Title of Invention

A FLUORO SUBSTITUTED COMPOUND OF FORMULA (1A) USEFUL AS SELECTIVE ESTROGEN RECEPTOR MODULATORS AND PHARMACEUTICAL COMPOSITION THEREOF

Abstract The present invention discloses compounds of Formula Ia, Or a pharmaceutical acid addition salt thereof useful as selective estrogen receptor modulators and pharmaceutical composition thereof.
Full Text Field of the Invention
The present invention relates to compounds of formula (la) that are selective
estrogen receptor modulators (SARM) for the treatment of Vasomotor Symptoms, and to
pharmaceutical compositions thereof. Particularly, the present invention relates to fluoro
substituted compounds useful as selective estrogen receptor modulators.
Background of the Invention
"Vasomotor symptoms", i.e., hot flashes, night sweats, vaginal dryness, sleep
disturbances, nausea and mood swings commonly affect women around menopause. In
fact, a majority of postmenopausal women will experience vasomotor symptoms with a
significant percentage of these women continuing to suffer symptoms for more than five
years (Psychosom. Med. 1965,27,266; Med. Gynecol. Soc. 1969, 4, 268). Women who
have undergone bilateral oophorectomy, radiotherapy or treatment with GnRH
(gonadotropin releasing hormone) agonists are particularly prone to experiencing hot
flashes (Br. J. Obstet. Gynaecol. 1977, 84,769). Men have also been reported to
experience vasomotor symptoms following treatment with a GnRH agonist (N. Engl. J.
Med. 1981, 305,663) or after orchidectomy (Urology 1980, 16,620).
In spite of being identified as an ailment of menopause for hundreds of years, the
precise mechanism underlying the cause of vasomotor symptoms is not clear. However, a
link with declining estrogen levels (due to natural menopause or otherwise) is widely
accepted. Interestingly, women with low estrogen levels due to ovarian dysgenesis
generally do not suffer from vasomotor symptoms unless they are first given hormone
replacement therapy (HRT) and then have it discontinued (Clin. Endocrinol.'(Oxf) 1985,
22,293), suggesting that estrogen withdrawal may be an underlying cause of vasomotor
instability. HRT is currently a preferred standard treatment for vasomotor symptoms and
is effective in >80% of women who initiate treatment, which again is supportive of an
estrogenic role in the etiology there'of.
Hot flashes (flushes) are characterised by a warming sensation that begins in the
chest and moves towards the neck and head, and are often accompanied by sweating,
palpitations and cutaneous flashing. The episodes last from 30 seconds to 10 minutes.
The hot flash event itself is thought to be centrally mediated resulting from a transient
lowering of the thermoregulatory set point in the hypothalamus (for a review, see: Can. J.
Physiol. Pharmacol. 1987,65, 1312). Regulation of the thermoregulatory process may
involve catecholamines, estrogen, testosterone, opioids and serotonin, among others (for a

review, see: Mayo. Clin. Proc. 2002, 77, 1207). In fact, compounds that modulate the
signaling pathway of each of these hormones/neurotransmitters have been evaluated for
the treatment of hot flashes. See, e.g., Ann. Intern. Med. 2000, 132, 788; Br. Med. J.
1974, i, 409; Maturitas, 1978, 1, 21; Med. J. Aust. 1986, 144, 369; Fertil. Steril. 1985,43,
401; Br. J. Obstet. Gynaecol. 1981, 88, 919; J. Clin. Endocrinol. Metab. 1984, 58, 578;
Clin. Endocrinol. 1985, 22, 293; Maturitas 2000, 36, 155; J. Clin. Oncol 2002, 20, 1583;
JAMA 2003,289, 2827; Lancet 2000, 356, 2059; N. Engl. J. Med. 1994, 331, 347;
Obstet. Gynecol. 1984, 63, 1; Obstet. Gynecol. 1999, 94, 225; Br. J. Obstet. Gynecol.
1998, 105, 904; Neurology 2000, 54, 2161; Obstet. Gynecol. 1998, 72, 688; J. Clin.
Oncol. 1998, 16, 495; J. Clin. Oncol. 2001, 19, 2739; and J. Nutr. 2001, 131 (11, supl),
3095s.
In spite of the apparent large number of treatments for hot flashes, all the current
therapies suffer from poor efficacy, are associated with unacceptable side effects or are
contraindicated for certain patient populations. For example, HRT is not recommended
for women with a history of breast cancer, uterine cancer, ovarian cancer, or venous
thromboembolism. Recent data also suggests HRT may not be suitable for women with
coronary artery disease. Non-hormonal treatments generally are not fully efficacious (e.g.
clonidine) and/or cause adverse effects (e.g., venlafaxine, gabapentin).
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 or to have a non-estrogenic effect in the uterus. However,
the actual use of a SERM in the treatment of vasomotor symptoms has also been
hampered by problems with efficacy, e.g., during Phase III clinical studies of raloxifene
for the treatment/prevention of post-menopausal osteoporosis, raloxifene was associated
with a slight increased incidence of hot flash compared to placebo and tamoxifen is
known to induce hot flashes in more than 50% of patients (Arch. Intern. Med. 1991, 151,
1842).

There, therefore, remains an unmet medical need for vasomotor symptom
therapies that overcome the liabilities of current treatments. In particular, there is a need
for a medication that possesses the positive attributes of previously disclosed SERMs
such as raloxifene (i.e., positive effects on bone, uterus, breast and cardiovascular system)
but also alleviates vasomotor symptoms.
Summary of Invention
The present invention relates to a compound of formula I:

wherein:
m is 0, 1 or 2;
n is 1,2, 3 or 4 ;
R is H or methyl provided that if m is 1 or 2, then R must be H and that if m is 0,
then R must be methyl;
R1 is H, SO2(n-C4-C6 alkyl) or COR2;
X is O or NR3;
X1 is O, CH2 or CO;
R6 is H or F or R6 combines with X1 to form a moiety of the formula:

wherein Y is O, S, SO or NR4;

R2 is C1-C6 alkyl; C1-C6 alkoxy; NR5R5a; phenoxy; or phenyl optionally
substituted with halo;
R3 and R4 are independently H or C1-C6 alkyl; and
R5 and R5a are independently H, C1-C6 alkyl or phenyl; 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 one or more vasomotor symptoms.
The present invention also relates to methods for treating one or more vasomotor
symptoms 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 one or more vasomotor
symptoms. 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 one or more vasomotor symptoms.
The present invention also releates to a compound of formula II:

or an acid addition salt thereof; wherein m, n, R,and X1 are as defined above for a
formula I compound and:
Rla is H, SO2CH3, SO2(n-C4-C6 alkyl), COR2, C1-C6 alkyl or benzyl;
R6 is H or F or R6 combines with X1 to form a moiety of the formula:


wherein Y is as defined above for a formula I compound;
X2 is O or NR7; and
R7 is H, C1-C6 alkyl or CO2(C1-C6 alkyl); provided that if R1a is H,
SO2(n-C4-C6 alkyl) or COR2, then X2 is NR7 and R7 is CO2(C1-C6 alkyl); useful as an
intermediate to a compound of formula I.
The present invention also relates to a compound of formula III:

or an acid addition salt thereof, wherein m, n, R and-R1a are as defined above for a
formula II compound and wherein:
X2 is O or NR7;
R8 is.OH, O(C1-C6 alkyl), S(C1-C6 alkyl) or NR4(CO2(C1-C6 alkyl))
Z is C=O or CHOH;and
- R7 is H, C1-C6 alkyl or CO2(C1-C6 alkyl); useful as an intermediate to a
compound of formula I where R6 combines with X1.
Statement of the Invention
The present invention relates to a fluoro substituted compound of formula la:

wherein:
m is 0, 1 or 2;
n is 1,2, 3 or 4 ;

R is H or methyl provided that if m is 1 or 2, then R must be H and that if m is 0,
then R must be methyl;
Rl is H, SO2(n-C4-C6 alkyl) or COR2;
X is O or NR3;
Y is O, S, SO or NR4;
R2 is C1-C6 alkyl; C1-C6 alkoxy; NR5R5a;
phenoxy; or phenyl optionally
substituted with halo;
R3 and R4 are independently H or C1-C6 alkyl; and
R5 and R5a are independently H, C1-C6 alkyl or phenyl; or a pharmaceutical acid
addition salt thereof.
The present invention also relates to pharmaceutical composition comprising a compound
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
diluents or excipient.
Detailed Description
Unless specified otherwise, reference hereafter to "a compound of formula I"
includes the pharmaceutical acid addition salts thereof.
The compounds of the present invention have one or more chiral centers and may
exist in a variety of stereoisomeric configurations. As a consequence of these chiral

centers, the compounds of the present invention occur as racemates, mixtures of
enantiomers and as individual enantiomers, as well as diastereomers and mixtures of
diastereomers. All such racemates, enantiomers, and diastereomers are within the scope
of the present invention.
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 "C1-C6 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 and cyclopropylmethyleneyl are also included within the
scope of a C1-C6 alkyl group. The term "C1-C4 alkyl" refers specifically to methyl,
ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl,
cyclopropylmethyl and cyclobutyl. The term "n- C4-C6 alkyl" refers specifically to n-
butyl, n-pentyl and n-hexyl. A "C1-C6 alkoxy" group is a C1-C6 alkyl moiety connected
through an oxy linkage.
The term "pharmaceutical" when used herein as an adjective means substantially
non-deleterious.
A pharmaceutical "acid addition salt" is a salt formed by reaction of the free base
form of a compound of formula I with a pharmaceutical acid, such as described in the
Encyclopedia of Pharmaceutical Technology, editors James Swarbrick and James C.
Boylan, Vol 13, 1996 "Preservation of Pharmaceutical Products to Salt Forms of Drugs
and Absorption". Specific salt forms include, but are not limited to the: acetate, benzoate,
benzenesulfonate, 4-chlorobenzenesulfonate; citrate; ethanesulfonate; fumarate; d-
gluconate; d-glucuronate; glutarate; glycolate; hippurate; hydrochloride; 2-
hydroxyethanesulfonate; dl-lactate; maleate; d-malate; 1-malate; malonate; d-mandelate; 1-
mandelate; methanesulfonate; 1,5 napthalenedisulfonate; 2-naphthalenesulfonate;
phosphate; salicylate; succinate; sulfate; d-tartrate; l-tartrate; and p-toluenesulfonate.
The terms "treating" and "treat" as used herein, means alleviating, ameliorating,
preventing, prohibiting, restraining, slowing, stopping, or reversing the progression or
severity of a pathological condition, or sequela thereof, described herein. The term

"preventing" means reducing the likelihood that the recipient of a compound of formula I
will incur, further incur or develop any of the pathological conditions, or sequela thereof,
described herein.
A "vasomotor symptom" is a condition selected from the list of: hot flash, night
sweats, vaginal dryness, sleep disturbances, nausea and mood swings; wherein said
condition results from a decrease of circulating endogenous estrogen that occurs in a
woman following cessation or reduction of menstration due to natural, surgical, or other
processes.
The term "woman in need thereof is a woman either suffering from the claimed
pathological condition, or is a woman at a recognized risk thereof, as determined by
medical diagnosis, i.e., as determined by the attending physician.
As used herein, the term "effective amount" means an amount of a compound of
formula I that is capable of treating the conditions described herein.
Preferred Compounds and 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. The following numbering system will be used
to describe the preferred positions of the fluoro moieties:

a) m is 1;
b) R6 is H or F and nis1, 2 or 3;
c) n is 1, 2 or 3;
d) n is 1 or 2;
e) n is 1;

f) n is 2;
g) R6 is H or combines with X1, n is 1 and the corresponding fluoro moiety is in
the 4-position;
h) R6 is H or combines with X1, n is 2 and the corresponding fluoro moieties are
in the 3,5-positions;
i) R1 is H;
j) R1 is H or COR2 and R2 is C1-C6 alkyl or phenyl;
k) R1 is H or COR2 and R2 is C1-C4 alkyl, NHCH3 or phenyl;
I) R3 is H, methyl or ethyl;
m) R3 is H;
n) X is O;
o) X is NR3 and R3 is H or methyl;
p) X1 is O;
q) R6 is H or F;
r) R6 combines with X1;
s) the hydrochloride salt form.
With respect to the chiral center designated below:

an enantiomeric excess (ee) of greater than 90% is preferred, an ee of greater than 95% is
most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric
enrichment is readily determined by one of ordinary skill in the art using standard
techniques and procedures, such as gas or high performance liquid chromatography with a
chiral column (see, e.g., J. Jacques, et al., "Enantiomers, Racemates, and Resolutions".
John Wiley and Sons, Inc., 1981; E.L. Eliel and S.H. Wilen," Stereochemistry of Organic
Compounds", (Wiley-Interscience 1994), and European Patent Application No. EP-A-

838448, published April 29, 1998). Of course, the preferred enantiomer is that which
possesses favorable activity in the biological assays disclosed herein. Employing the
chiral chromatography techniques disclosed herein, the preferred enantiomer (the
enantiomer with favorable activity) typically possesses the slower retention time, i.e.,
elutes second. In order to verify the identify of the preferred enantiomer in any given
racemic mixture, the activity of the individual isomers should be verified in the biological
assays described herein.
The compound of formula I is preferably employed in the treatment of hot flashes.
The compound of formula I is preferably formulated in a dosage unit form, i.e., in
an individual delivery vehicle, for example, a tablet or capsule, prior to administration to
the recipient woman.
The compound of formula I is preferably administered orally.
Synthesis
The compound of formula I may be prepared as described in the following Scheme
(where R8a is R8, H, or F), Preparations and Examples.


In Scheme 1, a compound of formula V is reacted with a compound of formula IV
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 trifluoromethyl sulfonate, to
provide a compound of formula VI (when R8a is R8 then of formula III). When X1 is CO
in the formula VI compound, the keto group may be reduced under standard conditions,
e.g., employing borane to provide the corresponding benzyl alcohol. This reduced

product may be cyclized under standard conditions, e.g., when R8a is F, base catalyzation
with potassium t-butoxide or when R8a is other than F, acid catalyzation with HCl, to
provide the corresponding compound of formula I or II. Alternatively, the keto group
may be reduced under conditions that promote the cyclization reaction thus performing
both steps in "one-pot" (see, e.g., Examples 96 and 108 below).
When R1a is SO2CH3, C1-C6 alkyl or benzyl (preferably methyl, benzyl or
SO2CH3) said hydroxy protecting 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 R1 is H. Similarly, when X2 is NR7 and R7 is CO2(C1-C6 alkyl), said
amino protecting group may also be removed as taught in the Greene. A formula I
compound where R1 is H may be further derivatized employing standard acylation or
sulfonylation methodology to prepare a compound of formula I where R1 is COR2 or
SO2(n-C4-C6 alkyl).
Compounds of formula IV may be prepared as shown below or by procedures
analogous to those found in the art. Compounds of formula V are, in general,
commercially available or can be prepared by procedures readily available to the
ordinarily skilled synthetic organic chemist or as shown below.
Preparations and Examples
Chiral Separation Conditions:
All prep conditions use Chiralpak AD columns.
Conditions A: 3:2 heptane/IPA w/0.2% dimethylethylamine (DMEA), 8x30 cm
365 nm, 350 ml/min.
Conditions B: 3:2 heptane/IPA w/0.2% DMEA, 8x30 cm, 365 nm, 350 ml/min.
Conditions C: 80/10/10 heptane/3A/MeOH w/0.2% DMEA, 8x34 cm, 260 nm,
375 ml/min.
Conditions D: 75/15/10 heptane/IPA/MeOH w/0.2% DMEA, 8x34 cm, 260 nm,
375 ml/min.
Conditions E: 70/30 heptane/IPA w/0.2% DMEA, 8x34 cm, 260 nm, 375 ml/min.

Conditions F: 4:1 heptane/IPA w/0.2% DMEA, 8x30 cm, 350 nm, 350 ml/min.
Conditions G: 3:1 heptane/IPA w/0.2% DMEA, 8x33 cm, 340 nm, 375 ml/min.
Conditions H: 3:1 heptane/IPA w/0.2% DMEA, 8x33 cm, 340 nm, 375 ml/min.
Conditions I: 3:1 heptane/IPA w/0.2% DMEA, 8x33 cm, 360 nm, 375 ml/min.
Conditions J: 4:1 heptane/IPA w/0.2% DMEA, 8x30 cm, 260 nm, 350 ml/min.
Conditions K: 70/30 heptane/IPA w/0.2% DMEA, 8x34 cm, 320 nm, 350 ml/min.
Conditions L: 100% 3A w/0.2% DMEA, 8x30 cm, 260 nm, 300 ml/min.
Conditions M: 70/30 heptane/IPA w/0.2% DMEA, 8x30 cm, 260 nm, 350 ml/min.
Conditions N: 70/30 heptane/IPA w/0.2% DMEA, 8x30 cm, 260 nm, 350 ml/min.
Conditions O: 65/35 3A/heptane w/0.2% DMEA, 8x30 cm, 260 nm, 350 ml/min.
Conditions P: 100% 3A w/0.2% DMEA, 8x30 cm, 260 nm, 350 ml/min.
Conditions Q: 70/30 heptane/IPA w/0.2% DMEA, 8x30 cm, 260 nm, 350 ml/min.
Preparation 1
Trifluoromethanesulfonic 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 1-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-1-bromo-6-methoxy-naphthalene
(86.2%).
Combine toluene (200 mL), 2-benzyloxy-1 -bromo-6-methoxy-naphthalene (30 g,
87.4 mmol), 4-(2-piperidin-1-yl-ethoxy)phenol (23.2 g, 105 mmol) and cesium carbonate
(34.4 g, 105 mmol), and heat 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 HCI (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-1-yloxy)-phenoxy]-ethyl}-piperidine
(30%).
Add 1 -{2-[4-(2-benzyloxy-6-methoxy-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 men filter the
mixture. Concentrate the filtrate to provide 9.9 g of 6-methoxy-1 -[4-(2-piperidin-1 -yl-
ethoxy)-phenoxy]-naphthalene-2-ol (98.5%).
Cool dichloromethane (290 mL), triethylamine (3.08 g, 30.4 mmol) and 6-
methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalene-2-ol (9.2 g, 23.4 g) to
-50°C and add trifluoromethane sulfonic 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 for an additional hour. Add brine (150 mL) and separate the
organics. Wash the organics with NaHCO3 then dry before concentrating to a residue.
Crystallize the residue with ethyl ether - hexanes to provide 11.2 g of the title compound
(90.9%).

Example 1
1 -(2-{4-[2-(2,6-Difluoro-phenyl)-6-methoxy-naphthalen-1 -yloxy]-phenoxy}-ethyl)-
piperidine

Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
phenoxy]-naphthalen-2-yl ester (1.0 gm., 1.9 mmoles) in 20 ml DMF. To this solution
add 2,6difluorophenylboronic acid (0.6 gm., 3.8 mmoles), potassium phosphate (2.42 gm.,
11.4 mmoles) and tetrakis(triphenylphosphine)palladium (0) (0.44 gm., 0.38 mmoles) and
heat to 100 °C for 18 hours. Cool and filter the mixture and purify on an SCX column,
eluting the impurities with methanol, then eluting the product with 2N
ammonia/methanol. Purify further on a silica gel column eluting with a gradient of 50-
100% methylene chloride/hexane containing 1% isopropyl amine to give 300 mg (32 %)
of the title compound.
Example 2
6-(2,6-Difluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol
hydrochloride
Dissolve l-(2-{4-[2-(2,6-difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-
phenoxy}-ethyl)-piperidine (300 mg., 0.61 mmoles) in 20 ml methylene chloride and chill
in ice. To this add 2.0 ml of boron tribromide with swirling and allow to warm to room
temperature. Pour this mixture into a two-phase mixture consisting of saturated sodium
bicarbonate and a 3/1 mixture of chloroform/isopropanol. Wash the organic layer with
brine and dry over 3A molecular sieves. Purify further using reverse phase
chromatography to give 138 mg of the title compound (48%). Convert to hydrochloride
salt and lyophilize. 1H-NMR (CDC13, 300 MHz) £7.92 (d, J = 9.0 Hz, 1H); 7.59 (d, J =
8.4 Hz, 1H); 7.35 (d, J = 8.4 Hz, 1H); 7.20-7.17 (m, 2H); 7.03 (dd, J = 9.0, 2.1 Hz, 1H);

6.85-6.80 (m, 2H); 6.52 (s, 4H); 3.95 (t, J = 5.7 Hz, 2H); 2.73 (t, J = 6.0 Hz, 2H); 2.52-
2.52 (m, 4H); 1.64-1.59 (m, 4H); 1.46-1.44 (m, 2H).
Example 3
l-(2-{4-[2-(2-Fluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine
hydrochloride

Charge an oven-dried 100 mL round-bottom flask with trifluoromethanesulfonic
acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (300mg,
0.57 mmol.) and place under nitrogen. Dissolve the solid in acetonitrile (lOmL) and add
2-fluorophenylboronic acid (240mg, 1.71 mmol), tricyclohexylphosphine (48mg, 0.17
mmol), palladium acetate (38mg, 0.17 mmol), and cesium fluoride (780mg, 5.14 mmol).
Bring the solution to 85 °C and stir for 1 hour. Filter the solution over a pad of celite,
rinse with acetonitrile and concentrate in vacuo. Purify the crude product using radial
chromatography to give 295 mg (110%) of the free base of the title compound. Dissolve
die free base in 3mL ether and add 0.8 mL of IN HC1. Immediately dry to give 305 mg of
the titlte compound: mass spectrum (ion spray) m/z =472(M-C1).
Example 4
6-(2-Fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol
hydrochloride
Charge a 100 mL round-bottom flask with l-(2-{4-[2-(2-fluoro-phenyl)-6-
methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine hydrochloride (290 mg, 0.57
mmol) in 5mL anhydrous CH2CI2 and cool to 0 °C under nitrogen. Add 2.90 mL (2.90
mmol) of a 1M CH2CI2 solution of BBr3 and monitor the reaction by ES-MS. After
stirring for 1 hour, pour the reaction into a cold saturated solution of aqueous sodium
bicarbonate and methylene chloride (150 mL). Dry the organic layer over sodium sulfate

and concentrate in vacuo. Purify the crude product using radial chromatography eluting
with 8% MeOH/CFbCb to give 137 mg (52%) of the free base of the title compound.
Prepare the hydrochloride salt by adding 0.8 mL of a IN HC1 in Et20 solution: mass
spectrum (ion spray) m/z =458 (M-CI).
Example 5
l-(2-{4-[2-(2,4-Difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-
piperidine hydrochloride

Combine trifluoromethanesulfonic acid 6-methoxy-1-[4-{2-piperidin-1-yl-ethoxy)-
phenoxyl-naphthalen-2-yl ester (2.99 g, 5.70 mmol), 2,4-difluoro-benzeneboronic acid
(2.70 g, 17.09 mmol), palladium(II)acetate (0.13 g, 0.57 mmol), tricyclohexylphosphine
(240 mg, 0.85 mmol), cesium fluoride (7.79 g, 51.25 mmol) and acetonitrile (70 mL) and
heat at 90°C. After 10 minutes, cool to ambient temperature, filter and remove solvent
under vacuum. Dissolve in dichloromethane and wash with IN aqueous hydrochloric
acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry with
magnesium sulfate, filter and remove solvent under vacuum. Chromatograph on silica gel
with dichloromethane/methanol mixtures and add 1M hydrogen chloride in ether (10 mL)
to give 3.0 g (100%) of the title compound: mass spectrum (ion spray) m/z:=488 (M-Cl).
Example 6
6-(2,4-Difluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol
hydrochloride
Dissolve 1 -(2-{4-[2-(3,4-difluoro-phenyl)-6-methoxy-naphthalen-1 -yloxy]-
phenoxy}-ethyl)-piperidine hydrochloride (3.00 g, 5.70 mmol) in dichloromethane (90
mL) and cool in an ice bath. Add boron tribromide (1M in dichloromethane, 18.0 mL,
18.0 mmol) and stir for 2.5 hours. Add methanol (20 mL), warm to ambient temperature

and remove solvent under vacuum. Dissolve in dichloromethane with a minimum of
methanol and wash with saturated aqueous sodium bicarbonate and remove solvent under
vacuum. Crystallize with ethyl acetate/dichloromethane, filter solid to give the free base
of the title compound. Dissolve the free base in dichloromethane/methanol, add 1M
hydrogen chloride in ether (10 mL) and remove solvent under vacuum to give 2.68 g
(92%) of the title compound: mass spectrum (ion spray) m/z=476 (M-Cl).
Example 7
l-(2-{4-[2-(2,5-Difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-
piperidine hydrochloride

Combine trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
phenoxy]-naphthalen-2-yl ester (154 mg, 0.29 mmol), 2,5-difluorophenyl boronic acid
(139 mg, 0.88 mmol), [l,l'-bis(diphenylphosphino)-ferrocene)dichloropalladium (IT),
complex with dichloromethane (1:1) (239 mg, 0.29 mmol), cesium fluoride (400 mg, 2.63
mmol) and acetonitrile (6 mL), stir and heat at 90°C. After 4 hours, cool to ambient
temperature and remove solvent under vacuum. Suspend and sonicate the residue in ethyl
ether, filter and remove the solvent under vacuum. Chromatograph the crude mixture on
silica gel with dichloromethane/methanol mixtures, combine fractions containing product,
add 1M hydrogen chloride in ether (1 mL) and remove solvent under vacuum to give 140
mg of the title compound: mass spectrum (ion spray) m/z=490 (M-Cl).
Example 8
6-(2,5-Difluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol
hydrochloride
Dissolve l-(2-{4-[2-(2,5-difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-
phenoxy}-ethyl)-piperidine hydrochloride (133 mg, 0.25 mmol) in dichloromethane (5

mL), cool in an ice bath and add boron tribromide (1M in dichloromethane, 0.76 mL, 0.76
mmol). Let slowly warm to ambient temperature over 18 hours, quench with saturated
aqueous solution of sodium bicarbonate, dry organic layer with magnesium sulfate, filter
and chromatograph on silica gel with dichloromethane/methanol mixtures. Combine
fractions containing product, add 1M hydrogen chloride in ether (1 mL) and remove
solvent under vacuum to give 108 mg (83%) of the title compound: mass spectrum (ion
spray) m/z=476 (M-Cl).
Example 9
l-(2-{4-[6-Methoxy-2-(3,4,5-trifluoro-phenyl)-naphthalen-1-yloxy]-phenoxy}-ethyl)-
piperidine

Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-
yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (800 mg, 1.52 mmoi), 3,4,5-trifluorobenzene
boronic acid (804 mg, 4.57 mmol) and cesium fluoride (1.1 g, 7.6 mmol) and purge with
nitrogen. In a separate flask, charge palladium(II)acetate (34 mg, 0.15 mmol) and
tricyclohexylphosphine (64 mg, 0.23 mmol) and purge with nitrogen. Add degassed
acetonitrile and sonicate under nitrogen for 10 minutes. Add the catalyst solution to the
solids and plunge into an 80 °C oil bath for 10 minutes. Cool to room temperature and
filter through celite. Concentrate and redissolve in methylene chloride. Wash with
saturated aqueous sodium bicarbonate, separate, dry, filter and concentrate. Purify the
residue over silica gel, eluting with 0 to 5% methanol in methylene chloride, to yield 720
mg (93%) of the title compound: mass spectrum (ion spray) 508.3 (M+H).

Example 10
6^3,4,5-Trifluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol
hydrochloride
Dissolve 1 -(2-{4-[6-methoxy-2-(3,4,5-trifluoro-phenyl)-naphthalen-1 -yloxy]-
phenoxy}-ethyl)-piperidine (720 mg, 1.4 mmol) in methylene chloride (15 mL). Add 2M
HCI in ether (1.4 mL, 2.8 mmol) and concentrate in vacuo. Dissolve the residue in
methylene chloride (15 mL) and add boron tribromide (0.53 mL, 5.6 mmol) dropwise at 0
°C under nitrogen. Pour into cold saturated aqueous sodium bicarbonate after 45 minutes
and extract with methylene chloride. Concentrate the organic layer and purify the residue
over silica gel, eluting with 0 to 12% methanol in methylene chloride, to yield 554 mg
(80%) of the free base of the title compound. Dissolve the free base (554 mg, 1.1 mmol)
in ethyl acetate (6 mL) and ether (12 mL). Add 2M HCI in ether (1.1 mL, 2.2 mmol) and
collect the precipitate. Dry in a vacuum oven at 50 °C overnight to yield 467 mg (79%)
of the title compound: mass spectrum (ion spray) m/z = 494.3 (M-Cl).
Example 11
1 -(2- {4-[2-(2,3-Difluoro-phenyl)-6-methoxy-naphthalen-1 -yloxyl-phenoxy} -ethyl)-
piperidine

Using the procedure demonstrated in Example 9, react trifluoromethanesulfonic
acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (800 mg,
1.52 mmol), 2,3-difluorobenzene boronic acid (720 mg, 4.57 mmol), cesium fluoride (2.1
g, 13.7 mmol), palladium(II)acetate (34 mg, 0.15 mmol) and tricyclohexylphosphine (64
mg, 0.23 mmol) to obtain 622 mg (84%) of the title compound: mass spectrum (ion
spray) 490.4 (M+H).

Example 12
6-(2,3-Difluoro-phenyl)-5-[4-{2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol
hydrochloride
Using the procedure demonstrated in Example 10, react l-(2-{4-[2-(2,3-difluoro-
phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine (622 mg, 1.27
mmol), 2M HC1 in ether (1.3 mL, 2.6 mmol) and boron tribromide (0.60 mL, 6.4 mmol)
to give 309 mg (48%) of the title compound: mass spectrum (ion spray) 476.4 (M-Cl).
Example 13
l-(2-{4-[2-(3,5-Difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-
piperidine

Using the procedure demonstrated in Example 9, react trifluoromethanesulfonic
acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxyJ-naphmalen-2-yl ester (3.5 g,
6.67 mmol), 3,5-difluorobenzene boronic acid (3.1 g, 19.6 mmol), cesium fluoride (9.2 g,
60.4 mmol), palladium(ll)acetate (145 mg, 0.64 mmol) and tricyclohexylphosphine (290
mg, 1.03 mmol) to obtain 3.3 g (100%) of the title compound: mass spectrum (ion spray)
490.3 (M+H).
Example 14
6-(3,5-Difluoro-phenyl)-5-[4-(2-piperidin-1 -yl-ethoxy)-phenoxy]-naphthalen-2-ol
hydrochloride
Using the same procedure as for 6-(3,4,5-trifluoro-phenyl)-5-[4-(2-piperidin-1-yl-
ethoxy)-phenoxy]- naphthalen-2-ol hydrochloride salt; react l-(2-{4-[2-(3,5-difluoro-
phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine (3.8 g, 7.9 mmol),
2M HC1 in ether (7.9 mL, 15.8 mmol) and boron tribromide (3.7 mL, 39.2 mmol) to give

2.6 g (64%) of the title compound after silica gel chromatography: mass spectrum (ion
spray) 476.3 (M-CI).
Example 15
6-(3,4-Difluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol
hydrochloride

Prepare 6-(3,4-Difluoro-phenyl)-5-[4-(2-piperidin-l -yl-ethoxy)-phenoxyl-
naphthalen-2-ol hydrochloride in a manner similar to Examples 7 and 8 to provide 1.79 g
of the title compound: mass spectrum (km spray): m/z=476 (M-Cl).
Preparation 2
4-[2-(3-Fluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenol

Charge an oven-dried 250 mL round-bottom flask with 6-methoxy-1-tetralone
(3.0g, 17.0 mmol.) and place under nitrogen. Dissolve the solid in toluene (30mL) and
add 1-bromo-3-fluorobenzene (4.7 mL, 42.6 mmol), sodium t-butoxide (6.5g, 68.1
mmol), palladium acetate (76mg, 0.34 mmol), and racemic BINAP (212mg, 0.34 mmol).
Heat the solution to 115°C and stir for 18 hours. Dilute the solution with cold 5N HCI
(50mL) and ethyl acetate (200mL). Separate the organic layer and dry over sodium
sulfate, filter over a pad of celite and concentrate in vacuo. Purify the crude product using
radial chromatography to give 3.4 g (74%) of the title compound. This material is used
without further purification: mass spectrum (ion spray) m/z =267(M-H).

Dissolve 2-(3-fluoro-phenyl)-6-methoxy-naphthalen-1-ol (3.36g, 12.5 mmol) in
N-methyl-2-pyrrolidinone (NMP) (lOmL) and add sodium hydride (500mg, 60% oil
dispersion, 12.5 mmol) at room temperature. After stirring for 1 hour this solution is
added to a solution of 4-fluorobenzaldehyde (2.4mL, 22.5 mmol) in NMP (lOmL) that has
been heated to 185°C. Continue stirring for 2.5 hours. Cool the reaction to room
temperature and add pH 7 buffer (50mL) and extract with ethyl acetate (2 X lOOmL).
Wash the organic extracts with water and filter through a plug of silica gel. Purify the
crude product using radial chromatography giving 2.50g (54%) of the title compound and
use without further purification: mass spectrum (ion spray) m/z = 371(M-H).
Charge a 100 mL round-bottom flask with 4-[2-(3-fluoro-phenyl)-6-methoxy-
naphthalen-1-yloxy]-benzaldehyde (2.5g, 6.71 mmol) and ethyl acetate (5 mL). At room
temperature add 2 mL of 35% hydrogen peroxide. To this solution slowly add 2 mL of
concentrated sulfuric acid. The mixture warms to approximately 40 °C and returns to
room temperature where it is stirred for 2 hours. Dilute the reaction with water and ethyl
acetate (100 mL) and dry the organic layer over sodium sulfate, filter and concentrate in
vacuo. Purify the crude product using radial chromatography eluting with CH2CI2 to yield
540 mg (22%) of the title compound: mass spectrum (ion spray) m/z = 359 (M-H).
Example 16
l-(2-{4-[2-(3-Fluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine
hydrochloride

To 4-[2-(3-fluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenol (180 mg, 0.50
mmol) in lOmL anhydrous DMF is added sodium hydride (60 mg, 60% oil dispersion,
1.50 mmol) and the solution stirred 30 minutes at room temperature. Add l-(2-
chloroethyl)piperidine hydrochloride (138 mg, 0.75 mmol) and stir the reaction for 3 days.
Dilute the reaction with methylene choride, wash with saturated sodium bicarbonate (lx),
brine (lx), extract the organics and dry over sodium sulfate. Purify the crude product

using radial chromatography editing with 4% MeOH/CH^b to yield 234 mg (99%) of
the free base of the title compound. Form the hydrochloride by adding 0.8 mL of a IN
HCI in Et20 solution: mass spectrum (ion spray) m/z = 472 (M-Cl).
Example 17
6-(3-Fluoro-phenyl)-5-[4-{2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol
hydrochloride
Charge a lOOmL round-bottom flask with l-(2-{4-[2-(3-fluoro-phenyl)-6-
methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine hydrochloride (245mg,
0.48mmol) and cooled to 0 °C under nitrogen. Add 1.45mL of a 1M CH2CI2 solution of
BBr3 and monitor the reaction by ES-MS. After stirring for 1 hour, pour the reaction into
a cold saturated solution of aqueous sodium bicarbonate and methylene chloride (150mL).
Dry the organic layer over sodium sulfate and concentrate in vacuo. Purify the crude
product using radial chromatography eluting with 4% MeOH/CH2 to give 139 mg (63%)
of the free base of the title compound. Form the hydrochloride salt by adding 0.8 mL of a
IN HCI in Et20 solution: mass spectrum (ion spray) m/z =458(M-C1).
Preparation 3
4-[6-Benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1 -yloxyj-phenol

Add bromine (107 mL, 2.08 mol) into a solution of 6-benzyloxy-3,4-dihydro-2H-
naphthalen-1-one (250 g, 0.99 mol) in chloroform (2 L) at 5 °C over 1.5 hours. Add
sodium thiosulfate solution (250 mL) to quench the reaction at 0 °C. Add ethyl acetate (1
L) and separate layers. Extract the aqueous layer with CH2C12 (500 mL) and combine the
organic layers, wash with aqueous sodium bicarbonate solution and brine. Dry with
sodium sulfate and concentrate in vacuo. Triturate the residue by adding 10% ethyl

acetate in hexane (600 mL) to obtain a solid. Filter and dry the solid to get 405 g (100 %)
of 6-benzyloxy-2,2-dibromo-3,4-dihydro-2H-naphthalen-1 -one.
Add 1M sodium methoxide (215 mL, 0.99 mol) into a solution of 6-benzyloxy-
2,2-dibromo-3,4-dihydro-2H-naphthalen-1-one (205 g, 0.5 mol) in methanol (1.3 L). Heat
the suspension to dissolution. Cool the reaction mixture to 0 °C and add IN HC1 (540
mL). Add H2O (3 L) and cool to 3 °C to obtain a solid. Filter and dry the solid to obtain
152 g (92 %) of 6-benzyloxy-2-bromo-naphthalen-1-ol.
Add sodium hydride (24 g, 0.6 mmol) portionwise to a solution of
6-benzyloxy-2-bromo-naphthalen-1-ol (179 g, 0.54 mol) in THF (3.0 L) at 0 °C. Add
methanesulfonyl chloride (47 mL, 0.61 mol) over 45 minutes and stir the reaction for 1.5
hours at 10 °C. Add sodium bicarbonate solution (500 mL) and water (500 ml). Separate
the layers and extact the aqueous layer with ethyl acetate (500 mL x2). Combine the
organic layers and wash with brine (200 mL). Dry with magnesium sulfate, filter and
concentrate in vacuo. Triturate the residue by adding 20% ethyl acetate in hexane (1 L) to
obtain a solid. Filter, wash the solid with toluene (200 mL x 2) and dry the solid to get
176 g (80 %) of methanesulfonic acid 6-benzyloxy-2-bromo-naphthalen-1-yl ester.
Combine methanesulfonic acid 6-bcnzyloxy-2-bromo-naphthalen-1-yl ester (10.0
g, 24.4 mmol), 4-fluorophenylboronic acid (10.2 g, 72.9 mmol), sodium carbonate (7.8 g,
73.6 mmol) and tetrakistriphenylphosphine palladium (2.8 g, 2.4 mmol) in a mixture of
toluene (300 mL), ethanol (60 mL) and water (40 mL). Heat the mixture at 100 °C for 12
hours. Cool and filter the suspension through a pad of celite. Evaporate the solvent in
vacuo. Wash the residue with sodium bicarbonate solution and brine. Dry with
magnesium sulfate and concentrate in vacuo. Purify the residue over silica gel, eluting the
material with a step gradient of methanol/dichioromethane (0 to 10%), to obtain 10.1 g
(98%) of methanesulfonic acid 6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yl ester.
Dissolve methanesulfonic acid 6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yl
ester (5.2 g, 12.3 mmol) in 5M sodium hydroxide (12 mL, 60 mmol), THF (86 mL) and
MeOH (86 mL). Heat to 50 °C for 1 hour. Cool and add ethyl acetate (100 mL). Wash
the organic layer with IN HC1, saturated sodium bicarbonate solution and brine. Dry with
magnesium sulfate and concentrate in vacuo to obtain 3.4 g (89%) of 6-benzyloxy-2-(4-
fluoro-pheny l)-naphthalen- l-ol.

Add sodium hydride (400 mg, 10 mmol) into a solution of 6-benzyloxy-2-(4-
fluoro-phenyl)-naphthalen-1-ol in NMP (40 mL). Add the above aikoxide suspension into
a solution of 4-fluorobenzaldehyde (2 mL, 19 mmol) in NMP (30 mL) at 165 °C. Heat at
165 °C for 1 hour. Cool and add buffer solution (pH=7, 10 mL). Add diethyl ether (1 L).
Separate the layers and wash the aqueous layer with diethyl ether (2 x 200 mL). Combine
the organic layers, dry with magnesium sulfate and concentrate in vacuo. Chromatograph
the residue on a biotage column eluting the material with a step gradient of methanol/
dichloromethane (0 to 10%) to obtain 2.9 g (70%) of 4-[6-benzyloxy-2-(4-fluoro-phenyl)-
naphthalen-1 -y!oxy]-benzaldehyde.
Add 18M H2S04 (1 mL, 16.8 mmol) dropwise into a solution of H2O2 (1 mL, 9.7
mmol) and 4-[6-benzyloxy-2-(4-iluoro-phenyl)-naphthalen-1-yloxy]-benzaldehyde at 0 °C
and stir at room temperature for 12 hours. Add H2O (20 mL) and CH2CI2 (100 mL).
Separate layers and extract the aqueous layer with CH2CI2 (2 x 50 mL). Combine the
organic layers, dry with magnesium sulfate and concentrate in vacuo to obtain 1.88 g
(73%) of the title compound: mass spectrum (ion spray) m/z=435.1 (M-H).
Example 18
l^2-{4-[6-Benzyloxy-2^4-fluoro-plienyl)-naphthalen-1-yloxy]-phenoxy}-ethyl)-
piperidine

Dissolve 4-[6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-phenol (5.20 g,
11.91 mmol) in DMF (60 mL) under N2and add NaH (1.43 g, 35.74 mmol, 60%wt). Stir
the solution for 0.5 hours at room temperature then add l-(2-chloro-ethyl)-piperidine, HC1
salt (3.29 g, 17.87 mmol). Continue to stir the solution for and then add water (300 mL).
Extract the aqueous layer with CH2CI2 (3 x 300 mL) and then combine the organic layers.
Dry the organic layer with Na2SC«4, then filter, concentrate and purify it by flash column

chromatography (silica gel, 0-4% MeOH-NRtOH (10/1, v/v)/CH2Cl2) to give 6.5 g (99%)
of the title compound: mass spectrum (ion spray) m/z = 548.3 (M+H).
Example 19
6-(4-Fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol
hydrochloride
Dissolve 1 -(2-{4-[6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-l -yloxy]-
phenoxy}-ethyl)-piperidine (6.5 g, 11.87 mmol) in MeOH/THF (200 mL, v/v=l/l) under
N2. Add Pd/C (0.65 g, 10%) and exchange the N2 for H2 three times. Stir the reaction
mixture for two hours then filter out the Pd/C. Remove the solvent and purify the residue
by column chromatography (silica gel, 2-8% MeOH-NRjOH (10/1, v/v)/ CH2C12) to give
2.93 g (54%) of the free base of the title compound. Dissolve the free base (2.93 g, 6.41
mmol) in CH2C12 (100 mL), and cool it to -78 °C. Add HCI (10 mL, 2.0 M in Et20), and
stir the solution for 10 minutes. Remove the solvent under reduced pressure and at 40 °C,
overnight, in vacuo to give 3.17 g (100%) of the title compound: mass spectrum (ion
spray) m/z = 458.2 (M-Cl).
Preparation 4
Triftuoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-
naphthalen-2-yl ester

Add sodium hydride (18 g, 0.45 mol) into a solution of 4-benzyloxylphenol (41 g,
0.20 mol) and 2-(hexamethyleneimino)ethyl chloride hydrochloride (44 g, 0.22 mmol) in
THF (600 mL) and DMF (100 mL) at room temperature. Heat to 60°C for 30 minutes.
Pour the solution into ice and water. Dilute with ethyl acetate (500 mL) and separate
layers. Dry the organic layer with magnesium sulfate, filter and concentrate under reduced

pressure to give brown oil. Dissolve the oil in ethyl acetate (500 mL) and methanol (500
mL). Add ammonium formate (100 g, 1.59 mol) and palladium on carbon (10 g, 9.4
mmol). Heat the mixture to reflux for 30 minutes. Add ammonium formate (100 g, 1.59
mol) and palladium on carbon (10 g, 9.4 mmol). Heat the reaction mixture for 30
minutes. Filter the supension through a pad of celite and elute with ethyl acetate (500
mL). Evaporate solvent under reduced pressure and add water (100 mL). Dilute the
mixture with ethyl acetate (500 mL) and separate layers. Wash the organic layer with
saturated sodium bicarbonate solution (2 x 200 mL), dry with magnesium sulfate, filter
and evaporate solvent under reduced pressure to give 31 g (64 %) of 4-(2-azepan-1-yl-
ethoxy)-phenol.
Combine 2-benzyloxy-1-bromo-6-methoxy-naphthalene (31 g, 90 mmol), 4-(2-
azepan-1-yl-ethoxy)-phenol (31 g, 132 mmol), copper bronze (12 g, 189 mmol),
potassium carbonate (25 g, 181 mmol) and pyridine (400 mL). Heat the reaction mixture
to reflux for 85 hours. Cool and fitter the residue with celite and elute with methanol and
methylene chloride (500 mL, V/V = 1:5). Evaporate solvent under reduced pressure and
chromatograph the residue on a silica gel column eluting the material with a step gradient
of methanol/dichloromethane (0 to 10%) to get 19 g (43%) of l-{2-[4-(2-benzyloxy-6-
methoxy-naphrhalen-1 -yloxy)-phenoxy]-ethyl} -azepane.
Dissolve l-{2-[4-{2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-
azepane (19 g, 38 mmol) in ethyl acetate (500 mL) and methanol (600 mL). Heat the
mixture to obtain a clear solution. Cool to room temperature. Add ammonium formate
(30 g, 476 mmol) and palladium on carbon (2 g, 1.9 mmol). Heat to reflux for 30
minutes. Add ammonium formate (7 g, 111 mmol) and palladium on carbon (0.7 g, 0.7
mmol). Heat to reflux for 30 minutes. Filter the supension through a pad of celite and
elute with ethyl acetate (500 mL). Evaporate solvent under reduced pressure and add
water (100 mL). Dilute the mixture with ethyl acetate (500 mL) and separate layers.
Wash the organic layer with saturated sodium bicarbonate solution (2 x 200 mL), dry with
magnesium sulfate, filter and evaporate solvent under reduced pressure to give 15.1 g
(97%)of 1 -[4-(2-azepan-1 -yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-ol.
Add trifluoromethanesulfonic anhydride (7 mL, 42 mmol) into a solution of l-[4-
(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-ol (15 g, 37 mmol),
triethylamine (20 mL) and methylene chloride (500 mL) at -50°C. Warm the reaction

mixture to room temperature and stir for 1 hour at that temperature. Cool the reaction
mixture to -78°C and add brine (20 mL). Warm the reaction to room temperature.
Separate layer and wash the organic layer with saturated sodium bicarbonate solution (100
mL) and brine. Dry the organic layer with magnesium sulfate, filter and evaporate solvent
under reduced pressure. Chromatograph the residue on a silica gel column eluting the
material with a step gradient of methanol/dichloromethane (0 to 10%) to get 20 g (99%)
of trifluoro-methanesulfonic acid 1 -[4-{2-azepan-1 -yl-ethoxy)-phenoxy]-6-methoxy-
naphthalen-2-yl ester.
Example 20
l-(2-{4-[2-(3,5-Difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-
azepane

Dissolve trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-
methoxy-naphthalen-2-yl ester (435 mg, 0.80 mmol), cesium fluoride (864 mg, 5.7 mmol)
and 1,3-difluoro-benzene boronic acid (383 mg, 2.4 mmol) in dry acetonitrile (5 mL) and
stir for 10 minutes. In a separate flask suspend palladium acetate (18 mg, 0.08 mmol),
and tricyclohexyl phosphine (33 mg, 0.12 mmol) in dry acetonitrile (15 mL) and sonicate
under nitrogen for 10 minutes. Combine contents of both flasks and heat reaction at 60
°C for 15 minutes. Cool reaction and filter through celite and concentrate in vacuo.
Purify crude product by silica gel chromatography using a 1-3% gradient of methanol in
dichloromethane to yield 400 mg (98%) of the title compound: mass spectrum (ion spray)
m/z = 504.2 (M+H).

Example 21
5-[4-{2-Azepan-1-yl-ethoxy)-phenoxy]-6-{3,5-difluoro-phenyl)-naphthalen-2-oI
hydrochloride
Dissolve l-(2-{4-[2-(3,5-diiluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-
phenoxy}-ethyl)-azepane (583 mg, 1.2 mmol) in dichloromethane (10 mL). Cool to 0 °C,
add 2M HC1(1.2 mL, 2.3 mmol) and stir at room temperature for 15 minutes. Concentrate
in vacuo. Redissolve the salt in dichloromethane (10 mL) and cool to 0 °C. Add boron
tribromide (972 mg, 3.5 mmol) dropwise and bring to room temperature. Stir reaction for
1.5 hours and pour reaction mixture onto ice, saturated sodium bicarbonate (10 mL) and
methanol (10 mL). Extract with dichloromethane, combine extracts and wash with water
and saturated sodium bicarbonate. Dry with sodium sulfate, filter, and concentrate in
vacuo. Purify by silica gel chromatography using a 1-4% gradient of methanol in
dichloromethane to yield 366 mg (65%)of the free base of the title compound. Dissolve
free-base in 10 mL dichloromethane and add 2M HC1 (0.8 mL) stir for 10 minutes and
concentrate in vacuo to yield 343 mg (88%) of title compound: mass spectrum (ion spray)
m/z = 490.3 (M-Cl).
Example 22
l-(2-{4-[2-(3,4-Difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-
azepane

Combine palladium acetate (33 mg, 0.15 mmol), tricyclohexyl phosphine (61 mg,
0.22 mmol) and acetonitrile (6 mL). Sonicate the mixture for 5 minutes. Combine
trifluoromethanesulfonic acid 1 -[4-(2-azepan~l -yl-ethoxy)-phenoxy]-6-methoxy-
naphthalen-2-yl ester (787 mg, 1.46 mmol), cesium fluoride (2.00 g, 13.2 mmol), 3,4-
difluorophenylboronic acid (692 mg, 4.38 mmol) and acetonitrile (16 mL). Add the
sonicated Pd/Pcy3 suspension to reaction vessel and heat to 90 °C for 30 minutes. Cool to

room temperature and filter through pad of Celite and evaporate the solvent. Dissolve
residue in ethyl acetate (40 mL) and wash with saturated NaHCCb (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 S1O2 column eluting the material with
methanol in dichloromethane (0 to 5%) to give 630 mg (86 %) of the title compound:
mass spectrum (ion spray) m/z = 504.2 (M+H).
Example 23
5-[4-(2-Azepan-1-yl-ethoxy)-phenoxy]-6-(3,4-difluoro-phenyl)-naphthalen-2-ol
hydrochloride
Dissolve l-(2-{4-[2-(3,4-difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-
phenoxy}-ethyl)-azepane (630 mg, 1.25 mmol) in dichloromethane (20 ml). Add 2M HC1
in diethyl ether (1 mL, 2.0 mmol). Stir for 5 minutes. Concentrate the slurry and dry in
vacuo. Dilute the residue in dichloromethane (20 ml) and blanket with nitrogen. Cool the
solution to 0 °C with external ice bath. Add BBr3 (0.4 mL, 4.3 mmol). Stir the reaction at
room temperature for 30 minutes and add the reaction mixture in saturated aqueous
NaHCOj (20 ml), ice (5 g) and methanol (5 mL). Dilute with dichloromethane (20 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 SK>2 column eluting the material
with a step gradient of methanol/dichloromethane (0 to 5%) to get the free base of the title
compound. Dissolve the free base in diethyl ether (5.0 ml), ethyl acetate (6.0 ml) and
methanol (1.0 ml) and add 2M HC1 (1 mL, 2.0 mmol) in diethyl ether. Collect the
precipitate on filter paper, rinse with diethyl ether and dry in vacuo ( 310 mg (47 %) of the title compound: mass spectrum (ion spray) m/z = 490.3 (M-Cl).

Example 24
l-{2-{4-[2-(3-Fluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-azepane
hydrochloride

Prepare this compound following the procedure to make l-(2-{4-[2-(3-fluoro-
phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine above, using 2-
(hexamethyleneimino)-ethyl chloride hydrochloride to get a 100% yield of the free base of
the title compound after radial chromatography. Form the hydrochloride salt by adding
0.8 mL of a 1 M HCI in Et^O solution: mass spectrum (ion spray) m/z =486 (M-Cl).
Example 25
5-[4-(2-Azepan-1 -yl-ethoxy)-phenoxy]-6-{3-fluoro-phenyl)-naphthalen-2-ol
hydrochloride
Prepare this compound following the procedure to make 6-(3-fluoro-phenyl)-5-[4-
(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol hydrochloride above starting with 1-
(2- {4-[2-(3-fluoro-phenyl)-6-methoxy-naphthalen-1 -yloxy]-phenoxy} -ethyl)-azepane
hydrochloride, to get a 52% yield of the free of the title compound after radial
chromatography. Form the hydrochloride salt by adding 0.8mL of a 1 M HCI in Et20
solution: mass spectrum (ion spray) m/z =472 (M-Cl).
Example 26
l-(2-{4-[6-Benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-phenoxy}-ethyl)-azepane


Add sodium hydride (324 mg, 8.0 mmol) into a solution of 4-[6-benzyloxy-2-(4-
fluoro-phenyl)-naphthalen-1-yloxy]-phenol (1.18 g, 2.7 mmol) in DMF (10 mL) and stir
for 20 minutes at room temperature. Add 2-(hexamethyyleneimino)ethyl chloride
hydrogen chloride (1.07 g, 5.4 mmol) and stir at room temperature for 12 hours. Add
H2O (10 mL) and diethyl ether (100 mL). Separate layers and wash the aqueous layer
with diethyl ether (2 x 50 mL). Combine organic layers, dry with magnesium sulfate and
concentrate in vacuo. Purify the residue over silica gel, eluting the material with a step
gradient of methanol/dichloromethane (0% to 10%), to obtain 1.0 g of the title compound
(66%): mass spectrum (ion spray) m/z=562.3 (M+H).
Example 27
5-[4-(2-Azepan-1 -yl-ethoxy)-phenoxy]-6-(4-fluoro-phenyl)-naphthalen-2-ol
hydrochloride
Add ammonium formate (614 mg, 9.7 mmol) and palladium on carbon (10 mol%)
into a solution of l-(2-{4-[6-benzyloxy-2-{4-fluoro-phenyl)-naphthalen-1-yloxy]-
phenoxy}-ethyl)-azepane (709 mg, 1.26 mmol) in MeOH (20 mL) and ethyl acetate (12
mL). Heat to reflux for 1 hour. Cool and filter the suspension through a pad of celite.
Evaporate the solvent, dilute with CH2CI2 and wash with H2O (20 mL). Dry the organic
layer with magnesium sulfate and concentrate in vacuo to obtain the free base of the title
compound. Dissolve the free base in ethyl acetate (2 mL), diethyl ether (2 mL) and
MeOH (0.1 mL). Add 2M HC1 (1 mL, 20 mmol), concentrate the slurry and dry in vacuo
to give the title compound (270 mg, 50% yield): mass spectrum (ion spray) 472.3(M-C1).
Preparation 5
Trifluoromethanesul fonic acid 6-methoxy-1 -[4-(2-piperidin-1 -yl-ethoxy)-benzoyl]-
naphthalen-2-yl ester


In a dry round bottom flask equipped with stir bar, temperature probe and N2 line,
dissolve 2,6-dimethoxynaphthalene (1.0 eq) in CH2CI2 (5 volume equivalents) at ambient
temperature. Cool the solution to 0 °C in with an ice bath, and add 4-(2-piperidin-1-yl-
ethoxy)-benzoyl chloride (1.1 eq). Add aluminum chloride (2.0 eq). Once the reaction is
determined to be complete, quench the reaction slowly with 1 N NaOH and dilute with
additional water and CH2CI2. Wash the aqueous layer with (1 x 20 mL) of CH2CI2.
Combine the organic extracts and wash with brine and dry (Na2SC»4). Recrystallize the
crude product from methanol to give (2,6-dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1-
yl-ethoxy)-phenyl]-methanone (average yield 68%).
Dissolve (2,6-dimethoxy-naphthalen-1 -yl)-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-
methanone in CH2CI2 (10 volume equivalents) in a 3-neck round bottom flask equipped
with a pressure equalizing addition funnel, stirbar, and N2 source. Cool the flask in an
ice/brine bath and add 1.0 M BCI3 solution in CH2CI2 (1.2 equivalents) dropwise. The
reaction solution turns dark red and the temperature initially increases to 5 °C. Within
one hour, all starting material is consumed, as determined by TLC (1:1, EthenPetroleum
Ether). Quench the reaction with methanol (5 equivalents) and allow to warm to room
temperature. Dilute the organic solution with CH2CI2 (one volume equivalent) and add
to a 1.0 M NaHCC>3 solution (5 volume equivalents) and stir for one hour. Separate the
aqueous and organic layers. Wash the aqueous layer with CH2CI2 (one volume) and the
combine organic layers, wash with saturated NH4CI and dry over Na2SC»4. Purify the
product via column chromatography (50/1 silica gel) eluting with CH2Cl2/Hexanes (3/1)
to yield (2-hydroxy-6-methoxy-naphthalen-1 -yl)-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-
methanone (typical yield 87 %).
Dissolve (2-hydroxy-6-methoxy-naphthalen-1 -yl)-[4-(2-piperidin-1 -yl-ethoxy)-
phenylj-methanone in CH2CI2 (10 volumes) in a three neck round bottom flask equipped
with a stir bar and N2 source and chill to 0°C in an ice/brine bath. Add pyridine (1.3
equivalents). Add trifluoromethane sulfonyl chloride (1.2 equivalents) via syringe over
15 minutes. After 15 minutes, quench the reaction with H2O (10 volumes), wash with 1
N HC1 (5 volumes), wash with 1.0 N NaHCC
give the title compound in quantitative yield. Use the product without further
purification.
Example 28
[2-(2,4-Difluoro-phenyl)-6-methoxy-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenylj-methanone

Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester (12.4 g, 23.0 mmol) and 2,4-difluorophenylboronic acid
(7.0 g, 46.0 mmol) in degassed dimethoxyethane (620 mL). Add 2M aqueous sodium
carbonate (73 mL, 145 mmol) and stir at room temperature under nitrogen for S minutes.
Add palladium(U) acetate (520 mg, 2.3 mmol) and triphenylphosphine (1.2 g, 4.6 mmol)
and plunge into a 85 °C oil bath. Stir for 40 minutes and cool to room temperature. Pour
into saturated aqueous sodium bicarbonate and extract twice with methylene chloride.
Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo.
Purify the resultant oil with SCX columns (load in methanol, elute with 2M NfTj/MeOH)
to yield 10.8 g (93%) of the title compound: mass spectrum (ion spray) m/z = 502.3
(M+H).
Example 29
[2-(2,4-Difluoro-phenyl)-6-hydroxy-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenylj-methanone hydrochloride
Dissolve [2-(2,4-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-
yl-ethoxy)-phenyl]-methanone (10.8 g, 21.5 mmol) in methylene chloride (200 mL). Add
2M HCI in ether (21.5 mL, 43 mmol) and concentrate in vacuo. Redissolve the foam in
methylene chloride (200 mL) and cool to 0 °C under nitrogen. Slowly add boron

tribromide (10.1 mL, 107 mmol) and stir at 0 "C for 30 minutes. Slowly pour into
saturated aqueous sodium bicarbonate and extract with 20% IPA in chloroform. Dry the
organic layer with sodium sulfate, filter and concentrate in vacuo to yield 10.5 g (100%)
of the free base of the title compound: 'H-NMR (CDCIJ) £7.72 (d, J= 8.6 Hz, 1H), 7.49
(d, J= 8.6 Hz, 3H), 7.35 (d, J= 8.4 Hz, 1H), 7.18 (t, J= 7.8 Hz, 1H), 7.14 (d, J= 1.9 Hz,
1H), 6.96 (dd, J= 9.2, 2.3 Hz, 1H), 6.74-6.62 (m, 2H), 6.58 (d, J = 8.6 Hz, 2H), 4.08 (t, J
= 5.9 Hz, 2H), 2.79 (t, J= 5.6 Hz, 2H), 2.55 (bs, 4H), 1.63 (bs, 4H), 1.45 (m, 2H).
Dissolve the free base in a 1 :1 mixture of acetonitrile : water. Add an appropriate
amount of 5 M hydrochloric acid and lyopholize the mixture to afford the title compound.
Example 30
[2-(2,5-Difluoro-phenyl)-6-methoxy-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone

Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester (4.51 g, 8.4 mmol) in acetonitrile (140 mL). Add
Pd(OAc>2 (0.28 g, 1.3 mmol), tricyclohexylphosphine (0.59 g, 2.1 mmol), cesium fluoride
(11.4 g, 75.6 mmol) and 2,5-difluorobenzeneboronic acid (2.56 g, 16.2 mmol). Flush the
flask with nitrogen then heat the reaction mixture to 90 °C. Heat the reaction mixture for
one hour and then cool it to room temperature. Add water (400 mL) and extract the
aqueous layer with methylene chloride(3 x 400 mL). Combine the organic layers and dry
with sodium sulfate, filter, concentrate and purify by flash column chromatography (0-4%
MeOH-NH40H (10/1, v/v)/ CH2C12) to give 2.42 g (68%) of the title compound: mass
spectrum (ion spray) m/z = 502.3 (M+H).

Example 31
[2-(2,5-Difluoro-phenyl)-6-hydroxy-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone hydrochloride
Demethylate [2-(2,5-difluoro-phenyl)-6-methoxy-naphthalen-1 -yl]-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-methanone (2.42 g, 4.82 mmol) with BBr3 in a procedure
similar to the preparation of 2-(2,4-difluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-methanone to give 1.96 g (83%) of the free base of the
title compound: mass spectrum (ion spray) m/z = 488.3 (M+H). Dissolve the free base in
a 1 :1 mixture of acetonitrile : water. Add an appropriate amount of 5 M hydrochloric acid
and lyopholize the mixture to afford the title compound.
Example 32
Methanesulfonic acid 6-(2,4-difluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-
naphthalen-2-yl ester

Dissolve [2-(2,4-difluoro-phenyl)-6-hydroxy-naphthalen-1 -yl] -[4-(2-piperidin-1 -
yl-ethoxy)-phenyl]-methanone (540 mg, 1.11 mmoles), and methane sulfonyl chloride
(254 mg, 2.22 mmoles) in 10 ml acetonitrile and add triethylamine (224 mg, 2.22
mmoles). Stir the mixture for 5 days at room temp. Add equivalent amounts of the
sulfonyl chloride and triethylamine and stir for 30 minutes. Evaporate the mixture to
dryness, dissolve in methanol and pass through an SCX column. Wash the column with
methanol and elute the product with 2 N ammonia/methanol to yield 433 mg (69%) of the
title compound: mass spectrum (ion spray) m/z = 566 (M+H).

Example 33
[2-(2,6-Difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-
phenylj-methanone

Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-
yl-ethoxy)-benzoyI]-naphthaIen-2-yl ester (2.0 g, 3.7 mmol), 2,6-difluorophenyl boronic
acid (1.17 g, 7.4 mmol), tetrakis(triphenylphosphine)palladium (0) (855 mg, 0.74 mmol)
and potassium phosphate (4.7 g, 22.2 mmol) add 100 mL of dry DMF and heat under
nitrogen at 100 °C for two hours. Cool the reaction and filter. Purify on an SCX column
eluting with 2N ammonia/methanol. Purify further on a silica gel column eluting with a
gradient of 0-10% methanol/methylene chloride. The yield is 1.5 g (81%). 1H-NMR
(CDClj, 400 MHz) 8 7.90 (d, J = 8.4 Hz, 1H); 7.63 (d, J = 8.4 Hz, 1H); 7.62 (d, J = 92
Hz, 2H); 7.39 (d, J = 8.4 Hz, 1H); 723 (d, J = 2.8 Hz, 1H); 7.18-7.08 (m, 2H); 6.78 (d, J
= 10.4 Hz, 2H); 6.74 (s, 2H); 4.11-4.08 (m, 2H); 3.95 (s, 3H); 2.75 (t, J = 6.4 Hz, 2H);
2.49-2.49 (m, 4H); 1.63-1.58 (m, 4H); 1.47-1.44 (m, 2H).
Example 34
[2-(2,6-Difluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-
phenylj-methanone
Dissolve [2-(2,6-difluorophenyl)-6-methoxy-naphthalen-1 -yl]-[4-(2-piperidin-1 -
ylethoxy)-phenyl]-methanone (1.5 gm., 3.0 mmoles) in 500 ml methylene chloride and
chill in ice. To this solution add boron tribromide (6.0 ml, 63 mmoles) in portions with
swirling between additions. Allow to come to room temp, and stir for one hour. Pour
into a two-phase system consisting of an organic layer of 3/1 chloroform/isopropanol and
an aqueous layer of saturated sodium bicarbonate. Separate the phases and dry the
organic layer using 3A molecular sieves. Purify on a silica column eluting with a 0-10%

methanol/methylene chloride gradient. The yield of pure product is 600 mg (44%): 1H-
NMR (CD3OD, 400 MHz) 57.87 (d, J = 8.0 Hz, 1H); 7.56 (d, J = 8.4 Hz, 2H); 7.49 (d, J
= 9.2 Hz, 1H); 7.33 (d, J = 8.8 Hz, 1H); 7.27-7.25 (m, 1H); 7.23-7.21 (m, 1H); 7.06 (dd, J
= 8.8,2.4 Hz, 1H); 6.86-6.79 (m, 4H); 4.14 (t, J = 5.6 Hz, 2H); 2.76 (t, J = 5.6 Hz, 2H);
2.53-2.53 (m, 4H); 1.65-1.59 (m, 4H); 1.50-1.46 (m, 2H).
Preparation 6
Trifluoromethanesulfonic acid 6-benzyloxy-l -[4-(2-piperidin-1 -yl-ethoxy)-benzoyl]-
naphthalen-2-yl ester

Dissolve trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester (9.00 g, 17.2 mmol) in THF (540 mL). Stir the solution at
0 °C under N2 and add benzyl alcohol (2.78 g, 25.8 mmol), porymer-PPh3 (8.60 g, 25.8
mmol) and DIAD (5.21 g, 25.8 mmol). Continue to stir the reaction mixture at room
temperature for 2 hours. Add water (1000 mL), and extract the aqueous layer with
CH2CI2 (3 x 500 mL). Combine the organic layers and dry with Na2S04, filter,
concentrate and purify by flash chromatography (silica gel, 0-4% MeOH-NH4OH (10/1,
v/vyCH2Cl2) to give 10.0 g (96%) of the title compound: mass spectrum (ion spray) m/z =
614.1 (M+H).

Example 35
[6-Benzyloxy-2-(2-fluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-
methanone

Dissolve trifluoromethanesulfonic acid 6-benzyloxy-1-[4-(2-piperidin-1-yl-
ethoxy)-benzoyI]-naphthalen-2-yl ester (l.OOg, 1.63 mmoles) in 20 ml of acetonitrile and
add 2-flourobenzene boronic acid (0.46 g, 3.26 mmol),
trans[dichlorobis(triphenyiphosphine)] palladium II (0.23 gm., 0.33 mmoles) and sonicate
briefly. Next add cesium fluoride (2.23 g, 14.67 mmol) and heat to 75 °C for one hour.
Add Celite and filter. Concentrate the solvent under vacuum, dissolve in methanol and
purify on an SCX cartridge, eluting with 2N ammonia/methanol. Further purify on a
silica gel column eluting with a 0-10% methanol/methylene chloride gradient to isolate
550 mg of the title compound (60%).
Example 36
[2-(2-Fluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-
methanone hydrochloride
Dissolve [6-benzyloxy-2-(2-fluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-
ethoxy)-phenyl]- methanone (0.55 g, 0.98 mmoles) in 25 ml of ethanol and after a
nitrogen purge add 10% palladium on carbon (60 mg) and hydrogen (1 atm). After 12
hours, filter over celite and concentrate the solvent under vacuum, purify on a silica gel
column eluting with a 0-10% methanol/methylene chloride gradient to isolate 350 mg of
the title compound (76%). Convert to the hydrochloride salt to give the title compound.

Example 37
[6-Methoxy-2-(2,4,6-trifluoro-phenyI)-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone

Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester (752 mg, 1.4 mmol), 2,4,6-trifluorophenylboronic acid
(493 mg, 2.8 mmol), potassium phoshate (1.8 g, 8.4 mmol)) and
tetrakis(triphenylphosphine)palladium (324 mg, 0.3 mmol) in dry DMF (25 mL) and heat
at 100 °C for 20 minutes. Purify reaction on an SCX column to yield 674 mg (93%) of
the title compound: mass spectrum (ion spray) m/z = 520.2 (M+H).
Example 38
[6-Hydroxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyfj-methanone
Dissolve [6-methoxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-
l-yl-ethoxy)-phenyl]-methanone (670 mg, 1.3 mmol) in dichloromethane (10 mL). Cool
to 0 °C, add 2M HC1 (1.3 mL, 2.6 mmol) and stir at room temperature for 15 minutes.
Concentrate in vacuo. Redissolve the salt in dichloromethane (10 mL) and cool to 0 °C.
Add boron tribromide (1.1 g, 3.9 mmol) dropwise and bring to room temperature. Stir
reaction for 1.5 hours and pour reaction mixture onto ice, saturated sodium bicarbonate
(10 mL) and methanol (10 mL). Extract with dichloromethane, combine extracts and
wash with water and saturated sodium bicarbonate. Dry with sodium sulfate, filter, and
concentrate in vacuo. Purify by silica gel chromatography using a 1-3% gradient of
methanol in dichloromethane to yield 454 mg (70%) of the title compound: mass
spectrum (ion spray) m/z = 506.3 (M+H).

Preparation 7
Trifluoromethanesulfonic acid 6-methanesulfonyloxy-1 -[4-(2-piperidin-1 -yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester

Suspend trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester (12.5 g, 24 mmol) in dry methylene chloride (100 ml).
Add diisopropylethylamine (8.3 mL, 48 mmol). Slowly add methanesulfonyl chloride
(2.7 mL, 36 mmol). Pour reaction into saturated aqueous sodium bicarbonate after 20
minutes and extract with methylene chloride. Wash the organic layer with water, dry with
sodium sulfate, filter and concentrate in vacuo to yield 14.2 g (99%) of the title
compound.
Example 39
[6-Hydroxy-2-(2,3,5-trifluoro-phenyI)-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyll-methanone

Dissolve trifluoromethanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-
yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (7.0 g, 11.6 mmol) in degassed acetonitrile (100
mL). Add cesium fluoride (9.1 g, 58 mmol) and
bis(acetato)bis(triphenylphosphine)palladium (0.87 g, 1.2 mmol) followed by
bis(neopentyl glycolato)diboron (3.1g, 13.9 mmol) and plunge into a 75 °C oil bath under
nitrogen. After 15 minutes, add 1-bromo-2,3,5-trifluorobenzene (4.9 g, 23.2 mmol) to the
reaction and bis(acetato)bis(triphenylphosphine)palladium (200 mg) and stir at 75 °C for

2.5 hours. Cool the reaction to room temperature and filter through celite. Concentrate
the filtrate in vacuo and redissolve the residue in methanol (100 mL). Add KOH (5g) and
stir at room temperature overnight. Pour the reaction into saturated aqueous ammonium
chloride and extract with methylene chloride. Dry the organic layer with sodium sulfate,
filter and concentrate in vacuo. Purify on silica gel (0% to 6% methanol in methylene
chloride) to obtain 3.7 g (64%) of the title compound: mass spectrum (ion spray) m/z =
506.3 (M+H).
Example 40
[6-Methoxy-2-(2,3,6-trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenylj-methanone

Couple trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yI-ethoxy)-
benzoyl]-naphthalen-2-yl ester (1.81 g, 3.37 mmol) with 2-brorno-l,3,4-trifluoro-benzene
(1.42 g, 6.75 mmol) in a procedure similar to the preparation of 6-hydroxy-2-(2,3>5-
trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-methanone to
give 0.79 g (45%) of the title compound: mass spectrum (ion spray) m/z = 520.3 (M+H).
Example 41
[6-Hydroxy-2-(2,3,6-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-
phenyl]-methanone
Demethylate [6-methoxy-2-(2,3,6-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-methanone (0.79 g, 1.52 mmol) with BBr3 in a procedure
similar to the preparation of 2-(2,4-difluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-methanone to give 0.67 g (88%) of the title compound:
mass spectrum (ion spray) m/z = 506.3 (M+H).

Example 42
[6-Methoxy-2-(2,3,4-trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone

Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-
yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.13 g, 4.0 mmol), 2,3,4-trifluorophenyl
boronic acid (1.0 g, 5.7 mmol), trans-dichlorobis(triphenylphosphine)palladium II, (561
mg, 0.8 mmol) and cesium fluoride (5.5 g, 36 mmol) and add 50 mL of acetonitrile. Heat
the mixture at 80 °C for 4 hours. Cool and filter the mixture and purify on an SCX
column, eluting with 2N ammonia/methanol. Purify further on a silica column eluting
with 2% 2N amrnonia/methanol/methylene chloride to give 880 mg (43%) of the title
compound: 1H-NMR (CD3OD, 400 MHz) 5 7.93 (d, J=8.8Hz, 1H); 7.50 (d, J = 8.4 Hz,
3H); 7.39 (d, J = 8.8 Hz, 1H); 7.35 (d, J = 2.4 Hz, 1H); 7.07 (dd, J = 9.2, 2.8 Hz, 1H);
6.96-6.87 (m, 2H); 6.80 (d, J = 9.6 Hz, 2H); 4.10^1.07 (t, 2H); 3.91 (s, 3H); 2.72-2.69 (t,
2H); 2.48-2.48 (m, 4H); 1.61-1.55 (m, 4H); 1.46-1.43 (m, 2H).
Example 43
[6-Hydroxy-2-(2,3,4-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-
phenyl]-methanone
Dissolve [6-methoxy-2-(2,3,4-trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-
l-yl-ethoxy)-phenyl]-methanone (880 mg, 1.69 mmol) in 100 mL methylene chloride and
chill in ice. Add 4.0 mL of neat boron tribromide with swirling and stir in the ice bath for
30 minutes. Allow the mixture to come to room temp and stir for an additional 1 hour.
Carefully pour the mixture into a two-phase system consisting of saturated sodium
bicarbonate solution and a 3/1 mixture of chloroform/isopropanol. Separate the organic
layer, dry over 3 A molecular sieves and evaporate to give 800 mg of slightly impure

product. Purify on a silica gel column eluting with 3% methanol/methylene chloride to
give 635 mg (74%) of the title compound: 1H-NMR (CD3OD, 400 MHz) £7.89 (d, J =
8.8 Hz, 1H); 7.69-7.42 (m, 4H); 7.45-7.42 (m, 1H); 7.31 (d, J = 2.4 Hz, 1H); 7.14 (dd, J =
9.2, 2.4 Hz, 1H); 7.02-6.87 (m, 3H); 4.20 (t, J = 5.6 Hz, 2H); 2.84 (t, J = 5.6 Hz, 2H);
2.59-2.59 (m, 4H); 1.71-1.65 (m, 4H); 1.56-1.53 (m, 2H).
Example 44
[2-(2,3-Difluoro-phenyl)-6-hydroxy-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone

Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-
yl-ethoxy)-benzoyi]-naphthalen-2-yl ester (2.0 g, 3.7 mmol), 2,3 difluorophenyl boronic
acid (1.17 g, 7.4 mmol) palladium dichloride bis(triphenylphosphine) (518 mg, 0.74
mmol) and cesium fluoride (5.06 g, 33.3 mmol) and add 250 mL degassed acetonitrile.
Heat the mixture at 85 °C for two hours, cool the reaction and filter off any solids. Purify
on an SCX column eluting with 2N ammonia/methanol. Purify further on a silica gel
column eluting with a 0-10% methanol/methylene chloride gradient to give 1.3 g (70%) of
the title compound: 1H-NMR (CD3OD, 400 MHz) £7.92 (d, J = 8.8 Hz, 1H); 7.54 (dd, J
= 8.4,4.0 Hz, 3H); 7.43 (dd, J = 8.4, 1.6 Hz, 1H); 7.31 (d, J = 2.8 Hz, 1H); 7.09 (dd, J =
9.2, 2.4 Hz, 1H); 7.05-6.92 (m, 3H); 6.79 (d, J = 8.8 Hz, 2H); 4.10 (t, J = 5.6 Hz, 2H);
3.93 (s, 3H); 2.73 (t, J = 5.2 Hz, 2H); 2.50-2.50 (m, 4H); 1.62-1.57 (m, 4H); 1.48-1.43 (m,
2H).

Example 45
[2-(2,3-Difluoro-phenyl)-6-hydroxy-naphthalen- ] y |]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone
Charge a flask with [2-(2,3-difluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-methanone (1.3 g, 2.6 mmol) and add 200 mL methylene
chloride followed by 25 ml of HCI/ether and evaporate to dryness. Dissolve the solid in
200 mL methylene chloride and chill the solution in ice. Add to this solution boron
tribromide (4.0 mL, 42.4 mmol) with swirling. Stir the solution at room temperature for 1
hour at which point all the starting material is gone. Pour this into a two phase mixture
consisting of saturated sodium bicarbonate aqueous phase and a 3/1 mixture of
chloroform/isopropanol organic phase and extract using a separatory funnel. Separate the
organic phase and dry over 3A molecular sieves. Purify on a silica column eluting with 0-
10% methanol/methylene chloride, collecting the first traction that contains the product to
give 400 mg (32%) of the title compound: 1H-NMR (CD3OD, 400 MHz) SIM (d, J =
8.4 Hz, 1H); 7.55 (d, J = 9.2 Hz, 2H); 7.50 (d, J = 8.8 Hz, 1H); 7.40 (dd, J = 9.2, 1.6 Hz,
1H); 7.25 (d, J = 2.4 Hz, 1H); 7.10-7.03 (m, 2H); 6.99-6.95 (m, 2H); 6.83 (d, J = 9.2 Hz,
2H); 4.12 (t, J = 5.2 Hz, 2H); 2.76-2.73 (m, 2H); 2.58-2.52 (m, 4H); 1.64-1.58 (m, 4H);
1.49-1.45 (m,2H).
Preparation 8
6-Hydroxy-1 -[4-(2-piperidin-1 -yl-ethoxy)-benzoyl]-naphthalen-2-yl ester

Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester (240 g, 430 mmol) in dichloroethane (1.5 L). Cool to 0
°C. Bubble hydrogen chloride (36 g, 1 mol) into the reaction. Condense boron trichloride
(250 g, 2.1 mol) into a jacketed addition funnel and add dropwise into the reaction. Stir

48 - 72 h. Carefully add reaction to a mixture of 5 M sodium hydroxide (700 mL), water
(500 mL), and dichloromethane (1 L) at 0 °C. Adjust pH to 7 with 50% aqueous sodium
hydroxide. Dilute with 1 M sodium bicarbonate (1.7 L) and dichloromethane (500 mL).
Separate organic. Wash aqueous with dichloromethane (1 L). Combine organics and dry
over magnesium sulfate, filter, and concentrate in vacuo. Slurry material in
dichloromethane (200 mL) and obtain 196.2 g of the title compound (87%).
Example 46
[2-(3-Fluoro-phenyl)-6-hydroxy-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-
methanone hydrochloride

Charge a flask with trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-
yl-ethoxy)-benzoyl]-naphlnalen-2-yl ester (500 mg, 0.% mmol) and add 10 mL water
along with 2 mL of 1,2 dimethoxyethane. To this add 3-fluorophenylboronic acid (270
mg, 1.91 mmol), transdichlorobis(triphenylphosphine) palladium II (130 mg, 0.19 mmol)
and sodium carbonate (920 mg, 8.64 mmol). Heat the mixture to 80 °C and hold for one
hour. Cool and filter the mixture and purify on an SCX column, eluting with 2N
ammonia/methanol. Concentrate and purify on a silica column eluting with a 0-10 % 2N
ammonia in methanol/methylene chloride gradient. Concentrate and convert to the HC1
salt: 1H-NMR (CDC13, 300 MHz) 5 7.76 (d, J = 8.7 Hz, 1H); 7.52-7.41 (m, 5H); 7.21-
6.96 (m, 4H); 6.89-6.86 (m, 1H); 6.52 (d, J = 9.0 Hz, 2H); 4.09-4.05 (t, 2H); 2.78-2.78
(m, 2H); 2.56 (s, 4H); 1.67-1.63 (m, 4H); 1.48-1.46 (m, 2H)^_

Preparation 9
Trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-
methoxynaphthalen-2-yl ester

Dissolve 4-(2-azepan-1-yl-ethoxy)-benzoyl chloride (79.4 g, 249 mmol) and 2,6-
dimethoxynaphthalene (37.8 g, 201 mmol) in dichloromethane (800 mL). Cool to -5 °C
and add aluminum trichloride (134 g, 1 mo!). Warm to room temperature and stir
overnight. Add chilled water (1.5 L) and stir vigorously for 1 hour. Decant the mixture
away from the residue and separate organic. Wash the aqueous layer with
dichloromethane (500 mL). Combine with residue from the reaction vessel and wash
with saturated aqueous sodium bicarbonate (1 L). Separate the organic after prolonged
stirring (2 hours) and wash the aqueous layer with dichloromethane (300 mL). Combine
the organic layers and add Darco (30 g), silica gel (30 g), and magnesium sulfate. Filter
and concentrate in vacuo to give 72.4 g of [4-(2-azepan-1-yl-ethoxy)-phenyl]-(2-hydroxy-
6-methoxy-naphthalen-1-yl)-methanone (73%).
Dissolve [4-(2-azepan-1 -yl-ethoxy)-phenyI]-(2-hydroxy-6-methoxy-naphthalen-1 -
yl)-methanone (41.0 g, 88.0 mmol) and triethylamine (28.8 g, 284 mmol) in
dichloromethane (400 mL). Cool to -60 °C and add trifluoromethanesulphonic anhydride
(39.8 g, 141 mmol) in dichloromethane (100 mL). Warm to room temperature and stir.
Dilute with saturated aqueous sodium bicarbonate (500 mL) and separate the organic.
Wash the aqueous with dichloromethane (200 mL). Combine the organics and wash with
saturated aqueous sodium chloride. Dry over magnesium sulfate, filter, and concentrate
in vacuo. Purify the residue by column chromatography using a silica gel column eluting
with a linear gradient beginning with dichloromethane and ending with 30 : 1
dichloromethane : methanol to give 48.6 g of the title compound (96%).
Alternative Synthesis of Trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-
benzoyl]-6-methoxynaphthalen-2-yl ester

Add sodium hydride (18 g, 0.45 mol) into a solution of 4-benzyloxylphenol (41 g,
0.20 mol) and 2-(hexamethyleneimino)ethyl chloride hydrochloride (44 g, 0.22 mmol) in
THF (600 mL) and DMF (100 mL) at room temperature. Heat to 60°C for 30 minutes.
Pour the solution into ice and water. Dilute with ethyl acetate (500 mL) and separate
layers. Dry the organic layer with magnesium sulfate, filter and concentrate under reduced
pressure to give brown oil. Dissolve the oil in ethyl acetate (500 mL) and methanol (500
mL). Add ammonium formate (100 g, 1.59 mol) and palladium on carbon (10 g, 9.4
mmol). Heat the mixture to reflux for 30 minutes. Add ammonium formate (100 g, 1.59
mol) and palladium on carbon (10 g, 9.4 mmol). Heat the reaction mixture for 30
minutes. Filter the supension through a pad of celite and elute with ethyl acetate (500
mL). Evaporate solvent under reduced pressure and add water (100 mL). Dilute the
mixture with ethyl acetate (500 mL) and separate layers. Wash the organic layer with
saturated sodium bicarbonate solution (2 x 200 mL), dry with magnesium sulfate, filter
and evaporate solvent under reduced pressure to give 31 g (64 %) of 4-(2-azepan-1 -yl-
ethoxy)-phenol.
Combine 2-benzyloxy-1-bromo-6-methoxy-naphthalene (31 g, 90 mmol), 4-(2-
azepan-1-yl-ethoxy)-phenol (31 g, 132 mmol), copper bronze (12 g, 189 mmol),
potassium carbonate (25 g, 181 mmol) and pyridine (400 mL). Heat the reaction mixture
to reflux for 85 hours. Cool and filter the residue with celite and elute with methanol and
methylene chloride (500 mL, V/V = 1:5). Evaporate solvent under reduced pressure and
chromatograph the residue on a silica gel column eluting the material with a step gradient
of methanol/dichloromethane (0 to 10%) to get 19 g (43%) of l-{2-[4-(2-benzyloxy-6-
methoxy-naphthalen-1 -yloxy)-phenoxy]-ethyl} -azepane.
Dissolve l-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1 -yloxy)-phenoxy]-ethyl}-
azepane (19 g, 38 mmol) in ethyl acetate (500 mL) and methanol (600 mL). Heat the
mixture to obtain a clear solution. Cool to room temperature. Add ammonium formate
(30 g, 476 mmol) and palladium on carbon (2 g, 1.9 mmol). Heat to reflux for 30
minutes. Add ammonium formate (7 g, 111 mmol) and palladium on carbon (0.7 g, 0.7
mmol). Heat to reflux for 30 minutes. Filter the supension through a pad of celite and
elute with ethyl acetate (500 mL). Evaporate solvent under reduced pressure and add
water (100 mL). Dilute the mixture with ethyl acetate (500 mL) and separate layers.

Wash the organic layer with saturated sodium bicarbonate solution (2 x 200 mL), dry with
magnesium sulfate, filter and evaporate solvent under reduced pressure to give 15.1 g
(97%)of l-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-ol.
Add trifluoromethanesulfonic anhydride (7 mL, 42 mmol) into a solution of 1 -[4-
(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-ol (15 g, 37 mmol),
triethylamine (20 mL) and methylene chloride (500 mL) at -50°C. Warm the reaction
mixture to room temperature and stir for 1 hour at that temperature. Cool the reaction
mixture to -78°C and add brine (20 mL). Warm the reaction to room temperature.
Separate layer and wash the organic layer with saturated sodium bicarbonate solution (100
mL) and brine. Dry the organic layer with magnesium sulfate, filter and evaporate solvent
under reduced pressure. Chromatograph the residue on a silica gel column eluting the
material with a step gradient of methanol/dichloromethane (0 to 10%) to get 20 g (99%)
of trifluoro-methanesulfonic acid l-[4-{2-azepan-]-yl-ethoxy)-phenoxy]-6-methoxy-
naphthalen-2-yl ester.
Example 47
[4-(2-Azepan-l -yl-emoxy)-phenyl]-[6-methoxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1 -
yl]-methanone

Dissolve trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-
methoxy-naphthalen-2-yl ester (990 mg, 1.8 mmol), 2,4,6-trifluorophenylboronic acid
(634 mg, 3.6 mmol), potassium phoshate (2.2 g, 10.8 mmol),
tetrakis(triphenylphosphine)palladium (416 mg, 0.4 mmol) in dry DMF (25 mL) and heat
at 100 °C for 3 hours. Purify reaction by SCX column and by silica gel chromatography
using a 1-3% gradient of methanol in dichloromethane to yield 320 mg (35%) of the title
compound: mass spectrum (ion spray) m/z = 534 (M+H).

Example 48
[4-(2-Azepan-1 -yl-ethoxy)-phenyl]-[6-hydroxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1 -
yl]-methanone
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-methoxy-2-(2,4,6-trifluoro-
phenyl)-naphthalen-1-yl]-methanone (634 mg, 1.2 mmol) in dichloromethane (10 mL).
Cool to 0 °C, add HC1 (2M in ether, 1.2 mL, 2.4 mmol) and stir at room temperature for
15 minutes. Concentrate in vacuo. Redissolve the salt in dichloromethane (10 mL) and
cool to 0 °C. Add boron tribromide (949 mg, 3.6 mmol) dropwise and bring to room
temperature. Stir reaction for 1.5 hour and pour reaction mixture onto ice, saturated
sodium bicarbonate (20 mL) and methanol (20 mL). Extract with dichloromethane,
combine extracts and wash with water and saturated sodium bicarbonate. Dry with
sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography
using a 1-3% gradient of methanol in dichloromethane to yield 350 mg (57%) of the title
compound: mass spectrum (ion spray) m/z = 520 (M+H).
Example 49
[4-(2-Azepan-1 -yl-ethoxy)-phenyl]-t2-(2-fluoro-phenyl)-6-methoxy-naphthalen-1 -yl]-
methanone

Dissolve trifluoromethanesulfonic acid 1 -[4-(2-azepan-1 -yl-ethoxy)-benzoyl]-6-
methoxynaphthalen-2-yl ester (1.68 g, 3.05 mmol) in 30 mL of acetonitrile and add 2- .
fluorobenzene boronic acid (0.85 g, 6.10 mmol), trans[dichlorobis(triphenylphosphine)]
palladium II (0.43 g, 0.61 mmol) and sonicate briefly. Next add cesium fluoride (4.17 g,
27.45 mmol) and heat to 75 °C for 1 hour. Add Celite and filter. Concentrate the solvent
under vacuum, dissolve in methanol and purify on an SCX cartridge, eluting with 2 N
ammonia/methanol. Purify further on a silica gel column eluting with a 0-10%
methanol/methylene chloride gradient to isolate 1.10 g of the title compound (72%).

Example 50
[4-(2-Azepan-1 -yl-ethoxy)-phenylH2-(2-fl uoro-phenyl)-6-hydroxy-naphthalen-1 -yl]-
methanone hydrochloride
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2-fluoro-phenyl)-6-rnethoxy-
naphthalen-1-yl]-methanone (550 mg, 1.1 lmmol) in 20 mL methylene chloride and cool
in an ice bath. Boron tribromide is added (1.5 mL) and allow to come to room
temperature. Pour into a two phase solution of saturated sodium bicarbonate and 3/1
chloroform/isopropanol. Separate the organic layer, wash with water and dry over 3A
sieves. Evaporate the solvent and purify on a silica gel column eluting with a 0-10%
methanol/methylene chloride gradient to isolate 268 mg of the free base of the title
compound (50%). Dissolve the free base in a 1 :1 mixture of acetonitrile : water. Add an
appropriate amount of 5 M hydrochloric acid and ryopholize the mixture to afford the title
compound.
Example 51
5-[4-(2-Azepan-1 -yl-ethoxy)-benzyl]-6-(2-fluoro-phenyl)-naphthalen-2-ol Hydrochloride

Dissolve [4-(2-azepan-1 -yl-ethoxy)-phenyl]-[2-(2-fluoro-phenyl)-6-hydroxy-
naphthalen-1-yl]-methanone (223 mg, 0.48 mmol) in 15 mL tetrahydrofuran. To this
solution add 5ml lithium triethylborohydride (1M solution in tetrahydrofuran). Dilute
reaction with water and extract with ethyl acetate and concentrate. Dissolve the residue
(the alcohol product) in 20 mL methylene chloride and add triethylsilane (0.06 mL, 0.40
mmol) and 1.5 mL trifluoroacetic acid. Concentrate this reaction and purify on a silica
gel column eluting with a 0-10% methanol/methylene chloride gradient to give 70 mg
(31%) of the free base of the title compound. Dissolve the free base in a 1 :1 mixture of

acetonitrile : water. Add an appropriate amount of 5 M hydrochloric acid and lyopholize
the mixture to afford the title compound.
Example 52
[4-(2-Azepan-1 -yl-ethoxy)-phenyl]-[6-methoxy-2-(2,3,6-trifluoro-phenyl)-naphthalen-1 -
yl]-methanone

Couple trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-
methoxynaphthalen-2-yl ester (1.48 g, 2.67 mmol) with 2-bromo-l ,3,4-trifluoro-benzene
(1.13 g, 5.35 mmol) in a procedure similar to the preparation of [6-hydroxy-2-(2,3,5-
trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-methanone to
give 0.66 g (46%) of the title compound: mass spectrum (ion spray) m/z = 534.4 (M+H).
Example 53
[4-(2-Azepan-1 -yl-ethoxy)-phenyl]-[6-hydroxy-2-(2,3,6-triiluoro-phenyl)-naphthalen-1 -
yl]-methanone
Demethylate [4-(2-azepan-1 -yl-ethoxy)-phenyl]-[6-methoxy-2-(2,3,6-trifluoro-
phenyl)-naphthalen-1-yl]-methanone (0.66 g, 1.24 mmol) with BBn in a procedure
similar to the preparation of [4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-hydroxy-2-(2,4,6-
trifluoro-phenyl)-naphthalen-1-yl]-methanone to give 0.53 g (82%) of the title compound.
Analytical data obtained for the corresponding HC1 salt: mass spectrum (ion spray) m/z =
520.3 (M-Cl).

Example 54
[4-{2-Azepan-1 -yl-ethoxy^phenyJJ-p^^-difluoro-phenyl^-methoxy-naphthalen-1 -yl]-
methanone

Couple trifluoromethanesulfonic acid 1 -[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-
methoxynaphthalen-2-yl ester (1.4 g, 2.5 mmol) and 2,4-difluorophenyl boronic acid (1.2
g, 7.6 mmol) by the procedure described for the preparation of 2-(2,4-difluoro-phenyl)-6-
methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone to give 1.1 g
(85%) of the title compound: mass spectrum (ion spray) m/z = 516.3 (M+H).
Example 55
[4-{2-Azepan-1-yI-ethoxy)-phenyl]-[2-(2,4-difluoro-phenyI)-6-hydroxy-naphthalen-1-yI]-
methanone hydrochloride
Demethylate [4-{2-azepan-1 -yl-ethoxy)-phenyl]-[2- methoxy-naphthalen-1-yl]-methanone (1.1 g, 2.1 mmol) with BBr3 (1.0 mL, 10.5 mmol)
by the procedure described for the preparation of [2-(2,4-difluoro-phenyl)-6-hydroxy-
naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone. Purify on silica gel
(0% to 5% methanol in methylene chloride) to yield 790 mg (75%) of the free base of the
title compound: mass spectrum (ion spray) m/z = 502.3 (M+H). Convert to the
hydrochloride salt.

Example 56
[4-(2-Azepan-1 -yl-ethoxy)-phenyl]-[2-(2,6-difluoro-phenyl)-6-methoxy-naphthalen-1 -yl]-
methanone

Charge a flask with trifluoromethanesultonic acid l~[4-(2-azepan-1-yl-ethoxy)-
benzoyl]-6-methoxynaphthalen-2-yl ester (3.9 g, 7.06 mmol), 2,6-difluorophenyl boronic
acid (2.23 g, 14.12 mmol), potassium phosphate (9.0 g, 42.20 mmol) and
tetrakis(triphenylphosphine)palladium (0) (1.63 g, 1.40 mmol) followed by 125 mL dry
DMF. Heat the mixture under nitrogen at 100 °C for 90 minutes. Cool, filter, evaporate
the solvent and purify on an SCX cartridge, eluting with 2N ammonia/methanol. Purify
further on a silica gel column eluting with 0-10% methanol/methylene chloride. The yield
is 2.5 g (70%): 1H-NMR (CDCI3,400 MHz) 8 7.90 (d, J = 8.4 Hz, 1H); 7.66-7.61 (m,
3H); 7.39 (d, J = 8.4 Hz, 1H); 7.23-7.22 (m, 1H); 7.18-7.08 (m, 2H); 6.79-6.74 (m, 4H);
4.08-4.05 (t, 2H); 3.95 (s, 3H); 2.96-2.89 (t, 2H); 2.78-2.75 (m, 4H); 1.66-1.59 (m, 8H).
Example 57
[4-(2-Azepan-1 -yl-ethoxy)-phenyl]-[2-(2,6-difluoro-phenyl)-6-hydroxy-naphthalen-1 -yl]-
methanone
Convert [4-(2-azepan-1 -yl-ethoxy)-phenyl]-[2-(2,6-difluoro-phenyl)-6-methoxy-
naphthalen-1-yl]-methanone (2.5 g, 4.8 mmol) into the hydrochloride salt and charge a
flask with the solid salt. Dissolve the material in 200 mL methylene chloride and chill in
ice. Add to this mixture boron tribromide (5.0 mL, 53.0 mmol) while swirling. Stir the
reaction at room temperature for one hour and pour into a two phase system of saturated
sodium bicarbonate and an organic layer consisting of a 3/1 mixture of
chloroform/isopropanol. Shake to extract the product, separate the organic layer, dry over
3A molecular sieves and evaporate the solvent under vacuum. Purify on a silica gel

column eluting with a 0-10% methanol/methylene chloride gradient to give 1.3 g (54%) of
the title compound: 1H-NMR (CDC13, 400 MHz) 6 7.79-7.74 (d, 1H); 7.58 (d, J = 8.4
Hz, 2H); 7.50 (d, J = 8.8 Hz, 1H); 7.33-7.30 (d, 1H); 7.17 (d, J = 2.4 Hz, 1H); 7.16-7.08
(m, 1H); 6.99-6.95 (dd, 1H); 6.77-6.73 (m, 2H); 6.68 (d, J = 9.2 Hz, 2H); 4.11 (t, J = 6.0
Hz, 2H); 3.05-2.99 (t, 2H); 2.90-2.84 (m, 4H); 1.71-1.71 (m, 4H); 1.63-1.60 (m, 4H).
Example 58
[4-(2-Azepan-1-yl-ethoxy)-phenyl]-[2-{2,5-difluoro-phenyl)-6-methoxy-naphthalen-1-yI]-
methanone

Dissolve trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-
methoxynaphthalen-2-yl ester (2.00 g, 3.63 mmol) in 5 mL of degassed acetonitrile and
add 2,5-difluorophenyl boronic acid (1.15 g, 7.26 mmol),
trans[dichlorobis(triphenylphosphine)] palladium II (0.51 g, 0.73 mmol) and sonicate
briefly. Next add cesium fluoride (4.96 g, 32.76 mmol) and heat to 75 °C for one hour.
Add Celite and filter. Concentrate the solvent under vacuum, dissolve in methanol and
purify on an SCX cartridge, eluting with 2N ammonia/methanol to give 1.74 g (93%) of
the title compound.
Example 59
[4-(2-Azepan-1-yl-ethoxy)-phenyl]-[2-(2,5-difluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-
methanone
Dissolve [4-(2-azepan-1 -yl-ethoxy)-phenyl]-[2-(2,5-difluoro-phenyl)-6-rnethoxy-
naphthalen-1-yl]-methanone (1.74 g, 3.37 mmol) in 20 mL methylene chloride and chill
in ice. Add to this solution 2.0 mL of boron tribromide (5.3 g, 21.2 mmol) and allow to
come to room temperature. Pour into a two phase solution of saturated sodium

bicarbonate and 3/1 chloroform/isopropanol. Separate the organic layer, wash with water
and dry over 3A sieves. Evaporate the solvent and purify on a silica gel column eluting
with a 0-10% methanol/methylene chloride gradient. Evaporate the solvent to give 780
mg (46%) of the title compound: 1H-NMR (CDCI3, 300 MHz) 5 7.79 (d, J = 8.7 Hz, 1H);
7.60-7.55 (m, 3H); 7.41 (dd, J = 8.7, 1.8 Hz, 1H); 7.26-7.21 (m, 1H); 7.04-6.82 (m, 4H);
6.71-6.68 (m, 2H); 4.14-4.14 (m, 2H); 3.03-2.07 (m, 2H); 2.95-2.88 (m, 4H); 1.73-1.58
(m, 8H).
Example 60
[4-(2-Azepan-1-yl-ethoxy)-phenyl]-[6-methoxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-1-
ylj-methanone

Dissolve trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-
methoxynaphthalen-2-yl ester (2.60 g, 6.53 mmol) in 200 ml. acetonitrile and add to this
bis(pinacoloato)diboron (1.5 g, 7.96 mmol), bis(tricyclohexylphosphine)palladium (0)
(0.72 g, 1.50 mmol) and cesium fluoride (7.33 g, 67.0 mmol). Heat the reaction to 100 °C
until LC/MS indicates all starting material is consumed. Add to this mixture 1-bromo-
2,3,5-trifluorobenzene (2.00 g, 13.06 mmol) and another 720 mg of palladium catalyst
and heat at 80 °C for 24 hours. Filter the reaction, concentrate and purify on a silica gel
column eluting with a 0-10% methanol/methylene chloride gradient to give 1.85 g (53%)
of the title compound.

Example 61
[4-(2-Azepan-l -yl-ethoxy>phenyl]-[6-hydroxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-1 -
yl]-methanone
Dissolve [4-(2-azepan-1-yI-ethoxy)-phenyl]-[6-methoxy-2-(2,3,5-trifluorophenyl)-
naphthalen-1-yl]-methanone (2.85 g, 5.34 mmol) in 50 mL methylene chloride and cool to
0 °C. Add boron tribromide (3.0 mL, 31.7 mmol) and allow to come to room temperature.
Pour into a two phase system of saturated sodium bicarbonate and 3/1
chloroform/isopropanol. Wash the organic layer with brine and dry over 3A molecular
sieves. Concentrate to give 2.63 g (95%) of the title compound.
Preparation 10
Trifluoromethanesulfonicacid6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-
naphthalen-2-yl ester

Dissolve (2,6-dimethoxy-naphthalen-1 -yl)-[4-(2-piperid in-1 -yI-ethoxy)-phenyl]-
methanone (56.0 g, 123 mmol) in chloroform (500 mL). Cool to 0 °C. Add boron
trichloride (150 mL, 150 mmol, 1 M solution in dichloromethane) and stir 2 hours. Warm
to room temperature and stir 1.5 hours. Add additional boron trichloride (50 mL, 50
mmol) after cooling to 0 °C. Warm to room temperature and stir overnight. Carefully add
ice and saturated aqueous sodium bicarbonate. Separate organic and wash aqueous three
times with a 3 : 1 dichloromethane : isopropanol mixture. Concentrate in vacuo and
dissolve in dichloromethane. Dry over sodium sulfate, decant, and concentrate in vacuo.
Slurry in ether and filter, rinsing with hexanes to give 49.4 g of (2-hydroxy-6-methoxy-
naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone(99%).
Dissolve (2-hydroxy-6-methoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-
phenylj-methanone (12 g, 29.6 mmol) in tetrahydrofuran (200 mL). Add lithium
aluminum hydride (3.0 g, 78.0 mmol) and heat the reaction to reflux. Allow to cool to

room temperature and add ice. Adjust the pH of the mixture to 7 with 5 M hydrochloric
acid. Dilute with water (500 mL). Wash the mixture four times with dichloromethane
(500 mL each wash). Combine the organics, dry over sodium sulfate, decant, and
concentrate in vacvoto give l-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-6-
methoxy-naphthalen-2-ol.
Redissolve in chloroform and add trifluoroacetic acid (5.0 mL, 64.9 mmol) and
triethylsilane (10.0 mL, 62.6 mmol). Heat the reaction to reflux for 1 hour. Cool to room
temperature and dilute with saturated aqueous sodium bicarbonate (300 mL). Extract the
organic and wash the aqueous twice with dichloromethane (300 mL each wash).
Combine the organics, dry over sodium sulfate, decant, and concentrate in vacuo. Isolate
a residue containing 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol.
Purify the residue on an SCX column, eluting the impurities with methanol, then eluting
the product with 2N ammonia/methanol.
Dissolve 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol in
dichloroethane (300 mL) and add N-phenylbis(trifluoromemanesulfonimide (15.0 g, 42.0
mmol). Add triethylamine (20 mL, 143.5 mmol) and heat to reflux for 6 hours.
Concentrate in vacuo and purify the residue by column chromatography using a silica gel
column eluting with a linear gradient beginning with dichloromethane and ending with 20
: 1 dichloromethane : methanol to give 13.6 g of the title compound (88%).
Example 62
1 -(2- {4-[2-(2,5 -Difluoro-phenyl)-6-methoxy-naphthalen-1 -ylmethyl]-phenoxy} -ethyl)-
piperidine

Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-
yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.0 g, 1.91 mmol) and add 20 mL degassed
acetonitrile. To this solution add 2,5-difluorophenyl boronic acid (0.6 g, 3.82 mmol),
transdichlorobis(triphenylphosphine) palladium II, (270 mg, 0.38 mmol) and cesium

fluoride (2.61 g, 17.2 mmol). Sonicate the mixture briefly and heat to 75 °C. After 3
hours add an additional small amount of the acid, the catalyst and the cesium fluoride and
heat overnight. In the morning filter the mixture and run through and SCX column
eluting with 2N ammonia in methanol. Purify further on a silica gel column eluting with
a 0-10% methanol/methylene chloride gradient. Concentrate to give 430 mg (46%) of the
title compound; 1H-NMR (CDC13, 300 MHz) £7.85 (d, J - 9.3 Hz, 1H); 7.73 (d, J = 8.7
Hz, 1H); 7.33 (d, J = 8.4 Hz, 1H); 7.18 (d, J = 2.7 Hz, 1H); 7.11-6.89 (m, 4H); 6.86-6.82
(m, 2H); 6.73-6.69 (m, 2H); 4.34-4.19 (d, H); 4.04-3.99 (t, 2H); 3.93 (s, 3H); 2.72 (t, J =
6.3 Hz, 2H); 2.47 (t, J = 5.1 Hz, 4H); 1.58 (qui, J = 5.4 Hz, 4H); 1.46-1.41 (m, 2H).
Example 63
6-(2,5-Difluoro-phenyI)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol
hydrochloride
Dissolve 1 -(2- {4-[2-(2,5-difluoro-phenyl)-6-methoxy-naphthalen-l -ylmethyl]-
phenoxy}-ethyl)-piperidine in 20 mL acetonitrile and chill in an ice bath. Add 1.5 mL of
boron tribromide with swirling and allow to warm to room temperature. Pour this
mixture into a two-phase mixture of saturated sodium bicarbonate solution and a 3/1
mixture of chloroform/isopropanol. Wash the organic layer with water and dry over 3A
molecular sieves. Concentrate the organic layer and purify on a silica gel column, eluting
with a 0-10% methanol/methylene chloride gradient. Evaporate the solvent and convert
the compound to the salt with HCI to give 369 mg (82%) of the title compound: 1H-
NMR (CDCI3, 300 MHz) £7.77 (d, J = 8.7 Hz, 1H); 7.61 (d, J = 8.1 Hz, 1H); 7.28-7.25
(m, 1H); 7.11-6.94 (m, 4H); 6.89-6.83 (m, 1H); 6.74 (d, J = 8.7 Hz, 2H); 6.57-6.54 (m,
2H); 4.31-4.10 (d, 2H); 4.04 (t, J = 6.0 Hz, 2H); 2.80-2.80 (m, 2H); 2.59-2.59 (m, 4H);
1.68-1.65 (m, 4H); 1.48-1.46 (m, 2H).

Example 64
1 -{2-{4-[2-(2,4-Difluoro-phenyl)-6-methoxy-naphthalen-1 -ylmethyl]-phenoxy} -ethyl)-
piperidine

Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzyl]-naphthalen-2-yl ester (1.00 g, 1.91 mmol) in 20 mL of degassed acetonitrile and
add 2,4-difluorophenyl boronic acid (0.60 g, 3.82 mmol),
trans[dichlorobis(triphenylphosphine)] palladium II (0.27 g, 0.38 mmol) and sonicate
briefly. Next add cesium fluoride (2.61 g, 17.19 mmol) and heat to 75 °C for one hour.
Add Celite and filter. Concentrate the solvent under vacuum, dissolve in methanol and
purify on an SCX cartridge, eluting with 2N ammonia/methanol to isolate the title
compound.
Example 65
6-(2,4-Difluoro-phenyl)-5-t4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol
hydrochloride
Dissolve l-(2-{4-[2-(2,4-difluoro-phenyl)-6-methoxy-naphthalen-1-ylmethyl]-
phenoxy}-ethyl)-piperidine (0.72 g, 1.48 mmol) in 30 mL methylene chloride and chill in
ice. Add to this solution 2.0 mL of boron tribromide (21.2 mmol) and allow to come to
room temperature. Pour into a two phase solution of saturated sodium bicarbonate and
3/1 chloroform/isopropanol. Separate the organic layer, wash with water and dry over 3A
sieves. Evaporate the solvent and purify on a silica gel column eluting with a 0-10%
methanol/methylene chloride gradient. Evaporate the solvent to yield 300 mg (43%) of
the free base of the title compound. Dissolve the free base in a 1 :1 mixture of acetonitrile
: water. Add an appropriate amount of 5 M hydrochloric acid and lyopholize the mixture
to afford the title compound.

Example 66
l-(2-{4-[2-(4-Fluoro-phenyl)-6-memoxy-naphthalen-1-ylmethyl]-phenoxy}-ethyl)-
piperidine

Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzyl]-naphthalen-2-yl ester (1.0 g, 1.91 mmol), 4-fluorophenyl boronic acid (3.8 g, 3.8
mmol), trans[dichlorobis(triphenylphospbine)] palladium II (266 mg, 0.38 mmol) and
cesium fluoride (2.6 g, 17.1 mmol) in 125 mL degassed acetonitrile and heat at 85 °C for
8 hours. Cool and filter and purify on an SCX column and elute with 2 N
ammonia/methanol. Evaporate to an oil and purify on a silica gel column eluting with a
gradient of 0-10% methanol/methylene chloride: mass spectrum (ion spray) m/z = 470
(M+H).
Example 67
6-(4-Fluoro-phenyI)-5-[4-(2-piperidin-1-yI-ethoxy)-benzyl]-naphthalen-2-ol
hydrochloride
Dissolve l-(2-{4-[2-(4-fluoro-phenyl)-6-methoxy-naphthalen-1-ylmethyI]-
phenoxy}-ethyl)-piperidine (500 mg, 1.06 mmol) in 250 mL methylene chloride and chill
in ice. To this add 1.0 mL boron tribromide with swirling and allow the mixture to come
to room temperature. After one hour add another 1.0 mL of the boron tribromide, then
after 30 minutes add another 0.5 mL of the bromide and stir for another 30 minutes. Pour
the reaction into a two-phase system of saturated sodium bicarbonate and an organic layer
consisting of a 3/1 mixture of chloroform/isopropanol. Shake in a separatory funnel,
separate the organic layer and dry over 3A molecular sieves. Evaporate the solvent and
purify on a silica column eluting with a gradient of 0-10% methanol/methylene chloride

to give 300 mg of the free base of the title compound (62%). Convert the free base to the
salt by dissolving in acetonitrile and adding hydrochloric acid and lyophilizing the
resulting solution.
Example 68
l-(2-{4-[2-(2-Fluoro-phenyl)-6-methoxy-naphthalen-1-ylmethy]]-phenoxy}-ethyl)-
piperidine

Dissolve trifluoromethanesulfonic acio 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzylJ-naphthalen-2-yl ester (1.0 g, 1.9 nunol), 2-fluorophenyl boronic acid (532 mg, 3.8
mmol), trans[dichlorobis(triphenylphosphine)] palladium II (266 mg, 0.38 mmol) and
cesium fluoride (2.6 g, 17.1 mmol) in 150 mL degassed acetonitrile and heat at 85 °C for
2 hours. Cool the reaction, filter and purify on an SCX column, eluting with 2N
ammonia/methanol. Concentrate and purify on a silica column eluting with 1 0-10%
gradient of methanol/methylene chloride to give 560 mg (63%) of the title compound:
mass spectrum (ion spray) m/z = 470 (M+H).

Example 69
6-(2-Fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-ben2yI]-naphthalen-2-ol
hydrochloride
Dissolve l-(2-{4-[2-(2-fluoro-phenyl)-6-me*hoxy-naphthalen-1-ylmethyl]-
phenoxy}-ethyl)-piperidine (560 mg, 1.2 mmol) in 250 mL acetonitrile and chill in ice.
Add 2.0 mL of boron tribromide with swirling, stir one hour and allow to come to room
temp. Pour the reaction into a two-phase system consisting of saturated sodium
bicarbonate and an organic layer of a 3/1 mixture of chloroform/methanol. Shake in a
separatory funnel, separate the organic layer and dry over molecular sieves. Evaporate the
solvent and purify on an SCX column, eluting with 2N ammonia/methanol. Evaporate
the solvent to an oil and purify on a silica column eluting with a 0-10%
methanol/methylene chloride gradient to give 220 mg of the free base of the title
compound (48%). Convert to the HC1 salt by dissolving in acetonitrile and adding
hydrochloric acid and lyophilizing.
Example 70
l-(2-{4-[2-(3-Fluorophenyl)-6-methoxy-naphthalen-1-ylmethyl]-phenoxy}-ethyl)-
piperidine

Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-
yl-ethoxy)-benzyl]-naphthalen-2-yl ester (2.0 g, 3.82 mmol), 3-fluorophenyl boronic acid
(1.07 g, 7.64 mmol), trans-dichlorobis(triphenylphosphine)palladium II (536 mg, 0.76
mmol) and cesium fluoride (5.2 g, 34.4 mmol) along with 100 mL degassed acetonitrile
and heat at 85 °C for 4 hours or until all the starting triflate is consumed. Cool the
reaction, filter and purify on an SCX column eluting with 2N ammonia/methanol. The
crude yield is 1.5 g (83%). Further purify the crude material on a silica column, eluting

with 3% methanol/methylene chloride to give 1.1 g of the title compound (63%): 1H-
NMR (CDC13,400 MHz) 5 7.81 (d, J = 9.6 Hz, 1H); 7.73 (d, J = 8.4 Hz, 1H); 7.39 (d, J =
8.4 Hz, 1H); 7.28-7.25 (m, 1H); 7.19 (d, J = 2.4 Hz, 1H); 7.11-7.06 (m, 2H); 7.04-7.01
(m, 2H); 6.88 (d, J = 9.2 Hz, 2H); 6.75 (dd, J - 6.4, 2.4 Hz, 2H); 4.34 (s, 2H); 4.07 (t, J =
6.0 Hz, 2H); 3.93 (s, 3H); 2.81 (t, J = 6.0 Hz, 2H); 2.57-2.57 (m, 4H); 1.67-1.61 (m, 4H);
1.48-1.46 (m,2H).
Example 71
6-(3-Fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol
hydrochloride
Charge a flask with l-(2-{4-[2-(3-fluorophenyl)-6-methoxy-naphthalen-1-
ylmethyl]-phenoxy}-ethyl)-piperidine (1.1 g, 2.3 mmol) dissolved in 250 mL methylene
chloride and chill in ice. Add 6.0 mL of neat boron tribromide in portions with stirring
and stir the reaction in ice for one hour then at room temperature for 2 hours. Pour the
reaction into a two-phase mixture consisting of saturated sodium bicarbonate and an
organic phase of 3/1 chloroform/isopropanol. Extract the compound into die organic
phase using a separatory funnel, separate the phases and dry the organic layer over 3 A
molecular sieves. Evaporate and purify on a silica column eluting with 3%
methanol/methylene chloride. Convert to the hydrochloride salt and lyophilize to yield
650 mg (57%) of the title compound: 1H-NMR (data reported for the free base) (CDC13,
400 MHz) 8 7.73 (d, J = 9.6 Hz, 1H); 7.61 (d, J = 8.0 Hz, 1H); 7.32-7.30 (m, 1H); 7.28-
7.24 (m, H); 7.15 (d, J = 2.0 Hz, 1H); 7.04-6.94 (m, 4H); 6.79 (d, J = 8.4 Hz, 2H); 6.62-
6.59 (m, 2H); 4.28 (s, 2H); 4.13 (t, J = 5.6 Hz, 2H); 2.92-2.92 (m, 2H); 2.72-2.64 (m, 4H);
1.74 (d, J = 4.8 Hz, 4H); 1.51-1.51 (m, 2H).

Example 72
1 -(2-{4-[6-Methoxy-2-(2,3,4,5-tetrafluoro-phenyl)-naphthaIen-1 -ylmethylj-phenoxy}-
ethyl)-piperidine

Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzyl]-naphthalen-2-yl ester (259 mg, 0.49 mmol), bis(pinacolato)diboron (151 mg, 0.59
mmol), bis(tricyclohexylphosphine)paUadium (0) (75 mg, 0.11 mmol)and cesium fluoride
(764 mg, 5.03 mmol) in 20 mL degassed acetonitrile and heat at 100 °C under nitrogen in
a sealed vial. The reaction is complete in 10 minutes. Cool and add l-bromo-2,3,4,5-
tetrafluorobenzene (224 mg, 0.99 mmol) along with 10 mL acetonitrile, seal the vial,
purge with nitrogen and heat at 80 °C for 2 hours. Cool, fitter and purify on an SCX
column eluting with 2N ammonia/methanol. Evaporate the solvent and purify the
resulting oil on a silica column eluting with 3% methanol/methylene chloride to give 188
mg of the title compound (73%).
Example 73
5-[4-(2-Piperidin-1-yl-ethoxy)-benzyl]-6-(2,3,4,5-tetrafluoro-phenyl)-naphthalen-2-ol
hydrochloride
Dissolve l-(2-{4-[6-methoxy-2-(2,3,4,5-tetrafluoro-phenyl)-naphthalen-1-
ylmethyl]-phenoxy}-ethyl)-piperidine (180 mg, 0.34 mmol) in 50 mL methylene chloride
and chill in ice. Add 2.0 mL boron tribromide and stir in ice for 1 hour. Pour this
mixture into a 2-phase mixture consisting of saturated sodium bicarbonate and an organic
layer of 3/1 chloroform/isopropanol. Shake in a separatory funnel, separate the organic
layer, wash it with brine and dry over molecular sieves. Evaporate the solvent and purify
on a silica column eluting first with pure methylene chloride, then with 3%

methanol/methylene chloride. Repeat the purification to give 45 mg of the free base of
the title compound (26%). The free base is converted to the hydrochloride salt by
dissolving in acetonitrile, adding HCI and lyophilizing: mass spectrum (ion spray) m/z =
510(M-C1).
Preparation 11
(4-Bromo-phenyl)-(2-piperidin-1-yl-ethyl)-carbamic acid tert-butyl ester

Dissolve (4-bromo-phenyl)-carbamic acid tert-butyl ester (3.0 g, 11.0 mmol) in
N,N-dimethylformamide (30 mL). Add sodium hydride (1.1 g, 27. 6 mmol) and stir at
room temperature. Add l-(2-chloroethylpiperidine) monohydrochloride (3.0 g, 16.5
mmol). Stir overnight at room temperature and then overnight at 60 °C. Cool to room
temperature and dilute with ethyl acetate and water. Separate the organic layer and wash
the aqueous with ethyl acetate. Combine the organics and wash with saturated aqueous
sodium chloride. Dry over magnesium sulfate, filter, and concentrate in vacuo. Purify the
residue by column chromatography using a silica gel column eluting with a linear gradient
beginning with dichloromethane and ending with 9 : 1 dichloromethane : methanol to
give 1.2 g of the title compound.
Example 74
1 -(2- {4-[2-(2,6-Difluoro-phenyl)-6-methoxy-naphthalen-1 -ylmethylj-phenoxy} -ethyl)-
piperidine


Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzyI]-naphthalen-2-yl ester (1.50 g, 2.86 mmol) in 50 mL of acetonitrile and add 2,6-
difluorophenyl boronic acid (0.90 g, 5.73 mmol),
tetrakis(triphenylphosphine)pa)ladiurn(0) (0.66 g, 0.57 mmol). Next add potassium
phosphate (3.64 g, 17.16 mmol) and heat to 80 °C for one hour. Add Celite and filter.
Concentrate the solvent under vacuum to a dark oil, dissolve in methanol and purify on an
SCX cartridge, eluting with 2N ammonia/methanol. Purify further on a silica gel column
eluting with a 0-10% methanol/methylene chloride gradient. Evaporate the solvent to
yield 800 mg (58%) of the title compound.
Example 75
6-(2,6-Difluoro-phenyl)-5-[4-(2-piperidin-1-yI-ethoxy)-benzyl]-naphthalen-2-ol
hydrochloride
Dissolve l-(2-{4-[2-{2,6-difluoro-phenyl)-6-methoxy-naphthalen-1-ylmethyl]-
phenoxy}-ethyl)-piperidine (800 mg, 1.64 mmol) in 20 mL methylene chloride and cool
in an ice bath. To this solution add 2.0 mL boron tribromide (21.2 mmol) and allow to
come to room temperature. Pour into a two phase solution of saturated sodium
bicarbonate and 3/1 chloroform/isopropanol Separate the organic layer, wash with water
and dry over 3A sieves. Evaporate the solvent and purify on a silica gel column eluting
with a 0-10% methanol/methylene chloride gradient to give 670 mg (86%) of the free
base of the title compound. Dissolve the free base in a 1 :1 mixture of acetonitrile : water.
Add an appropriate amount of 5 M hydrochloric acid and lyopholize the mixture to afford
the title compound.

Example 76
l-(2-{4-[2-(2,3-Difluoro-phenyl)-6-niethoxy-naphthalen-1-ylmethyl]-phenoxy}-€thyl)-
piperidine

Using the method described in the preparation of l-(2-{4-[6-methoxy-2-(2,3,4,5-
tetrafluoro-phenyl)-naphthalen-1-ylmethyl]-phenoxy}-ethyl)-piperidine, prepare the title
compound in 49% yield: mass spectrum (ion spray) m/z = 488 (M+H).
Example 77
6-(2,3-Difluoro-phenyl)-5-[4-{2-piperidin-1 -yl-ethoxy)-benzyl]-naphthalen-2-ol
hydrochloride
Using the method described in the preparation of 5-[4-(2-piperidin-1-yl-ethoxy)-
benzyl]-6-(2,3,4,5-tetrafluoro-phenyl)-naphthalen-2-ol hydrochloride, obtain the title
compound in 39% yield: mass spectrum (ion spray) m/z = 474 (M+H).
Example 78
[6-hydroxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-
phenylj-methanone


Dissolve trifluoromethanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-
yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (10.0 g, 16.6 mmol) in degassed acetonitrile
(100 mL). Add cesium fluoride (13.0 g, 83 mmol) and
bis(acetato)bis(triphenylphosphine)palladium (1.2 g, 1.7 mmol) followed by bis(neopentyl
glyco!ato)diboron (4.5, 19.9 mmol) and plunge into a 75 °C oil bath under nitrogen. After
15 minutes, add l-bromo-2,3,5-trifluorobenzene (7.0 g, 33.2 mmol) to the reaction and
bis(acetato)bis(triphenylphosphine)palladium (500 mg) and stir at 75 °C for 2.5 hours.
Cool the reaction to room temperature and filter through celite. Concentrate the filtrate in
vacuo and redissolve the residue in methanol (100 mL). Add KOH (4 g) and stir at room
temperature overnight. Pour the reaction into saturated aqueous ammonium chloride and
extract with methylene chloride. Dry the organic layer with sodium sulfate, filter and
concentrate in vacuo. Purify on 5 SCX columns (loading with methanol and eluting with
2M NH3 in methanol) to obtain 8.4 g (100%) of the title compound. Mass spectrum (ion
spray): m/z = 506.4 (M+H).
Example79
5-{Hydroxy-[4^2^iperidin-1-yl-edioxy>-phenyl]-methyl}-6-{2,3,5-trifluoro-phenyl)-
naphthalen-2-ol
Charge a nitrogen-purged flask with (R)-(+)-a,a-diphenyl-2-pyrrolidinemethanol
(630 mg, 2.49 mmol), dissolve in 1M BHatetrahydrofuran (THF) (66 mL, 66 mmol) and
heat to 45 °C under nitrogen. Dissolve [6-hydroxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-
l-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (8.3g, 16.6 mmol) in THF (75 mL)
and add dropwise via syringe pump to the borane solution over 2.5 hours. Add
ethanolamine (20 mL, 332 mmol) slowly and heat at 45 °C for 2 hours. Pour the reaction
into saturated aqueous ammonium chloride and extract twice with methylene chloride.
Wash the combined organic layers with water, dry over sodium sulfate, filter and
concentrate. Dissolve the residue in methylene chloride (20 mL) and allow to slowly
precipitate. Collect the precipitate to yield 4.3 g (51%) of the title compound in >99% ee.
Purify the mother liquor over silica gel (eluting with 1 to 6% methanol in methylene

chloride) to yield 2.0 g (75% total yield) of the title compound in 91% ee. Mass spectrum
(ion spray): m/z = 508.3 (M+H).
Example 80
7,9-Difluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol

Dissolve 5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-6-(2,3,5-
trifluoro-phenyl)-naphthalen-2-ol (4.3 g, 3.0 mmol) in dry THF (85 mL). Add KOtBu
(2.4 g, 21.3 mmol) and stir at room temperature for 3 hours. Pour into saturated aqueous
ammonium chloride and extract twice with methylene chloride. Dry the organic layer
with sodium sulfate, filter and concentrate in vacuo to yield 3.7 g (90%) of the title
compound: mass spectrum (ion spray) m/z = 488.2 (M+H). The mixture is purified by
chiral chromatography (conditions P). The two isomers eluted with retention times of 6.9
and 8.6 minutes.
Example 81
7,9-Difluoro-5-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol hydrochloride
salt
Dissolve 7,9-difluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-
ol (1.6 g, 3.3 mmol) in methylene chloride (20 mL). Add 2M HC1 in ether (3.3 mL, 6.6
mmol) and concentrate in vacuo. Dissolve the residue in methylene chloride (5 mL) and
add dropwise to vigorously stirred ether (30 mL). Filter the precipitate and dry in a 50 °C
vacuum oven overnight to obtain 1.5 g (87%) of the title compound. Mass spectrum (ion
spray): m/z = 488.3 (M+H-HC1).

Example 82
[6-Methoxy-2-(2,4,6-trifluoro-phenyl>-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-
phenyll-methanone

Dissolve trifluoromethanesulfonic acid 6-methoxy-l -[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester (752 tng, 1.4 mmol), 2,4,6-trifluorophenylboronic acid
(493 mg, 2.8 mmol), potassium phoshate (1.8 g, 8.4 mmol)) and
tetrakis(triphenylphosphine)palladium (324 mg, 0.3 mmol) in dry dimethylformamide
(DMF, 25 mL) and heat at 100 "C for 20 minutes. Purify reaction on an SCX column to
yield 674 mg (93%) of the title compound. Mass spectrum (ion spray): m/z = 520.2
(M+H).
Alternatively, combine trifluoromethanesulfonic acid 6-methoxy-l -[4-(2-
pineridm-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (1.93 g, 3.60 mmol), cesium
fluoride (5.0 g, 33 mmol), bis(neopentyl glycolato)diboron (1.0 g, 4.4 mmol),
bis(tricyclohexylphosphine)palladium (0.50 g, 0.75 mmol) and acetonitrile (50 mL). Heat
the mixture to 90 °C for 20 minutes to obtain a dark-colored solution. Add 2-bromo-
1,3,5-trifluoro-benzene (5 g, 23.7 mmol) and heat at 90 °C for 2 hours. Add
bis(tricyclohexylphosphine)palladium (0.50 g, 0.75 mmol) and 2-bromo-l,3,5-trifIuoro-
benzene (5.0 g, 23 mmol)and heat at 90 °C for 4 hours. Cool to room temperature and
filter through a pad of celite and evaporate the solvent. Purify the residue over silica gel,
eluting the material with methanol in dichloromethane (0 to 5%), to give 1.30 g (67%) of
title compound: mass spectrum (ion spray) m/z=520.2 (M+H).

Example 83
[6-Hydroxy-2-(2,4,6-trifluoro-phenyl)-naphthalen l-yl]-[4-(2-piperidin-1-yl-ethoxy>-
phenyl]-methanone
Dissolve [6-methoxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-
l-yl-ethoxy)-phenyl]-methanone (670 mg, 1.3 mmol) in dichloromethane (10 mL). Cool
to 0 °C, add 2M HC1 (1.3 mL, 2.6 mmol) and stir at room temperature for 15 minutes.
Concentrate in vacuo. Redissolve the salt in dichloromethane (10 mL) and cool to 0 °C.
Add borontribromide (l.l g, 3.9 mmol) dropwise and bring to room temperature. Stir
reaction for 1.5 hours and pour reaction mixture onto ice, saturated sodium bicarbonate
(10 mL) and methanol (10 mL). Extract with dichloromethane, combine extracts and
wash with water and saturated sodium bicarbonate. Dry with sodium sulfate, filter, and
concentrate in vacuo. Purify by silica gel chromatography using a 1-3% gradient of
methanol in dichloromethane to yield 454 mg (70%) of the title compound. Mass
spectrum (ion spray): m/z = 506.3 (M+H).
Alternatively, dissolve [6-methoxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1-yl]-[4-
(2-piperidin-1-yl-ethoxy)-phenyl]-memanone (1.90 g, 3.67 mmol) in dichloromethane (10
ml). Add 2 M HC1 in diethyl ether (4.0 mL, 80 mmol). Concentrate the slurry and dry in
vacuo. Dilute the residue in dichloromethane (30 ml) and blanket with nitrogen. Cool the
solution to 0 °C with an external ice bath. Add boron tribromide (1 mL, 11 mmol). After
60 minutes, pour the reaction mixture into a mixture of ice (20 g), methanol (10 mL) and
saturated sodium bicarbonate solution (20 mL). Extract with dichloromethane (100 mL).
Separate the layers, wash the organic layer with brine (20 mL), dry with magnesium
sulfate, filter, and concentrate in vacuo. Purify the residue over silica gel, eluting the
material with a step gradient of methanol/dichloromethane (0 to 10%), to give 1.6 g
(87%) of the title compound: mass spectrum (ion spray) m/z=506.2 (M+H).

Example 84
5-{Hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-6-(2,4,6-trifluoro-phenyl)-
naphthalen-2-ol Hydrochloride
Dissolve [6-hydroxy-2-(2,4,6-trifluoro-phenyl)-naphthalen 1 -yl]-[4-(2-piperidin-l -
yl-ethoxy)-phenyl]-methanone (728 mg, 1.4 mmol) in THF (85 mL) and cool to 0 °C.
Add 1M lithium aluminum hydride in THF (5.8 mL, 5.8 mmol) and bring to room
temperature. Heat the reaction to reflux for 30 minutes. Cool reaction and pour onto
ice/chloroform to form a suspension. Add 6N HC1 dropwise to obtain a pH of 1. Extract
with 20% isopropyl alcohol in chloroform. Wash organic layer with brine, dry, filter, and
concentrate in vacuo to yield 730 mg (100%) of the title compound. HPLC R, (0.01%
heptafluorobutyric acid: 1.0% isopropylalcohokwater is mobile phase A and 0.01%
heptafluorobutyric acid: 1.0% isopropylalcohohacetonitrile is mobile phase B; gradient: 5
to 95% B, Purity @ 254 nm) = 2.41 (100%); mass spectrum (ion spray): m/z = 508.3
(M+H).
Alternatively, add (R)-(+)-c^«,-d'phenylprolinol (83 mg, 0.33 mmol) to a mixture
of 1M borane in THF (8 mL, 8 mmol) and THF (8 mL) at 45 °C. Dissolve [6-hydroxy-2-
(2,4,6-trifluoro^henyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-
methanone(0.83 g, 1.6 mmol) in THF (5 mL) and add to the reaction mixture over 3 hours
via a syringe pump at 45 °C. Cool to 0 °C and add 2-amino-ethanol (1.0 mL, 16 mmol)
dropwise. Heat at 45 °C for 30 minutes. Wash the mixture with water (10 mL) and extract
aqueous phase with ethyl acetate (20 mL). Combine the organic layers and wash with
brine. Dry with magnesium sulfate and concentrate in vacuo. Purify the residue over
silica gel, eluting the material with a step gradient of methanol/dichloromethane (0 to
10%), to give 804 mg (97%) of enantiomerically enriched title compound: mass spectrum
(ion spray) m/z=508.2 (M+H).

Example 85
8,10-Difluoro-5-[4-(2-piperidin-1 -yl-ethoxy)-phenyll-5H-6-oxa-chrysen-2-ol

Dissolve 5-{hydroxy-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-methyl}-6-(2,4,6-
trifluoro-phenyl)-naphthalen-2-ol hydrochloride (730 mg, 1.4 mmol) and potassium tert-
butoxide (5.36 mg, 4.8 mmol) in dry DMF (25 mL) and heat at 50 °C for 10 minutes.
Cool reaction and pour onto ice/ethyl acetate. Separate organic layer and wash with 10%
aqueous lithium chloride. Dry, filter, and concentrate in vacuo. Purify by silica gel
chromatography using a 1-6% gradient of methanol in dichloromethane to yield 532 mg
(76%) of the title compound.
Alternatively, dissolve enantiomerically enriched 5-{hydroxy-[4-(2-piperidin-1-yl-
ethoxy)-phenyl]-memyl}-6-(2,4,6-trifliK)ro-phenyl)-naphthalen-2-ol (804 mg, 1.59 mmol)
in DMF (10 mL). Add potassium te/f-butoxide (532 mg, 4.75 mmol). Heat at 50 °C for 2
minutes. Pour the reaction mixture into ice (5 g). Extract with ethyl acetate (100 mL).
Separate the layers and wash the organic layer with 10% aqueous lithium chloride
solution (20 mL x2). Dry with magnesium sulfate and concentrate in vacuo. Purify the
residue over silica gel, eluting the material with a step gradient of
methanol/dichloromethane (0 to 10%), to give the enantiomerically enriched title
compound.
Example 86
8,10-Difluoro-5-[4-(2-piperidin-l -yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol
hydrochloride salt
Dissolve 8,10-difluoro-5-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-
2-ol (532 mg, 1.1 mmol) in dichloromethane (10 mL) and add 2M HC1 (1.1 mL, 2.2
mmol) and stir for 10 minutes. Concentrate in vacuo to yield 536 mg (100%) of the title

compound. Mass spectrum (ion spray): m/z = 488 (M+H-HCI). Separate the racemate
into its constituent enantiomers by chiral chromatography. Conditions: Column: Chiralcel
OD 4.6 x 150mm; Eluent: 0.2% DMEA, 5% MeOH,)0% 3A Alcohol in Heptane.
Alternatively, dissolve enantomerically enriched free base in diethyl ether (4 mL),
ethyl acetate (1 mL) and methanol (0.5 mL) and cool to 0 °C. Add 2M HC1 in diethyl
ether (2 mL, 20 mmol). Concentrate the slurry and dry in vacuo to give enantiomerically
enriched title compound (480 mg, 58% yield): mass spectrum (ion spray) m/z=488.3 (M-
CI).
Example 87
[4-(2-Azepan-1 -yl-ethoxy)-phenyl]-[6-methoxy-2-(2,3,6-trifluoro-phenyl)-naphthalen-1 -
yl]-methanone

Couple trifluoromethanesulfonic acid l-[4-(2-azepan-1-vl-ethoxy)-benzoyi]-6-
methoxynaphthalen-2-yl ester (1.48 g, 2.67 mmol) with 2-bromo-l,3,4-trifluoro-benzene
(1.13 g, 5.35 mmol) in a procedure similar to the preparation of [6-hydroxy-2-(2,3,5-
trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanoneto
give 660 mg (46%) of the title compound: mass spectrum (ion spray): m/z = 534.4
(M+H).
Example 88
[4-(2-Azepan-1-yl-ethoxy)-phenyl]-[6-hydroxy-2-(2,3,6-trifluoro-phenyl)-naphthalen-1-
yl]-methanone
Demethylate [4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-methoxy-2-(2,3,6-trifluoro-
phenyl)-naphthalen-1-yl]-methanone (0.66 g, 1.24 mmol) with BBr3 in a procedure
similar to the preparation of [6-hydroxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-

piperidin-1-yl-ethoxy)-phenyll-methanone to give 530 mg (82%) of the title compound.
Mass spectrum (ion spray): m/z = 520.3 (M+H-HC1).
Example 89
5-[4-(2-Azepan-1-yl-ethoxy)-phenyl]-7,10-difluoro-5H-6-oxa-chrysen-2-oI hydrochloride
salt

Dissolve [4-(2-azepan-1 -yl-ethoxy)-phenyl]-[6-hydroxy-2-(2,3,6-trifluoro-phenyl)-
naphthalen-1-yl]-methanone (529 mg, 1.02 mmol) in dioxane (205 mL). Flush the flask
with N2, then add LiBHEt3 (4.1 mL, 4.1 mmol, 1.0 M in THF). Stir the reaction at room
temperature for one hour then heat the reaction to 100 °C. Continue to heat the reaction
for 4 hours men cool it to room temperature. Add saturated NH4CI solution (200 mL) and
extract the aqueous layer with CH2CI2 (3 x 200 mL). Combine the organic layers and dry
with Na2S04l filter, concentrate and purify by flash column chromatography (silica gel, 2-
8% methanol (MeOH)-NH40H (10/1, v/v)/ CH2C12) to give 401 mg (79%) of product.
Dissolve the above product (401 mg, 0.80 mmol) in CH2C12 (8 mL), and cool it to -78°C.
Add HC1 (0.8 mL, 2.0 M in Et20), and stir the solution for 10 minutes. Remove the
solvent under reduced pressure. Dry the resulting solid at 40 °C, overnight, in vacuo to
give 432 mg (100%) of the title compound. Mass spectrum (ion spray): m/z = 502.3
(M+H-HC1).
Example 90
[6-Methoxy-2-(2,3,6-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-
phenyll-methanone


Couple trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester (1.81 g, 3.37 mmol) with 2-bromo-l,3,4-trifluoro-benzene
(1.42 g, 6.75 mmol) in a procedure similar to the preparation of [6-hydroxy-2-(2,3,5-
trifluoro-phenyl)-naphthalen-l -yl]-[4-(2-piperidin-l -yl-ethoxy)-phenyl]-methanone to
give 0.79 g (45%) of the title compound: mass spectrum (ion spray): m/z = 520.3 (M+l).
Example 91
[6-Hydroxy-2-(2,3,6-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-
phenyfj-methanone
Dememylate [6-methoxy-2-(23,6-trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-memanone (0.79 g, 1.52 mmol) with BBr3 in a procedure
similar to the preparation of [6-hydroxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-methanone to give 0.67 g (88%) of the title compound:
mass spectrum (ion spray): m/z = 506.3 (M+H).
Example 92
5-{Hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyi}-6-(2,3,5-trifluoro-phenyl)-
naphthalen-2-ol
Add (R)-(+)-o;a-diphenyl-2-pyrroiidinemethanol (0.06 g, 0.24 mmol) to a
solution of BH3THF (6.0 mL, 6.0 mmol, 1.0 M in THF) in THF (10 mL) under a slow N2
purge with stirring. Heat the solution to 45 °C. Add dropwise a solution of [6-hydroxy-2-
(2,3,6-trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-methanone
(0.60g, 1.20 mmol) in dry THF (25 mL) with syringe pump over 1.5 hours at 45 °C.
Continue to heat the reaction for another hour at 45 °C then cool it to room temperature.

Add ethanolamine (0.66 g, 10.8 mmol), and continue to stir the mixture over night. Add
water (200 mL) and extract the aqueous layer with CH2C12 (3 x 200 mL). Combine the
organic layers and dry with Na2S04, filter, concentrate and purify by flash column
chromatography (silica gel, 2-8% MeOH-NH4OH (10/1, v/v)/ CH2CI2) to give 0.58 g
(96%) of the title compound.
Example 93
7,10-Difluoro-5-[4-(2-piperidin-l -yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol
hydrochloride

Dissolve 5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-6-{2,3,5-
trifluoro-phenyl)-naphthalen-2-ol (0.58 g, 1.14 mmol) in dry DMF (20 mL). Add t-BuOK
(0.39 g, 3.43 mmol) with stirring. Flush the flask with N2, then heat the reaction mixture
to 50 °C. Continue to heat the reaction mixture for 20 minutes then cool it to room
temperature. Add saturated NH4CI solution (100 mL), and extract the aqueous layer with
CH2CI2 (3 x 100 mL). Combine the organic layers and dry with Na2S04, filter,
concentrate and purify by flash column chromatography (silica gel, 2-8% MeOH-NFLOH
(10/1, v/v)/ CH2C12) to give 0.56 g (99%) of the free base of title compound. Dissolve the
free base (0.56 g, 1.14 mmol) in CH2C12 (10 mL), and cool it to -78 °C. Add HCl (1.20
mL, 2.0 M in Et20), and stir the solution for 10 minutes. Remove the solvent under
reduced pressure. Dry the solid at 40 °C, overnight, in vacuo to give 0.60 g (100%) of the
title compound: mass spectrum (ion spray) m/z = 488.2 (M-Cl).

Preparation 12
3,5-Difluoro-2-methylsulfanyl-benzene boronic acid

Dissolve 2-bromo-4,6-difluoroaniline (40 g, 192 mmol) in methyldisulfide (250
mL) and heat to 75 °C under nitrogen. Add isoamyl nitrite (67 mL, 500 mmol) dropwise
via an addition funnel trough a reflux condenser (~1 drop/sec). Large exotherm may
occur if addition is too fast. After addition is complete, heat the reaction to 95 °C for 1
hour and cool to room temperature and concentrate in vacuo. Purify dark brown residue
via silica gel chromatography eluting with hexanes to yield 30.3 g of l-bromo-3,5-
difluoro-2-methylsulfanyl-benzene (66%).
Charge a flask with isopropyl magnesium chloride (145 mL, 2M in THF, 290
mmol) and dilute with tetrahydrofuran (150 mL) and heat to 40 °C under nitrogen. Add
l-bromo-3,5-difluoro-2-methylsulfanyl-benzene (28 g, 117 mmol) slowly over 5 minutes.
After 30 minutes, cool the reaction to 0 °C and add trimethylborate (46 mL, 410 mmol)
diluted with tetrahydrofuran (100 mL) via an addition funnel over 5 minutes. Partition the
resulting gelatinous mixture between methylene chloride and IN HC1. Acidify the
aqueous layer to pH~l (if needed) and vigorously stir the biphasic mixture until all solids
are dissolved. Separate the organic layer. Dry over sodium sulfate, filter and concentrate.
Triturate with hexanes and filter to yield 14.7 g (61%) of the title compound.
Example 94
Methanesulfonic acid 6-(3,5-difluoro-2-methylsulfanyl-phenyl)-5-[4-(2-piperidin-l -yl-
ethoxy)-benzoyl]-naphthalen-2-yl ester


Charge a flask with trifluoromethanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-
piperidin-1-yI-ethoxy)-benzoyl]-naphthalen-2-yl ester (8.8 g, 14.6 mmol) and 3,5-
difluoro-2-methylsulfanyl-benzene boronic acid (9.0 g, 42 mmol) and flush with nitrogen.
Dissolve solids in degassed dioxane (240 mL). Add 2M sodium carbonate (120 mL) and
Pd(PPh3)4 (6.7 g, 5.9 mmol). Plunge into 110 °C oil bath and stir vigorously. After 30
minutes, cool the reaction to room temperature and filter off solids. Partition the filtrate
between water and methylene chloride. Wash the organic layer with water twice, dry over
sodium sulfate, filter and concentrate. Purify the residue over silica gel, eluting with 1 to
2% methanol in methylene chloride, to yield 8.0 g (90%) of the title compound. LCMS
Rt (0.01% heptafluorobutyric acid: 1.0% isopropylalcohol:water is mobile phase A and
0.01% heptafluorobutyric acid:1.0% isopropylalcohol:acetonitrile is mobile phase B;
gradient method 25 to 95% B, Purity @ 254 nm) = 3.18 min (99%); mass spectrum (ion
spray): m/z = 612.3 (M+H).
Example 95
Methanesulfonic acid 6-(3,5-difluoro-2-methylsulfanyl-phenyl)-5-{hydroxy-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-methyl}-naphtnalen-2-yl ester
Charge a flask with (S)-a,a-diphenyl-2-pyrrolidinemethanol (253 mg, 1.0 mmol)
and purge flask with nitrogen. Dilute with 1M borane in THF (43 mL, 43 mmol) and heat
to 45 °C under nitrogen. Dissolve methanesulfonic acid 6-(3,5-difluoro-2-methylsulfanyl-
phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (6.5g, 10.6 mmol)
in THF (40 mL) and add to the catalyst solution via syringe pump over 2 hours. After
complete addition, add ethanolamine (12.8 mL, 212 mmol) slowly and heat at 45 °C for 3
hours. Cool the reaction to room temperature and pour into saturated aqueous ammonium
chloride. Extract with methylene chloride, dry over sodium sulfate, filter and concentrate.
Purify over silica gel eluting with 3% methanol in methylene chloride to yield 7.4 g (93%)
of the title compound (60:40 mixture of diastereomers). LCMS Rt (0.01%
heptafluorobutyric acid:1.0% isopropylalcohol:water is mobile phase A and 0.01%
heptafluorobutyric acid: 1.0% isopropylalcohol:acetonitrile is mobile phase B; gradient
method 25 to 95% B, Purity @ 254 nm) = 2.91 and 2.94 min (100%); mass spectrum (ion
spray): m/z = 614.2 (M+H).

Example 96
Methanesulfonic acid 7,9-difluoro-5-[4-(2-piperidin-l -yl-ethoxy)-phenyl]-5H-6-thia-
chrysen-2-yl ester

Dissolve methanesulfonic acid 6-(3,5-difluoro-2-methylsulfanyl-phenyl)-5-
{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-naphthalen-2-yl ester (7.4 g, 12
mmol) in dry methylene chloride (200 mL) and purge with nitrogen. Add triethylamine
(8.3 mL, 60 mmol) followed by methanesulfonyl chloride (4.6 mL, 60 mmol). After 30
minutes, pour reaction into water and extract with methylene chloride. Wash organic
layer with water, dry over sodium sulfate, filter and concentrate. Purify over silica gel,
eluting with 0 to 3% methanol in methylene chloride, to yield 5.2 g (74%) of the title
compound. LCMS Rt (0.01% heptafluorobutyric acid: 1.0% isopropylalcohol:water is
mobile phase A and 0.01% heptafluorobutyric acid: 1.0% isopropylalcohokacetonitrile is
mobile phase B; gradient method 25 to 95% B, Purity @ 254 run) = 3.34 min (100%);
mass spectrum (ion spray): m/z = 582.2 (M+H).
Example 97
7,9-Difluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-thia-chrysen-2-ol hydrochloride
salt
Dissolve methanesulfonic acid 7,9-difluoro-5-[4-(2-piperidin-1-yl-etiioxy)-
phenyl]-5H-6-thia-chrysen-2-yl ester (5.2 g, 9.0 mmol) in methanol (150 mL). Add
potassium hydroxide (5.0 g, 90 mmol) and stir at room temperature. After 4 hours pour
into saturated aqueous ammonium chloride and extract with methylene chloride. Dry
over sodium sulfate, filter and concentrate. Dissolve residue in methylene chloride (90
mL) and add 2M HC1 in ether (9 mL, 18 mmol). Concentrate in vacuo to yield 4.8 g
(99%) of the title compound. LCMS R, (0.01% heptafluorobutyric acid: 1.0%

isopropylalcohol:water is mobile phase A and 0.01% heptafiuorobutyric acid: 1.0%
isopropylalcohohacetonitrile is mobile phase B; gradient method 15 to 95% B, Purity @
254 nm) = 3.21 min (100%); mass spectrum (ion spray): m/z = 504.3 (M+H). Chiral
HPLC: 87%.
Preparation 13
2-Methylsulfanyl-4-fluoro-benzene boronic acid

Dissolve 2-bromo-5-fluoroaniline (25g, 131 mmol) in methyldisulfide (220 mL)
and heat to 75 °C under nitrogen. Add isoamyl nitrite (46 mL, 342 mmol) drop wise via
an addition funnel trough a reflux condenser (~1 drop/sec). Large exotherm may occur if
addition is too fast. After addition is complete heat the reaction to 95 °C for 1 hour and
cool to room temperature and concentrate in vacuo. Purify residue twice via silica gel
chromatography eluting with hexanes to yield 22 g of l-bromo-4-fluoro-2-methylsulfanyl-
benzene (76%).
Dissolve l-bromo-4-fluoro-2-methylsulfanyl-benzene (22 g, 99.6 mmol) in dry
THF (500 mL) and cool to -78 °C under nitrogen. Add butyl lithium (2.5M in hexanes,
48 mL, 120 mmol) slowly and stir for 10 minutes after complete addition. Add trimethyl
borate (22 mL, 200 mmol) and warm to room temperature. Pour into 0.1 M NaOH and
extract with ether. Acidify the aqueous layer to pH 2 with concentrated HC1. Extract
with ether, rry the organic layer with sodium sulfate, filter and concentrate in vacuo to
yield 15.4 g (83%) of the title compound.

Example 98
Methanesulfonic acid 6-(4-fluoro-2-methylsulfanyl-phenyl)-5-[4-(2-piperidin-1-yl-
ethoxy)-benzoyl]-naphthalen-2-yl ester

Charge a flask with trifluoromethanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-
piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (10.0 g, 16.6 mmol), 2-
methylsulfanyl-4-fluoro-benzene boronic acid (7.7 g, 41.6 mmol), palladium acetate (371
mg, 1.66 mmol), tricyclohexylphosphine (700 mg, 2.5 mmol) and cesium fluoride (13 g,
83 mmol) and purge with nitrogen. Dilute with degassed acetonitrile (ISO mL) and
plunge into an 80 °C oil bath. Cool to room temperature after 1.5 hours and filter through
celite and concentrate in vacuo. Partition the residue between methylene chloride and
saturate aqueous sodium bicarbonate. Dry the organic layer with sodium sulfate, filter
and concentrate. Purify the residue over a silica gel column, editing with 2% methanol in
methylene chloride, to yield 9.0 g (92%) of the title compound. LCMS R, (0.01%
heptafluorobutyric acid: 1.0% isopropylalcohoi:water is mobile phase A and 0.01%
heptafluorobutyric acid: 1.0% isopropylalcohoi:acetonitrile is mobile phase B; gradient
method 25 to 95% B, Purity @ 254 ran) = 2.92 min (95%); mass spectrum (ion spray):
m/z = 594.3 (M+H).
Example 99
Methanesulfonic acid 8-fluoro-5-t4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-thia-chrysen-
2-yl ester


Charge a flask with (s)-(-)-a,a-diphenyl-2-pyrrolidinemethanol (380 mg, 1.5
mmol), dissolve with 1M borane in THF (60 mL, 60 mmol), purge with nitrogen and heat
to 45 °C. Dissolve methanesulfonic acid 6-(4-fluoro-2-methylsulfanyl-phenyl)-5-[4-(2-
piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (9.0 g, 15.1 mmol) in dry THF (80
mL) and add to the borane solution via syringe pump over 2 hours. After the addition is
complete, add ethanolamine (18.2 mL, 300 mmol) and stir at 45 °C for 3 hours. Pour the
reaction into saturated aqueous ammonium chloride and extract with methylene chloride.
Dry over sodium sulfate, filter and concentrate to a beige foam. Dissolve the crude foam
in dry THF (150 mL). Add triethylamine (12.4 mL, 90 mmol) and methanesulfonyl
chloride (7.0 mL, 90 mmol) and heat to reflux under nitrogen. Add more
methanesulfonyl chloride (0.45 mL, 5.8 mmol) after 2 hours to drive the reaction to
completion. Pour the reaction into saturated aqueous sodium bicarbonate and extract
twice with methylene chloride. Dry the combined organic layers with sodium sulfate,
fitter and concentrate. Purify the residue on silica gel (0% to 4% methanol in methylene
chloride) to yield 7.5 g (88%) of the title compound. HPLC R» (0.01% heptafluorobutyric
acid: 1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric
acid: 1.0% isopropylalcohohacetonitrile is mobile phase B; gradient method 25 to 95% B,
Purity @ 254 nm) = 2.96 min (100%); mass spectrum (ion spray): m/z = 564.3 (M+H).
Example 100
8-Fluoro-5-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-5H-6-thia-chrysen-2-ol hydrochloride
Dissolve methanesulfonic acid 8-fiuoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-
5H-6-thia-chrysen-2-yl ester (7.5 g, 13.3 mmol) in methanol (130 mL), add potassium
hydroxide (7.5g, 133 mmol) and stir at room temperature over night. Pour the reaction
into saturated aqueous ammonium chloride and extract with methylene chloride. Dry
organic layer with sodium sulfate, filter and concentrate in vacuo. Dissolve the resultant
residue in methylene chloride (50 mL) and add 2M HC1 in ether (10 mL). Remove the
solvent in vacuo and redissolve in methylene chloride (10 mL). Add slowly to vigorously
stirred ether. Collect the resulting precipitate and place in a 50 °C vacuum oven overnight
to yield 5.7 g (82%) of the title compound. HPLC R, (0.01% heptafluorobutyric
acid:1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric

acid: 1.0% isopropylalcohohacetonitrile is mobile phase B; gradient method 30 to 95% B,
Purity @ 254 nm) = 2.06 min (100%); mass spectrum (ion spray): m/z = 486.3 (M-CI).
Chiral HPLC: 84%ee.
Example 101
[6-Benzyloxy-2-(2,4-difluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone

Add trifluoromethanesulfonic acid 6-benzyloxy-1-[4-{2-piperidin-1-yl-ethoxy>-
benzoyl]-naphmalen-2-yl ester (0.45 g, 0.73 mmol), bis(neopentyl glycolato)diboron (0.18
g, 0.81 mmol), bis(tricyclohexylphosphine)palladium(0) (0.098 g, 0.15 mmol) and
acetonitrile (7.5 mL) to a round bottom flask. Stir at ambient temperature for
approximately 5 minutes to dissolve most of the reagents. Add cesium fluoride (1.00 g,
6.61 mmol), place the flask in a 90 °C oil bath, and stir under nitrogen for 2-3 minutes.
Now add 1-bromo-2,4-difluorobenzene (0.174 mL, 1.54 mmol) and stir for 20 minutes.
At this time add more l-bromo-2,4-difluorobenzene (0.06 mL, 0.53 mmol) and continue
stirring the reaction for 2 hours at 90°C. At this time add more 1 -bromo-2,4-
difluorobenzene (0.05 mL, 0.44 mmol) and continue stirring for another 2 hours. Cool
the reaction to ambient temperature and then filter it through a pad of Celite. Rinse the
pad with ample, hot ethyl acetate. Wash the filtrate in a separatory funnel with 50%
aqueous sodium carbonate, saturated aqueous ammonium chloride, H2O and brine; then
dry (sodium sulfate) and evaporate it in vacuo. Load resulting material onto an SCX
column, wash with dichloromethane, 50% dichloromethane/methanol, elute with
ammonia solution (2N NH3 in methanol) and remove solvent under vacuum. Purify the
resulting residue by flash chromatography (silica gel; 1.5%-3% methanol gradient in
dichloromethane) to provide 0.245 g (58%) of the title compound: mass spectrum (ion
spray) m/z = 578 (M+H).

Example 102
[2-(2,4-Difluoro-phenyl)-6-methoxy-naphtha]en-1-yl]-[4-(2-piperidin-1-yl-ethoxy>-
phenyl]-methanone
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester (12.4g, 23.0 mmol) and 2,4-difluorophenylboronic acid
(7.0 g, 46.0 mmol) in degassed dimethoxyethane (620 mL). Add 2M aqueous sodium
carbonate (73 mL, 145 mmol) and stir at room temperature under nitrogen for 5 minutes.
Add palladium(II) acetate (520 mg, 2.3 mmol) and triphenylphosphine (1.2 g, 4.6 mmol)
and plunge into a 85 °C oil bath. Stir for-40 minutes and cool to room temperature. Pour
into saturated aqueous sodium bicarbonate and extract twice with methylene chloride.
Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo.
Purify the resultant oil with SCX columns (load in methanol, elute with 2M NH3/MeOH)
to yield 10.8 g (93%) of the title compound: mass spectrum (ion spray) m/z = 502.3
(M+H).
Example 103
[2^2,4^ifluoro-phenyI)-6-hydroxy-naphthaIen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-
phenyl |-methanone
Dissolve [2-(2,4-difluoro-phenyl)-6-methoxynaphthalen-1-yl]-[4-(2-piperidin-1-
yl-ethoxy)-phenyl]-methanone (10.8 g, 21.5 mmol) in methylene chloride (200 mL). Add
2M HC1 in ether (21.5 mL, 43 mmol) and concentrate in vacuo. Redissolve the foam in
methylene chloride (200 mL) and cool to 0 °C under nitrogen. Slowly add boron
tribromide (10.1 mL, 107 mmol) and stir at 0 °C for 30 minutes. Slowly pour into
saturated aqueous sodium bicarbonate and extract with 20% IPA in chloroform. Dry the
organic layer with sodium sulfate, filter and concentrate in vacuo to yield 10.5 g (100%)
of the title compound.

Example 104
naphthalen-2-ol
Disslove [2-{2,4-difluoro-phenyl)-6-hydroxy-naphthalen-1 -yl]-[4-(2-piperidin-l -
yl-ethoxy)-phenyl]-methanone (3.3 g, 6.8 mmol) in dry THF (100 mL) and stir under
nitrogen. Slowly add lithium aluminum hydride (0.9 g, 24 mmol) and heat to reflux.
Cool to room temperature after 30 minutes and quench excess LiAlH4 with slow addition
of ice. Dilute with water and adjust the pH to 7 with 1M HC1. Extract five times with
20% IPA in chloroform. Dry the combined organic layers with sodium sulfate, filter and
concentrate in vacuo to yield 3.4 g (100%) of the title compound.
Example 105
8-Fluoro-5-[4-{2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol

Dissolve 6-(2,4-difluoro-phenyl)-5-{hydroxy-[4-(2-piperidin-l -yl-ethoxy)-
phenyl]-methyl}-naphthalen-2-ol (3.4g, 7.0 mmol) in dry DMF (70 mL). Slowly add
sodium hydride (440 mg, 18 mmol) and plunge into a 140 °C oil bath for 30 minutes.
Cool to room temperature and pour into water. Adjust the pH to 7 and extract three times
with methylene chloride. Wash combined organic layers with water, dry with sodium
sulfate, filter and concentratel. Triturate with ether to yield 2.2 g (69%) of the title
compound: mass spectrum (ion spray) m/z = 470.3 (M+H).

Example 106
[2-(2,6-Difluoro-phenyl)-6-methoxy-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone

Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-
yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.0 g, 3.7 mmol), 2,6-difluorophenyl boronic
acid (1.17 g, 7.4 mmol), tetrakis(triphenylphosphine)palladium (0) (855 mg, 0.74 mmol)
and potassium phosphate (4.7 g, 22.2 mmol) add 100 mL of dry DMF and heat under
nitrogen at 100 °C for two hours. Cool the reaction and filter. Purify on an SCX column
eluting with 2N ammonia/methanol. Purify further on a silica gel column eluting with a
gradient of 0-10% methanol/methylene chloride. The yield is 1.5 g (81 %). 1H-NMR
(CDCI3,400 MHz) £7.90 (d, J = 8.4 Hz, 1H); 7.63 (d, J = 8.4 Hz, 1H); 7.62 (d, J = 9.2
Hz, 2H); 7.39 (d, J = 8.4 Hz, 1H); 7.23 (d, J = 2.8 Hz, 1H); 7.18-7.08 (m, 2H); 6.78 (d, J
= 10.4 Hz, 2H); 6.74 (s, 2H); 4.11-4.08 (m, 2H); 3.95 (s, 3H); 2.75 (t, J = 6.4 Hz, 2H);
2.49-2.49 (m, 4H); 1.63-1.58 (m, 4H); 1.47-1.44 (m, 2H).
Example 107
[2-(2,6-Difluoro-phenyl)-6-hydroxy-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone
Dissolve [2-(2,6-difluorophenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-
ylethoxy)-phenyl]-methanone (1.5 g, 3.0 mmol) in 500 mL methylene chloride and chill
in ice. To this solution add boron tribromide (6.0 mL, 63 mmol) in portions with swirling
between additions. Allow to come to room temperature and stir for one hour. Pour into a
two-phase system consisting of an organic layer of 3/1 chloroform/isopropanol and an
aqueous layer of saturated sodium bicarbonate. Separate the phases and dry the organic

layer using 3A molecular sieves. Purify on a silica column eluting with a 0-10%
methanol/methylene chloride gradient to give 600 mg (44%) of the title compound.
Example 108
10-Fluoro-5-[4-(2-piperidin-l -yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol hydrochloride

Charge a flask with 100 mL of dioxane and add 1 M borane-THF (5.0 mL, 5.0
mmol) under nitrogen followed by R-Methyl CBS reagent (51 mg, 0.18 mmol) and heat
the mixture to 45 °C. Prepare a solution of [2-(2,6-difluoro-phenyl)-6-hydroxy-
naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyI]-methanone (580 mg, 1.19 mmol) in
200 mL dioxane and add this to the reaction mixture dropwise over one hour. Monitor
the reaction by LC/MS and continue heating until complete (about two hours). Add to
this reaction 20 mL of 1.0 M lithium triethylborohydride and heat at 95 °C for 24 hours or
until reaction is complete by LC/MS. Cool the reaction and quench with isopropanol.
Evaporate the solvent and partition between a 3/1 mixture of chloroform/isopropanol and
saturated sodium bicarbonate. Separate the organic layer and dry over 3 A molecular
sieves. Purify on a silica gel column eluting with a 0-10% methanol/methylene chloride
gradient. The yield is 460 mg (82%). Convert to HC1 salt: 1H-NMR (Free base CD3OD,
400 MHz) £8.11 (d, J = 8.8 Hz, 1H); 7.71 (d, J = 8.8 Hz, 1H); 7.57 (d, J = 9.2 Hz, 1H);
7.17 (d, J = 2.8 Hz, 1H); 7.02-6.89 (m, 5H); 6.67-6.57 (m, 4H); 3.84-3.79 (t, 2H); 2.56 (t,
J = 6.0 Hz, 2H); 2.36-2.36 (m, 4H); 1.52-1.46 (m, 4H); 1.37-1.35 (m, 2H).

Example 109
[2-(2,3-Difluoro-phenyl)-6-methoxy-naphthalen-l -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone

Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-
yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.0 g, 3.7 mmol), 2,3 difluorophenyl boronic
acid (1.17 g, 7.4 mmol) palladium dichloride bis(triphenylphosphine) (518 mg, 0.74
mmol) and cesium fluoride (5.06 g, 33.3 mmol) and add 250 mL degassed acetonitrile.
Heat the mixture at 85 °C for two hours, cool the reaction and filter off any solids. Purify
on an SCX column eluting with 2N ammonia/methanoi. Purify further on a silica gel
column eluting with a 0-10% methanol/methylene chloride gradient to give 1.3 g (70%) of
the title compound: 1H-NMR (CDjOD, 400 MHz) 57.92 (d, J = 8.8 Hz, 1H); 7.54 (dd, J
= 8.4,4.0 Hz, 3H); 7.43 (dd, J = 8.4,1.6 Hz, 1H); 7.31 (d, J = 2.8 Hz, 1H); 7.09 (dd, J =
9.2,2.4 Hz, 1H); 7.05-6.92 (m, 3H); 6.79 (d, J = 8.8 Hz, 2H); 4.10 (t, J = 5.6 Hz, 2H);
3.93 (s, 3H); 2.73 (t, J = 5.2 Hz, 2H); 2.50-2.50 (m, 4H); 1.62-1.57 (m, 4H); 1.48-1.43 (m,
2H).
Example 110
[2-(2,3-Difluoro-phenyl)-6-hydroxy-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone
Charge a flask with [2-(2,3-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-methanone (1.3 g, 2.6 mmol) and add 200 mL methylene
chloride followed by 25 mL of HC1 in ether (1 M) and evaporate to dryness. Dissolve the
solid in 200 mL methylene chloride and chill the solution in ice. Add to this solution
boron tribromide (4.0 mL, 42.4 mmol) with swirling. Stir the dark solution at room
temperature for 1 hour at which point all the starting material is gone. Pour this into a

two phase mixture consisting of saturated sodium bicarbonate aqueous phase and a 3/1
mixture of chloroform/isopropanol organic phase and extract using a separatory funnel.
Separate the organic phase and dry over 3A molecular sieves. Purify on a silica column
eluting with 0-10% methanol/methylene chloride, collecting the first fraction that contains
the product to give 400 mg of the title compound (32%).
Example 111
7-Fluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-oI hydrochloride

Charge a flask with R-methyl CBS reagent (50 m, 0.18 mmol) dissolved in 100
mL dioxane and warm to 45 °C. Dissolve [2-(2,3-difluoro-phenyl)-6-hydroxy-
naphthalcn-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (400 mg, 0.82 mmol) in
100 mL of dioxane and add dropwise to the reaction mixture over a two hour period.
Continue heating at 45 "C under nitrogen overnight and add lithium triethylborohydride
(15 mL of 1.0 M solution in THF, 15 mmol) and heat reaction to 100 °C for 24 hours.
Cool the reaction mixture and add 25 mL of isopropanol to quench the reaction.
Evaporate the reaction to an oil and add saturated sodium bicarbonate and a 3/1 mixture
of chloroform/isopropanol. Extract in a separatory funnel and remove the organic layer.
Dry the organic layer over 3A molecular sieves, evaporate to a paste and purify on a silica
column eluting with 0-10% methanol/methylene chloride. Convert the isolated product to
the HC1 salt using HC1 in ether to give 145 mg (35%) of the title compound. The two
enantiomers are separated using chiral chromatography (Conditions D). The preferred
isomer eluted second with a retention time of 16.5 minutes (98 mgs).

Example 112
[2-(2,5-Difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-
phenyl]-methanone

Add trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester (552 mg, 1.0 mmol), 2,6-difluorophenyl boronic acid (320
mg, 2.0 mmol), trans dichlorobis(triphenylphosphine)palladiurn II (70 mg, 0.1 mmol) and
cesium fluoride (1.3 g, 8.6 mmol) to a 20 mL vial along with 8.0 mL degassed
acetonitrile. Seal the vial with a septum and purge with nitrogen gas. Heat the mixture
with stirring at 80 °C for three hours. Cool, filter and purify on an SCX column, eluting
with 2N ammonia/methanol. The compound is further purified on a silica gel column,
eluting with a 0-5% 2N ammonia in methanol/methylene chloride gradient. The yield is
260mg(50%).
Example 113
[2-(2,5-Difluorophenyl)-6-hydroxynaphthalen-l -yl]-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-
methanone
Convert [2-(2,5-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-
yl-ethoxy)-phenyl]-methanone (1.8 g, 3.5 mmol) to the hydrochloride salt and dissolve it
in 300 mL methylene chloride. Chill the mixture in ice and slowly add boron tribromide
(5.0 mL, 53.0 mmol) with swirling. Allow the mixture to come to room temperature and
stir for two hours. Add to this mixture acetonitrile (15 mL) slowly and with stirring
which produces an orange precipitate. Pour the mixture into saturated sodium
bicarbonate with stirring, separate the organic layer and dry with molecular sieves to give
1.5 g of the title compound (86%).

Example i 14
9-Fluoro-5-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol hydrochloride

Charge a flask with (R)-(+)-a, a, diphenylprolinol (76.2 mg, 0.3 mmol) dissolved
in a mixture of 24 mL of a 1.0 M solution of borane/THF and 500 mL THF and heat to 45
°C. Add to this, via syringe pump over 8 hours, a solution of [2-(2,5-difluorophenyl)-6-
hydroxynaphthalen-1-yl]-[4-{2-piperidin-1-yl-ethoxy)-phenyl]-methanone (1.5 g, 3.0
mmol) dissolved in 100 mL THF. Continue heating for two hours after complete addition
and add 6.0 grams of potassium r-butoxide, and continue heating for two hours, then raise
the temperature to 60 °C and heat for another five hours. Quench the reaction by
cautiously adding saturated sodium bicarbonate solution. Evaporate most of the organic
layer under vacuum and add a 3/1 mixture of chloroform/isopropanol and extract in a
separatory funnel. Separate the layers and dry the organic layer over 3A molecular sieves.
Evaporate the solvent to yield 1.0 g of impure product. Purify on a silica gel column
eluting with 1.5% 2N ammonia/methanol/methylene chloride to give 620 mg (43%) of a
product mixture that contained both enantiomers. The enantiomers are further purified
and separated on a chiral column using a ChiralPak AD column, 4.6 X 250 mm using an
eluent of 100 % ethanol containing 0.2 % dimethylethylamine and a flow rate of 1.0
ml/min. The preferred isomer (the 2nd to elute) is converted to the HC1 salt yielding 330
mg of final product (23%).

Example 115
[6-Methoxy-2-(2,3,4-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-
phenyl]-methanone

Charge a round bottom flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-
(2-piperidin-1-yl-ethoxy)-beri2oyl]-naphthalen-2-yl ester (2.13 g, 4.0 mmol), 2,3,4-
trifluorophenyl boronic acid (1.0 g, 5.7 mmol), trans-
dichlorobis(triphenylphosphine)palladium II, (561 mg, 0.8 mmol) and cesium fluoride
(5.5 g, 36 mmol) and add 50 mL of acetonitrile. Heat the mixture at 80 °C for 4 hours.
Cool and filter the mixture and purify on an SCX column, eluting with 2N
ammonia/methanoi. Purify further on a silica column eluting with 2% 2N
ammonia/methanol/methylene chloride. The yield is 880 mg (43%): 1H-NMR (CD30D,
400 MHz) £7.93 (d, J = 8.8Hz, 1H); 7.50 (d, J = 8.4 Hz, 3H); 7.39 (d, J = 8.8 Hz, 1H);
7.35 (d, J = 2.4 Hz, 1H); 7.07 (dd, J = 9.2,2.8 Hz, 1H); 6.96-6.87 (m, 2H); 6.80 (d, J =
9.6 Hz, 2H); 4.10-4.07 (t, 2H); 3.91 (s, 3H); 2.72-2.69 (t, 2H); 2.48-2.48 (m, 4H); 1.61-
1.55 (m, 4H); 1.46-1.43 (m, 2H).
Example 116
[6-hydroxy-2-(2,3,4-trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-ethoxy)-
phenyl]-methanone
Dissolve [6-methoxy-2-(2,3,4-trifluoro-phenyl)-naphthalen-1 -yl]-[4-(2-piperidin-
l-yl-ethoxy)-phenyl]-methanone (880 mg, 1.69 mmol) in 100 mL methylene chloride and
chill in ice. Add 4.0 mL of neat boron tribromide with swirling and stir in the ice bath for
30 minutes. Allow the mixture to come to room temperature and stir for an additional 1
hour. Carefully pour the mixture into a two-phase system consisting of saturated sodium
bicarbonate solution and a 3/1 mixture of chloroform/isopropanol. Separate the organic

layer, dry over 3 A molecular sieves and evaporate to give 800 mg of slightly impure
product. Purify on a silica gel column eluting with 3% methanol/methylene chloride to
give 635 mg (74%) of the title compound.
Example 117
7,8-Difluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol
hydrochloride

Charge a flask with [6-hydroxy-2-(2,3,4-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-methanone (620 mg, 1.23 mmol) and add 250 mL
dioxanc. Start stirring and add to this 20 mL of a 1.0 M solution of lithium
triethylborohydride in THF at room temperature. Stopper flask and stir for one hour.
Heat the flask to 90 "C under nitrogen and follow reaction by LC/MS. Heat the reaction
for a total of 18 hours. Pour the reaction into 300 mL of a mixture of 3/1
chloroform/isopropanol and 300 mL of saturated sodium bicarbonate solution. Separate
the organic layer and dry over 3A molecular sieves. Evaporate to dryness and purify on a
silica gel column eluting with 3% methanol/methylene chloride. Evaporate and convert to
the hydrochloride salt using acetonitrile/water with IN HC1 and lyophilize. The yield is
295 mg (46%). 1H-NMR (CD3OD, 400 MHz) £7.90-7.87 (m, 1H); 7.79 (d, J = 8.8 Hz,
1H); 7.65 (d, J = 8.8 Hz, 1H); 7.59-7.55 (m, 1H); 7.19 (d, J = 2.4 Hz, 1H); 7.11-7.05 (m,
3H); 6.88-6.83 (m, 1H); 6.81-6.75 (m, 2H); 4.10-4.07 (m, 2H); 2.93-2.91 (m, 2H); 2.71-
2.71 (m, 4H); 1.67-1.63 (m, 4H); 1.51-1.50 (m, 2H). The racemic compound is purified
using chiral chromatography using chiral chromatography (conditions 0). The two
isomers eluted with retention times of 5.2 and 7.4 minutes.

Example 118
[4-(2-Azepan-1 -y l-ethoxy)-pheny l]-[2-(2,4-difl uoro-phenyl)-6-methoxy-naphthal en-1 -yl]-
methanone

Couple trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-
methoxynaphthalen-2-yl ester (1.4 g, 2.5 mmol) and 2,4-difluorophenyl boronic acid (1.2
g, 7.6 mmol) by the procedure used to prepare [2-(2,4-difluoro-phenyl)-6-methoxy-
naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanoneto give yields 1.1 g
(85%) of the title compound: mass spectrum (ion spray) m/z = 516.3 (M+H).
Example 119
[4-(2-azepan-1 -yl-e methanone
By the standard demethylation procedure found in the preparation of [2-(2,4-
difluoro-phenyl)-6-hydroxy-naphthalen-1 -yl]-f 4-(2-piperidin-l -yl-ethoxy)-phenyl]-
methanone, [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2,4-difluoro-phenyl)-6-methoxy-
naphthalen-1-yl]-methanone (1.1 g, 2.1 mmol) is demethylated with BBr3 (1.0 mL, 10.5
mmol) to afford crude product. Purify on silica gel (0% to 5% methanol in methylene
chloride) to yield 790 mg (75%) of the title compound: mass spectrum (ion spray) m/z =
502.3 (M+H).

Example 120
5-[4-(2-Azepan-1-yl-ethoxy)-phenyl]-8-fluoro-5H-6-oxa-chrysen-2-ol hydrochloride

Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2,4-difluoro-phenyl)-6-hydroxy-
naphthalen-1-yl]-methanone (760 mg, 1.5 mmol) in dioxane (30 mL) and add LiBEt3H
(1M in THF, 4.5 mL, 4.5 mmol) dropwise. Stir at room temperature for 30 minutes then
plunge into a 100 °C oil bath for 5 hours. Cool to room temperature overnight. Slowly
add methanol (5 mL) and concentrate in vacuo. Dissolve the residue in methylene
chloride and wash with saturated aqueous ammonium chloride and brine. Dry with
sodium sulfate, filter and concentrate in vacuo. Purify the residue on silica gel (0% to 3%
methanol in methylene chloride), concentrate, and suspend in methanol/chloroform. Add
2M HC1 in ether (1 mL) and remove the solvent. Dry the residue in a vacuum oven
overnight at 50 °C to yield 499 mg (64%) of the title compound: mass spectrum (ion
spray) m/z = 484.3 (M-Cl).
Example 121
[4-(2-Azepan-1 -yl-ethoxy)-phenyl]-[2-(2,5-difluoro-phenyl)-6-methoxy-naphthalen-1 -yl]-
methanone

Dissolve trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-
methoxynaphthalen-2-yl ester (2.00 g, 3.63 mmol) in 5 mL of degassed acetonitrile and
add 2,5-difluorophenyl boronic acid (1.15 g, 7.26 mmol),
trans[dichlorobis(triphenylphosphine)] palladium II (0.51 g, 0.73 mmol) and sonicate

briefly. Next add cesium fluoride (4.96 g, 32.76 mmol) and heat to 75 °C for one hour.
Add Celite and filter. Concentrate the solvent under vacuum, dissolve in methanol and
purify on an SCX cartridge, eluting with 2N ammonia/methanol to give 1.74 g (93%) of
the title compound.
Example 122
[4-(2-azepan-1 -yl-ethoxy)-phenyl]-[2-(2,5-difluorophenyl)-6-hydroxynaphthalen-1 -yl]-
methanone
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2,5-difluoro-phenyl)-6-methoxy-
naphthalen-1-yl]-methanone (1.74 g, 3.37 mmol) in 20 mL methylene chloride and chill
in ice. Add to this solution 2.0 mL of boron tribromide (5.3 g, 21.2 mmol) and allow to
come to room temperature. Pour into a two phase solution of saturated sodium
bicarbonate and 3/1 chloroform/isopropanol. Separate the organic layer, wash with water
and dry over 3A sieves. Evaporate the solvent and purify on a silica gel column eluting
with a 0-10% methanol/methylene chloride gradient. Evaporate the solvent to yield 780
mg (46%) of the title compound.
Example 123
5-{[4-{2-azepan-1-yl-ethoxy)-phenyl]-hydroxymethyl}-6-(2,5-difluorophenyl)-
naphthalen-2-ol
Dissolve [4-(2-azepan-1 -yl-ethoxy)-phenyl]-[2-(2,5-difluorophenyl)-6-
hydroxynaphthalen-1-yl]-methanone (770 mg, 1.54 mmol) in 10 mL THF and add 5.0 mL
(5.0 mmol) of lithium triethylborohydride (1.0 M solution in THF). After one hour at
room temp, add another 4.0 mL of the lithium triethylborohydride gently warm the
solution with a heat gun. After 'A hour the reaction is complete. Quench the reaction with
water and pour into a two phase system of saturated sodium bicarbonate and a 3/1 mixture
of chloroform/isopropanol. Separate the phases, dry the organic layer with 3A sieves and
evaporate to give the title compound to be taken on to the next step without purification.

Example 124
5-[4-(2-Azepan-1 -yl-ethoxy)-phenyll-9-fluoro-5H-6-oxa-chrysen-2-ol

Dissolve 5-{[4-(2-azepan-1-yl-emoxy)-phenyl]-hydroxymethyl}-6-(2,5-
difluorophenyl)-naphthalen-2-oI (770 mg, 1.54 mmol) in 20 mL dry DMF and add sodium
t-butoxide (1.18 g, 12.32 mmol). Heat the mixture to 50 °C for two hours. Dilute with
water and extract multiple times with methylene chloride. Dry the organic layer and
purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient.
The yield is 370 mg (50%). 1H-NMR (CDCI3,300 MHz) £7.76 (dd, J = 12.6, 8.4 Hz,
2H); 7.58 (d, J = 9.0 Hz, 1H); 7.43-7.40 (m, 1H); 7.15 (d, J = 2.4 Hz, 1H); 7.05-7.01 (m,
3H); 6.89 (s, 1H); 6.83-6.80 (m, 2H); 6.66-6.63 (m, 2H); 4.00-3.98 (m, 2H); 2.92-2.92
(m, 2H); 2.78-2.78 (m, 4H); 1.66-1.59 (m, 8H). The racemic compound is purified using
chiral chromatography (conditions P). The two isomers eluted with retention times of 9.9
and 13.5 minutes.
Example 125
[4-(2-azepan-1 -yl-ethoxy)-phenyl]-[2-(2,6-difluoro-phenyl)-6-methoxy-naphthalen-1 -yl]-
methanone

Charge a flask with trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-
benzoyl]-6-methoxynaphthalen-2-yl ester (3.9 g, 7.06 mmol), 2,6-difluorophenyl boronic
acid (2.23 g, 14.12 mmol), potassium phosphate (9.0 g, 42.20 mmol) and
tetrakis(triphenylphosphine)paIladium (0) (1.63 g, 1.40 mmol) followed by 125 mL dry

DMF. Heat the mixture under nitrogen at 100 °C for 90 minutes. Cool, filter, evaporate
the solvent and purify on an SCX cartridge, eluting with 2N ammonia/methanol. Purify
further on a silica gel column eluting with 0-10% methanol/methylene chloride. The yield
is 2.5 g (70%): IH-NMR (CDC13, 400 MHz) £7.90 (d, J = 8.4 Hz, 1H); 7.66-7.61 (m,
3H); 7.39 (d, J = 8.4 Hz, 1H); 7.23-7.22 (m, 1H); 7.18-7.08 (m,2H); 6.79-6.74 (m, 4H);
4.08-4.05 (t, 2H); 3.95 (s, 3H); 2.96-2.89 (t, 2H); 2.78-2.75 (m, 4H); 1.66-1.59 (m, 8H).
Example 126
[4-(2-Azepan-1 -yl-ethoxy)-phenyl]-[2-(2,6-difluoro-phenyl)-6-hydroxy-naphthalen-1 -yl]-
methanone
Convert [4-(2-azepan-1 -yl-ethoxy)-phenyl]-[2-(2,6-difiuoro-pheny l)-6-methoxy-
naphthalen-1-ylj-methanone (2.5 g, 4.8 mmol) into the hydrochloride salt and charge a
flask with the solid salt. Dissolve the material in 200 mL methylene chloride and chill in
ice. Add to this mixture boron tribromide (5.C mL, 53.0 mmol) while swirling. Stir the
reaction at room temperature for one hour and pour into a two phase system of saturated
sodium bicarbonate and an organic layer consisting of a 3/1 mixture of
chloroform/isopropanol. Shake to extract the product, separate the organic layer, dry over
3A molecular sieves and evaporate the solvent under vacuum. Purify on a silica gel
column eluting with a 0-10% methanol/methylene chloride gradient to give 1.3 g (54%) of
the title compound.
Example 127
5-[4-(2-Azepan-1 -yl-ethoxy)-phenyl]-10-fluoro-5H-6-oxa-chrysen-2-ol

Dissolve [4-(2-azepan-1 -yl-ethoxy)-phenyl]-[2-(2,6-difluoro-phenyl)-6-hydroxy-
naphthalen-1-yl]-rnethanone (1.3 g, 2.6 mmol) in 125 mL dioxane and add 20 mL (20

mmol) of a 1.0 M solution of lithium triethylborohydride in THF. Stir at room
temperature for one hour, then heat at 100 °C for three hours. Pour the reaction into a two
phase system consisting of saturated sodium bicarbonate and an organic phase of a 3/1
mixture of chloroform/isopropanol. Extract in a separatory funnel, separate the organic
layer and dry over 3 A molecular sieves. Evaporate to give 1.5 g of slightly impure
product. Purify on a silica column eluting with 0-10% methanol/methylene chloride
gradient to give 850 mg (68%)of racemic product. 1H-NMR (CDC13, 400 MHz) 58.18 (d,
J = 8.4 Hz, 1H); 7.73 (d, J = 8.8 Hz, 1H); 7.52 (d, J = 9.2 Hz, 1H); 7.21 (d, J = 2.4 Hz,
1H); 7.08-6.99 (m, 5H); 6.88 (s,lH); 6.72-6.61 (m, 4H); 4.24-4.23 (m, 2H); 3.26-3.26 (m,
6H); 1.87-1.87 (m, 4H); 1.66-1.66 (m, 4H). The racemic mixture is purified using chiral
chromatography (conditions F). The two isomers eluted with retention times of 7.9 and
9.0 minutes.
Example 128
[4-(2-Azepan-1-yl-ethoxy)-phenyl]-[6-metlK)xy-2-(23,5-trifluoro-phenyl>Haaphthalen-1-
yTJ-methanone

Dissolve trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-
methoxynaphthalen-2-yl ester (2.60 g, 6.53 mmol) in 200 mL acetonitrile and add to this
bis(pinacoloato)diboron (1.5 g, 7.96 mmol), bis(tricyclohexylphosphine)palladium (0)
(0.72 g, 1.50 mmol) and cesium fluoride (7.33 g, 67.0 mmol). Heat the reaction to 100 °C
until LC/MS indicates all starting material is consumed. Add to this mixture 1-bromo-
2,3,5-trifluorobenzene (2.00 g, 13.06 mmol) and another 720 mg of palladium catalyst
and heat at 80 °C for 24 hours. Filter the reaction, concntrate filtrate and purify on a silica
gel column eluting with a 0-10% methanol/methylene chloride gradient. The yield is 1.85
g(53%)

Example 129
[4-(2-azepan-1 -yl-ethoxy)-phenyl]-[6-hydroxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-1 -
yl]-methanone
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-methoxy-2-(2,3,5-trifluorophenyl)-
naphthalen-1-yl]-methanone (2.85 g, 5.34 mmol) in 50 mL methylene chloride and cool
to 0 °C. Add boron tribromide (3.0 mL, 31.7 mmol) and allow to come to room
temperature. Pour into a two phase system of saturated sodium bicarbonate and 3/1
chloroform/isopropanol. Wash the organic layer with brine and dry over 3A molecular
sieves. Concentrate to give 2.63 g (95%) of the title compound
Example 130
5-[4-(2-Azepan-1 -yl-ethoxy)-phenyl]-7,9-difluoro-5H-6-oxa-chrysen-2-ol

Dissolve [4-(2-azepan-1 -yl-ethoxyy-phenyll-Ifi-hydroxy^^^.S-trifluoro-phenyl)-
naphthalen-1-yl]-methanone (2.63 g, 5.1 mmol) in 60 mL dioxane and add 10 mL of a 1.0
M solution of lithium triethylborohydride in THF. At the end of one hour, add another
10 mL of the lithium reagent mixture is added and gently warm the reaction. After a
further one hour, add an additional 25 ml of lithium triethylborohydride and heat the
reaction to reflux and hold for 8 hours. Cool the reaction and quench with water. Extract
the water with methylene chloride, dry the organic layer with molecular sieves and
concentrate. Purify on a silica gel column eluting with a 0-10% methanol/methylene
chloride gradient.

Example 131
[4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-methoxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1-
yl]-methanone

Dissolve trifluoromethanesulfonic acid l-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-
methoxynaphthalen-2-yl ester (990 mg, 1.8 mmol), 2,4,6-trifluorophenylboronic acid (634
mg, 3.6 mmol), potassium phoshate (2.2 g, 10.8 mmol),
tetrakis(triphenylphosphine)palladium (416 mg, 0.4 mmol) in dry DMF (25 mL) and heat
at 100 °C for 3 hours. Purify reaction by SCX column. Additional purification is done by
silica gel chromatography using a 1-3% gradient of methanol in dichloromethane to yield
320 mg (35%) of the title compound: mass spectrum (ion spray) m/z = 534 (M+H).
Example 132
[4-(2-azer>an-1-yl-emoxy)-phenyiH6-hydroxy-2-(2,4,6-tri^
yl]-methanone
Dissolve [4-(2-azepan-l -yl-ethoxy)-phenyl]-[6-methoxy-2-(2,4,6-trifluoro-
phenyi)-naphthalen-1-yl]-methanone (634 mg, 1.2 mmol) in dichloromethane (10 mL).
Cool to 0 °C, add HC1 (2M in ether, 1.2 mL, 2.4 mmol) and stir at room temperature for
15 minutes. Concentrate in vacuo. Redissolve the salt in dichloromethane (10 mL) and
cool to 0 °C. Add boron tribromide (949 mg, 3.6 mmol) dropwise and bring to room
temperature. Stir reaction for 1.5 hours and pour reaction mixture onto ice, saturated
sodium bicarbonate (20 mL) and methanol (20 mL). Extract with dichloromethane,
combine extracts and wash with water and saturated sodium bicarbonate. Dry with
sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography
using a 1-3% gradient of methanol in dichloromethane to yield 350 mg (57%) of the title
compound: mass spectrum (ion spray) m/z = 520 (M+H).

Example 133
5-{[4-(2-a2epan-1-yl-ethoxy)-phenyl]-hydroxy-methyl}-6-(2,4,6-trifluoro-phenyI)-
naphthalen-2-ol
Charge a flask with 1M borane in THF (4 mL) and (R)-(+) a,ct-diphenylprolinol
(26 mg, 0.1 mmol). Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[6-hydroxy-2-(2,4,6-
trifluoro-phenyl)-naphthalen-1-yl]-methanone (348 mg, 0.7 mmol) in THF (3 mL) and
add to the catalyst solution via syringe pump over 1.5 hours at 45 °C. Upon completion
of the reaction add ethanolamine (0.8 mL, 13.4 mmol) and heat at 45 °C for 2 hours.
Cool the reaction to room temperature and add brine (5 mL) and stir for 1 hour. Filter the
reaction and separate layers. Dry the organic layer with sodium sulfate, filter and
concentrate in vacuo. Purify by silica gel chromatography using a 1.5-5% gradient of
methanol in dichloromethane to yield 306 mg (88%) of the title compound: mass
spectrum (ion spray) m/z = 522 (M+H).
Example 134
5^4-(2-Azer>an-1-yl-ethoxy)-phenyI]-8,10-difluoro-5H-6-oxa-chrvsen-2K)l hydrochloride

Dissolve 5-{[4-(2-azepan-1-yl-ethoxy)-phenyl]-hydroxy-methyl}-6-(2,4,6-
trifluoro-phenyl)-naphthalen-2-ol (305 mg, 0.6 mmol) and potassium r-butoxide (197 mg,
1.8 mmol) in dry DMF (10 mL) and heat at 50 °C for 10 minutes. Cool reaction and pour
onto ice/ethyl acetate. Separate organic layer and wash with 10% aqueous lithium
chloride. Dry, filter and concentrate in vacuo. Purify by silica gel chromatography using
a 1-6% gradient of methanol in dichloromethane to yield 285 mg (95%) of the free base of
the title compound. Dissolve the free base (285 mg, 0.6 mmol) in dichloromethane (10
mL) and add HC1 (2M in ether, 0.6 mL, 1.2 mmol) and stir for 10 minutes. Concentrate

in vacuo to yield 234 mg (77%) of the title compound: mass spectrum (ion spray) m/z =
502 (M-Cl).
Preparation 14
2-(2,4-Difluoro-phenyl)-6-methoxy-naphthalene-1 -carbaldehyde

Cool a solution of 2-hydroxy-6-methoxy-naphthalene-1-carbaldehyde (18 g, 88.7
mmol, see Wrobel, et. al. J. Med Chem. 1991, 34, 2504.) in dichloromethane (90 mL) to
-78 °C. Add pyridine (35.1 g, 443.6 mmol) and 4-dimethylaminopyridine (0.54 g, 4.4
mmol). Add trifluoromethanesulfonic anhydride (27.5 g, 97.6 mmol) and stir for 1 hour.
Dilute with 2 M aqueous hydrochloric acid. Separate the organic layer and dry over
magnesium sulfate. Filter, add silica gel, and concentrate in vacuo. Purify the residue by
column chromatography using an eluent of 2:1 hexanes:dichloromethane. Isolate 9.0 g of
trifluoromethanesulfonic acid l-formyl-6-methoxy-naphthalen-2-yl ester (30%).
Combine trifluoromethanesulfonic acid l-formyl-6-memoxy-naphthalen-2-yl ester
(2.53 g, 7.6 mmol) with dichlorobis(triphenylphosphine)palladium (II) (0.53 g, 0.8
mmol), cesium fluoride (5.75 g, 37.8 mmol), and 2,4-difluorophenylboronic acid (2.39 g,
15.1 mmol) in acetonitrile (25 mL). Heat to reflux for 1 hour. Cool to room temperature,
add DARCO, and filter. Concentrate in vacuo, dilute with dichloromethane and wash
with saturated aqueous sodium carbonate. Dry the organic layer over magnesium sulfate,
filter, add silica gel, and concentrate in vacuo. Purify the residue by column
chromatography using an eluent of 1.5:1 hexanes : dichloromethane to give 1.4 g of the
title compound (62%).

Example 135
[4-(8-FIuoro-2-methoxy-5H-6-oxa-chrysen-5-yl)-phenyl]-(2-piperidin-1-yi-ethyl)-
carbamic acid tert-butyl ester

Dissolve (4-bromo-phenyl)-(2-piperidin-1-yl-ethyl)-carbamic acid tert-butyl ester
in dry tetrahydrofuran (20 mL). Cool to -78 °C and add 1.6 M n-butyl lithium in hexanes
(0.79 mL). After 30 minutes, add 2-(2,4-difluoro-phenyl)-6-methoxy-naphthalene-1-
carbaldehyde (0.2S g, 0.839 mmol) and stir 45 minutes cold. Warm to room temperature
over 1 hour. Reflux 2 hrs. Cool to room temperature and dilute with dichloromethane
(20 mL) and saturated aqueous ammonium chloride (20 mL). Separate the organic layer
and wash the aqueous layer twice with dichloromethane. Combine the organics and dry
over magnesium sulfate. Filter and concentrate in vacuo. Purify the residue by column
chromatography using a silica gel column eluting with a linear gradient beginning with
dichloromethane and ending with 4 : 1 dichloromethane : methanol to give 0.45 g ( 92%)
of the title compound: mass spectrum (ion spray) m/z = 583.3 (M+H).
Example 136
8-Fluoro-5-[4-(2-piperidin-1-yl-ethylamino)-phenyl]-5H-6-oxa-chrysen-2-ol
dihydrochloride
Dissolve [4-(8-fluoro-2-methoxy-5H-6-oxa-chrysen-5-yl)-phenyl]-(2-piperidin-1 -
yl-ethyl)-carbamic acid tert-butyl ester in dichloromethane (25 mL). Add a 1.0 M
solution of hydrogen chloride in ether (5 mL). Concentrate in vacuo. Redissolve in
dichloromethane (20 mL). Cool to 0 °C. Add boron tribromide (0.238 mL, 2.52 mmol).
After 3 hrs dilute with saturated aqueous sodium bicarbonate (10 mL) and methanol (10

mL). Separate the organic layer and wash the aqueous layer twice with dichloromethane.
Combine the organics and dry over magnesium sulfate. Filter and concentrate in vacuo.
Purify the residue by column chromatography using a silica gel column eluting with a
linear gradient beginning with dichloromethane and ending with 4:1 dichloromethane :
methanol. Combine the product containing fractions and add 1.0 M hydrogen chloride in
ether (2 mL). Concentrate in vacuo to isolate the title compound: mass spectrum (ion
spray) m/z = 469.2 (M+H). Purify the mixture by chiral chromatography (conditions A).
The two isomers eluted with retention times of 4.02 and 5.46 minutes.
Example 137
7,9-Difluoro-6-oxo-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6-dihydro-6A.4-thia-chrysen-
2-ol hydrochloride
Dissolve 7,9-difluoro-5-[4-(2-piperidin-l -yl-ethoxy)-phenyl]-5H-6-thia-chrysen-2-
ol (130 mg, 0.26 mmol) in acetic acid (3 mL). Add sodium perborate (29 mg, 0.29 mmol)
and stir at room temperature for 3 days. Slowly pour the reaction into saturated aqueous
sodium bicarbonate and extract with 20% methanol/methylene chloride. Dry the organic
layer with sodium sulfate, filter and concentrate. Purify on silica gel (5% to 10%
methanol in methylene chloride) to yield 28 mg of impure product. The material is
dissolved in methylene chloride and 2M HC1 in ether (0.2 mL) is added and the solvent
removed in vacuo to yield 28 mg (20%) of the title compound: mass spectrum (ion spray)
m/z = 542.2 (M-Cl+Na).
Example 138
[2-(4-Fluoro-2-methylsulfanyl-phenyl)-6-methoxy-naphthalen-1 -yl]-[4-(2-piperidin-l -yl-
ethoxy>phenyl]-methanone


Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-
yI-ethoxy)-benzoyl]-naphthalen-2-yl ester (580 mg, 1.1 mmol), 2-methyIsulfanyl-4-
fluoro-benzene boronic acid (400 mg, 2.2 mmol) and cesium fluoride (830 mg, 5.4 mmol)
and fluch with nitrogen. In a separate flask, add palladium acetate (24 mg, 0.11 mmol)
and tricyclohexylphosphine (62 mg, 0.22 mmol) and suspend in dry degassed acetonitrile
(10 mL). Socinate under nitrogen for 10 minutes and add the catalyst solution to the
solids and plunge into an 80 °C oil bath for 30 minutes. Cool to room temperature, filter
through celite and concentrate in vacuo. Purify the residue by silica gel chromatography
(0 to 3% methanol in methylene chloride) to yield 476 mg (83%) of the title compound:
mass spectrum (ion spray) m/z = 530.2 (M+H).
Example 139
l-{2-[4-(8-Fluoro-2-methoxy-5H-6-thia-chrysen-5-yl)-phenoxy]-ethyl}-piperidine

Dissolve [2-(4-fluoro-2-methylsulfanyl-phenyl>-6-methoxy-naphthalen-1-yl]-[4-
(2-piperidin-1-yl-ethoxy)-phenyI]-methanone (1.2g, 2.2 mmol) in dry THF (20 mL). Add
litium aluminum hydride (1M in THF, 2.3 mL, 2.3 mmol) dropwise. After 10 minutes
slowly pour the black solution into saturated aqueous ammonium chloride and extract
with methylene chloride twice. Dry the combined organic layers with sodium sulfate,
filter and concentrate to yield a 2:1 mixture of rotational diastereomers. Dissolve the
crude foam in dry THF (15 mL). Add diisopropylethylamine (2.5 mL, 14.4 mmol) and
methanesulfonyl chloride (0.45 mL, 5.8 mmol) and heat to reflux under nitrogen. Add
more methanesulfonyl chloride (0.45 mL, 5.8 mmol) after 2 hours to drive the reaction to
completion. Pour the reaction into saturated aqueous sodium bicarbonate and extract
twice with methylene chloride. Dry the combined organic layers with sodium sulfate,
filter and concentrate. Purify the residue on silica gel (0% to 3% methanol in methylene

chloride) to yield 440 mg (44%) of the title compound: mass spectrum (ion spray) m/z =
500.3 (M+H).
Alternative Preparation of the Compound of Example 100
8-Fluoro-5-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-5H-6-thia-chrysen-2-ol hydrochloride
Dissolve l-{2-[4-(8-fluoro-2-methoxy-5H-6-thia-chrysen-5-yl)-phenoxy)-ethyl}-
piperidine (330 mg, 0.67 mmol) in methylene chloride (6.0 mL) and add 2M HC1 in ether
(0.67 mL). Concentrate in vacuo and dissolve in dry methylene chloride (6.0 mL). Add 2-
methyl-2-butene (0.71 mL, 6.7 mmol) and cool to 0 °C under nitrogen. Add boron
tribromidc (0.25 mL, 2.7 mmol) slowly and stir at 0 °C. for 20 minutes. Pour the reaction
into saturated aqueous sodium bicarbonate and extract with methylene chloride/methanol
(4:1). Dry organic layer with sodium sulfate, filter and concentrate in vacuo. Purify the
resultant oil over silica gel (0% to 3% methanol in methylene chloride). Dissolve the
resultant oil in methylene chloride (3 mL) and add 2M HC1 in ether (0.5 mL). Remove
the solvent in vacuo and place in a 50 °C vacuum oven overnight to yield 225 mg (65%)
of the title compound: mass spectrum (ion spray) m/z = 486.3 (M-Cl).
Preparation 15
(2-Bromo-5-fluoro-phenyl)-carbamic acid tert-butyl ester

Place 2-bromo-5-fluoroaniline (2.50 g, 13.16 mmol) and dichloromethane (50 mL)
in a round bottom flask. Add sodium hydride (60% dispersion in mineral oil) (0.58 g,
14.47 mmol) and stir this suspension at ambient temperature for 20 minutes. Now add di-
/-butyl dicarbonate (3.02 g, 13.82 mmol) and stir for 30 minutes at ambient temperature
followed by 2 hours at reflux. Cool this solution to ambient temperature and add more
sodium hydride (60% dispersion in mineral oil) (0.58 g, 14.47 mmol) and di-/-butyl
dicarbonate (0.30 g, 1.38 mmol). Heat this mixture at reflux overnight. Cool the reaction

to ambient temperature and quench with H20 and saturated aqueous ammonium chloride.
Extract the resulting mixture into ethyl acetate. Combine the extracts and wash with
saturated aqueous sodium bicarbonate, H20 and brine; then dry (sodium sulfate) and
concentrate in vacuo. Purify the resulting oil by flash chromatography (silica gel; 5%
Et20 /hexanes) to provide the desired product, 3.61 g (95%).
Example 140
(2-{6-Benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-5-fluoro-
phenyl)-carbamic acid tert-butyl ester

Add (2-bromo-5-fluoro-phenyI)-carbamic acid tert-butyl ester (1.06 g, 3.67
mmol), bis(pinacolato)diboron (1.03 g, 4.04 mmol), palladium(II) acetate (0.062 g, 0.28
mmol), tricyclohexylphosphine (0.103 g, 0.37 mmol) and acetonitrile (40 mL) to a round
bottom flask. Stir at ambient temperature for approximately 5 minutes to dissolve most of
the reagents. Add cesium fluoride (2.10 g, 13.82 mmol), place the flask in a 90°C oil
bath, and stir for 30-45 minutes. Remove the oil bath and allow the reaction mixture to
cool to ambient temperature. To this mixture, add trifluoromethanesulfonic acid 6-
benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (0.75 g, 1.22
mmol), palladium(II) acetate (0.062 g, 0.28 mmol), tricyclohexylphosphine (0.103 g, 0.37
mmol) and place the reaction in a 90°C oil bath. Stir the reaction for 4 hours at 90°C.
Cool the reaction to ambient temperature, filter it through a pad of Celite and rinse the
pad with ample, hot ethyl acetate. Wash the filtrate with 50% aqueous sodium carbonate,
saturated aqueous ammonium chloride, H2O and brine; then dry (sodium sulfate) and
evaporate it in vacuo. Load the resulting material onto an SCX column. Wash with
dichloromethane, 50% dichloro-methane/methanol, elute with ammonia solution (2N NH3
in methanol) and remove solvent under vacuum. Purify the resulting residue by flash
chromatography (silica gel; l%-5% methanol gradient in dichloromethane: followed by a

second chromatography 2% of 2N NH3 in methanol/25% THF/hexanes: followed by
purification on a Chromatotron; 2% MeOH/dichloromethane) to provide 0.300 g (36%) of
the title compound: mass spectrum (ion spray) m/z = 675 (M + H).
Example 141
(5-Fluoro-2-{6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-
phenyl)-carbamic acid tert-butyl ester
To a round bottom flask add (2-{6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl}-5-fluoro-phenyl)-carbamic acid tert-butyl ester (0.075 g, 0.11
mmol), ammonium formate (0.056 g, 0.89 mmol), methanol (5 mL) and a slurry of 10%
Pd/C (0.012 g, ~15% by weight) and ethanol (2 mL). Heat the mixture, with stirring, at
reflux for 30 minutes. Cool the reaction to ambient temperature and filter it through a pad
of Celite, then rinse the Celite with hot methanol. Evaporate the filtrate in vacuo and
purify the resulting residue by radial chromatography over silica (4-9% MeOH gradient in
CH2CI2) to provide the product 61 mg (94%): mass spectrum (ion spray) m/z = 585 (M +
H).
Example 142
8-Fluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6-dihydro-benzo[i]phenanthridin-2-ol

To around bottom flask add (5-fluoro-2-{6-hydroxy-1-[4-(2-piperidin-1-yl-
ethoxy)-benzoyl]-naphthalen-2-yl}-phenyl)-carbamic acid tert-butyl ester (0.060 g, 0.103
mmol), dichloromethane (1.25 mL), anisole (0.15 mL, 1.39 mmol) and trifluoroacetic acid
(0.25 mL). Stir the reaction for 1.5 hour at ambient temperature. Add trifluoroacetic acid
(2.0 mL) and sodium borohydride (0.024 g, 0.62 mmol) and stir the reaction at ambient
temperature for 1.5 hours. Add more sodium borohydride (0.024 g, 0.62 mmol) and stir

the reaction at ambient temperature an additional 2 hours. After aqueous work-up and
purification LC/MS showed significant amounts of the (M-2) intermediate, so take this
material up in acetic acid (3.0 mL) and to it add sodium cyanoborohydride (0.032 g, 0.51
mmol). Stir this mixture for 1.5 hours at ambient temperature. Add more sodium
cyanoborohydride (0.032 g, 0.51 mmoi) and stir an additional 1.5 hours at ambient
temperature. Quench the reaction with saturated aqueous sodium bicarbonate. Extract
the resulting aqueous mixture into ethyl acetate. Wash the combined extracts with
saturated aqueous sodium bicarbonate, H20 and brine; then dry (sodium sulfate) and
evaporate the filtrate in vacuo. Purify the resulting residue by radial chromatography over
silica (5%-10% methanol gradient in dichloromethane) to provide 17 mg (35%) of the
title compound: mass spectrum (ion spray) m/z = 469 (M + H).
Preparation 16
(2-Bromo-5-fluoro-phenyl)-methyl-carbamic acid tert-butyl ester

Place (2-bromo-5-fluoro-phenyl)-carbamic acid tert-butyl ester (2.00 g, 6.90
mmol) and dimethylformamide (40 mL) in a round bottom flask. Cool the solution to
0°C, add sodium hydride (60% dispersion in mineral oil) (0.303 g, 7.59 mmol), remove
the ice bath and stir this suspension for 25 minutes allowing it to warm slowly towards
ambient temperature. Cool the resulting mixture to 0°C once again, and add iodomethane
(0.56 mL, 8.96 mmol). Stir the resulting mixture overnight, allowing it to warm to
ambient temperature. Quench the reaction with brine and extract the resulting mixture
into ethyl acetate. Combine the extracts and wash with brine; then dry (sodium sulfate)
and concentrate in vacuo. Purify the resulting material by flash chromatography (silica
gel; 35%-50% dichloromethane gradient in hexanes) to provide the desired product.

Example 143
(2-{6-Benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl}-5-fluoro-
phenyl)-methyl-carbamic acid tert-butyl ester

Add trifluoromethanesulfonic acid 6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl ester (0.73 g, 1.18 mmol), bis(neopentyl glycolato)diboron (0.29
g, 1.30 mmol), bis(tricyclohexylphosphine)palladium(0) (0.16 g, 0.24 mmol) and
acetonitrile (14 mL) to a round bottom flask. Stir at ambient temperature for
approximately 5 minutes to dissolve most of the reagents. Add cesium fluoride (1.62 g,
10.64 mmol), place the flask in a 90°C oil bath, and stir under nitrogen for 2-3 minutes.
Now add a solution of (2-bromo-5-fluoro-phenyl)-methyl-carbamic acid tert-butyl ester
(0.86 g, 2.84 mmol) and acetonitrile (3 mL). Continue stirring the reaction for 2 hours at
90 °C. Cool the reaction to ambient temperature and then filter it through a pad of Celite.
Rinse the pad with ample, hot ethyl acetate. Wash the filtrate in a separatory funnel with
50% aqueous sodium carbonate, saturated aqueous ammonium chloride, H2O and brine;
then dry (sodium sulfate) and evaporate it in vacuo. Purify the resulting residue by flash
chromatography (silica gel; 2% methanol/dichloromethane) to provide 0.320 g (39%) of
the title compound: mass spectrum (ion spray) m/z = 689 (M + H).

Example 144
2-Benzyloxy-8-fluoro-6-methyl-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6-dihydro-
benzo[i]phenanthridine

To a round bottom flask add (2-{6-benzyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-
benzoyl]-naphthalen-2-yl}-5-fluoro-phenyl)-methyl-carbamic acid tert-butyl ester (0.070
g, 0.10 mmol), dichloromethane (1.25 mL), anisole (0.012 mL, 0.11 mmol) and
trifluoroacetic acid (0.2S mL). Stir the reaction for 1 hour at ambient temperature. Add
trifluoroacetic acid (1.0 mL) and sodium cyanoborohydride (0.064 g, 1.02 mmol) and stir
the reaction at ambient temperature for 1 hour. Add more sodium cyanoborohydride
(0.064 g, 1.02 mmol) and trifluoroacetic acid (1.0 mL) and stir the reaction at 50°C for 1
hour. Quench the reaction with saturated aqueous sodium bicarbonate. Extract the
resulting aqueous mixture into ethyl acetate. Wash the combined extracts with saturated
aqueous sodium bicarbonate, H20 and brine; then dry (sodium sulfate) and evaporate the
filtrate in vacuo. Purify the resulting residue by radial chromatography over silica (2%-
6% methanol gradient in dichloromethane) to provide the product, 32 mg (55%): mass
spectrum (ion spray) m/z = 573 (M + H).
Example 145
8-Fluoro-6-methyl-5-[4-(2-piperidin-1 -y I-ethoxy)-phenyl]-5,6-dihydro-
benzo[i]phenanthridin-2-6l
To a round bottom flask add 2-benzyloxy-8-fluoro-6-methyl-5-[4-(2-piperidin-1-
yl-ethoxy)-phenyl]-5,6-dihydro-benzo[i]phenanthridine (0.030 g, 0.052 mmol),
ammonium formate (0.026 g, 0.42 mmol), methanol (5 mL) and a slurry of 10% Pd/C
(0.005 g, -15% by weight) and ethanol (2 mL). Heat the mixture, with stirring, at reflux
for 30 minutes. Cool the reaction to ambient temperature and filter it through a pad of

Celite, then rinse the Celite with hot methanol. Evaporate the filtrate in vacuo and purify
the resulting residue by radial chromatography over silica (5-10% MeOH gradient in
CH2CI2) to provide the product 20 mg (80%): mass spectrum (ion spray) m/z = 483 (M +
H).
Example 146
[2-(4,5-Difluoro-2-methoxy-phenyl)-6-methoxy-naphthalen-1 -yl]-[4-(2-piperidin-1 -yl-
ethoxy)-phenyi]-methanone

Add trifluoromethanesulfonic acid 6-memoxy-I-[4-(2-piperidin-1-yI-ethoxy)-
benzoylJ-naphthalen-2-yl ester (2.3 gm, 4.2 mmoles), bis (pinacolato)diboron (1.3 gm, 5.1
mmoles), palladium II acetate (97 mg, 0.4 mmoles), triphenylphosphine (222 mg, 0.84
mmoles) and cesium fluoride (2.1 gm, 14.1 mmoles) in a 250 ml round bottom flask
under nitrogen and add 100 ml of anhydrous acetonitrile. Stir and heat to reflux for 2
hours. Allow the mixture to cool and to this mixture add 2-bromo-4,5-difluoroanisole
(2.8 gm, 12.5 mmoles), palladium II acetate (96 mg, 0.43 mmoles) triphenylphosphine
(222 mg, 0.84 moles) and cesium fluoride (1.8 gm, 12.2 mmoles). Reflux the mixture for
18 hours and filter through Celite. Evaporate the solvent and pass through an SCX
column eluting the product with 2N ammonia/methanol. The product is purified on a
silica column eluting with a gradient of 25% THF/hexane to 5% 2N ammonia/methanol in
25 %THF/Hexane. LC/MS gives a peak with the proper mass.

Preparation 17
8,9-Difluoro-5-methoxy-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol

Convert [2-(4,5-Difluoro-2-methoxy-phenyl)-6-methoxy-naphthalen-1 -yl]-[4-(2-
piperidin-1-yl-ethoxy)-phenyl]-methanone to the HC1 salt and add 1.6 grams of said salt
to a 250 ml round bottom flask. Add 100 ml methylene chloride and place under
nitrogen. Cool the solution to 0 degrees Celsius and add 3.0 ml of boron tribromide.
Allow the reaction to warm to room temperature and stir for one hour. Quench the
reaction with methanol and wash with saturated sodium bicarbonate solution. Extract the
water with methylene chloride, combine the organic portions and remove the solvent.
Purify the residue on an SCX column, eluting the product with 2N ammonia/methanol.
Purify the compound further using a silica column eluting with a gradient of 0-5% 2 M
ammonia/methanol in methylene chloride (78%).
Example 147
8,9-Difluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-2-ol

Dissolve 8,9-Difluoro-5-methoxy-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-
oxa-chrysen-2-ol (1.1 gm, 21. mmoles) in 30 ml of methylene chloride and add 2 ml of
triethylamine and 2 ml of trifluoroacetic acid. Stir at room temperature for 1 hour,
neutralize with sodium bicarbonate solution and separate the organic layer. Wash the
water layer with methylene chloride and combine the organic layers. Dry the liquid over
sodium sulfate and remove the solvent. Purifiy as described in Preparation 17 to obtain
an 18% yield of the racemic. Obain the individual enantiomers by chiral chromatography

using a Chiralpak AD column eluting with ethanol containing 0.2 % dimethylethylamine
and monitoring at 225 nm.
Example 148
5-[4-(2-Diethylamino-ethoxy)-phenyl]-8,9-difluoro-5H-6-oxa-chrysen-2-oI hydrochloride
Dissolve 8,9-Difluoro-5-methoxy-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-
oxa-chrysen-2-ol (1.72g, 3.32mmol) in chloroform (100 mL) and add triethylsilane
(l.OmL, 6.26mmol) and trifluoroacetic acid (2.5mL, 32.45mmol). Heat the reaction to
reflux for four hours. After cooling to room temperature, pour reaction into ice and 1.0 M
sodium hydroxide (200mL). Add saturated sodium bicarbonate solution until basic.
Separate the organic and extract the aqueous with 25% isopropanol/chloroform
(3x200mL). Combine the organics, dry with sodium sulfate, and remove the solvent.
Isolate the product by flash chromatography on silica gel [0-5% (2M
amrnonia/methanol)/(25% THF/hexanes)]. Wash the resulting solid with ether and collect
by filtration. Dissolve solid in 1:1 acetonitrile/1 0M HCI (4mL), freeze at -78°C, and
lyophilize for 16 hours to afford 659.0 mg (37.9%) of the title compound: LCMS(5 min):
3.04 min, 488 (M+l).
Preparation 18
6-Boronic acid-5-[4-(2-piperidin-1 -yl-ethoxy)-phenoxy]-naphthalen-2-ol hydrochloride

Charge a flask with trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-
yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (10.0 g, 19.0 mmol) and dissolve in methylene
chloride (100 mL). Add 2M HCI in ether (19 mL, 38 mmol) and remove solvent in vacuo.
Redissolve in dry methylene chloride (200 mL) and cool to 0 °C under nitrogen. Add
BBr3 (9.0 mL, 95 mmol) slowly, and stir at 0 °C for 30 minutes. Pour reaction slowly into

saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry over
sodium sulfate, filter and concentrate in vacuo. Dissolve crude material in methylene
chloride (200 mL) and add N,N-diisopropylethylamine (16.5 mL, 95 mmol) and 4-
dimethylaminopyridine (120 mg, 1.9 mmol) and stir at room temperature. Add acetic
anhydride (3.6 mL, 38 mmol). Stir for 20 minutes and pour into saturated aqueous sodium
bicarbonate. Extract with methylene chloride. Wash the organic layer with water, dry over
sodium sulfate, filter and concentrate in vacuo to yield 10.5 g (100%) of acetic acid 5-[4-
(2-piperidin-1-yl-ethoxy)-phenoxy]-6-trifluoromethanesulfonyloxy-naphthalen-2-yl ester.
Degas dry acetonitrile (100 mL) with nitrogen bubble for 10 minutes. Add
palladium acetate (450 mg, 1.8 mmol), tricyclohexylphosphine (850 mg, 2.7 mmol) and
cesium fluoride (11.6 g, 76 mmol) and stir for 20 minutes with degas. Add acetic acid 5-
[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-6-trifluoromethanesuIfonyIoxy-naphthalen-2-yl
ester (5.6 g, 10.1 mmol) and stir under nitrogen for 3 minutes. Add bis(neopentyl
glycolato)diboron (13.7g, 60.6 mmol) and plunge into a 60 °C oil bath and stirred for 1 hr.
Cool to room temperature and fitter through celite and concentrate in vacuo. Dissolve the
resulting solid in ether (100 mL) and add diethanolamine (1.0 g, 10.1 mmol) and stir for 1
hr. Filter the resulting white precipitate. Suspend the precipitate in water and add IN HC1
followed by methanol to dissolve the suspension. Stir for 36 hr. Extract with methylene
chloride (x3), dry over sodium sulfate, filter and concentrate in vacuo to yield 2.7 g (66%)
of the title compound. Mass spectrum (ion spray): m/z = 408.2 (M + 1 - HC1).
Example 149
5-[4-(2-Piperidin-1-yl-ethoxy)-phenoxy]-6-(2,3,4-trifluoro-phenyl)-naphthalen-2-ol
trifluoroacetate salt

Add 6-boronic acid-5-[4-(2-piperidin-1 -yl-ethoxy)-phenoxy]-naphthalen-2-ol
hydrochloride salt (20 mg, 0.05 mmol) and freshly distilled dimethoxyethane and 2M
sodium carbonate (9:1, 3 mL total volume) to a Quest210 under nitrogen. Add 2,3,4-

trifluoro-bromobenzene (3 eq) followed by trans-dichlorobis(tri-o-
toiylphosphine)palladium (10 mg, 0.01 mmol) and heat to 70 °C overnight under
nitrogen. Cool reaction to room temperature and filter into tubes containing -400 mg
TsOH-MP and agitate for 3 hours. Solvent filtered off and washed with DME. Add 3N
ammonia in methanol and filter. Wash resin three times with 3N ammonia in methanol.
Concentrate in vacuo and purify by reverse phase HPLC.
Preparative HPLC's may be obtained, e.g., on a Mass Guided Waters Preparative
System using a 20 x 100 mm C18 Symmetry column. The eluent is a binary system of
bottle and bottle A (0.1% trifluoroacetic acid in water) B (0.1% trifluoroacetic acid in
acetonitrile). The standard method is a gradient of 10-95% B. MS (1S+) m/e 494 (M + 1 -
TFA).
Formulation (Pharmaceutical Composition)
Because the free base form of a compound of formula I contains a basic moiety
(i.e., amino), said compound may be formulated as a pharmaceutical acid addition salt,
e.g., as the hydrochloride salt or as a salt described in "Handbook of Pharmaceutical Salts:
Properties, Selection and Use", Weinheim, New York: VHCA; Wiley-VCH, 2002.
The present pharmaceutical compositions are prepared by known procedures using
well-known and readily available ingredients. In making the formulations of the present
invention, the active ingredient (a formula 1 compound) will usually be mixed with a
carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a
capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a
solid, semisolid or liquid material that acts as a vehicle, excipient or medium for the
active ingredient.
Some examples of suitable carriers, excipients, and diluents include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,
tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,
magnesium stearate and mineral oil. The formulations can additionally include
lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents,
sweetening agents or flavoring agents.

Biological Assays
Ishikawa Cell Proliferation Assay. This assay measures cell proliferation (using
an alkaline phosphatase readout) in both an agonist mode in the presence of a compound
of the present invention alone, and in an antagonist mode in which the ability of a
compound of the present invention to block estradiol stimulation of growth is measured.
Ishikawa human endometrial tumor cells are maintained in MEM (minimum
essential medium, with Earle's salts and L-Glutamine, Gibco BRL, Gaithersburg, MD),
supplemented with 10% fetal bovine serum (FBS) (V/V), (Gibco BRL). One day prior to
assay, growth media is changed to assay medium, DMEM/F-12 (3:1) (Dulbecco's
Modified Eagle Medium: Nutrient Mixture F-12, 3:1 Mixture, phenol red-free, Gibco
BRL) supplemented with 5% dextran coated charcoal stripped fetal bovine serum (DCC-
FBS) (Hyclone, Logen, UT), L-Glutamine (2mM), MEM sodium pyruvate (1 mM),
HEPES (N-[2-hydroxyethyl]piperazine-N' - [2-ethanesulfonic acid] 2 mM) all from
Gibco BRL). After an overnight incubation, Ishikawa cells are rinsed with Dulbecco's
Phosphate Buffered Saline (1X) (D-PBS) without Ca+2 and Mg+2 (Gibco BRL), and
trypsinized by a 3 minute incubation with 025% Trypsin/EDTA, phenol red-free (Gibco
BRL). Cells are resuspended in assay medium and adjusted to 250,000 cells/mL.
Approximately 25,000 cells in a 100ul media are added to flat-bottom 96 wells
microculture plates (Costar 3596) and incubated at 37°C in a 5% CO2 humidified
incubator for 24 hours. The next day, serial dilutions of compounds are prepared in assay
medium (at 6 times the final concentration in the assay). The assay is run in dual mode,
agonist and antagonist modes.
For the agonist mode, plates receive 25 ul/well of assay medium followed by 25
ul/well of a diluted compound of the present invention (at 6x the final concentrations).
For the antagonist mode, plates receive 25 ul/well of 6 nM E2 (β-Estradiol, Sigma, St.
Louis, MO) followed by 25 µl/well of a diluted compound of the present invention (at 6x
the final concentrations). After an additional 48-hour incubation at 37°C in a 5% CO2
humidified incubator, media is aspirated from wells and 100 µl fresh assay medium is
added to each microculture. Serial dilutions of compounds are prepared and added to the
cells as described above. After an additional 72 hour incubation at 37°C in a 5% CO2
humidified incubator, the assay is quenched by removing media and rinsing plates twice
in Dulbecco's Phosphate Buffered Saline (1X) (D-PBS) (Gibco BRL). The plates are

dried for 5 minutes and frozen at -70°C for at least 1 hour. The plates are then removed
from the freezer and allowed to thaw at room temperature. To each well, 100 µl of 1 -
Step™ PNPP (Pierce Chemical Company, Rockford, IL) is added. After a 20-minute
incubation, plates are read on a spectophotometer at 405nm.
The data is fitted to a linear interpolation to derive EC50 (for agonist mode) or
IC50 (for antagonist mode) values. For the antagonist mode, a % efficacy for each
compound is calculated versus E2 (InM) alone. For the agonist mode, a % efficacy for
each compound is calculated versus the response to tamoxifen.
3-Day Rat Uterus Antagonist Assay: This model for uterine antagonism utilizes
immature (3 week old) female rats that are highly sensitive to estrogenic stimulation of
the uterus given that their circulating estrogen levels are prepubertal. The uteri from
immature rats are fully responsive to exogenous estrogen, yet are quiescent in the absence
of exogenous estrogen. Administration of exogenous estrogen to immature rats produces
a reliable elevation of uterine weight, which can be used to study uterine antagonist
effects. The rats are treated with both estradiol and 4 different concentrations of a
compound of the present invention for 3 days and then uterine wet weights are measured.
Nineteen to twenty-one day old (or 45-50g) female rats are orally treated with E2
(0.1 mg/kg, a maximal stimulatory estrogenic stimulus for reliably increasing uterine
weight) and 10,1.0,0.1 and 0.01 mg/kg test compound for 3 days, 6 rats per group. Test
compounds are dissolved in 20% p-hydroxycyclodextrin and administered by oral gavage
in a volume of 0.2 mL daily (15 min. prior to the ethynyl estradiol gavage). A vehicle
control, E2 alone and E2 + raloxifene are also done as controls. The animals are fasted
overnight following the final dose. On the following morning, the animals are weighed,
then euthanized (by carbon dioxide asphyxiation) and the uteri rapidly collected (via a
mid-line ventral incision) and weighed.
Uterine weight/body weight ratios (UWR) are calculated for each animal. The
percent inhibition of the estrogen-induced response is then calculated by the following
formula: percent inhibition = 100 x (UWRestrogen - UWRtest compound/UWRestrogen
- UWRcontrol) ED50 values are derived from a semi-log regression analysis of the
linear aspect of the dose response curve. Both the UWR data and the percent inhibition
data are statistically analyzed by one way analysis of variance (ANOVA) with post-hoc

testing by Fisher's PLSD when indicated by a p ≤ 0.05. Statistical analyses are performed
using the Statview® 4.0 software package.
Morphine withdrawal, rat hot flash model: Simpkins et al. (1983) first published
morphine withdrawal in the rat as a putative model for hot flashes, based on observations
highlighting the similarity of symptoms of gonadal steroid withdrawal to those of opioid
withdrawal. Although less severe, the signis and symptoms associated with clinical hot
flashes, or estrogen deficiency, in the rat parallel those produced by naloxone-precipitated
withdrawal in morphine dependent rats, including: 1) an increase in tail skin temperature,
2) a surge in luteinizing hormone and 3) an increase in heart rate. Each of these responses
are associated with an increase in sympathetic outflow, which is a current mechanistic
hypothesis for hot flashes. As a corollary, morphine addicted humans show a withdrawal
pattern suggesting increased sympathetic outflow and symptoms that include hot flashes.
A key feature of animal models, is that they mimic the treatment efficacy observed with
the human disease. The morphine withdrawal hot flash model, either in its originally
described form, or with the modifications described herein, is responsive to agents
typically used in the treatment of human hot flashes. This includes various forms of
estrogen (Simpkins et al., 1983; LRL data), clonidine (LRL data), tibolone (LRL data),
and medroxyprogesterone (LRL data). Furthermore, the model is sensitive to agents
known to be associated with the induction of hot flashes in postmenopausal women.
A modification of the original procedure of Simpkins et al. (1983) is used which
employs ovariectomized Sprague-Dawley rats. Animals at 60 days of age (or 200-225
grams) are ovariectomized, and allowed a 14-day rest period to insure surgical recovery
and clearance of endogenous ovarian hormones. Administration of a compound of the
present invention (po or sc) is initiated on day 14 post-ovariectomy in a volume of 1
ml/kg. Once daily adminstration of test compound continues through the end of the
experiment. On days 15 and 17 post-ovariectomy, the rats are lightly anesthetized with
isoflurane and a single 75 mg morphine (free base) pellet is surgically implanted
subcutaneously.
On day 21 post-ovariectomy, animals are given ketamine (80 mg/kg; IM) 2-hours
after final administration of the test compound. Following induction of the anesthesia,
rats are then placed in individual plexiglass cages and temperature sensitive probes are

applied to the dorsal side of the tail base. Temperature monitoring is initiated 30 minutes
after administration of ketamine and is recorded every 15 seconds for a 1 -hr period. To
induce morphine withdrawal, 1 mg/kg naloxone is given subcutaneously 15 minutes after
start of temperature monitoring. A sharp rise in tail skin temperature typically occurs
within 5 minutes post-naloxone injection, and two quantitative endpoints are made: 1)
tail skin temperature at 15 min post-naloxone, and 2) area under the temperature response
curve for the 45-min post-naloxone measurement period. Following the 1-hour
temperature collectuion period, the animals are sacrificed by decapitation and trunk blood
is collected for assessment of serum LH levels (by ELISA). Uteri are also removed at this
time, and wet weight recorded.
Representative compounds of formula I were tested at or below 30 mg/kg PO and
caused an attenuation of tail skin temperature increase, as measured by temperature
change 15 minutes post naloxone injection or AUC over 45 minutes post naloxone
administration.
Utilities
As previously stated, the compound of formula I is useful in the treatment of
vasomotor symptoms, particularly hot flashes, in a woman, particularly a post-tnenopausal
woman. Typically, the compounds of the present invention are employed in a woman
who has suffered at least one vasomotor symptom event. Thus, the compounds of the
present invention are most typically employed to reduce the likelihood that the patient
will ftuther incur vasomotor symptoms.
Dose
The specific dose administered is determined by the particular circumstances
surrounding each situation. These circumstances include, the route of administration, the
prior medical history of the recipient, the symptom being treated, the severity of the
symptom being treated, and the age of the recipient. The recipient patient's attending
physician should determine the therapeutic dose administered in light of the relevant
circumstances.
Generally, an effective minimum daily dose of a compound of formula I will
exceed about 5 mg. Typically, an effective maximum daily dose will not exceed about

350 mg. The exact dose may be determined, in accordance with the standard practice in
the medical arts of "dose titrating" the recipient; that is, initially administering a low dose
of the compound, and gradually increasing the dose until the desired therapeutic effect is
observed.

We Claim:
1. A fluoro substituted compound of formula Ia:

wherein:
m is 0, 1 or 2;
n is 1, 2, 3 or 4 ;
R is H or methyl provided that if m is 1 or 2, then R must be H and that if m is 0,
then R must be methyl;
R1 is H, SO2(n-C4-C6 alkyl) or COR2;
X is O or NR3;
Y is O, S, SO or NR4;
R2 is C1-C6 alkyl; C1-C6 alkoxy; KR5R5a; phenoxy; or phenyl optionally
substituted with halo;
R3 and R4 are independently H or C1-C6 alkyl; and
R5 and R5a arc independently H, C1-C6 alkyl or phenyl; or a pharmaceutical acid
addition salt thereof.
2. The compound as claimed in claim 1 wherein m is 1 or 2, R1 is H or
COR2, R2 is C1-C4 alkyl, NHCH3 or phenyl, X is O and Y is O or S.
3. The compound as claimed in claim 1 or 2 wherein R1 is H.

4. The compound as claimed in any one of claims 1-3 wherein m is 1, and Y
is O.
5. The compound as claimed in any one of claims 1-3 wherein m is 1, and Y
is S.
6. The compound as claimed in any one of claims 1-5 wherein n is 2 and the
corresponding fluoro moieties are at the 3- and 5-positions.
7. The compound as claimed in any one of claims 1-4 wherein n is 1 and the
corresponding fluoro moiety is at the 4-position.
8. A compound as claimed in 1 which is

or a pharmaceutical acid addition salt thereof.
9. A compound as claimed in any one of claims 1-8 for use in treating one or
more vasomotor symptoms.
10. A pharmaceutical composition comprising a compound or a
pharmaceutically acceptable salt thereof as claimed in any of the preceding
claims, and a pharmaceutically acceptable carrier, diluents or excipient.
11. A fluoro substituted compound substantially as herein described with
reference to the given examples.




The present invention discloses compounds of Formula Ia,

Or a pharmaceutical acid addition salt thereof useful as selective estrogen receptor
modulators and pharmaceutical composition thereof.

Documents:

02478-kolnp-2006 abstract.pdf

02478-kolnp-2006 assignment.pdf

02478-kolnp-2006 claims.pdf

02478-kolnp-2006 correspondence others.pdf

02478-kolnp-2006 description[complete].pdf

02478-kolnp-2006 form-1.pdf

02478-kolnp-2006 form-2.pdf

02478-kolnp-2006 form-3.pdf

02478-kolnp-2006 form-5.pdf

02478-kolnp-2006 international publication.pdf

02478-kolnp-2006 international search authority report.pdf

02478-kolnp-2006 pct form.pdf

02478-kolnp-2006-correspondence others-1.1.pdf

02478-kolnp-2006-form-1-1.1.pdf

2478-KOLNP-2006-(11-01-2012)-CORRESPONDENCE.pdf

2478-KOLNP-2006-ABSTRACT 1.1.pdf

2478-KOLNP-2006-CLAIMS.pdf

2478-kolnp-2006-correspondance 1.1.pdf

2478-kolnp-2006-correspondence.pdf

2478-KOLNP-2006-DESCRIPTION (COMPLETE) 1.1.pdf

2478-kolnp-2006-drawings.pdf

2478-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

2478-kolnp-2006-examination report.pdf

2478-KOLNP-2006-FORM 1 1.1.pdf

2478-KOLNP-2006-FORM 13-1.1.pdf

2478-kolnp-2006-form 13-1.2.pdf

2478-KOLNP-2006-FORM 13.pdf

2478-kolnp-2006-form 18.pdf

2478-KOLNP-2006-FORM 2 1.1.pdf

2478-kolnp-2006-form 26.pdf

2478-KOLNP-2006-FORM 3 1.1.pdf

2478-kolnp-2006-form 3-1.2.pdf

2478-kolnp-2006-form 3.pdf

2478-kolnp-2006-form 5.pdf

2478-KOLNP-2006-FORM-27.pdf

2478-kolnp-2006-granted-abstract.pdf

2478-kolnp-2006-granted-claims.pdf

2478-kolnp-2006-granted-description (complete).pdf

2478-kolnp-2006-granted-form 1.pdf

2478-kolnp-2006-granted-form 2.pdf

2478-kolnp-2006-granted-specification.pdf

2478-kolnp-2006-others-1.1.pdf

2478-KOLNP-2006-OTHERS.pdf

2478-KOLNP-2006-PA.pdf

2478-KOLNP-2006-PETITION UNDER RULE 137.pdf

2478-kolnp-2006-petiton under rule 137 1.1.pdf

2478-kolnp-2006-reply to examination report.pdf

abstract-02478-kolnp-2006.jpg


Patent Number 247909
Indian Patent Application Number 2478/KOLNP/2006
PG Journal Number 22/2011
Publication Date 03-Jun-2011
Grant Date 01-Jun-2011
Date of Filing 22-Aug-2006
Name of Patentee ELI LILLY AND COMPANY
Applicant Address LILLY CORPORATE CENTER, CITY OF INDIANAPOLIS, STATE OF INDIANA
Inventors:
# Inventor's Name Inventor's Address
1 FRANK, SCOTT, ALAN 5421 CRANLEY CIRCLE, INDIANAPOLIS, INDIANA 46220
2 SHEPHERD, TIMOTHY, ALAN 8705 COUNTRY WOODS COURT, INDIANAPOLIS, INDIANA 46217
3 WALLACE, OWEN, BRENDAN 4341 CHASE CIRLCE, ZIONSVILLE, INDIANA 46077
4 DALLY, ROBERT, DEAN 9656 LOGANBERRY LANE, INDIANAPOLIS, INDIANA 46256
5 HINKLIN, RONALD, JAY 3515 BLUESTEM AVENUE, LONGMONT, COLORADO 80503
6 DODGE, JEFFREY, ALAN 7110 LANTERN ROAD, INDIANAPOLIS, INDIANA 46256
PCT International Classification Number C07D 295/08
PCT International Application Number PCT/US2005/000020
PCT International Filing date 2005-01-18
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/538,342 2004-01-22 U.S.A.
2 60/538,442 2004-01-22 U.S.A.