ZA200605665B

ZA200605665B - Selective estrogen receptor modulators for the treatment of vasomotor symptoms

Info

Publication number: ZA200605665B
Application number: ZA200605665A
Authority: ZA
Inventors: Dally Robert Dean; Frank Scott Alan; Shepherd Timothy Alan; Dodge Jeffrey Alan; Hinklin Ronald Jay; Wallace Owen Brendan
Original assignee: Lilly Co Eli
Priority date: 2004-01-22
Filing date: 2006-07-10
Publication date: 2008-05-28
Also published as: CN1910167A; CN1910167B

Description

SELECTIVE ESTROGEN RECEPTOR MODULATORS FOR THE

TREATMENT OF VASOMOTOR SYMPTOMS

Background of the Invention

S

“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 thereof. :

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, €.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 ITI 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,

: 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: (CH), ( -Enex

Q

WIC

OF wherein: : mis 0,1 or2; nis1,2,30r4;

R is H or methyl provided that if m is 1 or 2, then R must be H and that ifmisO, then R must be methyl,

R1 is H, SO(n-C4-Cg alkyl) or COR;

X is O or NR3; x1 is O, CH or C=0;

RS is H or F or RO combines with X1 to form a moiety of the formula: (CH), (jem S

R Y

3} Nee wherein Y is O, S, SO or NR4;

R2 is C1-Cg alkyl; C1-Cg alkoxy; NRSR58; phenoxy; or phenyl optionally substituted with halo;

R3 and R# are independently H or C1-Cg alkyl; and

RS and R32 are independently H, C1-Cg 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, 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], 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:

CH),

N—(CH,),-X 8 Q xR ”

Rr! oO 9%

I; or an acid addition salt thereof; wherein m, n, R, and X1 areas defined above for a formula I compound and:

R12 is H, SO,CHj, SO;(n-C4-Cg alkyl), COR, C1-Cg alkyl or benzyl;

RS is H or F or R6 combines with X1 to form a moiety of the formula:

oc i

N—(CH,);—X < : Y

R

RY: 0 CO wherein Y is as defined above for a formula I compound;

X2 is O or NR7; and

R7 is H, C1-Cg alkyl or CO(C}-Cg alkyl); provided that if Rlais H, SOo(n-C4-Cg alkyl) or COR2, then X2 is NR7 and R7 is CO9(C1-Cg alkyl); useful as an intermediate to a compound of formula L

The present invention also relates to a compound of formula III: (Cenc

N—(CH,);—X

SOAK

R z ”

R20 CC

Cm or an acid addition salt thereof, wherein m, n, R and R12 are as defined above for a formula II compound and wherein:

X2 is O or NR7,

R8 is OH, O(C1-Cg alkyl), S(C1-Cg alkyl) or NR4(CO5(C1-Cg alkyl)

Z is C=0 or CHOH; and

R7 is H, C1-Cg alkyl or CO2(C1-Cg alkyl); useful as an intermediate to a compound of formula I where RO combines with X1.

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-Cg alkyl” represents a straight, branched or cyclic hydrocarbon moiety having from one to six carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec- butyl, t-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl and the like. Moieties such as a cyclobutylmethylenyl and cyclopropylmethyleneyl are also included within the scope of a C1-Cg alkyl group. The term “Cq-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-Cg alkyl” refers specifically to n- butyl, n-pentyl and n-hexyl. A “C1-Cg alkoxy” group is a C1-Cg alkyl moiety connected through an oxy linkage. } The term “pharmaceutical” when used herein as an adjective means substantially non-deleterious.

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; l-malate; malonate; d-mandelate; 1- mandelate; methanesulfonate; 1,5 napthalenedisulfonate; 2-naphthalenesulfonate; phosphate; salicylate; succinate; sulfate; d-tartrate; I-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 ina 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: (CH, {x —(CHy,-x (CH),

R Q 3 (erm 2) 3

RE

5

R'O LC ° R'O CC 6 a) mis 1; b) ROisHorFandnis 1,2 or3;

C) nisl, 2or3; d) nis 1 or?2; e) nisi;

D nis 2; 2) RO is H or combines with X1, n is 1 and the corresponding fluoro moiety is in the 4-position; h) RO is H or combines with X1, n is 2 and the corresponding fluoro moieties are in the 3,5-positions; i) Rlis H; h) R1 is H or COR2 and R2 is C1-Cg alkyl or phenyl; kf RI is H or COR2 and R2 is C1-Cy4 alkyl, NHCH3 or phenyl;

D R3 is H, methyl or ethyl; m) R3isH; n) X is O; 0) X is NR3 and R3 is H or methyl;

Pp) X1is 0; q RbisHorF; r) R6 combines with X1;

S) the hydrochloride salt form.

With respect to the chiral center designated below: (CH), Chiral Center (mr e

R Y nee 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- i

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.€., 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 R82 is RS, H, or F), Preparations and Examples.

Scheme 1 ag! RE

A D

: ©

R'%0 .

Iv | \Y%

CH),

N-(CH,);~ ag! Rr%

R X' , pes

VI

When X! is CO and R32 / is other than H When R32 is H or F

Y

Carbonyl reduction then cyclization ~~

Removal of Hydroxy/Amino

Protecting Group(s) if Present

Optional R! Derivatization

Formula I

Compound

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 R82 is R8 then of formula IT). 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 R82 is F, base catalyzation with potassium t-butoxide or when R84 is other than F, acid catalyzation with HCI, 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 R12 is SO»CHj3, C-Cg alkyl or benzyl (preferably methyl, benzyl or

SO, CH3) 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 Rl is H. Similarly, when X2 is NR7 and R7 is CO2(C1-Cg 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 CORZ or

SO2(n-Cy4-Cg 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/TPA 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

SARE

0

OSO,CF,

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 1-bromo-6-methoxy-naphthalen-2-ol (66.7 g, 264 mmol), potassium carbonate (KpCO3,40.0 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 3X

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 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxyl-ethyl }-piperidine (30%).

Add 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-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); on carbon (20 % ww, 1.58 g, 1.12 mmol). Reflux for 50 minutes then 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 NaHCOj 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

SARE! o F 9 seat :

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 heatto 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 1-(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 Iyophilize. 1H-NMR (CDCls, 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, } = 6.0 Hz, 2H); 2.52- 2.52 (m, 4H); 1.64-1.59 (m, 4H); 1.46-1.44 (m, 2H).

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

SRC!

CH 0 0)

SIT

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 (10mL) and add 2-fluorophenylboronic acid (240mg, 1.71 mmol), tricyclohexylphosphine 43mg, 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 the free base in 3mL ether and add 0.8 mL of 1N HCI. Immediately dry to give 305 mg of the titlte compound: mass spectrum (ion spray) m/z =472(M-CI).

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 1-(2-{4-[2-(2-fluoro-phenyl)-6- methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine hydrochloride (290 mg, 0.57 mmol) in 5SmL anhydrous CHCl, and cool to 0 °C under nitrogen. Add 2.90 mL (2.90 mmol) of a 1M CH,C]l, solution of BBr; 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/CH,Cl, 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 HCl in Et,O solution: mass spectrum (ion spray) m/z =458 (M-Cl). .

Example 5 1-(2- {4-[2-(2,4-Difluoro-phenyl)-6-methoxy-naphthalen- 1-yloxy]-phenoxy } -ethyl)- piperidine hydrochloride

OT

CH 0 0) ]

Combine trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)- phenoxy]-naphthalen-2-yl ester (2.99 g, 5.70 mmol), 2,4-difluoro-benzeneboronic acid (2.70 g, 17.09 mmol), palladium(IT)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 1N 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-CI).

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 1-(2-{4-[2-(2,5-Difluoro-phenyl)-6-methoxy-naphthalen- 1-yloxy]-phenoxy } -ethyl)- piperidine hydrochloride

SHAS

CH 0 C] ~ o C1) F

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), [1,1’-bis(diphenylphosphino)-ferrocene)dichloropalladium (II), 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-CI).

Example 8 6-(2,5-Difluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol hydrochloride

Dissolve 1-(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-CI).

Example 9 1-(2-{4-[6-Methoxy-2-(3,4,5-trifluoro-phenyl)-naphthalen-1-yloxy] -phenoxy}-ethyl)- piperidine

OQ, J o) (] F

OJ

~o

Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1- yl-ethoxy)-phenoxyl-naphthalen-2-yl ester (800 mg, 1.52 mmol), 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(IT)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 HCl 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-yloxy]-phenoxy}-ethyl)- piperidine

OA

AO

0

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(Il)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-Diflucro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol hydrochloride

Using the procedure demonstrated in Example 10, react 1-(2-{4-[2-(2,3-difluoro- phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy} -ethyl)-piperidine (622 mg, 1.27 mmol), 2M HCl 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 : 1-(2-{4-[2-(3,5-Difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy} -ethyl)- piperidine

OQ, J tL

J

~o

Using the procedure demonstrated in Example 9, react trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-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(Il)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 1-(2-{4-[2-(3,5-difluoro- phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine (3.8 g, 7.9 mmol), 2M HCl 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-Cl).

Example 15 6-(3.,4-Difluoro-phenyl)-5-[4-(2-piperidin- 1-yl-ethoxy)-phenoxy}-naphthalen-2-ol hydrochloride

Shae! .

F

CH Q 4g

HO g 3

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

Preparation 2 4-[2-(3-Fluoro-phenyl)-6-methox y-naphthalen-1-yloxy]-phenol

QL

9

SOA

~ ©

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 SN 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) (10mL) 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 (10mL) 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 100mL).

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 CH,Cl, to yield 540 mg (22%) of the title compound: mass spectrum (ion spray) m/z = 359 (M-H). : Example 16 1-(2-{4-[2-(3-Fluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine hydrochloride

OT

CI 0 C oy ~o

To 4-[2-(3-fluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenol (180 mg, 0.50 mmol) in 10mL anhydrous DMF is added sodium hydride (60 mg, 60% oil dispersion, 1.50 mmol) and the solution stirred 30 minutes at room temperature. Add 1-(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 (1x), brine (1x), extract the organics and dry over sodium sulfate. Purify the crude product using radial chromatography eluting with 4% MeOH/CH,Cl, 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 Et,O 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 100mL round-bottom flask with 1-(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 CHCl, solution of

BBr; 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/CH; 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 Et,0 solution: mass spectrum (ion spray) m/z =458(M-Cl).

Preparation 3 4-[6-Benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-phenol “QL oY

BnO

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 CH,Cl; (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 IM 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 1N HCI (540 mL). Add H,O (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 (3.0L) 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-benzyloxy-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/dichloromethane (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 SM 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 1N HCI, 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-phenyl)-naphthalen-1-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 alkoxide 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-yloxy]-benzaldehyde.

Add 18M H,SO4 (1 mL, 16.8 mmol) dropwise into a solution of H,O; (1 mL, 9.7 mmol) and 4-[6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen- 1-yloxy]-benzaldehyde at 0 °C and stir at room temperature for 12 hours. Add H,O (20 mL) and CH,Cl, (100 mL).

Separate layers and extract the aqueous layer with CH,Cl, (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 1-(2-{4~[6-Benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-phenoxy}-ethyl)- piperidine

SAAC

BnO CC

Dissolve 4-[6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-phenol (5.20 g, 11.91 mmol) in DMF (60 mL) under N; and add NaH (1.43 g, 35.74 mmol, 60%wt). Stir the solution for 0.5 hours at room temperature then add 1-(2-chloro-ethyl)-piperidine, HCI salt (3.29 g, 17.87 mmol). Continue to stir the solution for and then add water (300 mL).

Extract the aqueous layer with CH,Cl, (3 x 300 mL) and then combine the organic layers.

Dry the organic layer with Na;SOy, then filter, concentrate and purify it by flash column chromatography (silica gel, 0-4% MeOH-NH,OH (10/1, vIV)ICH,C,) 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-1-yloxy]- phenoxy }-ethyl)-piperidine (6.5 g, 11.87 mmol) in MeOH/THF (200 mL, v/v=1/1) under

N,. Add Pd/C (0.65 g, 10%) and exchange the N; for Hj 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-NH4OH (10/1, v/v)/ CH2Cl) 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 CH,Cl, (100 mL), and cool it to —78 °C. Add HCI (10 mL, 2.0 M in Et,0), 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

Trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy- naphthalen-2-yl ester

SARS

0]

OSO,CF,

LIC

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 (S00 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 1-{2-[4-(2-benzyloxy-6- methoxy-naphthalen- 1-yloxy)-phenoxy]-ethyl } -azepane.

Dissolve 1-{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 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 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy- naphthalen-2-yl ester.

Example 20 1-(2-{4-[2-(3,5-Difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy} -ethyl)- azepane

Rae! :

CO) 0 4

J

~o

Dissolve trifluoromethanesulfonic acid 1-{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-ol hydrochloride

Dissolve 1-(2-{4-[2-(3,5-difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]- phenoxy}-ethyl)-azepane (583 mg, 1.2 mmol) in dichloromethane (10 mL). Cool to 0 °C, add 2M HCI(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 HCI (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-CI).

Example 22 1-(2-{4-[2-(3 4-Difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy} -ethyl)- azepane

AR

C 0 0) F oy ~0

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-1-yl-ethoxy)-phenoxyl-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/Pcy; 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 NaHCOj3 (10 mL). Separate the layers, wash the organic layer with brine (10 ml), dry with MgSO, filter, and concentrate in vacuo. Chromatograph the residue on a SiO, 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 1-(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 HCI 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

NaHCO; (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 MgSO, filter, and concentrate in vacuo. Chromatograph the residue on a SiO; 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 HCI (1 mL, 2.0 mmol) in diethyl ether. Collect the precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2mm of Hg) to give 310 mg (47 %) of the title compound: mass spectrum (ion spray) m/z = 490.3 (M-Cl).

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

IG

J GH 0 CO) or ~o

Prepare this compound following the procedure to make 1-(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 a1 M HCI in Et,0 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 HCl in Et,0 solution: mass spectrum (ion spray) m/z =472 (M-Cl).

Example 26 1-(2-{4-[6-Benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-phenoxy}-ethyl)-azepane

OQ

0 4g F

BnO CC

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

H,0 (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 1-(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 CH,Cl, and wash with H,O (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 HCI (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-Cl).

Preparation 5

Trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl}- naphthalen-2-yl ester

OQ

0)

EC

LI

In a dry round bottom flask equipped with stir bar, temperature probe and N» line, dissolve 2,6-dimethoxynaphthalene (1.0 eq) in CHCl» (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 CHCl. Wash the aqueous layer with (1 x 20 mL) of CHCl.

Combine the organic extracts and wash with brine and dry (NapSOy4). Recrystallize the crude product from methanol to give (2,6-dimethoxy-naphthalen-1 -y)-[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 CHCl (10 volume equivalents) in a 3-neck round bottom flask equipped with a pressure equalizing addition funnel, stirbar, and Nj source. Cool the flask in an ice/brine bath and add 1.0 M BCl3 solution in CHpClj (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, Ether:Petroleum

Ether). Quench the reaction with methanol (5 equivalents) and allow to warm to room temperature. Dilute the organic solution with CHCl (one volume equivalent) and add to a 1.0 M NaHCO3 solution (5 volume equivalents) and stir for one hour. Separate the aqueous and organic layers. Wash the aqueous layer with CH, Cl) (one volume) and the combine organic layers, wash with saturated NH4Cl and dry over NapSOy4. Purify the product via column chromatography (50/1 silica gel) eluting with CHpCly/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)- phenyl]-methanone in CHCl (10 volumes) in a three neck round bottom flask equipped with a stir bar and Ny 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 H>O (10 volumes), wash with 1

NHCI(S volumes), wash with 1.0 N NaHCO3, and dry over NapSQOy4. Concentrate to y give the title compound in quantitative yield. Use the product without further purification.

Example 28 [2-(2,4-Difluoro-phenyl)-6-methox y-naphthalen- 1-yl]-[4-(2-piperidin- 1-yl-ethoxy)- phenyl]-methanone

N ~_©O oO 2) F

JT

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 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 29 [2-(2,4-Difluoro-phenyl)-6-hydroxy-naphthalen-1-y1]-[4-(2-piperidin- 1-yl-ethoxy)- phenyl]-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 HCl 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 (CDCl) 67.72 (d, J = 8.6 Hz, 1H), 7.49 (d,/=8.6Hz,3H),7.35(d,J=84Hz, 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

OQ J

Oo O)

JEavs

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), (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-NH,OH (10/1, v/v)/ CH,Cl,) 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 BBr; 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 al :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

NO ge

SOE

MsO

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 mi 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 ammonija/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-yi]-[4-(2-piperidin-1-yl-ethoxy)- phenyl]-methanone

NO i

SIT

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 (CDCl3, 400 MHz) 6 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 34 [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 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 (CD;OD, 400 MHz) 67.87 (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-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]- naphthalen-2-yl ester

Shae

Oo

BnO 9

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 N; and add benzyl alcohol (2.78 g, 25.8 mmol), polymer-PPh; (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

CHCl, (3 x 500 mL). Combine the organic layers and dry with Na;SO,, filter, concentrate and purify by flash chromatography (silica gel, 0-4% MeOH-NH4OH (10/1, vIv)/ICH,Cl) 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

Shae 5g of rads

Dissolve trifluoromethanesulfonic acid 6-benzylox y-1-[4-(2-piperidin-1-yl- ethoxy)-benzoyl]-naphthalen-2-yl ester (1.00g, 1.63 mmoles) in 20 ml of acetonitrile and add 2-flourobenzene boronic acid (0.46 g, 3.26 mmol), trans[dichlorobis(triphenylphosphine)] 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%). © Example36 [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-phenyl)-naphthalen- 1-y1]-{4-(2-piperidin-1-yl-ethoxy)- phenyl]-methanone

She pred

ATT

:

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)- phenyl}-methanone

Dissolve [6-methoxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin- 1-yl-ethoxy)-phenyl]-methanone (670 mg, 1.3 mmol) in dichloromethane (10 mL). Cool to 0 °C, add 2M HCI (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

Sage 0

MsO oe

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 m}).

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-triftuoro-phenyl)-naphthalen-1-y1]-[4-(2-piperidin-1-yl-ethoxy)- phenyl]-methanone

OTL J

0) prset

HO F :

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)paliadium (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)- phenyl]-methanone

NO 7) | F

Pe

AIT

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-1,3,4-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-ethox y)- phenyl]-methanone

Demethylate [6-methoxy-2-(2,3,6-trifluoro-phenyl)-naphthalen-1-yl1]-[4-(2- piperidin-1-yl-ethoxy)-phenyl]-methanone (0.79 g, 1.52 mmol) with BBr; 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

She F

ALC

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 ammonia/methanol/methylene chloride to give 880 mg (43%) of the title compound: 1H-NMR (CD;0D, 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); 2.72-2.609 (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-ethox y)- phenyl]-methanone

Dissolve [6-methoxy-2-(2,3 4-trifluoro-phenyl)-naphthalen- 1-y1}-[4-(2-piperidin- 1-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 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 3A 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 (CD;0D, 400 MHz) 57.89 (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, ] = 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

Pe

LSE

0

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/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: IH-NMR (CD3;OD, 400 MHz) 67.92 (d, J = 8.8 Hz, 1H); 7.54 (dd, J =84,4.0Hz, 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-1-yl]-[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 HCV/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 atwo 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 (32%) of the title compound: 1H-NMR (CDs;OD, 400 MHz) 67.84 (d,J= 8.4 Hz, 1H); 7.55 (d, ] =9.2 Hz, 2H); 7.50 (d, ] = 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, 1 =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

Se 0

ATS

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-y1]-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]- methanone hydrochloride

SNe

CH 7° C]

J

HO

Charge a flask with trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1- yl-ethoxy)-benzoyl] -naphthalen-2-yl ester (500 mg, 0.96 mmol) and add 10 mL water along with 2 mL of 1,2 dimethoxyethane. To this add 3-flucrophenylboronic 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 HCI salt: 1H-NMR (CDCl3, 300 MHz) 8 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 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl}-6- methoxynaphthalen-2-yl ester

SARS

Oo

AT

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 mol). 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)-phenyl]}-(2-hydroxy-6-methoxy-naphthalen-1- yD)-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 1-[4-(2-azepan-1-yl-ethoxy)- benzoyl]-6-methoxynaphthalen-2-yl ester

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 1-{2-[4-(2-benzyloxy-6- methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl }-azepane.

Dissolve 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl } - azepane (19 g, 38 mmol) in ethyl acetate (S00 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.

~-49-

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 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.

Example 47 [4-(2-Azepan-1-yl-ethoxy)-phenyl]-[6-methoxy-2-(2,4,6-trifluoro-phenyl)-naphthalen-1- yl]-methanone

Shs

Sv ~o oe j

Dissolve trifluoromethanesulfonic acid 1-[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 HCI (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]-[2-(2-fluoro-phenyl)-6-methoxy-naphthalen-1-yl]- methanone

Oa } ATT I

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 IT (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)-phenyl]-[2-(2-fluoro-phenyl)-6-hydroxy-naphthalen-1-yl]- methanone hydrochloride

Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2-fluoro-phenyl)-6-methoxy- naphthalen- 1-yl]-methanone (550 mg, 1.11mmol) 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 lyopholize 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 apsoys

ANT

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

N ~0 F

Pe

SOOA

Couple trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6- methoxynaphthalen-2-yl ester (1.48 g, 2.67 mmol) with 2-bromo-1,3,4-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-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 BBr; 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 HCI salt: mass spectrum (ion spray) m/z = 520.3 (M-CD).

Example 54 : [4-(2-Azepan-1-yl-ethoxy)-phenyl]-[2-(2,4-difluoro-phenyl)-6-methoxy-naphthalen-1-y1]- methanone

Sais

O 7) F as

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-yl-ethoxy)-phenyl]- [2-(2,4-difluoro-phenyl)-6-hydroxy-naphthalen-1-y1]- methanone hydrochloride

Demethylate [4-(2-azepan-1-yl-ethoxy)-phenyl]}-[2-(2,4-difluoro-phenyl)-6- methoxy-naphthalen-1-yl]-methanone (1.1 g, 2.1 mmol) with BBr; (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

NO

Ory oO

Charge a flask with trifluoromethanesulfonic acid 1-[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 (CDCls, 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 (CDCls, 400 MHz) § 7.79-7.74 (4, 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 (in, 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-y1]- methanone

NE 4 F ie

ALT

©

Dissolve trifluoromethanesulfonic acid 1-[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-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 give 780 mg (46%) of the title compound: 1H-NMR (CDCls, 300 MHz) 6 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); 3.03-2.97 (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- yl]-methanone

NAO F

GAN ULE

F os

Dissolve trifluoromethanesulfonic acid 1-[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-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.

Preparation 10

Trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]- naphthalen-2-yl ester

OQ ow ~o

Dissolve (2,6-dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-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 toroom 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)- phenyl]-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 vacuo to give 1-{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(trifluoromethanesulfonimide (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

OTOL J

Pets

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 a0-10% methanol/methylene chloride gradient. Concentrate to give 430 mg (46%) of the title compound: 1H-NMR (CDCl3, 300 MHz) 67.85 (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 (mm, 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-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl] -naphthalen-2-ol hydrochloride

Dissolve 1-(2-{4-[2-(2,5-difluoro-phenyl)-6-methoxy-naphthalen-1-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 (CDCls, 300 MHz) 67.77 (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

OC

7) F

Paty

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-difluoropheny! boronic acid (0.60 g, 3.82 mmol), trans dichlorobis(triphenylphosphine)] palladium 1 (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-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol hydrochloride

Dissolve 1-(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 1-(2-{4-[2-(4-Fluoro-phenyl)-6-methoxy-naphthalen-1-ylmethyl]-phenoxy }-ethyl)- piperidine 0 oY

LOC

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(triphenylphosphine)] 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-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol hydrochloride

Dissolve 1-(2-{4-[2-(4-fluoro-phenyl)-6-methoxy-naphthalen-1-ylmethyl]- 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 1-(2-{4-[2-(2-Fluoro-phenyl)-6-methoxy-naphthalen-1-ylmethyl]-phenoxy}-ethyl)- piperidine - 25% 0e

JT

Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)- benzyl]-naphthalen-2-yl ester (1.0 g, 1.9 mmol), 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).

Claims

PC'1/US2005/000020 S125 - We claim

1. A compound of formula I: (CH, ( N—(CH,),-x R Q Re X : WSC I; wherein: mis 0, 1 or2; nisl, 2,3o0r4; R is H or methyl provided that if m is I or 2, then R must be H and that if m 1s 0, then R must be methyl; R1 is H, SOy(n-C4-Cg alkyl) or CORZ; X is O or NR3; X1is 0, CHj or C=0; RO is H or F or RO combines with X1 to form a moiety of the formula: (CH,),, N—(CH,);—X 2) Y R 8 - Cre R'O wherein Y is O, S, SO or NR4; RZ is C|-Cg alkyl; C-Cg alkoxy; NRSRS4; phenoxy; or phenyl optionally substituted with halo; R3 and R% are independently H or C-Cg alkyl; and RS and R32 are independently H, C|-Cg alkyl or phenyl; or a pharmaceutical acid addition salt thereof; wherein said compound of formula I is not: AMENDED SHEET

PCT/US2005/000020 ® 126- SRC ? DO HO

2. The compound of claim | whereinm is 1 or 2, R! is H or CORZ, RZ is C- C4 alkyl, NHCH3 or phenyl, X is O, xX) is Oor CHpand YisOorS.

3. The compound of claim | or 2 wherein R1 is H.

4. The compound of any one of claims 1-3 wherein m is 1, RO is H or F; and xliso.

5. The compound of any one of claims 1-3 wherein mis 1, RO combines with X! and Y is O.

0. The compound of any one of claims 1-3 whereinm is 1, RO combines with Xl and Y is S.

7. The compound of any one of claims 1-4 wherein the total number of fluorine atoms at nn and RO is 1,2 or 3.

8. The compound of any one of claims 1-4 wherein the total number of fluorine atoms at n and RO is 1 or 2.

9. The compound of any one of claims 1-3, 5 or 6 wherein RO combines with X1 nis 2 and the corresponding fluoro moieties are at the 3- and 5- positions. AMENDED SHEET

PCT/US2005/000020 ® -127 -

10. The compound of any one of claims 1-3, 5 or 6 wherein RO combines with X1, nis 1 and the corresponding fluoro moiety is at the 4-position.

I. The compound of any one of claims 1-4, 7 or 8 wherein RO is H, nis 2 and the corresponding fluoro moieties are at the 3- and 5-positions.

12. The compound of any one of claims 1-4, 7 or 8 wherein RO is H, nis 1 and the corresponding fluoro moiety is at the 4-position.

13. A compound of the formula: 0) NT F (

HO . or a pharmaceutical acid addition salt thereof.

14. A compound of any one of claims 1-13 for usc in treating one or more vasomotor symptoms.

15. The compound of claim 14 wherein one symptom is treated and that symptom is hot flash. AMENDED SHEET

PCT/US2005/000020 ® 128

16. A compound of formula II: (CH,),, { N—(CH,),-x R Q : x! RS a Hes 11; wherein: misO, 1 or2; nisl,2,3o0r4; R is H or methyl provided that if m is 1 or 2, then R must be H and that it m is 0, then R must be methyl; Rais H, SO»CH3, SO9(n-C4-Cg alkyl), CORZ?, C-Cg alkyl or benzyl, X!1 is 0, CHy or C=0; X2 is O or NR7, RO is H or F or RO combines with X1 to form a moiety of the formula: (CH,),, ie 2 N—(CH,);—X 0) R Y (F), RO 8 8 wherein Y is O, S, SO or NR#4; RZ is C-Cg alkyl; C1-Cg alkoxy; NRIRS2; phenoxy; or phenyl optionally substituted with halo; R% is H or C-Cg alkyl; RS and R34 are independently H, C1-Cg alkyl or phenyl; AMENDED SHEET

PCT/US2005/000020 ® - 129 - R7 is H, C{-Cg alkyl or CO9(C|-Cg alkyl); provided that if R12 is H, SO(n-Cy4- Cg alkyl) or CORZ, then X2 is NR7 and R7 is COy(Cy-Cg alkyl); or an acid addition salt thereof; wherein the compound of formula 11 is not: oa, J ge. F

17. The compound of claim 16 wherein m is 1, Rlajg SO»CH3, benzyl or methyl, RO combines with X1, Yis O or S, and X2 is O.

18. The compound of any one of claim 16 or 17 wherein n is 2 and the corresponding fluoro moieties are at the 3- and 5-positions.

19. The compound of claim 16 which is NO F bg SO CH,S0;0 ] or an acid addition salt thereof. AMENDED SHEET

PCT/US2005/000020 ® 130

20. A compound of formula III: (CHy),, 5 R z poses a rR'?0 ® HI, wherein: mis 0, 1 or 2; nisl, 2,3or4, 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; R1a is H, SO9CH3, SOp(n-C4-Cg alkyl), CORZ, C-Cg alkyl or benzyl; R8 is OH, O(C1-Cg alkyl), S(C-Cg alkyl) or NR4(CO»(Cy-Cq alkyl)) X2 is O or NR7; Z is C=0 or CHOH; RZ is C|-Cg alkyl; C1-Cg alkoxy; NRIR32; phenoxy; or phenyl optionally substituted with halo; R4 is H or C|-Cg alkyl, RS and R32 are independently H, C1-Cg alkyl or phenyl; and R7 is H, C|-Cg alkyl or CO(C|-Cg alkyl); or an acid addition salt thereof.

21. The compound of claim 20 whereinm is I, nis 1 or 2, Rla js H, SO»CH3, benzyl or methyl and X2 is 0.

22. The compound of claim 20 or 21 wherein n is 2 and the corresponding fluoro moieties are at the 3- and 5-positions. AMENDED SHEET

PCT/US2005/000020 ® - 131 -

23. The compound of any one of claims 20-22 wherein RE is OH, O(CH3), OCH(CH3)y, S(CH3) or NR4(CO7(t-butyl)) and R* is H or methyl.

24. The compound of claim 20 selected from the group consisting of: NP E NO = () ) 9 CH,SO;0 ~S CH,SO,0 ~S 32 and 3ITT2 : or an acid addition salt thereof.

25. Use of a compound of any one of claims 1 -13 in the manufacture of a medicament for treating one or more vasomotor symptoms.

26. A compound according to any one of claims 1 to 24, substantially as herein described with reference to and as illustrated in any of the examples.

27. Use according to claim 25, substantially as herein described with reference to and as illustrated in any of the examples. AMENDED SHEET