WO 2004/009086
PCT/IB2003/003349
2.
SELECTIVE ESTROGEN RECEPTOR MODULATORS CONTAINING A PHENYLSULFONYL GROUP
Background of the Invention
Uterine leiomyoma/leiomyomata (uterine fibroid disease) is a clinical problem that
goes under a variety of names, including uterine fibrosis, uterine hypertrophy, uterine
leiomyomata, myometrial hypertrophy, fibrosis uteri, and fibrotic metritis. Essentially,
uterine fibrosis is a condition where there is an inappropriate deposition of fibroid tissue
on the wall of the uterus. This condition is a cause of dysmenorrhea and infertility in
women.
Endometriosis is a condition of severe dysmenorrhea, which is accompanied by
severe pain, bleeding into the endometrial masses or peritoneal cavity and,often leads to
infertility. The symptoms' cause appears to be ectopic endometrial growths that respond
inappropriately to normal hormonal control and are located in inappropriate tissues.
Because of the inappropriate locations for endometrial growth, the tissue seems to initiate
local inflammatory-] ike responses causing macrophage infiltration and a cascade of events
leading to initiation of the painful response. Evidence suggests that a cause of uterine
fibrosis and endometriosis is an inappropriate response of fibroid tissue and/or
endometrial tissue to estrogen.
Many publications have appeared within the last ten years disclosing selective
estrogen receptor modulators (SERMs), e.g., U.S. Patent No.'s 5,484,795, 5,484,798,
5,510,358,5,998,401 and WO 96/09040. Many of these SERMs, generally speaking,
have been found to have a beneficial estrogen agonist activity in the bone and
cardiovascular systems with a concomitant beneficial estrogen antagonist activity in the
breast. A small, particularly useful subset of such compounds has also been found to have
an estrogen antagonist effect in the uterus. A compound with this SERM profile holds
particular promise in treating uterine fibroid disease and/or endometriosis.
However, the clinical use of such SERM compounds for the treatment of uterine
fibroid disease and/or endometriosis, particularly in pre-menopausal women, has been
hampered by the propensity of said compounds to have significant ovarian stimulatory
effects. A great need currently exists, therefore, for new SERM compounds that behave
as estrogen antagonists in the uterus that do not significantly stimulate the ovaries.

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Summary of Invention
The present invention relates to a compound of formula I:

wherein:
m, q and r are independently 0, 1 or 2;
n is 0 or 1;
R is H or COR2;
R0 is independently at each occurrence OH, CF3, halo, C\-Cft alkyl or
Cj-Cgalkoxy;
R1 and R1' are independently Cj-Cg alkyl, Cj-Cg alkoxy, NR3R3a, CF3
or CH2CF3; or when n and q are 0. the -SO2R1 moiety may combine with the phenyl ring
to which it is attached to form a moiety of formula (a) or (b):

wherein t and v are 0, 1 or 2 provided that the sum of t + v must be 2;
R2 is Cj-Cg alkyl; Cj-Cg alkoxy; NRR; phenoxy; or phenyl optionally
substituted with halo;
R3 is C]-Cg alkyl or phenyl;
Ra and R4 are independently at each occurrence H, Ci-Cg alkyl or
phenyl;
X is O, CH2 or CO;
xUsOorNRS;

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R5 is H or Ci-C6 alkyl;
R8 is H or methyl provided that if r is 1 or 2, then R8 must be H and that if
r is 0, then R° must be methyl; and
Y is S, CH2CH2 or CH=CH; or a pharmaceutical acid addition salt
thereof.
The present invention also relates to a pharmaceutical composition that comprises
a compound of formula I, or a pharmaceutical acid addition salt thereof* and a
pharmaceutical carrier. In another embodiment, the pharmaceutical composition of the
present invention may be adapted for use in treating endometriosis and/or uterine fibrosis.
The present invention also relates to methods for treating endometriosis and/or
uterine fibrosis employing a compound of formula I, or a pharmaceutical acid addition
salt thereof.
In addition, the present invention relates to a compound of formula I, or a
pharmaceutical acid addition salt thereof, for use in treating endometriosis and/or uterine
fibrosis. The present invention is further related to the use of a compound of formula I, or
a pharmaceutical acid addition salt thereof, for the manufacture of a medicament for
treating endometriosis and/or uterine fibrosis.
The present invention further relates to a compound of formula II:

wherein:
m, n, q. are as described above for the
formula I compound;
u is 0,1 or 2;
R is H, C1 -Cg alkyl, benzyl or COR2 wherein R is as described above
for the formula I compound;
X2 is O or NR?; and

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5R7 is H, C i -Cg alkyl or CO2(Ci -Cg alkyl); provided that u can only be 2
when is C1-Cg alkyl or benzyl; or art acid addition salt thereof; provided that the
compound of formula 11 is not:

useful, e.g., as chemical intermediates to the formula I compounds.
Detailed Description
For the purposes of the present invention, as disclosed and claimed herein, the
following terms are defined below.
The term "halo" refers to fluoro, chloro, bromo and iodo. The term "C]-Cg alkyl"
represents a straight, branched or cyclic hydrocarbon moiety having from one to six
carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-
butyl, t-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl and the like. Moieties
such as a cyclobutylmethylenyl are also included within the scope of a C1-Cg alkyl group.
The term "CJ-C4 alkyl" refers specifically to methyl, ethyl, n-propyl, isopropyl,
cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropylmethyl and cyclobutyl. A
"C1-Cg alkoxy" group is a C1-Cg alkyl moiety connected through an oxy linkage.
The term "pharmaceutical" when used herein as an adjective means substantially
non-deleterious.
Preferred Compounds Embodiments) of the Invention
Certain compounds of the invention are particularly interesting and are preferred.
The following listing sets out several groups of preferred compounds. It will be
understood that each of the listings may be combined with other listings to create
additional groups of preferred compounds.

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PCT/1B2003/003349

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a) m is 0 or 2;
b) m is 0;
c) m is 2;
d) n is 0;
e) n is 1;
f) q is 0 or 1;
g) q is 0;
h) r is 1;
i) r is 2;
j) R is H;
k) R is COR2;
1) R0 is OH, methoxy, CF3, fluoro, chloro, methyl or ethyl;
m) R0 is OH, CF3, fluoro, chloro, methyl or ethyl;
n) R0 is CF3 or fluoro;
0) the -SO2R1 moiety is at the para-position of the phenyl ring to which it is
attached;
p) the -SO2R' moiety does not combine with the phenyl ring to which it is
attached to form a moiety of formula (a) or (b);
q) RIisC1-C4alkylorCF3;
r) Rl is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-
butyl, t-butyl, cyclobutyl or CF3;
s) R* is methyl, ethyl, cyclopropyl or CF3;
t) R1 is methyl ethyl or CF3;
u) Rl is methyl;
v) R1 is ethyl;
w) Rl is cyclopropyl;
x) R1 is CF3;

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y) R1'isC]-C4alkylorCF3;
z) R*' is methyl ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-
butyl, t-butyl, cyclobutyl or CF3;
aa) Rl' is methyl, ethyl, cyclopropyl or CF3;
bb) R1' is methyl, ethyl or CF3;
cc) Rl'is methyl;
dd) R1' is ethyl;
ee) Rl is cyclopropyl;
ff) RisCF;
gg) R2 is Ci -C'6 alkyl or phenyl;
hh) R2 is C] -C6 alkyl, NHCH3 or phenyl;
ii) R2 is Cj -C4 alkyl, NHCH3 or phenyl;
jj) R is H, methyl or ethyl;
kk) R5 is H;
11) X is O:
mm) X* is O;
nn) X1 is NR5;
00) Y is S;
pp) Y is CH=CH;
qq) Y is CH2CH2;
rr) the compound of formula I is the hydrochloride salt.
Synthesis
The compound of formula I may be prepared as described in the following
Schemes, Preparations and Examples.

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8

In Scheme 1, a compound of formula IV is reacted with a compound of formula III
under usual "Suzuki" or "Stille" reaction conditions, i.e.,. wherein one of substituent "A"
or "D" is a boronic acid/ester or alkyl stannane moiety and the other is a leaving group,
e.g., chloro, bromo or iodo or a sulfonate group such as trifluoromethy] sulfonate. When
R0" is alkyl (preferably methyl) or benzyl, said R.6 groups may be removed under standard
conditions (see, e.g., the procedures that follow or the latest edition of Greene, Protective
Groups in Organic Synthesis, John Wiley & Sons, New York, N.Y.) to provide the
compound of formula I where R is H. When u is 0 or 1, the coupled product may be
oxidized under standard conditions (see preparations below) to prepare the corresponding

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9
mono or bis-sulfone of formula 1(a) where m is 2. A formula I or 1(a) compound where R
is H may then be further derivatized to prepare a compound of formula I where R is
COR2.

In Scheme 2, the compound of formula 1(b) is formed by first reacting a compound
of formula VI (prepared essentially as taught in U.S. Pat. No. 5,929,090 which is
incorporated herein by reference) with a compound of formula VIII under standard

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nucleophilic displacement conditions to give a product compound that may be deprotected
and further derivatizcd as described supra to give the compound of formula 1(b).
The compound of formula 1(c) may also be prepared from a compound of formula
Vas depictedin Scheme 2. The compound of formula VII may be prepared by first
reacting the compound of formula V with a base followed by the addition of 4-fluoro-
benzaldehyde. The product aldehyde may be converted to the corresponding
hydroxy/sulfonyl compound of formula VII by reaction, e.g., first with hydrogen peroxide
followed by reaction with sodium perborate monohydrate. The compound of formula VII
may then be reacted with a compound of formula VIII under standard nucleophilic
displacement conditions to give a product compound that maybe deprotected and further
derivatized as described supra to give the compound of formula 1(c).

In Scheme 3, an alternative preparation of a compound of formula I where R and
R.1' are independently C] -Cg alkyl, CF3 or CH2CF3 and the SO2RI moiety does not
combine with the R moiety is shown. A compound of formula IX (prepared in an
analogous fashion to the reaction of a compound of formula III with a compound of

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formula IV described in Scheme 1) may be reacted with the thiolate of a compound of the
formula HSR*a where Rla is C1-Cg alkyl, CF3 or CH2CF3, e.g., sodium methanethiolate
which results in displacement of the "Lg" substituent(s). The "Lg" moiety found in the
compound of formula IX is a substituent that activates the phenyl group to which it is
attached toward nuclcophilic aromatic substitution. The thioether formula X product may
then be oxidized to form the corresponding sulfone (or sulfoxide) compound that may be
deprotected and further derivatized as described supra to give the compound of formula
1(d). When more than Lg substituent may be introduced into a compound of formula IV,
the methodology of Scheme 3 is especially adaptable to prepare a compound of formula
1(e) where nisi and m is 0 or 1.
Compounds of formula III, IV and VIII maybe prepared as shown below or by
procedures analogous to those found in the art. Compounds of formula V may be
prepared by analogous procedures to those described in U.S. Pat. No. 5,929,090 or as
described below. Compounds of formula HSR*3 arc, in general, commercially available
or can be prepared by procedures readily available to the ordinarily skilled synthetic
organic chemist.
General Experimental Details
Electrospray mass spectra is obtained, e.g., on a Finnigan LCQ Duo instrument
using a mobile phase of 50% acetonitrile, 25% methanol, and 25% 2mM aqueous
ammonium acetate.
Preparative HPLC is performed, e.g., on a Gilson Preparative System with
Unipoint Software and dual wavelength detection at 220 and 254 ran as well as Finnigan
aQa MS. A 20-mm x 250-mm ODS-AQ column with a particle size of 15 microns may
be used as the stationary phase. The eluent is a binary system of bottle A (0.1 %
trifluoroacetic acid (TFA), 1 % isopropyl alcohol (IPA) in water) and bottle B (0.05%
TFA, 1% IP A in acetonitrile). The standard method is a gradient of 30-95% B unless
otherwise indicated. The compounds purified by this method were isolated as TFA salts.
Preparative HPLC's may also be performed on a Biotage ParallelFlex system with
proprietary dual wavelength detection and software. A 30-mm x 150-mm or 19-mm x
250 mm Xterra column with a particle size of 10 microns is used as the stationary phase

WO 2004/009086 PCT/IB2003/003349
12.
and 10mM NH/HCOO/ 10mM NH4OH is used as mobile phase A and 100% acetonitrile
is used as a mobile phase B.
Preparation 1
Trifluoro-methanesu 1 fonic acid 6-methoxy-1 -[4-(2-piperidin-1 -yl-ethoxy)-phenoxy] -
naphthalen-2-yl ester
Add 6-methoxynaphthalene-2-ol (20 g, 114.8 mmol) to dimethylformamide
(DMF, 250 mL) at ambient temperature followed by N-bromosuccinimide (NBS, 21.5 g,
120 mmol) over a 30 minute period. After 45 minutes, dilute with water (800 mL),
collect and dry the precipitate to provide 25.5 g (87%) of l-bromo-6-methoxy-naphthalen-
2-ol.
Add l-bromo-6-methoxy-naphthalen-2-ol (66.7 g, 264 mmol), potassium
carbonate (K2CO3, 40.0 g, 290 mmol) and benzyl bromide (49.6 g, 290.mmol) to DMF
(800 mL). Stir the mixture at ambient temperature for 1 hour. Add water (400 mL) to
precipitate the product. Collect the precipitate and wash the filter cake with heptane (3 X
125 mL) then dry to provide 83.7 g of 2-benzyloxy-l-bromo-6-methoxy-naphthalene
(86.2%).
Combine toluene (200 mL), 2-benzyloxy-l-bromo-6-methoxy-naphthalene (30 g,
87.4 mmol), 4-(2-pipcridin-l -yl-ethoxy)phenol (23.2 g, 105 mmol) and cesium carbonate
(34.4 g, 105 mmol), heal the mixture to reflux. Remove a portion of the toluene (100
mL). Add ethyl acetate (390 mg, 4.37 mmol) and copper triflate benzene complex (2.20
g, 4.37 mmol) to the reaction mixture and stir for 5 minutes. Remove the solvent by
distillation and heat the resulting residue to 174°C for 1,5 hours. Dissolve the residue in a
mixture of ethyl acetate (200 mL) and aqueous HC1 (1 N, 90 mL). Separate and
concentrate the organics to a residue. Column -chromatograph the residue to give 12.4 g
of l-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-l-yloxy)-phenoxy]-ethyl}-piperidine
(30%).
Add l-{2-[4-(2-benzyloxy-6-metlioxy-naphthalen-l-yloxy)-phenoxy]-ethyl}-
piperidine (12.4 g, 25.5 mmol) to a methanol/ethyl acetate mixture (1:1, 490 mL) and heat
to form a solution. Remove the heat and add ammonium formate (4.83 g, 76.6 mmol) and
Pd(OH)2 on Carbon (20 % ww, 1.58 g, 1.12 mmol). Reflux for 50 minutes then filter the

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mixture. Concentrate the filtrate to provide 9.9 g of 6-methoxy-l-[4-(2-piperidin-l-yl-
ethoxy)-phenoxy]-naphthalene-2-ol(98.5%).
Cool dichloromethane (290 mL), triethylamine (3.08 g, 30.4 mmol) and 6-
methoxy-l-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalene-2-61 (9.2 g, 23.4 g) to -
50°C and add trifluoromethanesulfonic acid anhydride (7.26 g, 25.7 mmol). Stir the
resulting mixture at -50°C for 2 hours then allow the mixture to warm to ambient
temperature before stirring an additional hour. Add brine (150 mL) and separate the
organics. Wash the organics with NaHCO3 then dry before concentrating to a residue.
Crystallized the residue with ethyl ether - hexanes to provide 11.2 g of the title compound
(90.9%).
Preparation 2
Trifiuoro-methanesulfonicacid6-hydroxy-l-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
naphthalen-2-yl ester
Add 2M hydrogen chloride in ether (1.5 mL, 3 mmol) to a solution of the
compound of Preparation 1 (1.07 g, 2.04 mmol) in dichloromethane (20 mL) and remove
solvent under vacuum. Dissolve the hydrochloride salt in dichloromethane (40 mL) and
cool in ice bath. Add boron tribromide (0.58 mL, 6.12 mmol), stir for 3.5 hours, warm to
ambient temperature and stir for 15 minutes, cool in ice bath and quench with ice cold
saturated aqueous sodium bicarbonate. Extract aqueous layer with dichloromethane,
combine organic layers and dry with magnesium sulfate, remove solvent under vacuum
and chromatograph on silica gel using dichlorornethane/methanol mixtures to give 990
mg of the title compound (95%).

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Preparation 3
Trifluoro-methanesulfonic acid 6-benzyloxy-l -[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
riaphthalen-2-yl ester
Combine trifluoromethanesulfonic acid 6-hydroxy-l-[4-(2-piperidin-l-yl-efhoxy)-
phenoxy]-naphthalen-2-yl ester (247 mg, 0.48 mniol), triphenylphosphine (190 mg, 0.725
mmol), benzyl alcohol (0.075 mL, 0.725 mmol) arid tetrahydrofuran (5 mL) in a flask
placed in an ice bath. Add diisopropyl azodicarboxylate (0.14 mL, 0.725'mmol), stir for 1
hour, warm to ambient temperature and stir for 30 minutes. Dilute with ethyl acetate and
wash with 50% saturated aqueous sodium bicarbonate, saturated aqueous sodium
chloride, dry with magnesium sulfate and remove solvent under vacuum. Chromatograph
on silica gel with dichloromethane/methanol mixtures to give 213 mg of the title
compound (73%).
Example 1
l-(2-{4-[2-(4-Methanesulfonyl-phenyl)-6-methoxy-naphthalen-l-yloxy]-phenoxy}-ethyl)-
piperidine

Combine 4-(methanesulfonyl)phenylboronic acid (6.8 g, 34 mmol), the compound
of Preparation 1 (6.6 g, 12.6 mmol), cesium fluoride (17.2 g, 113 mmol) and acetonitrile
(130 mL) in a 500 mL flame-dried flask fitted with a reflux condenser. In a separate flask
combine palladium (II) acetate (283 mg, 1.26 mmol) and tricyclohexylphosphine (530 mg,
1.9 mmol). Add acetonitrile (65 mL) and sonicate for 10 minutes under nitrogen. Add the
catalyst slurry to the mixture of substrates and heat in a 90°C oil bath for 30 minutes.
Cool the suspension to room temperature and filter through packed celite. Rinse the celite
with ethyl acetate and wash the filtrate with a 50:50 mixture of water and saturated
aqueous Na2C03, saturated aqueous NEUCl, and brine. Dry the organic layer (Na2S04),

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15
filter, and evaporate to obtain 10 grams of crude material. Treat this crude material with a
solution of 1% methanol (MeOH) in CH2CI2 and remove the resulting white solid
impurity (400 mg) by filtration. Concentrate the filtrate and pre-adsorb the crude product
on to silica gel. Chromatograph the residue on a Si02 column eluting the material with
methanol in dichloromethane (0 to 10%) to give 5.2 grams of the title compound (78%).
Concentrate the crude fractions,, evaporate, and recrystallize from ethyl acetate to obtain
another 1.2 grams of the title compound (18%): mass spectrum (ion spray): m/z = 532.3
(M+H).
Example 2
1 -(2-{4-[2-(4-Methanesulfonyl-phenyl)-6-methoxy-naphthalen-l -yloxy]-phenoxy} -ethyl)-
piperidine Hydrochloride
Dissolve the product of Example 1 (6.4 g, 12.1.mmol) in a mixture of ethyl
acetate, dichloromethane, and methanol (300 mL; 2.5:2.5:1). Cool the resulting solution
in an ice bath and treat with 2M HC1 in diethyl ether (9.1 mL, 18.2 mmol). Concentrate
the solution in vacuo and dry at 50°C (<2mm of Hg) for 18 hours to give 6.6 grams of the
title compound (96%): mass spectrum (ion spray): m/z = 532.3 (M+H-HC1).
Example 3
6-(4-Methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-ol
Dissolve the product of Example 2 (6,45 g, 11.4 mmol) in dichloromethane (200
mL) and cool to 3°C in an ice bath. Treat this solution with neat BBr3 (5.4 mL, 57
mmol), dropwise over 5 minutes, and stir for 3 hours at 0 to 10°C. Slowly pour the
reaction mixture into a 1 -liter separatory funnel containing saturated aqueous NaHCO3
(300mL) and ice. Dilute the two-phase mixture with a solution of 7.5% MeOH in ethyl
acetate (EtOAc, 400mL) and brine (lOOmL). Separate the layers and back extract the
aqueous layer with 5% MeOH in EtOAc (2 X 150mL). Wash the combined organic
layers with brine (lOOmL), dry (Na2S04), filter and evaporate to obtain 5.3 g of crude
product. Chromatograph the residue on a Si02 column eluting the material with methanol

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in dichloromethane (2.5 to 12%) to give 4.99 grams of the title compound (85%). Dry at
45°C (<2 mm of Hg) for 18 hours: mass spectrum (ion spray): m/z = 518.3 (M+H).
Example 4
6-(4-Methanesulfonyl -phenyl)-5-[4-(2-piperidin-1 -yl-ethoxy)-phenoxy]-naphthalen-2-ol
Hydrochloride
Slurry the product of Example 3 (2.8 g, 5.4 mmol) in a mixture of ethyl acetate,
ethyl ether, and methanol (50 mL; 5:1:4). Cool the mixture in an ice bath and treat with
2M HC1 in diethyl ether (4.1 mL, 8.2 mmol). Collect the resulting solid on filter paper,
rinse with diethyl ether and dry at 45°C (<2mm of Hg) for 18 hours to give 2.84 grams of
the title compound (95%): mass spectrum (ion spray): m/z =518.3 (M+H-HC1).
Example 5
2,2-Dimethyl-propionic acid 6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1 -yl-
ethoxy)-phenoxy]-naphthalen-2-yl ester Hydrochloride

Dissolve the product of Example .3 (220 mg, 0.43 mmol) in pyridine (5 mL) and
treat sequentially with trimethylacetyl chloride (0.144 mL, 1.17 mmol) and
dimethylaminopyridine (DMAP, catalytic amount). Stir at ambient temperature for 18
hours and evaporate pyridine. Re-constitute the residue in ethyl acetate and wash with
saturated aqueous NH4C1, saturated aqueous NaHCOj, and brine. Dry the organic layer
(NaaSCU), filter, and evaporate to obtain 277 mg of crude material. Pre-adsorb onto silica
gel and chromatograph on a SiO2 column eluting the material with methanol in
dichloromethane (0 to 6%) to give 235 mg of 2,2-dimethyl-propionic acid 6-(4-
methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester.
Dissolve the free base in a mixture of ethyl acetate and diethyl ether (20 mL; 1:1). Cool

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in an ice bath and treat with 2M HC1 in diethyl ether (0.3 mL, 0.6 mmol). Collect the
precipitate on filter paper and rinse with diethyl ether to obtain 220 mg of the title
compound (80%): mass spectrum (ion spray): m/z = 602.4 (M+H-HC1).
Example 6
Benzoic acid 6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
naphthalen-2-yl ester Hydrochloride

Dissolve the product of Example 3 (220 mg, 0.43 mmol) in pyridine (5 mL) and
treat sequentially with benzoyl chloride (0.067 mL, 0.58 mmol), and DMAP (catalytic
amount). Stir at ambient temperature for 18 hours and evaporate pyridine. Partition
between saturated aqueous NH4C1 and ethyl acetate (containing 8% MeOH). After
separation of the layers extract the aqueous layer with ethyl acetate (containing 5%
MeOH) and combine the two organic layers. Wash with saturated aqueous NaHCCb and
brine. Dry the organic layer QSCu), filter, and evaporate to obtain 276 mg of crude free
base material. Pre-adsorb on to silica gel and chromatograph on a'SiCh column eluting
with methanol in dichloromethane (0 to 6%) to give 260 mg of benzoic acid 6-(4-
methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester.
Dissolve the free base in hot ethyl acetate (20 mL) and dilute with diethyl ether (20 mL).
Cool in an ice bath and treat with 2M HC1 in diethyl ether (0.31 mL, 0.62 mmol). Collect
the precipitate on filter paper and rinse with diethyl ether to obtain 255 mg of the title
compound (91%): mass spectrum (ion spray): m/z =622.3 (M-HH-HC1).

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Example 7
4-Fluoro-benzoicacid6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-
phenoxy]-naphthalen-2-yl ester

Dissolve the compound of Example 3(111 mg, 0.21 mmol) in dichloromethane (2
mL). Add 4-fluorobenzoyl chloride (30 jxL, 0.25 mmol) dropwise. After stirring for 10
minutes, pour the reaction mixture into saturated aqueous sodium bicarbonate (10 mL)
and extract with dichloromethane (10 mL). Dry the organic layer with sodium sulfate,
filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting
with methanol in dichloromethane (0 to 3%) to give 99 mg of the title compound (73%):
mass spectrum (ion spray): m/z = 640.3 (M+H).
Example 8
4-Fluoro-benzoic acid 6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-
phenoxy]-naphthalen-2-yl ester Hydrochloride
Dissolve the compound of Example 7 (99 mg, 0.15 mmol) in dichloromethane (3
mL) and add 2M HC1 in ether (400 pL, 0.8 mmol). Remove the solvent in vacuo to yield
111 mg of the title compound (100%): mass spectrum (ion spray): m/z = 640.3 (M+H-
HC1).

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Example 9
Carbonic acid isobutyl ester 6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-
phenoxy]-naphthalen-2-yl ester

Dissolve the compound of Example 3 (120 mg, 0.23 mmol) in dichloromethane (3
mL) and add isobutylchloroformate (38 jUL, 0.30 mmol) dropwise. After stirring for 10
minutes, pour the reaction into vigorously stirred ether (10 mL) and filter. Dissolve the
solids in dichloromethane (10 mL) and wash with saturated aqueous sodium bicarbonate.
Dry the organic layer with sodium sulfate, filter and concentrate in vacuo.
Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane
(4%) to give 104 mg of the title compound (73%): mass spectrum (ion spray): m/z =
618.4 (M+H).
Example 10
Carbonic acid isobutyl ester 6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-
phenoxy]-naphthalen-2-yl ester Hydrochloride
Dissolve the compound of Example 9 (104 mg, 0.17 mmol) in dichloromethane (3
mL) and add 2M HC1 in ether (400 \iL, 0.8 mmol). Remove the solvent in vacuo to yield
81 mg of the title compound (73%): mass spectrum (ion spray): m/z = 618.3 (M+H-HC1).

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Example 11
Methyl-carbamic acid 6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1 -yl-ethoxy)-
phenoxy]-naphthalen-2-yl ester

Dissolve the compound of Example 3 (201 mg, 0.38 mmol) in dichloromethane (4
L) and add triethylamine (0.50 mL, 3.5 mmol) followed by methylisocyanate (500 mg, 8.7
mmol). After stirring for 30 minutes, pour the reaction mixture into saturated aqueous
sodium bicarbonate and extract with dichloromethane. Dry the organic layer with sodium
sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column
eluting with methanol in dichloromethane (0 to 4%) to give 130 mg of the title compound
(60%): mass spectrum (ion spray): m/z = 575.3 (M+H) and 518.3 (M-MeNCO).
Example 12
Methyl-carbamic acid 6-(4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-
phenoxy]-naphthalen-2-yl ester Hydrochloride
Dissolve the compound of Example 11 (130 mg, 0.23 mmol) in dichloromethane
(3 mL) and add 2M HC1 in ether (400 (iL, 0.8 mmol), Remove the solvent in vacuo to
yield 81 mg of the title compound (73%): mass spectrum (ion spray): m/z = 575.3 (M+H-
HC1) and 518.3 (M+H-HCl-MeNCO).

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Example 13
1-(2-{4-[2-(4-Ethanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-
piperidine Hydrochloride

Combine 4-(ethanesulfonyl)phenyl)boronic acid (1.83 g, 8.6 mmol), the
compound of Preparation 1 (1.5 g, 2.86 mmol), cesium fluoride (3.9 g, 25.7 mmol) and
acetonitrile (32 mL) in a 100 mL flame-dried flask fitted with a reflux condenser. In a
separate dried flask combine palladium (II) acetate (65 mg, 0.29 mmol) and
tricyclohexylphosphine (120 mg, 0.43 mmol). Add acetonitrile (16 mL) and sonicate for
10 minutes under nitrogen. Add the catalyst slurry to the mixture of substrates and heat in
a 90°C oil bath for 30 minutes. Cool the suspension to room temperature and filter
through packed celite, Rinse the celite with ethyl acetate and wash the filtrate with a
50:50 mixture of water and saturated aqueous Na2C03, saturated aqueous NH4CI, and
brine. Dry the organic layer (NazSCM), filter, and evaporate to obtain 2 grams of crude
material. Pre-adsorb the crude material onto silica gel and chromatograph on a S1O2
column eluting with methanol in dichloromethane (0 to 10%) to give 1.5 grams of l-(2-
{4-[2-(4-ethanesulfonyl-phenyl)-6-methoxy-naphthalen-l-yloxy]-phenoxy}-ethyl)-
piperidine. Dissolve the free base in a mixture of ethyl acetate and diethyl ether (60 mL;
1:1). Cool in an ice bath and treat with 2M HC1 in diethyl ether (2 mL, 4 mmol). Collect
the precipitate on filter paper and rinse with diethyl ether to obtain 1.5 grams of the title
compound (90%): mass spectrum (ion spray): m/z = 546.3 (M+H).

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Example 14
6-(4-Ethanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-ol
Hydrochloride
Using the product from Example 13(1.5 g, 2.58 mmol) and the procedure
described in Example 3, prepare 1.35 grams of 6-(4-ethanesulfonyl-phenyl)-5-[4-(2-
piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-ol. Dissolve the free base in a mixture of
ethyl acetate and diethyl ether (60 mL; 1:1). Cool in an'ice bath and treat with 2M HC1 in
diethyl ether (2 mL, 4 mmol), Collect the precipitate on filter paper, rinse with diethyl
ether and dry at 50°C (<2mm of Hg) for 18 hours to give 1.3 grams of the title compound
(89%): mass spectrum (ion spray): m/z = 532.3 (M+H).
Example 15
l-(2-{4-[2-(3-Methanesulfonyl-phenyl)-6-methoxy-naphthalen-l-yloxy]-phenoxy}-ethyl)-
piperidine

Combine palladium (II) acetate (17 mg, 0.076 mmol), tricyclohexylphosphine
(PO'3, 32 mg, 0.11 mmol) and acetonitrile (4 mL). Sonicate the mixture for 5 minutes.
Combine the compound of Preparation 1 (400 mg, 0.76 mmol), cesium fluoride (1.00 g,
6.62 mmol,) 3-(methancsulfonyl)phenylboronic acid (460 mg, 2.30 mmol) and
acetonitrile (12 mL). Add the sonicated Pd/PCy3 suspension to the reaction vessel and
heat to 90°C for 30 minutes. Cool to room temperature and filter through a pad of Celite
and evaporate the solvent. Dissolve the residue in ethyl acetate (20 mL) and wash with
saturated aqueous NaHC03 (10 mL). Separate the layers, wash the organic layer with
brine (10 mL), dry with MgS04, filter, and concentrate in vacuo. Chromatograph the
residue on a SiOj column eluting with methanol in dichloromethane (0 to 5%) to give 270
mg of title compound (67%): mass spectrum (ion spray): m/z = 532.3 (M+H).

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Example 16
6-(3-Methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-ol
Hydrochloride
Dissolve the product of Example 15 in ethyl acetate (10 mL) and diethyl ether (5
mL). Add 2M HC1 in diethyl ether (1 mL, 2.0 mmol). Concentrate the slurry and dry in
vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool
the solution to 0°C with an external ice bath and add 1M BBr3 in dichloromethane (1.0
mL, 1.0 mmol). After 20 minutes, dilute the reaction mixture with ethyl acetate (25.0
mL) and add saturated aqueous NaHCOa in parts (2 x 10 mL),.-Separate the layers, wash
the organic layer with brine (10 mL), dry with MgSCU, filter, and concentrate in vacuo.
Chromatograph the residue on a S1O2 column eluting 6-(3-methanesulfonyl-phenyl)-5-[4-
(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol in
dichloromethane (0 to 5%). Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate
(6.0 mL) and methanol (1.0 mL) and add 2M HC1 in diethyl ether (1 mL, 2.0 mmol).
Collect the precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2mm of
Pig) at 65°C for 48 hours to give 73 mg of the title compound (26%): mass spectrum (ion
spray): m/z - 518.5(M[free base]+l).
Preparation 4
3-Fluoro-4-(methanesulfqnyl)phenyl boronic acid
Combine 4-bromo-2-fluorothioanisole (US Patent No. 6,307,047,2.7 g, 12 mmol),
oxone (38 g, 62 mmol) and methanol (200 mL) and stir for 12 hours. Filter through a pad
of silica gel and elute with ethyl acetate (500 mL). Evaporate solvent and partition
between dichloromethane (200 mL) and water (100 mL). Separate the layers, wash the
organic layer with saturated aqueous NaHCO3 (10 mL), brine (10 mL), dry with MgS04,
filter, and concentrate in vacuo. Wash the crude solid with hexane (20 hiL), ether (10
mL) and dry in vacuo to obtain 2.4 g of 4-bromo-2-fluoro-l-methanesulfonyl-benzene
(78%).

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Combine 4-bromo-2-fluoro-l-methanesulfonyl-benzene (1.7 g, 6.7 mmol), [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane
(Pd(dppfjCl2-CH2Cl2s 164 mg, 0.20 mmol), bis(pihacolato)diboron (1.79 g, 7.0 mmol),
potassium acetate (2 g, 20 mmol) and dimethylsulfoxide (DMSO, 100 mL). Heat the
reaction mixture at 90°C for 1 hour. Cool to room temperature and dilute with ethyl
acetate (20 mL). Wash with brine (10 mL), dry with MgSCu, filter, and concentrate in
vacuo. Chromatograph the residue on a SiO2 column eluting the material with ethyl
acetate in hexane (30%) to give 1.74 g (80%) of 2-(3-fluoro-4-methanesulfonyl-phenyl)-
4,4,5,5-tetramethyl-[l,3,2]dioxaborolane.
Combine 2-(3-fiuoro-4-methanesulfonyl-phenyl)-4,4,5,5-tetramethyl-
[l,3,2]dioxaborolane (222 mg, 0.74 mmol), NaI04 (474 mg, 2.2 mmol),.tetrahydrofuran
(THF, 4 mL) and water (1 mL). Stir for 2 hours and add 2M HC1 in diethyl ether (0.2
mL). Stir another 12 hours and filter away the solid. Wash the filtrate with brine (10 mL),
dry with MgSC and evaporate the solvent. Wash the solid with hexane (2x10 mL) and
ether (10 mL). Dry the solid under vacuum to obtain 68 mg of the title compound (42%).
Example 17
l-(2-{4-[2-(3-Fluoro-4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-l-yloxy]-
phenoxy} -ethyl)-piperidine

Combine palladium (II) acetate (4.2 mg, 0.019 mmol), tricyclohexylphosphine (10
mg, 0.036 mmol), the compound of Preparation 1 (92 mg, 0.18 mmol), cesium fluoride
(201 mg, 1.33 mmol,) 3-fluoro-4-(methanesulfonyl)phenyl boronic acid (68 mg, 0.31
mmol) and acetonitrile (10 mL). Heat to 90°C for 1 hour. Cool to room temperature and
dilute the solution with ethyl acetate (20 mL) and wash with saturated aqueous NaHCOj
(10 mL). Separate the layers, wash the organic layer with brine (10 mL), dry with
MgS04, filter, and concentrate in vacuo. Chromatograph the residue on a Si02 column

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eluting with methanol in dichloromethane (2 to 4%) to give 69 mg of title compound
(72%): mass spectrum (ion spray): m/z = 550.4 (M+H).
Example 18
6-(3-Fluoro-4-methancsulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
naphthalen-2-ol Hydrochloride
Dissolve the product of Example 17 in ethyl acetate (10 mL) and diethyl ether (5
mL). Add 2M HC1 in diethyl ether (1 mL, 2.0 mmol). Concentrate the slurry and dry in
vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool
the solution to 0°C with an external ice bath. Add 1M BBr3 in dichloromethane (0.1 mL,
1.1 mmol) and stir for 1 hour. Add water (1.0 mL) and dichloromethane (10 mL).
Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL) and
brine (10 mL), dry with MgSC-4, filter, and concentrate in vacuo. Chromatograph the
residue on a Si02 column eluting 6-(3-fluoro-4-methanesulfonyl-phenyl)-5-[4-(2-
piperidin-l-yl-emoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol in
dichloromethane (0 to 5%). Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate
(6.0 mL) and methanol (1.0 mL) and add 2M HC1 in diethyl ether (1 mL, 2.0 mmol).
Collect the precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2mm of
Hg) at 65°C for 48 hours to give 19 mg of the title compound (26%): mass spectrum (ion
spray): m/z = 536.3 (M+H).
Preparation 5
2-(4-Trifluoromethanesulfonyl-phenyl)-4,4)5,5-tetramethyl-[l,3,2]dioxaborolane
Dissolve l-bromo-4-trifluoromethyl sulfide (2.5g, 9.7 mmol) in dichloromethane
(100 mL) in a 250 mL flask equipped with a reflux condenser, Add meta-
chloroperbenzoic acid (mCPBA, 6.1 g, 24.3 mmol, 68%) and heat the reaction to reflux
for 3 days. Cool the reaction to room temperature and wash the organic layer with IN
aqueous NaOH (100 mL). Separate and dry the organic layer with sodium sulfate. Filter
and concentrate in vacuo to yield 2.5 g of l-bromo-4-trifluoromethanesulfonyl-benzene
(90%).

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Charge a flame-dried flask with l-bromo-4-trifluoromethanesulfonyl-benzene
(500 mg, 1.73 mmol), bis(pinacolato)diboron (523 mg, 2.07 mmol), [1,1'-
bis(diphenylphosphino)feiTOcene]dichloropalladium(II), complex with dichloromethane
(1:1) (42 mg, 0.05 mmol) and potassium acetate (467 mg, 5.2 mmol). Dissolve the solids
with dimethylsulfoxide (9 mL) and heat to 80°C under nitrogen for 4 hours-. Cool the
reaction to room temperature and dilute with benzene (50 mL). Wash the organic layer
with water (20 mL) and brine (20 mL). Dry the organic layer with sodium sulfate, filter
and concentrate in vacuo. Chromatograph the resultant oil on a Si02 column eluting with
ethyl acetate in hexanes (20%) to yield 560 mg of the title compound (96%).
Example 19
1 -(2- {4-[6-Methoxy-2-(4-trifluoromethanesulfonyl-phenyl)-naphthalen-l -yloxy]-
phenoxy}-ethyl)-piperidine

Combine 2-(4-trifluoromethanesulfonyl-phenyl)-4)4,5,5-tetramethyl-
[l,3,2]dioxaborolanc (560 mg, 1.67 mmol), the compound of Preparation 1 (300 mg, 0.57
mmol) and cesium fluoride (433 mg, 2.85 mmol) in a flame-dried flask fitted with a
reflux condenser. In a separate dried flask combine palladium (II) acetate (25 mg, 0.11
mmol) and tricyclohexylphosphine (48 mg, 0.17 mmol). Add dry acetonitrile (6 mL) and
sonicate for 10 minutes under nitrogen. Add the catalyst mixture to the solids and plunge
the flask into a 90°C oil bath. After 25 minutes cool the black suspension to room
temperature and filter through celite with dichloromethane. Concentrate the filtrate in
vacuo. Chromatograph the resultant residue on a SiO2 column eluting with 2.5%
methanol in dichloromethane with 0.2% ammonium hydroxide to give 254 mg of the title
compound (76%): mass spectrum (ion spray): m/z = 586 (M+H).

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Example 20
5-[4.(2-Piperidin-l-yl-ethoxy)-phenoxy]-6-(4-trifluoromethanesulfonyl-phenyl)-
naphthalen-2-ol
Dissolve the compound of Example 19 (250 mg, 0.42 mmol) in dichloromethane
(5 ml.). Add 2M HC1 in ether (0.42 mL, 0.84 mmol) and stir for 1 minute. Remove the
solvent in vacuo and place on a high vacuum pump for 10 minutes. Dissolve the foam in
dry dichloromethane (5 mL), cool to 0°C and add BBr3 (0.20 mL, 2.1 mmol), dropwise.
After 25 minutes, slowly pour into saturated aqueous sodium bicarbonate (10 mL) and
extract with dichloromethane (2x10 mL). Dry the combined organic layers with sodium
sulfate and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting.
with methanol (3 to 5%) in dichloromethane with 0.2% ammonium hydroxide to yield
196 mg of the title compound (81%): mass spectrum (ion spray) m/z = 572.3 (M+H).
Example 21
5-[4-(2-Piperidin-l-yl-ethoxy)-phenoxy]-6-(4-trifluoromethanesulfonyl-phenyl)-
naphthalen-2-ol Hydrochloride
Dissolve the compound of Example 20 (196 mg, 0.34 mmol) in ethyl acetate (1
mL) and diethyl ether (9 mL). Add 2M HC1 in diethyl ether (340 (.d, 680 (imol) to the
stirred solution. Allow the suspension to stir for 10 minutes. Filter the solids through a
Buchner funnel. Dry the solids overnight at 45°C in a vacuum oven to yield 98 mg of the
title compound (47%): mass spectrum (ion spray) m/z = 572.3 (M+H-HC1).
Preparation 6
2-(l,l-Dioxo-2,3-dihydro-lH-a6-benzo[b]thiophen-5-yl)-4,4,5,5-tetramethyl-
[ 1,3,2] dioxaborolane
Dissolve 5-bromo-2,3-dihydro-benzo[b]thiophene (/. Am. Chem. Soc, 1973, 1916-
1925, 4.3 g, 20 mmol) in MeOH (100 mL) and add oxone (36.9 g, 60 mmol). Stir the
reaction mixture at room temperature overnight, and then remove the solid by filtration.
Concentrate the filtrate and purify the residue by flash column chromatography (silica gel,

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20-40% EtOAc/Hexane) to give 4.24 g of 5-bromo-2,3-dihydro-benzo[b]thiophenel.,l-
dioxide (86%).
Dissolve 5-bromo-2,3-dihydro-benzo[b]thiophene 1,1-dioxide (2.0 g, 8.1 mmol)
in DMSO (60 mL). Add bis(pinacolato)diboron (2.26 g, 8.9 mmol), PdCl2(dppi>CH2Ci2
(330 mg, 0.41 mmol), and potassium acetate (KOAc, 2.38 g, 24.3 mmol). Flush the flask
with N2, and then heat the reaction mixture to 80°C with stirring. Continue to heat the
reaction mixture for 3 hours, and then cool to room temperature. Add water (100 mL)
and extract the aqueous layer with EtOAc (3 x 100 mL). Combine the organic layers and
dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica
gel, 10 to 50% ethyl acetate in hexanes) to give 1.4 g (59%) of the title compound.
Example 22
l-(2-{4-[2-(l)l-Dioxo-2,3-dihydro-lH-lX,6-benzo[b]thiophen-5-yl)-6-methoxy-
naphthalen-1 -yloxy]-phenoxy} -ethyl)-piperidine

Dissolve 2-(l, 1 -dioxo-2,3-dihydro-1H-1 X6-benzo[b]thiophen-5-yl)-4,4,5,5-
tetramethyl-[l,3,2]dioxaborolane (590 mg, 2.02 mmol) and the compound of Preparation
1 (350 mg, 0.67 mmol) in CH3CN (8 mL). Add palladium (II) acetate (Pd(OAc)2,15 mg,
0.007 mmol), tricyclohexylphosphine (28 mg, 0.1 mmol), and CsF (910 mg, 6 mmol).
Flush the flask with N2, and then heat the reaction mixture to 90°C with stirring.
Continue to heat the reaction mixture for 6 hours, and then cool to room temperature.
Add water (50 mL) and extract the aqueous layer with CH2CI2 (3 x 25 mL). Combine the
organic layers and dry with Na2S04, filter, concentrate and purify by flash column
chromatography (silica gel, 0-4% MeOH-NH4OH (10/1, v/v)/ CH2C12) to give 160 mgof
the title compound (44%): mass spectrum (ion spray): m/z = 544.3 (M+H).

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Example 23
6-(l,l-Dioxo-2,3-dihydro-lH-lX,6-benzo[b]thiophen-5-yl)-5-[4-(2-piperidin-l-yl-ethoxy)-
phenoxy]-naphthalen-2-ol Hydrochloride
Dissolve the compound of Example 22 (160 mg, 0.29 mmol) in CH2CI2 (5 mL)
and cool the solution to -7S°C. Add HC1 (0.2 mL, 2.0 M in diethyl ether (Et20)) and stir
the reaction mixture for 10 minutes. Remove the solvent under reduced pressure and then
dissolve the solid in CH2CI2 (5 mL) under N2. Cool the solution to 0°C and add BBr3
(370 mg, 1.46 mmol). Stir the reaction for one hour and add water (20 mL). Extract the
aqueous layer with CH2CI2 (3 x 20 mL). Combine the organic layers and dry with
NaiSCM, filter, concentrate and purify by flash column chromatography (silica gel, 2-8%
MeOH-NH4OH (10/1, v/v)/ CH2C12) to give 6-(l,l-dioxo-2,3-dihydro-lH-a6-
benzo[b]thiophen-5-yl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-ol.
Dissolve the free base in CH2C12 (5 mL) and cool to -78°C. Add HC1 (0.5 mL, 2.0 M in
Et20) and stir the solution for 10 minutes. Remove the solvent under reduced pressure to
give a solid. Dry the solid at 40°C, overnight, in vacuo to give 42 mg of the title
compound (27%): mass spectrum (ion spray): m/z = 530.3 (M+H).
Preparation 7
(2,2-Dioxo-2,3-dihydro-lH-2A.6-benzo[c]thiophen-5-yl)-trimethyl-stannane
Dissolve 4-bromo-l,2-bis-bromomethyl-benzene (J. Org. Chem., 1418-1421,
1985; 3.42 g, 9.96 mmol) in a 2 to 1 mixture of ethanol (EtOH) and THE (1196 mL) and
heat the solution to 70°C with stirring. Add a solution of Na2S»9H20 (2.63 g, 10.96
mmol) in water (40 mL), dropwise, over 10 hours using a syringe pump. Continue to heat
and stir for another 10 hours. Cool to room temperature and remove the organic solvent
under reduced pressure. Add water (200 mL) to the residue and extract the aqueous layer
with EtOAc (3 x 200 mL). Combine the organic layers and dry with NaaSCM, filter,
concentrate and purify by flash column chromatography (silica gel, hexanes) to give 1.27
g of 5-bromo-l,3-dihydro-benzo[c]thiophene (59%).
Dissolve 5-bromo-l,3-dihydro-benzo[c]thiophene (1.25 g, 5.79 mmol) in
methanol (25 mL) and add oxone (10.7 g, 17.4 mmol). Stir the reaction mixture for 2

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-30-
hours at 0°C and then add a 1M aqueous sodium bisulfite solution (100 mL). Stir the
reaction mixture for 10 minutes and add saturated NaHCCb solution (200 mL). Extract
the aqueous layer with CH2C12 (3 x 100 mL). Combine the organic layers and dry with
Na2S04, filter, concentrate and purify by flash column chromatography (silica gel, 0-5%
MeOH/CH2Cl2) to give 930 mg of 5-bromo-l,3-dihydro-benzo[c]thiophene 2,2-dioxide
(65%).
Dissolve 5-bromo-l,3-dihydro-benzo[c]thiophene (860 mg, 3.50 mmol) and
hexamethylditin (3 eq.) in toluene and add tetrakis(triphenylphosphine)palladium(0)
(Pd(PPh3)4, 0.1 eq.). Flush the flask with N2 and then heat the mixture to 120°C with
stirring. Continue to heat the mixture for 5 hours and then cool to room temperature.
Add water (50 mL) and extract aqueous layer with EtOAc (3 x 50 mL). Combine the
organic layers and dry with Na2SO4, filter, concentrate and purify by flash
chromatography (silica gel, 10-30% EtOAc/hexane) to give 1.22 g of the title compound
(100%).
Example 24
1 -(2- {4-[2-(2,2-Dioxo-2,3-dihydro- lH-2X6-benzo[c]thiophen-5-yl)-6-methoxy-
naphthalen-1 -yloxy]-phenoxy} -ethyl)-piperidine

Dissolve (2,2-dioxo-2,3-dihydro-lH-2A,<5-benzo[c]thiophen-5-yl)-trimethyl-
stannane (1.19 g, 3.6 mmol, 2.7 eq.) and the compound of Preparation 1 (630 mg, 1.2
mmol) in CH3CN. Add Pd(OAc)2 (0.1 eq.), tricyclohexylphosphine (0.15 eq.), and CsF
(4 eq.). Flush the flask with N2 and then heat the reaction mixture to 90°C with stirring.
Continue to heat the reaction mixture for one hour and then cool to room temperature.
Add water (100 mL), separate, and extract the aqueous layer with CH2C12 (3 x 100 mL).
Combine the organic layers and dry with Na2S04, filter, concentrate and purify by flash

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column chromatography (silica gel, 0-5% MeOH-NH4OH (10/1, v/v)/ CH2C12) to give
140 mg of the title compound (22%): mass spectrum (ion spray): m/z = 544.2 (M+H).
Example 25
6-(2,2-Dioxo-2,3-dihydro-lH-2A,6-benzo[c]thiophen-5-yl)-5-[4-(2-piperidin-l-yl-ethoxy)-
phenoxy]-naphthalen-2-ol Hydrochloride
Demethylatel-(2-{4-[2-(2,2-dioxo-2,3-dihydro-lH-2A-6-benzo[c]thiophen-5-yl)-6-
methoxy-naphthalen-l-yloxy]-phenoxy}-ethyl)-piperidine (140 mg, 0.26 mmol) with
BB13 and salify in a procedure similar to that used in Example 23 to give 130 mg (94%)
of the title compound: mass spectrum (ion spray): m/z = 530.2 (M+H-HC1).
Preparation 8
(4-Methanesulfonyl-3-methoxy-phenyl)-trimethyl-stannane
Dissolve 6-hydroxy-l,3-benzoxathiol-2-one (16.8 g, 0.1 mol) in THF (1650 mL)
and cool to 0°C. Sequentially add benzyl alcohol (16.2 g, 0.15 mol), triphenylphosphine
(PPh3, 39.3 g, 0.15 mol), and diisopropylazodicarboxylate (30.3 g, 0.15 mol). Stir the
reaction mixture at room temperature overnight. Add water (1500 mL) and extract the
aqueous layer with EtOAc (3 x 1500 mL). Combine the organic layers and dry with
Na2S04, filter, concentrate and purify by flash column chromatography (silica gel, 10-
25% of EtOAc/hexanc) to give 24.33 g of 6-benzyloxy-benzo[l,3]oxathiol-2-one (94%).
Dissolve 6-benzyloxy-benzo[l,3]oxathiol-2-one (24.33 g, 94.29 mmol) in dioxane
(1000 mL) and add a KOH solution (94.29 mL, 188 mmol, 2M in water) with stirring.
Flush the flask with N2 and then heat the reaction mixture to 80°C for 2 hours. Cool the
reaction mixture to room temperature and remove the solvent under reduced pressure.
Adjust the pH to <2 with HC1 (200 mL, 1.0 M in water). Extract the aqueous layer with
EtOAc (3 x 500 mL). Combine the organic layers and dry with Na2S04, filter and
concentrate to give 17.8 g of 5-benzyloxy-2-mercapto-phenol (81.4%).
Dissolve 5-benzyloxy-2-mercapto-phenol (17.8 g, 76.72 mmol) in DMF (300 mL)
and add K2C03 (31.8 g, 0.23 mol) and Mel (32.7 g, 0.23 mol). Stir the reaction mixture
at room temperature overnight. Add water (800 mL) and extract the aqueous layer with

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EtOAc (3 x 800 mL). Combine the organic layers and dry with Na2S04, filter,
concentrate and purify by flash column chromatography (silica, 5-20% of EtOAc/hexane)
to give 13.5 g of 4-benzyloxy-2-methoxy-l-methylsulfanyl-benzene (68%).
Dissolve 4-benzyloxy-2-methoxy-l-methylsulfanyl-benzene (5.2 g, 20 mmol) in
CH2C12 (250 mL) and treat with m-CPBA (15.2 g, 60 mmol, 68%). Stir the reaction
mixture at room temperature for 6 hours. Add saturated K2CO3 (200 mL), and extract the
aqueous layer with EtOAc (3 x 200 mL), Combine the organic layers and dry with
Na2S04, filter, concentrate and purify by flash column chromatography (silica gel, 20-
50% of EtOAc/hexane) to give 5.57 g of 4-benzyloxy-l-methanesulfonyl-2-methoxy-
benzene (96%).
Dissolve 4-benzyloxy-l-methanesulfonyl-2-methoxy-benzene (5.57 g, 19.09
mmol) in MeOH (200 mL), under N2, and add 5% Pd-C (900 mg). Evacuate the reaction
vessel and flush with hydrogen gas (3 times). Stir the reaction mixture at room
temperature for 3 hours, under 1 atmosphere of hydrogen gas. Filter, concentrate, and
purify the reaction mixture by flash column chromatography (silica gel, 30-60% of
EtOAc/hexane) to give 3.24 g of 4-methanesulfonyl-3-methoxy-phenol (100%).
Dissolve 4-methanesulfonyl-3-methoxy-phenol (3.24 g, 19.04 mmol), 2,6-lutidine
(4.08 g, 38.08 mmol) and DMAP (230 mg, 1.9 mmol) in CH2C12 (190 mL). Cool the
solution to -78°C and then add trifluoromethanesulfonic acid anhydride (Tf20, 6.44 g,
22.85 mmol), dropwise. Stir the reaction mixture for 6 hours. Add water (200 mL) and
extract the aqueous layer with EtOAc (3 x 200 mL). Combine the organic layers and dry
with Na2S04, filter, concentrate and purify by flash column chromatography (silica gel,
10-30% of EtOAc/hexane) to give 4.6 g of trifluoro-methanesulfonic acid 4-
methanesulfonyl-3-methoxy-phenyl ester (72%).
Dissolve trifluoro-methanesulfonic acid 4-methanesulfonyl-3-methoxy-phenyl
ester (3 g, 9 mmol) in toluene (180 mL) and add hexamethylditin (14.7 g, 44.9 mmol) and
Pd(PPh3)4 (1.04 g, 0.9 mmol). Heat the reaction mixture to 120°C with stirring for 4
hours and then cool to room temperature. Add water (250 mL) and extract the aqueous
layer with EtOAc (3 x 250 mL). Combine the organic layers and dry with Na2S04, filter,
concentrate and purify by flash column chromatography (silica gel, 5-40% of EtOAc in
hexane) to give 1.9 g of the title compound (61%).

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Example 26
1 -(2- {4-[2-(4-Methanesulfonyl-3-methoxy-phenyl)-6-methoxy-naphthalen-l -yloxy]-
phenoxy}-ethyl)-piperidine

Add (4-methanesulfonyl-3-methoxy-phenyl)-trimethyl-staniiane (300 mg,.0.86
mmol, 1.5 cq.) and the compound of Preparation 1 (300 mg, 0.57 mmol) to a suspension
of cesium fluoride (2.9 cq.) in acetonitrilc (40 mL). Combine palladium (II) acetate (0.2
eq.) and tricyclohexylphosphine (0.3 eq.) in acetonitrile (15 mL) and sonicate for 10
minutes before adding to the above mixture. Heat the reaction mixture to 90°C for 18
hours. Concentrate in vacuo and partition residue between ethyl acetate (50 mL) and
saturated aqueous NaHC03 (50 mL). Wash the organic layer with saturated aqueous
NH4CI (50 mL) and brine (50 mL). Dry with NajSCU, filter, and concentrate in vacuo.
Chromatograph the residue on a S1O2 column eluting with methanol in dichloromethane
to give 180 mg of the title compound (56%): mass spectrum (ion spray): m/z = 562.4
(M+H).
Example 27
6-(3-Hydroxy-4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
naphthalen-2-ol Trifluoroacetate
Demethylate l-(2-{4-[2-(4-methanesulfonyl-3-methoxy-phenyl)-6-methoxy-
naphthalen-l-yloxy]-phenoxy}-ethyl)-piperidine (240 mg, 0.43 mmol) with BBr3 in a
procedure similar to that used in Example 23 to give 220 mg of crude product as a white
solid (95%). Purify the impure product by preparative HPLC (Gilson) to give 120 mg of
the title compound (46%): mass spectrum (ion spray): m/z = 534.3 (M+H-TFA).

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Preparation 9
4-Bromo-2-chloro-1 -methanesulfonyl-benzene
Combine 2-chloromcthyl-benzenethiol (10 mL, 88 mmol), potassium carbonate
(25 g, 180 mmol), iodomethane (11 mL, 177 mmol) and DMF (100 mL)T Stir for 12
hours. Filter the suspension through a pad of silica gel and elute with ethyl acetate (500
mL). Evaporate half of the solvent and wash the remaining solution with 10% aqueous
LiCl (100 mL). Dry with MgS04 and evaporate the solvent. Chromatograph the residue
on a SiO2 column eluting with hcxane to give 13 g of l-chloro-2-methylsulfanyl-benzene
(93%)..
Combine l-niethylsulfanyl-2-chloromethyl-benzene (3.7 g, 23 mmol), iron (130
nig, 2.3 mmol), bromine (1.2 mL, 238 mmol), and dichloromethane (150 mL). Stir for 2
hours. Add water (10 mL), aqueous saturated sodium thiosulfate (100 mL) and ethyl
acetate (100 mL). Separate the organic layer and wash with brine, dry with MgS04, filter
and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with
hexane to give 4.8 g of 4-bromo-2-chloro-l-methylsulfanyl-benzene (87%).
Dissolve 4-bromo-2-chloro-l-methylsulfanyl-benzene (4.8 g, 20 mmol) and
mCPBA (20 g, 80 mmol) in dichloromethane (100 mL). Stir for 2 hours. Dilute with
dichloromethane (300 mL) and water (100 mL). Separate the organic layer and wash with
aqueous saturated NaHCCb (2x 100 mL) and brine'(100 mL). Dry with MgSCv, filter and
concentrate in vacuo. Wash the solid with ether (2 x 10 mL) and dichloromethane (10
mL) to give 1.7 g of the title compound (31%).
Example 28
l-(2-{4-[2-(3-Chloro-4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-l-yloxy]-
phenoxy} -ethyl)-piperidine


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Combine palladium (II) acetate (32 mg, 0.14 mmol), tricyclohexylphosphine (67
mg, 0.24 mmol), cesium fluoride (1.3 g, 8.6 mmol) and acetonitrile (20 mL). Stir for 5
minutes and add the compound of Preparation 1 (500 mg, 0.95 mmol) and
bis(neopentylglycolato)diboron (322 mg, 1.42 mmol). Heat to 90°C and add 4-bromo-2-
chloro-1-methanesulfonyl-benzene in acetonitrile (2 mL). Stir at 90°C for 10 minutes.
Cool to room temperature and dilute the solution with ethyl acetate (20 mL) and wash
with saturated aqueous NaHCCb (10 mL). Separate the layers, wash the organic layer
with brine (10 mL), dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the
residue on a SiO2 column eluting with methanol in dichloromethane (0 to 5%) to give 180
mg of the title compound (33%): mass spectrum (ion spray): m/z = 566.2 (M+H).
Example 29
6-(3-Chloro-4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
naphthalen-2-ol
Dissolve the product of Example 28 in ethyl acetate (10 mL) and diethyl ether (5
mL). Add 2M HC1 in diethyl ether (0.6 mL, 1.2 mmol). Concentrate the slurry and dry in
vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool
the solution to 0°C with external ice bath. Add BBr3 (0.1 mL, 1.1 mmol). After 1 hour,
add water (1.0 mL) and dichloromethane (10 mL). Separate the layers, wash the. organic
layer with saturated aqueous NaHCCh (10 mL), brine (10 mL), dry with MgSCU, filter,
and concentrate in vacuo. Chromatograph the residue on a SiOi column eluting with a
step gradient of methanol/dichloromethane (0 to 5%) to give 120 mg of the title
compound (68%): mass spectrum (ion spray): m/z= 552.2 (M+H).
Example 30
6-(3-Chloro-4-methauesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
naphthalen-2-ol Hydrochloride
Dissolve the product of Example 29 in diethyl ether (5.0 mL), ethyl acetate (6.0
nL) and methanol (1.0 mL) and add 2M HC1 in diethyl ether (0.6 mL, 1.2 mmol). Collect
he precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2mm of Hg) at

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20°C for 4 hours lo give 16 mg of the title compound (26%): mass spectrum (ion spray):
m/z= 552.3 (M+H-HC1).
Preparation 10
4-Bromo-1 -methanesulfonyl-2-trifluoromethyl-benzene
Dissolve 2-trifiuoromethyl-benzenethiol (10 g, 56 mmol), potassium carbonate (25
g, 180 mmol), iodomethane (11 mL, 177 mmol) in DMF (100 mL). Stir for 12 hours.
Filter the suspension through a pad of silica gel and elute with ethyl acetate (500 mL).
Evaporate half of the solvent and wash the remaining solution with 10% aqueous LiCl
(100 mL). Dry with MgS04 and evaporate solvent. Chromatograph the tesidue on a
S1O2 column eluting with hexane to give 9.5 g of l-methylsulfanyl-2-trifmoromethyl-
benzene (88%).
Combine l-methylsulfanyl-2-trifluoromethyl-benzene (3.5 g, 18 mmol), iron (1O0
mg, 1.79 mmol), bromine (0.95 mL, 18 mmol), aluminum chloride (242 mg, 1.8 mmol)
and dichloromethane (50 mL) and stir for 2 hours. Add water (10 mL), aqueous saturated
sodium thiosulfate (100 mL) and ethyl acetate (100 mL). Separate the organic layer and
wash with brine, dry with MgSO4, filter and concentrate in vacuo. Chromatograph the
residue on a SiO2 column eluting with hexane to give 3.6 g of 4-bromo-l-methylsulfanyl-
2-trifluoromethyl-benzene (83%).
Combine 4-bromo-l-methylsulfanyl-2-trifluoromethyl-benzene (3.6 g, 15 mmol),
mCPBA (7.7 g, 30 mmol) and dichloromethane (100 mL). Stir for 2 hours. Dilute with
dichloromethane (300 mL) and water (100 mL). Separate the organic layer and wash with
aqueous saturated NaHCO3 (2x 100 mL) and brine (100 mL). Dry with MgS04, filter and
concentrate in vacuo. Wash the solid with diethyl ether (2 x 10 mL) and dichloromethane
(10 mL) to give 2,06 g of the title compound (44%).
Example 31
l-(2-{4-[2-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-l-(4-methoxy-phenyl)-
propenyloxy] -phenoxy} -ethyl)-piperidine

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Combine palladium (II) acetate (6 mg, 0.029 mmol), tricyclohexylphosphine (13
mg, 0.047 mmol), cesium fluoride (258 mg, 1.7 mmol,) and acetonitrile. (1.0 mL). Stir for
5 minutes. Add the compound of Preparation 1 (92 mg, 0.18 mmol) and
bis(neopentylglycolato)diboron (64 mg, 0.89 mmol) and heat to 90°C. Add 4-b0romo-l-
methanesulfonyl-2-trifluoromethyl-benzene in acetonitrile (1 mL) and stir at 90°C for 10
minutes. Cool to room temperature and dilute the solution with ethyl acetate (20 mL) and
wash with saturated aqueous NaHC03 (10 mL). Separate the layers, wash the organic
layer with brine (10 mL), dry with MgSCU, filter, and concentrate in vacuo.
Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane
(0 to 5%) to give 62 mg of the title compound (54%): mass spectrum (ion spray): m/z =
600.3 (M+H).
Example 32
6-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
naphthalen-2-ol Hydrochloride
Dissolve the product of Example 31 in ethyl acetate (10 mL) and diethyl ether (5
mL). Add 2M HC1 in diethyl ether (0.1 mL, 0.2 mmol). Concentrate the slurry and dry in
vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool
the solution to 0°C with external ice bath. Add BBr3 (0.1 mL, 1.1 mmol) and stir for 1
hour. Dilute with water (1.0 mL) and dichloromethane (10 mL). Separate the layers and
wash the organic layer with saturated aqueous NaHC03 (10 mL) and brine (10 mL). Dry
with MgS04, filter, and concentrate in vacuo. Chromatograph the residue on a Si02
column eluting the 6-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-5-[4-(2-piperidin-l-
y]-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol/dichloromethane (0
to 5%). Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and

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methanol (1.0 mL) and add 2M HG1 in diethyl ether (0.1 mL, 0.2 mmol). Collect the •
precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2mm of Hg) at 65°C
for 48 hours to give 34 rag of the title compound (53%).
Preparation 11
1 -Bromo-2,3-dichloro-4-methanesulfonyl-benzene
Combine 4-bromo-2-chloro-l-methylsulfanyl-benzene (1.9 g, 20 mmol) and
mCPBA (5.0 g, 80 mmol) in dichloromethane (30 mL). Stir for 2 hours. Dilute with
dichloromethane (20 mL) and water (20 mL). Separate the organic layer and wash with
aqueous saturated NaHC03 (2x 100 mL) and brine (100 mL). Dry with MgSCU, filter and
concentrate in vacuo. Wash the solid with diethyl ether (2x 10 mL) and dichloromethane
(10 mL) to give 890 mg of the title compound (52%).
Example 33
l-(2-{4-[2-(2,3-Dichloro-4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-l-yloxy]-
phenoxy} -ethyl)-piperidine

Combine palladium (II) acetate (32 mg, 0.14 mmol), tricyclohexylphosphine (67
mg, 0.24 mmol), cesium fluoride (1.3 g, 8.6 mmol,) and acetonitrile (20 mL). Stir for 5
minutes. Add the compound of Preparation 1 (500 mg, 0.95 mmol) and
bis(neopentylglycolato)diboron (322 mg, 1.42 mmol). Heat to 90°C and add 1-bromo-
2,3-dichloro-4-methanesulfonyl-benzene in acetonitrile (2 mL). Stir at 90°C for 10
minutes. Cool to room temperature and dilute the solution with ethyl acetate (20mL) and
wash with saturated aqueous NaHCOj (10 mL). Separate the layers, wash the organic
layer with brine (10 mL), dry with MgS04, filter, and concentrate in vacuo.
Chromatograph the residue on a column eluting with methanol in dichloromethane (0 to
5%) to give 180 mg of the title compound (33%): mass spectrum (ion spray): m/z = 566.2.

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Example 34
6-(2,3-Dichloro-4-methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
naphthalen-2-ol Hydrochloride
Dissolve the product of Example 33 in ethyl acetate (10 mL) and diethyl ether (5.
mL). Add 2M HC1 in diethyl ether (0.5 mL, 1.0 mmol). Concentrate the slurry and dry in
vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool
the solution to 0°C with external ice bath. Add BBr3 (0.1 ml, 1.1 mmol) and stir for 1
hour. Quench with water (1.0 mL) and and dilute with dichloromethane (10 mL).
Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL) and
brine (10 mL). Dry with MgSCU, filter, and concentrate in vacuo. Chromatograph the
residue on a Si02 column eluting the 6-(2,3-dichloro-4-methanesulfonyl-phenyl)-5-[4-(2-
piperidin-1 -yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of
methanol/dichloromethane (0 to 5%). Dissolve the free base in diethyl ether (5.0 mL),
ethyl acetate (6.0 mL) and methanol (1.0 mL) and add 2M HC1 in diethyl ether (0.5 mL,
1.0 mmol). Collect the precipitate on filter paper, rinse with diethyl ether to give 38 mg
of the title compound (30%): mass spectrum (ion spray): m/z= 586.2.
Preparation 12
4-Bromo-l,2-bis-methanesulfonyl-benzene
Combine 4-bromo-2-fluoro-l-methylsulfanyl-benzene (4.8 g, 22 mmol) and
sodium methanethiolate (1.6 g, 22 mmol) in DMF (50 mL). Stir for 48 hours. Pour the
reaction mixture into ice (10 g). Separate the layers and wash the organic layer with
aqueous saturated NaHC03 and brine. Dry with MgSCM, filter and concentrate in vacuo.
Chromatograph the residue on a column eluting with diethyl ether in hexane (0 to 5%) to
give 4.82 g of 4-bromo-1,2-bis-methylsulfanylbenzene (89%).
Combine 4-bromo-1,2-bis-methylsulfanylbenzene (1.4 g, 5.5 mmol) and mCPBA
(8.6 g, 34 mmol) in dichloromethane (100 mL). Stir for 2 hours. Add dichloromethane
(300 mL) and water (100 mL). Separate the organic layer and wash with aqueous
saturated NaHC03 (2 x 100 mL) and brine (100 mL). Dry with MgS04, filter and

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concentrate in vacuo. Wash the solid with ether (2 x 10 mL) and dichloromethane (10
mL) to give 800 mg of 4-bromo-1,2-bis-methanesulfonylbenzene (46%).
Example 35
l-(2-{4-[2-(3,4-Bis-meihanesulfonyl-phenyl)-6-methoxy-naphthalen-l-yloxy]-phenoxy}-
ethyl)-piperidine

Combine palladium (II) acetate (13 mg, 0.058 mmol), tricyclohexylphosphine (27
mg, 0.096 mmol), cesium fluoride (518 mg, 3.4 mmol,) and acetonitrile (20 mL). Stir for
5 minutes and add the compound of Preparation 1 (200 mg, 0.38 mmol) and
bis(neopentylglycolato)diboron (130 mg, 0.58 mmol). Heat to 90°C, add 4-bromo-1,2-
bis-methanesulfonyl-benzene in acetonitrile (2 mL), and stir for 10 minutes. Cool to
room temperature and dilute the solution with ethyl acetate (20mL) and wash with
saturated aqueous NaHCO (10 mL). Separate the layers, wash the organic layer with
brine (10 mL), dry withMgS04, filter, and concentrate in vacuo. Chromatographthe
residue on a column eluting with methanol in dichloromethane (0 to 5%) to give 130 mg
of the title compound (56%).
Example 36
6-(3,4-Bis-methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-
2-ol Hydrochloride
Dissolve the product of Example 35 in ethyl acetate (10 mL) and diethyl ether (5
mL). Add 2M HC1 in diethyl ether (0.1 mL, 0.2 mmol). Concentrate the slurry and dry in
vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool
the solution to 0°C with an external ice bath. Add BBi-3 (0.1 mL, 1.1 mmol) and stir for 1
hour. Quench with water (1.0 mL) and dilute with dichloromethane (10 mL). Separate

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the layers, wash the organic layer with saturated aqueous NaHC03 (10 mL) and brine (10
mL). Dry with MgS04, filter, and concentrate in vhcuo. Chromatograph the residue on a
column eluting the 6-(3,4-bis-methanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-
phenoxy]-naphthalen-2-ol with a step gradient of methanol/dichloromethane (0 to 5%).
Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0
mL) and add 2M HC1 in diethyl ether (0.1 mL, 0.2 mmol). Collect the precipitate on filter
paper, rinse with diethyl ether and dry in vacuo (<2mm of Hg) at 65°C for 48 hours to
give 61 mg of the title compound (45%): mass spectrum (ion spray): m/z: 594.9 (M+H-
HC1).
Preparation 13
l-Bronio-4-(2,2,2-trifiuoro-ethanesulfonyl)-benzene
Dissolve 4-bromo-benzenethiol (1.0 g, 5.3 mmol) in diy dimethylformamide (50
mL) and cool to 0°C under nitrogen. Add dry sodium hydride (152 mg, 6.4 mmol),
portionwise. After the vigorous gas evolution stops, add tolucne-4-sulfonic acid 2,2,2-
triiluoro-ethyl ester (2.0 g, 8.0 mmol) and stir the reaction overnight at room temperature.
Slowly pour the reaction into water (400 mL) and extract with ethyl acetate (2x150 mL).
Wash the combined organic layers with water (100 mL) and brine (100 mL). Dry the
organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the
resultant residue on a Si02 column with hexanes to yield 640 mg of l-bromo-4-(2,2,2-
trifluoro-ethylsulfanyl)-benzene (45%).
Dissolve l-bromo-4-(2,2,2-trifluoro-ethylsulfanyl)-benzene (640 mg, 2.4 mmol) in
dichloromethane (25 mL) and cool to 0°C. Add mCPBA (1.8g, 7.1 mmol, 68%) in
portions and stir the reaction for 2 hours at room temperature. Filter the white precipitate
and wash the filtrate with IN aqueous NaOH. Dry the organic layer with sodium sulfate,
filter and concentrate in vacuo to yield 700 mg of the title compound (98%).

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Example 37
l-[2-(4-{6-Methoxy-2-[4-(2,2)2-trifluoro-ethanesulfonyl)-phenyl]-naphthalen-l-yloxy}-
phenoxy)-ethyl]-piperidine

Charge a flame-dried flask with palladium (II) acetate (6.4 mg, 0.029 mmol),
tricyclohexylphosphine (13.3 mg, 0.048 mmol) and cesium fluoride (260 mg, 1.71 mmol).
Add dry acetonitrile (2 mL) and stir under nitrogen. Add the compound of Preparation 1
(100 mg, 0.19 mmol) followed by bis(neopentylgylcolato)diboron (64 mg, 0.29 mmol).
Plunge the reaction into an 80°C oil bath. Once the reaction turns black (~3 to 5 minutes)
immediately add l-bromo-4-(2,2,2-trifluoro-ethanesulfonyl)-benzene (116 mg, 0.38
mmol) and continue heating. After 45 minutes, cool the reaction to room temperature and
filter through celite. Concentrate the filtrate in vacuo and purify on a SiO2 column with
methanol in dichloromethane (0 to 3%) to yield 26 mg of the title compound (23%):
LRMS (ESI, positive ion) m/z= 600.5 (M+H).
Example 38
5-[4-(2-Piperidin-l-yl-ethoxy)-phenoxy3-6-[4-(2,2,2-trifluoro-ethanesulfonyl)-phenyl]-
naphthalen-2-ol
Dissolve the compound of Example 37 (26 mg, 0.043 mmol) in dichloromethane
(1 mL) and add 2M HC1 in diethyl ether (43 (iL, 0.086 mmol). Remove the solvents in
vacuo and place on a high vacuum pump for 10 minutes. Dissolve the resultant foam in
dry dichloromethane (1 mL) and cool to 0°C. Add BBr3 (20 |iL, 0,22 mmol) dropwise and
stir at 0°C for 1 hour. Pour the reaction into cold saturated aqueous sodium bicarbonate
(5 mL) and extract with dichloromethane (2x5 mL). Dry the combined organic phases
with sodium sulfate, filter, and concentrate in vacuo. Purify the resultant oil on a SiCb

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43
column with methanol in dichloromethane (0 to 8%) to yield 16 mg of the title compound
(64%): mass spectrum (ion spray) m/z = 586.4 (M+H).
Example 39
5-[4-(2-Piperidin-l-yl-ethoxy)-phenoxy]-6-[4-(2,2,2-trifluoro-ethanesulfonyl)-phenyl]-
naphthalen-2-ol Hydrochloride
Dissolve the compound of Example 38 (30 mg, 0.051 mmol) in dry
dichloromethane (1 mL) and add 2M HC1 in diethyl ether (0.10 mL, 0.20 mmol). Stir at
room temperature for 1 minute. Remove the solvent by blowing nitrogen over the liquid.
Place the residue on a high vacuum pump for 1 hour. Dry the product in a vacuum oven
at 45°C overnight to yield 30 mg of the title compound (97%): mass spectrum (ion spray)
m/z = 586.3 (M+H-HC1).
Preparation 14
2-(4-Isopropylsulfanyl-phenyl)-boronic acid
Dissolve 4-bromo-benzenethiol (1.0 g, 5.3 mmol) in dry dimethylformamide (50
mL) and cool to 0°C under nitrogen. Add dry sodium hydride (153 mg, 6.4 mmol) in
portions. After the vigorous gas evolution stops, add 2-bromo-propane (0.60 mL, 6.4
mmol) and stir the reaction overnight at room temperature, Slowly pour the reaction into
water (300 mL) and extract with ethyl acetate (2x150 mL). Wash the combined organic
layers with water (100 mL) and brine (100 mL). Dry the organic layer with sodium
sulfate, filter and concentrate in vacuo. Chromatograph the resultant residue on a S1O2
column with 5% ethyl acetate in hexanes to yield l.lg of l-bromo-4-isopropylsulfanyl-
benzene (92%).
dissolve l-bromo-4-isopropylsulfanyl-benzene (2.5 g, 10.8 mmol) in dry
tetrahydrofuran (100 mL) and cool the solution to -78°C. Add 2,5 M n-butyllithium in
hexanes (5.2 mL, 12.9 mmol) dropwise and allow the reaction to warm to -40°C and stir
for 30 minutes. Cool the reaction to -78°C and add triisopropyl borate (7.4 mL, 32.4
mmol) and allow the reaction to slowly warm to room temperature. Add 10% aqueous
potassium hydroxide (96 mL, 172 mmol) and stir overnight. Slowly pour the reaction

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into a mixture of concentrated HC1 and ice. Extract the aqueous solution with
dichloromethane, dry with sodium sulfate and concentrate in vacuo to yield 1.9 g of the
title compound (90%).
Example 40
1 -(2- {4-[2-(4-Isopropylsulfanyl-phenyl)-6-methoxy-naphthalen-1 -yloxy]-phenoxy} -
ethyl)-piperidine

Combine 2-(4-isopropylsulfanyl-phenyl)-boronic acid (223 mg, 1.14 mmol), the
compound of Preparation 1 (300 mg, 0.57 mmol) and cesium fluoride (433 mg, 2.85
mmol) in a flame-dried flask fitted with a reflux condenser and purge with nitrogen. In a
separate dried flask combine palladium (II) acetate (13 mg, 0.06 mmol) and
tricyclohexylphosphine (24 mg, 0.09 mmol). Add dry acetonitrile (5 mL) and sonicate for
10 minutes under nitrogen. Add the catalyst shiny to the solids and plunge the flask into
a 90°C oil bath. After 20 minutes cool the black suspension to room temperature and
filter through celite, rinsing with dichloromethane. Concentrate the filtrate in vacuo.
Chromatograph the resultant residue on a SiO2 column with 3% methanol in
dichloromethane with 0.2% ammonium hydroxide to give 300 mg of the title compound
(95%): mass spectrum (ion spray) m/z = 528.3 (M+H).
Example 41
6-(4-Isopropylsulfanyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-ol
Dissolve the compound of Example 43 (300 mg, 0.57 mmol) in dichloromethane
(3 mL). Add 2M HC1 in diethyl ether (0.51 mL, 1.14 mmol) and stir for 1 minute.
Remove the solvent in vacuo and place on a high vacuum pump for 20 minutes. Dissolve
the foam in dry dichloromethane (6 mL) and cool to 0°C. Add BBr3 (0.21 mL, 2.3

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45
mmol), dropwise. Stir for 45 minutes and quench by adding methanol (1 mL). Slowly
pour the reaction mixture into saturated aqueous sodium bicarbonate (10 mL) and extract
with dichloromethane (2 x 10 mL). Dry the combined organic layers with sodium sulfate
and concentrate in vacuo. Chromatograph the residue on a S1O2 column with 5%
methanol in dichloromethane with 0.2% ammonium hydroxide to yield 236 mg of the title
compound (81%): mass spectrum (ion spray) m/z = 514.3 (M+H).
Example 42
5-[4-(2-Piperidin-l-yl-ethoxy)-phenoxy]-6-[4-(propane-2-sulfonyl)-phenyl]-naphthalen-2-
ol
Dissolve the compound of Example 41 (236 mg, 0.46 mmol) in glacial acetic acid
(5 mL) and add sodium perborate (92 mg, 0.92 mmol). Stir the reaction overnight and
pour the mixture into saturated aqueous sodium bisulfite (20 mL). Extract with
dichloromethane (2x20 mL) and wash the combined organic layers with saturated
aqueous sodium bicarbonate (10 mL). Dry the organic layer with sodium sulfate, filter
and concentrate in vacuo. Chromatograph the residue on a Si02 column with 4%
methanol in dichloromethane with 0.2% ammonium hydroxide to yield 197 mg of the title
compound (79%): mass spectrum (ion spray) m/z=546.3 (M+H).
Example 43
5-[4-(2-Piperidin-l-yl-ethoxy)-phenoxy]-6-[4-(propane-2-sulfonyl)-phenyl]-naphthalen-2-
ol Hydrochloride
Dissolve the compound of Example 42 (123 mg, 0.36 mmol) in dry
dichloromethane (0.5 mL). Dilute the solution with diethyl ether (4 mL) and add 2M HC1
in diethyl ether (0.36 mL, 0.72 mmol). Stir at room temperature for 10 minutes. Filter
the white precipitate through paper and dry the solids in a vacuum oven at 50°C overnight
to yield 102 mg of the title compound (78%): mass spectrum (ion spray) m/z=546.3
(M+H-HC1).

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Preparation 15
2-Methyl-4-mcthylthiophenylboronicacid
Add 1M 3-methyl-phenylmagnesium bromide in THF (25 mL,25 ramol) to -30°C
diethyl ether (50 mL). Add dimethyl disulfide (1.8 mL, 20 mmol) to the reaction over 3
minutes allowing the reaction to warm to room temperature. Dilute the reaction in H2O.
(75 mL) and diethyl ether (50 mL). Separate and extract the cloudy aqueous layer with
diethyl ether (25 mL). Combine the organic layers and wash with H20 (25 mL).. Diy the
organic layer with Na2S04 (30 g), filter over Celite 501 (10 g) and concentrate in vacuo to
give 3.0 g of crude material. Combine with another batch of crude title compound that
yielded 6.0 g crude. Chromatograph the entire 9.0 g crude on a SiO2 column in hexanes
to give 7.2 g (70%) of 1 -methyl-3-methylsulfanyl-benzene.
Combine iron (25 mg, 0.45 mmol) and l-methyl-3-methylsulfanyl-benzene.(204
mg, 1.47 mmol) in dichloromethane (DCM, 2 mL). Cool, the slurry to 3°C and add Br2
(74JJ.L, 1.44 mmol) over 5 minutes. Stir at 3°C for 10 minutes and remove the external
cooling bath. Stir at room temperature for 4 hours, then quench with 10% aqueous
Na2S2O3 solution. Dilute the reaction with dichloromethane (10 mL) and separate. Wash
the organic layer with brine, concentrate and chromatograph with dichloromethane in
hexanes (0 to 5%) to give 125 mg of l-bromo-2-methyl-4-methylsulfanyl-benzene (53%).
Add l-bromo-2-methyl-4-methylsulfanyl-benzene (608 mg, 2.80 mmol) to diethyl
ether (60 mL) and cool to -78°C under a nitrogen blanket. Add t-BuLi (3.4 mL, 5.78
mmol) over a 15 minute period, stir for 2 minutes, add trimethyl borate ((MeO)3B, 340
|AL, 2.99 mmol) over 2 minutes, stir for 15 minutes at-78°C and then let warm to room
temperature. Quench the reaction with saturated aqueous NH4CI (7 mL), stir for 15
minutes, add 1M aqueous HC1 (6 mL), stir for another 2 minutes and separate. Dry'with
Na2SO4, filter (wash the drying agent with ethyl acetate (3 x 20 mL)),.and concentrate.
Chromatograph the crude material on a Si02 column with 20% ethyl acetate in hexanes to
5 % methanol in ethyl acetate to give 267 mg of the title compound (52%).
Example 44
l-(2-{4-[6-Methoxy-2-(2-methyl-4-methyl'sulfanyl-phenyl)-naphthalen-l-yloxy]-
phenoxy} -ethyl)-piperidine Hydrochloride

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Add the compound of Preparation 1 (300 mg, 0.57 mmol), 2-methyl-4-
methylthiophenylboronic acid (267 mg, 1.47 mmol) and cesium fluoride (672 mg, 4.42
mmol) into acetonitrile (3.0 mL) in a flame-dried flask fitted with a reflux condenser. In a
separate dried flask combine palladium (II) acetate (14.5 mg, 0.06 mmol) and
tricyclohexylphosphine (27.5 mg, 0.10 mmol). Add dry acetonitrile (2.5 mL) and sonicate
for 10 minutes under nitrogen. Add the catalyst suspension to the reaction slurry and
plunge the flask into a 90°C oil bath. After 40 minutes, cool the black suspension to room
temperature, filter and wash the solids with acetonitrile (3x10 mL). Concentrate the
filtrate in vacuo. Partition the residue between ethyl acetate (25 mL) and 5% aqueous
sodium carbonate (10 mL). Separate the layers and wash the organic layer with saturated
aqueous NH4CI (10 mL) and brine (10 mL). Concentrate the organic layer in vacuo and
chromatograph the residue on a SiO2 column with methanol in dichloromethane (0 to
2.5%) to give 331 mg of l-(2-{4-[6-methoxy-2-(2-methyl-4-methylsulfanyl-phenyl)-
naphthalen-l-yloxy]-phenoxy}-ethyl)-piperidine (94%). Dissolve the free base material
in ethyl acetate (10 mL), add 2M HC1 in diethyl ether (350 |iL) and concentrate in vacuo
to give the title compound: mass spectrum (ion spray) m/z = 514.3 (M+H).
Example 45
6-(2-Methyl-4-methylsulfanyl-phenyl)-5-[4-(2-piperidin-1 -yl-ethoxy)-phenoxy]-
naphthalen-2-ol
Dissolve 1 -(2- {4-[6-methoxy-2-(2-methyl-4-methylsulfanyl-phenyl)-naphthalen-l -
yloxy]-phenoxy}-ethyl)-piperidine hydrochloride (331 mg, 0.603 mmol) in
dichloromethane (15 mL) and cool to 5°C. Add BBr3 (285 |lL, 3.02 mmol) to the light
suspension over 5 minutes. Quench the reaction after 1 hour with saturated aqueous

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NaHC03(15mL). Separate the layers and extract the aqueous layer with
dichloromethane (2x10 ml). Pour the solution onto a Si02 plug (20 g) and elute with
methanol'in dichloromethane (5 to 15%). Concentrate the fractions in vacuo to give 301
mg of the title compound (100%): mass spectrum (ion spray) m/z = 500.3 (M+H).
Example 46
6-(4-Methanesulfonyl-2-methyl-phenyl)-5-[4-(2-piperidin-1 -yl-ethoxy)-phenoxy]-
naphthalen-2-ol Trifluoroacetate
Dissolve the compound of Example 45 (301 mg, 0.060 mmol) in glacial acetic
acid (5 mL) and add NaBCVEfeO (120 mg, 1.20 mmol). Concentrate the reaction after 14
hours and partition between 10% aqueous NaHSO3 (30 mL), MeOH (3 mL) and
dichloromethane (50 mL). Separate the layers and extract the aqueous layer with
dichloromethane (10 mL). Combine the organic layers and wash with saturated aqueous
NaHC03 (10 mL) and H20 (10 mL). Dry with Na2S04, filter, and concentrate in vacuo.
Chromatograph on a Si02 column with methanol in dichloromethane (0 to 10%) to obtain
impure product. This crude material is purified by preparative HPLC to give 97 mg of the
title compound (23%): mass spectrum (ion spray) m/z = 532.3 (M+H-TFA).
Example 47
1 -(2- {4-[6-Methoxy-2-(3-methyl-4-methylsulfanyl-phenyl)-naphthalen-l -yloxy]-
phenoxy} -ethyl)-piperidine

Combine palladium (II) acetate (21 mg, 0.094 mmol), tricyclohexylphosphine (53
mg, 0.19 mmol), the compound of Preparation 1 (500 mg, 0.95 mmol), cesium fluoride
(l.OOg, 6.62 mmol,) 3-methyl-4-(methythio)benzeneboronic acid (US Patent No.
6,307,047; 520 mg, 2.86 mmol) and acetonitrile (40 mL). Heat to 90°C for 1 hour. Cool
to room temperature and dilute the solution with ethyl acetate (20 mL) and wash with

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saturated aqueous Na.HC03 (10 mL). Separate the layers, wash the organic layer with
brine (10 mL), dry with MgS04, filter, and concentrate in vacuo. Chromatograph the
residue on a SiOi column eluting the material with methanol in dichloromethane (2 to
4%) to give 371 mg of the title compound (75%): mass spectrum (ion spray): m/z = 514.3
(M+H).
Example 48
6-(3-Methyl-4-methylsulfanyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
naphthalen-2-ol
Dissolve the product of Example 47 in ethyl acetate (10 mL) and diethyl ether (5
mL). Add 2M HC1 in diethyl ether (5 mL, 10.0 mmol). Concentrate the slurry and dry in
vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool
the solution to 0°C with external ice bath and add BBr3 (0.3 mL, 3.2 mmol). After 1 hour,
add water (1.0 mL) and ethyl acetate (10 mL). Separate the layers, wash the organic layer
with saturated aqueous NaHCCb (10 mL) and brine (10 mL). Dry with MgSCu, filter, and
concentrate in vacuo. Chromatograph the residue on a column eluting the material with a
step gradient of methanol in dichloromethane (0 to 0.5%) to give 330 mg of the title
compound (92%): mass spectrum (ion spray): m/z = 500.3(M+H).
Example 49
6-(4-Methanesulfonyl-3-methyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
naphthalen-2-ol Hydrochloride
Combine the compound of Example 48 and sodium perborate (162 mg, 1.62
mmol) in acetic acid (4 mL). After 2 days, add dichloromethane (20 mL) and water (5
mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10
mL), brine (10 mL), dry with MgS04, filter, and concentrate in vacuo. Chromatograph
the residue on a S1O2 column eluting the 6-(4-methanesulfonyl-3-methyl-phenyl)-5-[4-(2-
piperidin-l-yl~ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol in
dichloromethane (0 to 5%). Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate
(6.0 mL) and methanol (1.0 mL) and add 2M HC1 in diethyl ether (1 mL, 2.0 mmol).

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Collect the precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2mm of
Hg) at 65°C for 48 hours to give 40 mg of the title compound (11%): mass spectrum (ion
spray): m/z = 537.0 (M+H-HC1).
Preparation 16
2-Benzo[b]thiophen-5-yl-4,4,5,5-tetramethyl-[l,3,2] dioxaborolane
Dissolve 5-bromo-benzo[b]thiophene (J. Mater. Chem., 10:2069-2081, 2000; 49
g, 7.0 mmol) in DMSO (40 mL). Add bis(pinacolato)diboron (7 mmol),
PdCl2(dppf)-CH2Cl2 (0.33 mmol), and KOAc (20 mmol). Flush the flask with N2, and
then heat the reaction mixture to 80°C with stirring. Continue to heat the reaction mixture
for 3 hours, and then cool to room temperature. Add water (66 mL) and extract the
aqueous layer with EtOAc (3 x 66 mL). Combine the organic layers and dry with
Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 0-'5%
Et20/pentane) to give 1.56 g of the title compound (86%).
Example 50
1 - {2-[4-(2-Benzo[b]thiophen-5-yl-6-methoxy-naphthalen-1 -yloxy)-phenoxy]-ethyl}-
piperidine

Dissolve 2-benzo[b]thiophen-5-yl-4,4,5,5-tetramethyl-[ 1,3,2] dioxaborolane (400
mg, 1.54 mmol) and the compound of Preparation 1 (270 g, 0.51 mmol) in CH3CN (24
mL). Add Pd(OAc)2 (0.05 mmol), tricyclohexylphosphine (0.075 mmol), and CsF (4.5
mmol). Flush the flask with N2, then heat the reaction mixture to 90°C with stirring.
Continue to heat the reaction mixture for 6 hours, and then cool to room temperature.
Add water (50 mL), and extract the aqueous layer with CH2CI2 (3 x 25 mL). Combine the

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organic layers and dry with Na2S04, filter, concentrate and purify by flash column
chromatography (silica gel, 0-4% MeOH-NH4OH (10/1, v/v) in CH2C12) to give 240 mg
of the title compound (93%): ]H NMR (CDC13) 8 7.99 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 9.2
Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.4,1.2 Hz, 1H),
7.41 (d, J = 5.6 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 7.11 (dd, J =
9.2, 2.8 Hz, 1H), 6.73 (d, J = 5.6 Hz, 1H), 6.60-6.63 (m, 4H), 4.04(t, J = 5.0 Hz, 2H),
3.94 (s, 3H), 2.93 (t, J = 5.0 Hz, 2H), 2.67-2.79 (m, 4H), 1.66-1.75 (m, 4H), 1.44-1.55 (m,
2H).
Example 51
6-Benzo[b]thiophen-5-yl-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-ol
Trifluoroacetate
Dissolve the compound of Example 50 (240 mg, 0.48 mmol) in
dimethylformamide (DMF, 7 mL), add sodium ethanethiolate (EtSNa, 100 mg, 1.19
mmol). Flush the flask with N2 and then heat the reaction mixture to 150°C. Continue to
heat the reaction mixture for 0.5 hours, cool to room temperature. Add water (15 mL),
and extract the aqueous layer with CH2CI2 (3x15 mL). Combine the organic layers and
dry with Na2S04, filter, concentrate and purify by flash column chromatography (silica
gel, 0-8% MeOH-NH4OH (10/1, v/v) in CH2C12) to give 140 mg of crude 6-
benzo[b]thiophen-5-yl-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthaien-2-ol. Purify
the impure product by preparative HPLC (Gilson) to give 95 mg of the title compound
(55%): mass spectrum (ion spray): m/z = 496.3 (M+H-TFA).
Example 52
Acetic acid 6-(l,l-dioxo-lH-l>v6-benzo[b]thiophen-5-yl)-5-[4-(2-piperidin-l-yl-ethoxy)-
phenoxy]-naphthalen-2-yl ester
Dissolve 6-beiizo[b]thiophen-5-yl-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-
naphthalen-2-ol (560 mg, 1.13 mmol) in CH2C12 (20 mL), and cool the solution to 0°C.
Add DMAP (28 mmol), triethylamine (Et3N, 8 mmol) and acetic anhydride (Ac20,1.9
mmol). Stir the reaction mixture for 3 hours at 0°C and then add water (40 mL). Extract

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the aqueous layer with CH2C12 (3 x 40 mL). Combine the organic layers and dry with
Na2S04, filter, concentrate and purify by flash column chromatography (silica gel, 0-5%
MeOH in CH2CI2) to give 360 mg of the acylated product (59%): mass spectrum (ion
spray): m/z = 53.8.3 (M+H). Dissolve the acylated product (110 mg, 0.2 mmol) in acetic
acid (AcOH, 1.1 mL) and add H202 (110 mg, 1.0 mmol, 30%wt). Heat the reaction
mixture to 90°C for one hour and then cool to room temperature. Add 1M aqueous
bisulfite solution (1 mL) and stir the reaction mixture for 10 minutes. Add saturated
aqueous NaHC03 solution (20 mL) and extract the aqueous layer with CH2C12 (3 x 20
mL). Combine the organic layers and dry with Na2S04, filter, concentrate and purify by
flash column chromatography (silica gel, 0-5% MeOH in CH2C12) to give 51 mg of the
title compound (44%): mass spectrum (ion spray): m/z = 570.3 (M+H).
Example 53
6-( 1,1 -Dioxo-1H-1 ?.6-benzo [b] thiophen-5-yl)-5-[4-(2-piperidin-1 -yl-ethoxy)-phenoxy]-
naphthalen-2-ol Trifluoroacetate
Dissolve the compound of Example 52 (51 mg, 0.089 mmol) in MeOH (2 mL).
Add NaHC03 (0.10 mmol) and stir the reaction mixture for 3 hours at room temperature.
Remove the solids by filtration. Concentrate the filtrate and purify the residue by flash
column chromatography (silica gel, 2-10% MeOH-NH4OH (10/1, v/v) in CH2C12). Dry
the pooled materials at 40°C for overnight in vacuo to give 67 mg of the deprotected
product (85%). Dissolve the deprotected product (67 mg, 0.13 mmol) in CH2C12 (10 mL)
and cool it to -78°C. Add CF3C02H (0.13 mL, 1.0 M in CH2C12) and then remove the
solvent under reduced pressure to give a solid. Dry the solid at room temperature
overnight in vacuo to give 82 mg of the title compound (100%): mass spectrum (ion
spray): m/z = 528.3 (M+H-TFA).
Preparation 17
6-(3,5-Difluoro-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-ol
Combine the compound of Preparation 1 (440 mg, 0.84 mmol), 3,5-difluoro-
benzeneboronic acid (400 mg, 2.50 mmol), palladium(II)acetate (19 mg, 0.083 mmol),

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53
tricyclohexylphosphine (35 rag, 0.125 mmol), cesium fluoride (1.14 g, 7.52 mmol),
acetonitrile (10 mL) and heat at 90°C. After 10 minutes, cool to ambient temperature,
dilute with dichloromethane, load onto a 10 g SCX cartridge, wash with dichloromethane,
methanol, water, methanol, elute with ammonia solution (2N NH3 in methanol, 80 mL)
and remove solvent under vacuum. Dissolve in dichloromethane, chromatograph on
silica gel with dichloromethane/methanol mixtures and add 1M hydrogen chloride in
diethyl ether (0.8 mL) to give 410 mg of l-(2-{4-[2-(3,5-difluoro-phenyl)-6-methoxyr
naphthalen-l-yloxy]-phenoxy}-ethyl)-piperidine hydrochloride (93%).
Dissolve l-(2-{4-[2-(3,5-difluoro-phenyl)-6-methoxy-naphthalen-l-yloxy]-
phenoxy}-ethyl)-piperidine hydrochloride (410 mg, 0.76 mmol) in dichloromethane (10
mL) and cool in an ice bath. Add boron tribromide (0.22 mL, 2.28 mmol) and stir for 2.5
hours. Add methanol (5 mL), warm to ambient temperature, dilute with'dichloromethane
and wash with saturated aqueous sodium bicarbonate, dry with solid magnesium sulfate,
filter and remove solvent under vacuum. Chromatograph on silica gel with
dichloromethane/methanol mixtures to give 350 mg of the title compound (96%).
Example 54
6-(3,5-Bis-ethylsulfanyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-oi

Combine 6-(3,5-ditluoro-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]- .
naphthalen-2-ol (300 mg, 0.63 mmol), sodium ethane thiol (530 mg, 6.33 mmol) and 1-
methyl-2-pyrrolidinone (10 mL) and heat to 130°C for 4.5 hours. Cool to ambient
temperature, dilute with dichloromethane, wash with brine and a saturated sodium
bicarbonate solution. Load organic phase onto a 10 g SCX cartridge, wash with
dichloromethane, methanol, elute with ammonia solution (2N NH3 in methanol, 80 mL)
and remove solvent under vacuum. Dissolve in dichloromethane and chromatograph on

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silica gel with dichloromethane/methanol mixtures to give 260 mg of the title compound
(74%). Mass spectrum (ion spray): m/z= 560 (M+H).
Example 55
6-(3,5-Bis-ethanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-
ol
Dissolve the compound of Example 54 (160 mg, 0.29 mmol) in glacial acetic acid
(5 mL). Add an acetic acid solution of 77% mCPBA (300 mg, 1.31 mmol theoretical)
dropwise over 10 minutes and stir at ambient temperature for 1 hour. Remove solvent
under reduced pressure. Partition with dichloromethane and saturated sodium bicarbonate
solution, dry with solid magnesium sulfate, filter and chromatograph on silica gel with
dichloromethane/methanol mixtures to give 130 mg of the title compound (72%). Mass
spectrum (ion spray): m/z= 624 (M+H).
Example 56
6-(3,5-Bis-ethanesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-naphthalen-2-
ol Hydrochloride
Dissolve the compound of Example 55 in dichloromethane and add 1N-HC1 in
Et20 (0.180 mL). Evaporate to dryness to give the title compound.
Preparation 18
{4-[2-(4-Methanesulfonyl-phenyl)-6-methoxy-naphthalen-1 -yloxy]-phenyl} -carbamic
acid tert-butyl ester
Heat a solution of 6-methoxytetralone (9.6 g, 54 mmol), 4-bromothioanisole (25
mL, 123 mmol), sodium tcrt-butoxide (20.9 g, 217 mmol), palladium (II) acetate (610 mg,
2.72 mmol), racemic 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (1.8 g, 2.72 mmol) and
toluene (150 mL) at reflux for 18 hours, then cool to ambient temperature and evaporate
to dryness under reduced pressure. Dissolve the residue in dichloromethane and wash
with aqueous hydrochloric acid (IN), filter through celite and chromatograph twice on

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silica gel with hexane/ethyl acetate mixtures to give 2.41 g of 6-methoxy-2-(4-
methylsulfanyl-phenyl)-naphthalen-1 -ol (15%).
Stir a solution of 6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-l-ol (1.98 g,
6.68 mmol), 4-fiuoro-nitrobenzene (0.78 mL, 7.34 mmol) and phosphazene base P4-t-
butyl (6.7 mL of 1M in hexane, 6.7 mmol) in N,N-dimethylformamide (30 mL) at
ambient temperature for 4 hours. Dilute the reaction with dichloromethane, wash with IN
aqueous hydrochloric acid, water, dry with solid magnesium sulfate and chromatograph
on silica gel with hexane/ethyl acetate mixtures to give 2.18 g of 6-methoxy-2-(4-
methylsulfanyl-phenyl)-1 -(4-nitro-phenoxy)-naphthalene (78%)
Add 77% mCPBA (340 mg, 2.00 mmol) to a solution of 6-methoxy-2-(4-
methylsulfanyl-phenyl)-l-(4-nitro-phenoxy)-naphthalene (270 mg, 0.66 mmol) in
dichloromethane (10 mL). Stir the reaction for 30 minutes, wash with saturated sodium
carbonate solution, dry with solid magnesium sulfate and filter through a 1 inch pad of
silica gel to give 290 mg of 2-(4-methanesulfonyl-phenyl)-6-methoxy-l-(4-nitro-
phenoxy)-naphthalene (98%).
Heat a solution of 2-(4-methanesulfonyl-phenyl)-6-methoxy-l-(4-nitro-phenoxy)-
naphthalene (1.67 g, 3.7 mmol), ammonium formate (4.7 g, 74 mmol), wet 20%
palladium hydroxide on carbon (420 mg, 25 wt%) and absolute ethanol (80 mL) at reflux
for 1 hour, then cool to ambient temperature, filter and evaporate to dryness under
reduced pressure. Partition the residue with dichloromethane/water. Dry the organic
layer with solid magnesium sulfate and chromatograph on silica gel with
dichloromethane/methanol mixtures to give 1.15 g of4-[2-(4-methanesulfonyl-phenyl)-6-
methoxy-naphthalen-1 -yloxyj-phenylamine (75%).
Heat a solution of 4-[2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-l-
yloxy]-phenylamine (170 mg, 0.41 mmol) and di-tert-butyl dicarbonate (140 mg, 0.66
mmol) in tetrahydrofuran (10 mL) at reflux for 4 hours, then cool to ambient temperature
and evaporate to dryness under reduced pressure. Chromatograph the residue on silica gel
with dichloromethane/ethyl acetate mixtures to give 210 mg of {4-[2-(4-methanesulfonyl-
phenyl)-6-methoxy-naphthalen-l-yloxy]-phenyl}-carbamic acid tert-butyl ester (97%).

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56
Example 57
{4-[2-(4-Methanesulfonyl-phenyl)-6-methoxy-naphthalen-l-yloxy]-phenyl}-(2-piperidin-
1 -yl-ethyl)-carbamic acid tert-butyl ester

Heat a solution of {4-[2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-l-yloxy]-
phenyl}-carbamic acid tert-butyl ester (200 mg, 0.38 mmol), 2-chloroethyl-l-piperidine
hydrochloride (100 mg, 0.57 mmol) and 60% sodium hydride (38 mg, 0.94. mmol) in
N,N-dimethylformamide to 60°C and stir for 18 hours. Add potassium tert-butoxide (760
mg, 0.67 mmol) and 2-chloroethyl-l-piperidine hydrochloride (46 mg, 0.25 mmol) and
stir for an additional 2 hours, then cool to ambient temperature. Dilute the reaction with
dichloromethane, wash with saturated sodium bicarbonate, dry with magnesium sulfate
and chromatograph on silica gel with dichloromethane/methanol mixtures to give 120 mg
of the title compound (50%). Mass spectrum (ion spray): m/z= 631.3 (M+H).
Example 58
6-(4-Methariesulfonyl-phenyl)-5-[4-(2-piperidin-l-yl-ethylamino)-phenoxy]-naphthalen-
2-ol Dihydrochloride
Add 4M HCl/dioxane (3 mL, 12 mmol) to a solution of the compound of Example
57 (110 mg, 0.17 mmol) in dichloromethane (3 mL) and stir the reaction for 40 minutes,
then evaporate to dryness under reduced pressure. Dissolve the residue in
dichloromethane (4 mL) and add boron tribromide (0.068 mL, 0.72 mmol). Stir the
reaction for 3.5 hours, then add aqueous saturated sodium bicarbonate (5 mL) and allow
the phases to separate. Dry the organic layer with solid magnesium sulfate and
chromatograph on silica gel with dichloromethane/methanol mixtures. Evaporate the
fractions containing product to dryness and redissolve in 5% methanol/dichloromethane

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57
(3 mL). Add 1M hydrogen chloride in diethyl ether (0.28 mL) then evaporate the solution
under reduced pressure to give 82 mg of the title compound (77%). Mass spectrum (ion
spray): m/z= 517.5 (M+H).
Example 59
5-[4-(2-Azepin-l-yl-ethylamino)-phenoxy]-6-(4-methanesulfonyl-phenyl)-naphthalen-2-
ol Dihydrochloride

Using procedures similar- to Preparation 18 and Example 58, convert {4-[2-(4-
methanesulfonyl-phenyl)-6-methoxy-naphthalen-l-yloxy]-phenyl}-carbamicacidtert-
butyl ester (200 mg, 0.39 mmol) and 2-(hexamethyleneimino)-ethyl chloride
hydrochloride (140 mg, 0.70 mmol) to 77 mg of the title compound (37%). Mass
spectrum (ion spray): m/z= 531 (M+H).
Preparation 19
4-[2-(4-Methancsulfonyl-phenyl)-6-methoxy-naphthalen-l-yloxy]-phenol
Add 4-fluoro-bcnzaldehyde (2.20 mL, 20.3 mmol) to a solution of 6-methoxy-2-
(4-methylsulfanyl-phenyl)-naphthalen-l-ol (3.0 g, 10.1 mmol) and 60% sodium hydride
(400 mg, 10.1 mmol) in 1 -methyl-2-pyrrolidinone (30 mL). Heat the reaction to 170°C
for 70 minutes, then cool to ambient temperature. Dilute the reaction with ethyl acetate
(200 mL) and wash twice with 5% aqueous lithium chloride (500 mL), brine, IN aqueous
hydrochloric acid, dry with solid magnesium sulfate and chromatograph on silica gel with
dichloromethane/hexane mixtures to give 1.29 g of 4-[6-methoxy-2-(4-methylsulfanyl-
phenyl)-naphthalen-l -yloxy]-benzaldehyde (32%).
Combine 4-[6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-l-yloxy]-
benzaldehyde (970 mg, 2.49 mmol), sodium perborate monohydrate (2.5 mmol) and

WO 2004/009086 PCT/IB2003/003349
58
glacial acetic acid (16 mL). Stir for 4 hours at ambient temperature, then evaporate to
dryness under reduced pressure. Partition with dichloromethane/50% saturated aqueous
sodium bicarbonate solution. Wash the organic layer with brine, dry with solid
magnesium sulfate, filter and chromatograph on silica gel with dichloromethane/methanol
mixtures to give 280 mg of the title compound (27%). Mass spectrum (ion spray): m/z=
419 (M-l).
Example 60
We Claim:
1. A compound of Formula I:

Wherein:
m, q and r are independently 0,1 or 2;
n is 0 or 1;
R is H or COR2;
R° is independently at each occurrence OH, CF3, halo, C1-C6 alkyl or C1-C6 alkoxy;
R1 and R1' are independently C1-C6 alkyl, C1-C6 alkoxy, NR3R3a, CF3 or CH2CF3; or
when n and q are 0, the -SO2R moiety may combine with the phenyl ring to which
it is attached to form a moiety of formula (a) or (b):

wherein t and v are 0,1 or 2 provided that the sum of t +v must be 2;
R is C1-C6 alkyl; C1-C6 alkoxy; NR4R; phenoxy; or phenyl optionally substituted
with halo;
R3 is C1-C6 alkyl or phenyl;
R3a and R are independently at each occurrence H, C1-C6 alkyl, or phenyl;
X is O, CH2 or CO;

109
Xi is O or NR5;
R5 is H or C1-C6 alkyl; and
R is H or methyl provided that if r is 1 or 2, then Rs must be H and that if r is 0, then
R° must be methyl; and
Y is CH2CH2 or CH=CH; or a pharmaceutical acid salt thereof.
2. A compound as claimed in claim 1, wherein m is 2; r is 1 or 2; or a pharmaceutical
acid addition salt thereof.
3. A compound as claimed in claim 1 or 2 wherein R2 is Q.-C6 alkyl, NHCH3 or phenyl
and the -SO2R1 moiety does not combine with the phenyl ring to which it is attached
to form a moiety of formula (a) or (b); or a pharmaceutical acid addition salt.
4. A compound as claimed in any one of claims 1-3 wherein n is 0; q is 0 or 1; the -
SO2R moiety is at the para-position of the phenyl ring to which it is attached; R° is
OH, CF3, fluoro, chloro, methyl or ethyl; R1 is methyl, ethyl, n-propyl, isopropyl,
cyclopropyl, n-butyl, isobutyl, sec- butyl, t-butyl, cyclobutyl or CF3; R2 is Q-C6 alkyl
or phenyl; and Y is CH=CH; or a pharmaceutical acid addition salt thereof.

5. A compound of any one of claim 1-4 wherein X and X : are O; or a pharmaceutical
acid addition salt thereof.
6. A compound of formula 1 such as herein described with reference to the
foregoing examples.
Dated this 5th day of December 2007

The present invention relates to a selective estrogen receptor modulator of formula I or a
pharmaceutical acid addition salt thereof; useful, e.g., for treating endometriosis and/or
uterine leiomyoma/leiomyomata.