

{4-[4-(4-Methoxyphenyl)-5-(4-trifluoromethylphenyl)thiazol-

2-ylmethoxy]-2-propylphenoxy}acetic Acid (40f). ¹H NMR

(400 MHz, CDCl₃) δ = 7.56 (d, J = 8.4 Hz, 2H), 7.43 (d,

J = 8.0 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 3.0 Hz,

1H), 6.86 (d, J = 8.8 Hz, 2H), 6.79 (dd, J = 3.0, 9.0 Hz, 1H),

6.71 (d, J = 9.0 Hz, 1H), 5.37 (s, 2H), 4.63 (s, 2H), 3.82 (s, 3H),

2.63 (t, J = 7.6 Hz, 2H), 1.63 (m, 2H), 0.95 (t, J = 7.4 Hz,

3H). MS m/z 558.2 [M þ H]^þ. HRMS calcd C₂₉H₂₇F₃NO₅S

[M þ H]^þ558.1557; found 558.1555.

2-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)-3-methylphenoxy)acetic Acid (40g). ¹H

NMR (400 MHz, CDCl₃) δ = 7.57 (d, J = 8.4 Hz, 2H), 7.46

(d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 6.86 (d, J =

8.8 Hz, 2H), 6.84 (m, 2H), 6.71 (dd, J = 3.2, 8.8 Hz, 1H), 5.36

(s, 2H), 4.63 (s, 2H), 3.82 (s, 3H), 2.31 (s, 3H). MS m/z 530.1

[M þ H]^þ. HRMS calcd C₂₇H₂₃F₃NO₅S [M þ H]^þ530.1244;

found 530.1243.

2-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)phenoxy)acetic Acid (40a). Methyl 2-

(4-hydroxyphenoxy)acetate (21 mg, 0.12 mmol) and 2-bro-

momethyl-4-(4-methoxyphenyl)-5-(4-trifluoromethylphenyl)-

thiazole 39 (0.034 g, 0.079 mmol) were dissolved in MeCN

(1.5 mL). Cesium carbonate (0.047 g, 0.14 mmol) was added,

and the mixture was vigorously stirred at room temperature

for 3 h. The reaction mixture was acidified with 1 N HCl

(5 mL), then extracted with DCM, dried (MgSO₄), and con-

centrated to give the ester as an oil. The ester was dissolved in

THF (3 mL), treated with 1 N LiOH (0.3 mL), and stirred at

room temperature for 6 h. Then the reaction mixture was

acidified with 1 N HCl (5 mL), extracted with EtOAc (10 mL),

dried (MgSO₄), filtered, concentrated, and purified on reverse

phase HPLC to afford 40a (56 mg, 92%) as an off-white

solid: ¹H NMR (400 MHz, CDCl₃) δ = 7.56 (d, J = 8.2 Hz,

2H), 7.44 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 6.98

(d, J = 9.1 Hz, 2H), 6.89 (d, J = 9.1 Hz, 2H), 6.85 (d, J =

8.8 Hz, 2H), 5.35 (s, 2H), 4.62 (s, 2H), 3.83 (s, 3H). MS m/z

516.3 [M þ H]^þ. HRMS calcd C₂₆H₂₁F₃NO₅S [M þ H]^þ

516.1087; found 516.1086.

2-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methylthio)-2-methylphenoxy)acetic Acid (40h).

¹H NMR (400 MHz, CDCl₃) δ = 7.30 (d, J = 8.4 Hz, 2H),

7.14 (d, J = 8.0 Hz, 2H), 7.05 (m, 4H), 6.58 (d, J = 8.8 Hz,

2H), 6.41 (d, J = 8.4 Hz, 1H), 4.41 (s, 2H), 4.16 (s, 2H), 3.56

(s, 3H), 2.01 (s, 3H). MS m/z 546.3 [M þ H]^þ. HRMS calcd

C

₂₇H₂₃F₃NO₄S₂[M þ H]^þ546.1015; found 546.1017.

3-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)-2-methylphenyl)propanoic Acid (40i).

¹H NMR (400 MHz, CD₃CN) δ = 7.64 (d, J = 8.0 Hz,

2H), 7.51 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.10

(d, J = 8.4 Hz, 1H), 6.89 (d, J = 2.8 Hz, 1H), 6.83 (d, J =

8.8 Hz, 2H), 6.83 (dd, J = 2.8, 8.4 Hz, 1H), 5.36 (s, 2H), 3.78

(s, 3H), 2.83 (t, J = 7.2 Hz, 2H), 2.52 (t, J = 7.2 Hz, 2H), 2.29

(s, 3H). MS m/z 528.2 [M þ H]^þ. HRMS calcd C₂₈H₂₅F₃-

NO₄S [M þ H]^þ528.1451; found 528.1451.

Compounds 40b-s were prepared according to the pro-

cedure for 40a, using the appropriate phenol or thiophenol

headgroups.

3-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)-2-(trifluoromethyl)phenyl)propanoic Acid

1

(40j). H NMR (400 MHz, CDCl₃) δ = 7.57 (d, J = 8.4 Hz,

2-(3-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)phenoxy)acetic Acid (40b). ¹H NMR

(400 MHz, CDCl₃) δ = 7.56 (d, J = 8.4 Hz, 2H), 7.44 (d,

J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz,

1H), 6.85 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.0 Hz, 1H), 6.66

(dd, J = 2.8, 8.8 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 5.39 (s,

2H), 4.65 (s, 2H), 3.82 (s, 3H). MS m/z 516.3 [M þ H]^þ.

HRMS calcd C₂₆H₂₁F₃NO₅S [M þ H]^þ516.1087; found

516.1084.

2-(2-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)phenoxy)acetic Acid (40c). ¹H NMR

(400 MHz, CDCl₃) δ = 7.56 (d, J = 8.4 Hz, 2H), 7.43 (d,

J = 8.4 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.10 (dd, J = 2.0

Hz, 8.8 Hz, 1H), 7.01 (m, 3H), 6.85 (d, J = 8.8 Hz, 2H), 5.49

(s, 2H), 4.71 (s, 2H), 3.81 (s, 3H). MS m/z 516.3 [M þ H]^þ.

HRMS calcd C₂₆H₂₁F₃NO₅S [M þ H]^þ516.1087; found

516.1083.

2-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)thia-

zol-2-yl)methoxy)phenoxy)-2-methylpropanoic Acid (40d). ¹H

NMR (400 MHz, CDCl₃) δ = 7.55 (d, J = 8.2 Hz, 2H), 7.44

(d, J = 8.2Hz, 2H), 7.40 (d, J = 8.8Hz, 2H), 6.92 (s, 4H), 6.84 (d,

J = 8.8 Hz, 2H), 5.34 (s, 2H), 3.81 (s, 3H), 1.52 (s, 6H). MS

m/z 544.4 [M þ H]^þ. HRMS calcd C₂₈H₂₅F₃NO₅S [M þ H]^þ

544.1401; found 544.1397.

2-Ethoxy-3-(4-(5-(4-(trifluoromethyl)phenyl)-4-(4-methoxy-

phenyl)thiazol-2-yl)methoxyphenyl)propanoic Acid (40e). ¹H

NMR (400 MHz, CDCl₃) δ = 7.57 (d, J = 8.4 Hz, 2H), 7.43

(d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.21 (d, J =

8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H),

5.42 (s, 2H), 4.08 (dd, J = 7.6, 4.4 Hz, 1H), 3.83 (s, 3H), 3.61

(m, 1H), 3.47 (m, 1H), 3.10 (dd, J = 14.4, 4.4 Hz, 1H), 2.98 (dd,

J = 14.4, 7.6 Hz, 1H), 1.18 (t, J = 7.2 Hz, 3H). MS m/z 558.1

2H), 7.46 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.34

(s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.15 (dd, J = 8.4, 2.8 Hz, 1H),

6.88 (d, J = 8.8 Hz, 2H), 5.41 (s, 2H), 3.82 (s, 3H), 3.10 (t, J =

7.6 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H). MS m/z 568.1 [M þ H]^þ.

HRMS calcd C₂₇H₂₀F₆NO₄S [M þ H]^þ582.1169; found

582.1169.

2-(1-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)naphthalen-4-yloxy)acetic Acid (40k).

¹H NMR (400 MHz, CDCl₃) δ = 8.33 (m, 1H), 8.27 (m,

1H), 7.59 (m, 4H), 7.48 (d, J = 8.1 Hz, 2H), 7.43 (d, J =

8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.6 Hz, 1H),

6.70 (d, J = 8.6 Hz, 1H), 5.51 (s, 2H), 4.83 (s, 2H), 3.83 (s,

3H). MS m/z 566.4 [M þ H]^þ. HRMS calcd C₃₀H₂₃F₃NO₅S

[M þ H]^þ566.1244; found 566.1243.

2-(2-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)naphthalen-5-yl)acetic Acid (40l). ¹H

NMR (400 MHz, CDCl₃) δ = 7.87 (d, J = 10.0 Hz, 1H),

7.64 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.36 (m,

5H), 7.23 (m, 3H), 6.79 (d, J = 8.8 Hz, 2H), 5.44 (s, 2H), 3.99

(s, 2H), 3.75 (s, 3H). MS m/z 550.2 [M þ H]^þ. HRMS calcd

C

₃₀H₂₃F₃NO₄S [M þ H]^þ550.1295; found 550.1291.

2-(5-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)-1H-indol-1-yl)acetic Acid (40m). ¹H

NMR (400 MHz, CDCl₃) δ = 7.49 (d, J = 8.3 Hz, 2H),

7.38 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.18-6.91

(m, 4H), 6.79 (d, J = 8.8 Hz, 2H), 6.45 (d, J = 3.1 Hz, 2H),

5.36 (s, 2H), 4.81 (s, 2H), 3.76 (s, 3H). MS m/z 539.1 [M þ H]^þ.

HRMS calcd C₂₈H₂₂F₃N₂O₄S [M þ H]^þ539.1247; found

539.1246.

5-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)thia-

zol-2-yl)methoxy)benzofuran-2-carboxylic Acid (40n). ¹H NMR

(400 MHz, CDCl₃) δ = 7.73 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H),

102 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1

Epple et al.

7.44 (d, J = 7.6 Hz, 1H), 7.33 (m, 4H), 7.22 (d, J = 8.0 Hz, 1H),

6.94 (d, J = 8.4 Hz, 2H), 5.79 (s, 2H), 3.90 (s, 3H). MS m/z 526.1

[M þ H]^þ. HRMS calcd C₂₇H₁₉F₃NO₅S [M þ H]^þ526.0931;

found 526.0924.

5-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)thiazol-

2-yl)methoxy)-2,3-dihydrobenzofuran-2-carboxylic Acid (40o).

¹H NMR (400 MHz, CDCl₃) δ = 7.58 (d, J = 8.0 Hz, 2H),

7.42 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 6.4 Hz, 2H), 6.92-6.84 (m,

5H), 5.43 (s, 2H), 5.25 (dd, J = 6.4, 10.4 Hz, 1H), 3.83 (s, 3H),

3.62 (dd, J = 10.8, 16.0 Hz, 1H), 3.41 (dd, J = 5.6, 16.0 Hz, 1H).

MS m/z 528.0 [M þ H]^þ. HRMS calcd C₂₇H₂₁F₃NO₅S [M þ H]^þ

528.1087; found 528.1082.

2-(4-((4-(4-Isopropoxyphenyl)-5-(4-biphenyl)thiazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (44). ¹H NMR

(400 MHz, CD₃OD) δ = 7.61-7.57 (m, 4H), 7.40-7.35 (m,

6H), 7.29 (t, J = 6.8 Hz, 1H), 6.88 (d, J = 2.8 Hz, 1H),

6.80-6.71 (m, 4H), 5.28 (s, 2H), 4.56 (s, 2H), 4.53 (m,

1H), 2.17 (s, 3H), 1.22 (s, 3H), 1.21 (s, 3H). MS m/z 566.2

[M þ H]^þ. HRMS calcd C₂₉H₂₇F₃NO₆S [M þ H]^þ566.1996;

found 566.1994.

2-(4-((4-(4-Morpholinophenyl)-5-(4-biphenyl)thiazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (45). ¹H NMR (400

MHz, CDCl₃) δ = 7.52 (d, J = 8.4 Hz, 2H), 7.47 (t, J =

8.4 Hz, 4H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 (m, 3H), 7.04 (d,

J = 8.8 Hz, 2H), 6.81 (d, J = 2.8 Hz, 1H), 6.70 (dd, J = 2.8,

8.8 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.27 (s, 2H), 4.55 (s,

2H), 3.90 (m, 4H), 3.26 (m, 4H), 2.20 (s, 3H). MS m/z 593.2

[M þ H]^þ. HRMS calcd C₃₅H₃₃N₂O₅S [M þ H]^þ593.2105;

found 593.2103.

2-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)thiazol-

2-yl)methoxy)phenyl)acetic Acid (40p). ¹H NMR (400 MHz,

CDCl₃) δ = 7.56 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H),

7.40 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 10.0 Hz, 2H), 7.01 (d, J =

8.7 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.40 (s, 2H), 3.82 (s, 3H), 3.62

(s, 2H). MS m/z 500.3 [M þ H]^þ. HRMS calcd C₂₆H₂₁F₃NO₄S

[M þ H]^þ500.1138; found 500.1135.

2-(4-((5-(4-Biphenyl)-4-(pyridin-3-yl)oxazol-2-yl)methoxy)-2-

methylphenoxy)acetic Acid (46). ¹H NMR (400 MHz, CD₃OD)

δ = 8.89 (bs, 1H), 8.64 (bs, 1H), 8.22 (d, J = 8.0 Hz, 1H),

7.80-7.56 (m, 7H), 7.49 (t, J = 7.4 Hz, 2H), 7.40 (t, J = 7.0 Hz,

1H), 6.96 (d, J = 2.8 Hz, 1H), 6.91-6.79 (m, 2H), 5.25 (s, 2H),

4.64 (s, 2H), 2.24 (s, 3H). MS m/z 493.0 [M þ H]^þ. HRMS calcd

C₃₀H₂₅N₂O₆[M þ H]^þ493.1758; found 493.1755.

2-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)-2-methylphenyl)acetic Acid (40q). ¹H

NMR (400 MHz, CDCl₃) δ = 7.56 (d, J = 8.4 Hz, 2H),

7.44 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.16 (d, J =

8.4 Hz, 1H), 6.90 (m, 1H), 6.85 (m, 3H), 5.40 (s, 2H), 3.82 (s,

3H), 3.64 (s, 2H), 1.32 (s, 3H). MS m/z 514.1 [M þ H]^þ.

HRMS calcd C₂₇H₂₃F₃NO₄S [M þ H]^þ514.1295; found

514.1294.

2-(4-((4-(2-Methoxypyrimidin-5-yl)-5-(4-propylphenyl)oxazol-

2-yl)methoxy)-2-methylphenoxy)acetic Acid (47). ¹H NMR

(400 MHz, CD₃OD) δ = 8.66 (s, 2H), 7.41 (d, J = 8.0 Hz,

2H), 7.21 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 2.8 Hz, 1H),

6.77-6.67 (m, 2H), 5.09 (s, 2H), 4.53 (s, 2H), 3.95 (s, 3H), 2.56

(t, J = 7.6 Hz, 2H), 2.16 (s, 3H), 1.61-1.55 (m, 2H), 0.87 (t, J =

7.4 Hz, 3H). MS m/z 490.2 [M þ H]^þ. HRMS calcd C₂₇H₂₈N₃O₆

[M þ H]^þ490.1973; found 490.1969.

2-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methoxy)-3-chlorophenyl)acetic Acid (40r). ¹H

NMR (400 MHz, CDCl₃) δ = 7.56 (d, J = 8.4 Hz, 2H),

7.46 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.36 (d, J =

2.0 Hz, 1H), 7.16 (dd, J = 2.0, 8.4 Hz, 1H), 7.03 (d, J = 8.4

Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 5.46 (s, 2H), 3.82 (s, 3H),

3.59 (s, 2H). MS m/z 534.3 [M þ H]^þ. HRMS calcd

C₂₆H₂₀ClF₃NO₄S [M þ H]^þ534.0749; found 534.0751.

2-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-methoxyphenyl)-

thiazol-2-yl)methylthio)-3-chlorophenyl)acetic Acid (40s). ¹H

NMR (400 MHz, CDCl₃) δ = 7.46 (d, J = 8.0 Hz, 2H), 7.29

(m, 6H), 7.06 (dd, J = 1.6, 8.0 Hz, 1H), 6.76 (d, J = 8.8 Hz,

2H), 4.44 (s, 2H), 3.73 (s, 3H), 3.52 (s, 2H). MS m/z 550.3

[M þ H]^þ. HRMS calcd C₂₆H₂₀ClF₃NO₃S₂[M þ H]^þ

550.0520; found 550.0522.

Biology. Transactivation Reporter Gene Assay. GAL4-

hPPARRLBD, GAL4-hPPARγLBD, and GAL4-hPPARδLBD

constructs were as described previously. The reporter construct,

pG5-Luc was purchased from Promega (catalog no. E2440) and

contains five copies of GAL4 binding sites followed by a TATA

box and the firefly luciferase gene. 293T cells were grown to

60-70% confluence prior to transfection in 10% FBS DMEM

þ 1% Antibiotic-Antimycotic. Briefly, cells were washed with PBS

(pH 7.2) and trypsinized. The cells were subsequently resuspended

in 5% charcoal-dextran treated FBS (Hyclone catalog no.

SH30068.03) in DMEM medium. Cells were then transfected in

suspension using 9 μL of Fugene6 þ 3 μg of DNA (1:3 ratio of

GAL4-hPPAR/pg5-Luc) per 1 ꢀ 10⁶cells. Then 5000 cells/well

were plated in 384-well format. Following 6 h of incubation, cells

were treated with compounds diluted to a 1ꢀ final concentration

(final DMSO concentration was 1%). Plates were incubated for

18-20 h at 37 ꢀC, after which the cells were lysed with Britelite

reagent (Perkin-Elmer, catalog no. 6016979) diluted to 60% with

distilled H₂O, and the plates were read on the CLIPR (Molecular

Devices, Sunnyvale CA). Data were obtained in quadruplicate,

two replicate data points from one transfection and two from

another transfection performed on separate days. Data for each

day were averaged and normalized to the DMSO control using

Microsoft Excel. Coefficients of variation (CVs) were <15%

across two plates within the same day. EC₅₀values were generated

using Graphpad Prism, version 4, using the sigmoidal dose re-

sponse with variable slope equation. The bottom was fit to a

normalized value of 1 (DMSO control). The % efficacy was

calculated on the basis of the highest normalized activity of

GW501516 for the PPARδ assay, rosiglitazone for the PPARγ

assay, or KRP-927 for the PPARR assay, which represented 100%

efficacy in each case.

The syntheses of compounds 41-47 in Table 7 are according

to the general synthetic procedures described above, and analy-

tical data for these compounds are listed below. Analytical data

for entries 35h, 35aa, 35k, 35ac, 38c, 38ac, 38e, 38ae, 38f, and

38ag are listed above.

2-(4-((5-(4-(Trifluoromethyl)phenyl)-4-(4-isopropoxyphenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (41). ¹H

NMR (400 MHz, CDCl₃) δ = 7.70 (d, J = 8.0 Hz, 2H), 7.58

(d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 6.98 (d, J =

2.8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.90 (dd, J = 2.8, 8.8 Hz,

1H), 6.83 (d, J = 8.8 Hz, 1H), 5.41 (s, 2H), 4.67 (m, 3H), 2.32 (s,

3H), 1.37 (s, 3H), 1.36 (s, 3H). MS m/z 558.2 [M þ H]^þ. HRMS

calcd C₂₉H₂₇F₃NO₅S [M þ H]^þ558.1557; found 558.1551.

2-(4-((4-(4-Isopropoxyphenyl)-5-(3-(trifluoromethoxy)phenyl)-

thiazol-2-yl)methoxy)-2-methylphenoxy)acetic Acid (42). ¹H NMR

(400 MHz, CD₃OD) δ = 7.47 (t, J = 8.0 Hz, 1H), 7.39-7.34

(m, 3H), 7.26-7.24 (m, 1H), 7.17 (s, 1H), 6.94 (d, J = 3.2 Hz, 1H),

6.89-6.78 (m, 4H), 5.35 (s, 2H), 4.64 (s, 2H), 4.62 (m, 1H), 2.27 (s,

3H), 1.33 (s, 3H), 1.31 (s, 3H). MS m/z 574.2 [M þ H]^þ. HRMS

calcd C₂₉H₂₇F₃NO₆S [M þ H]^þ574.1506; found 574.1509.

2-(4-((4-(4-Isopropoxyphenyl)-5-(4-propylphenyl)thiazol-2-yl)-

methoxy)-2-methylphenoxy)acetic Acid (43). ¹H NMR (400 MHz,

CD₃OD) δ=7.26(d, J = 8.8 Hz, 2H), 7.13-7.04 (m, 4H), 6.81 (d,

J = 2.8 Hz, 1H), 6.74-6.66 (m, 2H), 5.21 (s, 2H), 4.52 (s, 2H),

4.51-4.46 (m, 1H), 2.49 (t, J = 7.6 Hz, 2H), 2.16 (s,

3H), 1.57-1.51 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H), 0.85 (t, J =

7.4 Hz, 3H). MS m/z 532.2 [M þ H]^þ. HRMS calcd C₃₁H₃₄NO₅S

[M þ H]^þ532.2152; found 532.2155.

Fluorescence Resonance Energy Transfer (FRET) Assay. The

binding of a ligand to a nuclear receptor induces a conforma-

tional change that leads to increased or decreased binding of

transcriptional coactivator and/or corepressor molecules. A

coactivator-dependent receptor ligand assay (CARLA), which

measures PPAR ligand-dependent coactivator recruitment in

Article

Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1 103

the TR_FRET format, was used to measure the binding of and

activation by PPAR ligands to the human PPARR LBD,

PPARγLBD, and PPARδ LBD. EC₅₀values were obtained as

mean values ( SEM from three independent measurements

and calculated with XLfit. The efficacy response is calculated

relative to the “y-range” or efficacy response of GW501516

(set as 100%).

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In Vivo Acute Dosing Induced Gene Assay. C57BL/6 male

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vehicle (0.5% carboxymethylcellulose (CMC), 2% Tween-80)

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Acknowledgment. All authors are currently or were

employees of The Genomics Institute of the Novartis

Research Foundation. We thank Diana Dubiel and Brian

Boettcher (Novartis International AG) for providing the

FRET assay data displayed in Table 7.

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Article Doi

Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor δ agonists

DOI: 10.1021/jm9007399

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Full text of DOI:10.1021/jm9007399

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