KR20050019912A - Selective estrogen receptor modulators containing a phenylsulfonyl group - Google Patents

Abstract

The present invention relates to selective estrogen receptor modulators of formula (I) or pharmaceutical acid addition salts thereof useful for treating, for example, endometriosis and / or leiomyoma / leiomyoma of the uterus.

<Formula I>

Description

Selective ESTROGEN RECEPTOR MODULATORS CONTAINING A PHENYLSULFONYL GROUP}

Leiomyoma / leiomyoma of the uterus (fibromyoma of the uterus) is a clinical problem that progresses under various names (including fibrosis of the uterus, hypertrophy of the uterus, myoma of the uterus, myometrial hypertrophy, uterine fibrosis, and fibrous uteritis). In essence, uterine fibrosis is a condition where there is an inappropriate deposition of fibroblastic tissue on the uterine wall. This condition is the cause of dysmenorrhea and infertility in women.

Endometriosis is a condition of severe dysmenorrhea, which is accompanied by severe pain, endometrial masses or bleeding into the abdominal cavity, often leading to infertility. The cause of the symptoms is thought to be ectopic endometrial growth that is inappropriately responding to normal hormonal regulation and is located in inappropriate tissue. Because of the improper location of endometrial growth, the tissue appears to initiate a local inflammatory-like response that results in a series of processes leading to macrophage infiltration and the onset of painful responses. Evidence suggests that the cause of uterine fibrosis and endometriosis is an inappropriate response of fibroid tissue and / or endometrial tissue to estrogen.

Many publications describing selective estrogen receptor modulators (SERMs) have appeared in recent decades (US Pat. Nos. 5,484,795, 5,484,798, 5,510,358, 5,998,401 and WO 96/09040). Many of these SERMs, generally speaking, have been known to have beneficial estrogen agonist activity in the bone and cardiovascular system and beneficial estrogen antagonist activity in the breast. Small, particularly useful subsets of such compounds have also been known to have estrogen antagonist effects in the uterus. Compounds with this SERM profile have particular prospects for treating uterine fibroid disease and / or endometriosis.

However, in the treatment of uterine fibroid disease and / or endometriosis, especially in premenopausal women, the clinical use of such SERM compounds has been hampered by the properties of these compounds with significant ovarian stimulatory effects. Thus, there is a great need for new SERM compounds that act as estrogen antagonists in the uterus that do not significantly stimulate the ovaries.

Summary of the Invention

The present invention relates to a compound of formula (I) or a pharmaceutical acid addition salt thereof:

Where

m, q and r are independently 0, 1 or 2;

n is 0 or 1;

R is H or COR ² ;

R ⁰ is independently at each occurrence OH, CF ₃ , halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

R ¹ and R ^{1 ′} are independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ³ R ^3a , CF ₃ or CH ₂ CF ₃ ; Or when n and q are 0, the —SO ₂ R ¹ residue may be combined with an attached phenyl ring to form a residue of formula (a) or (b)

(Where t and v are 0, 1 or 2 provided that the sum of t + v is 2);

R ² is C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; NR ⁴ R ⁴ ; Phenoxy; Or phenyl optionally substituted with halo;

R ³ is C ₁ -C ₆ alkyl or phenyl;

R ^3a and R ⁴ are independently at each occurrence H, C ₁ -C ₆ alkyl or phenyl;

X is O, CH ₂ or CO;

X ¹ is O or NR ⁵ ;

R ⁵ is H or C ₁ -C ₆ alkyl;

R ⁸ is H or methyl, provided that when R is 1 or 2 R ⁸ must be H and when r is 0 R ⁸ must be methyl;

Y is S, CH ₂ CH ₂ or CH = CH.

The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutical acid addition salt thereof and a pharmaceutical carrier. In another embodiment, the pharmaceutical compositions of the present invention may be suitable for use in treating endometriosis and / or fibrosis of the uterus.

The invention also relates to a method of treating endometriosis and / or fibrosis of the uterus using a compound of formula (I) or a pharmaceutical acid addition salt thereof.

The invention also relates to a compound of formula (I) or a pharmaceutical acid addition salt thereof for use in treating endometriosis and / or fibrosis of the uterus. In addition, the present invention relates to the use of a compound of formula (I) or a pharmaceutical acid addition salt thereof for the manufacture of a medicament for treating endometriosis and / or fibrosis of the uterus.

The present invention also relates to compounds of formula (II) or acid addition salts thereof which are useful, for example, as chemical intermediates for compounds of formula (I):

Where

m, n, q, r, R ⁰ , R ¹ , R ^{1 ′} , R ⁸ , X and Y are as described for Formula I compounds;

u is 0, 1 or 2;

R ⁶ is H, C ₁ -C ₆ alkyl, benzyl or COR ² (R ^{2 as} described for Formula I compounds);

X ² is O or NR ⁷ ;

R ⁷ is H, C ₁ -C ₆ alkyl or CO ₂ (C ₁ -C ₆ alkyl);

Provided that when R ⁶ is C ₁ -C ₆ alkyl or benzyl u is only 2 and the compound of formula II is

or

This is not it.

For the purposes of the present invention disclosed and claimed herein, the following terms are defined below.

The term "halo" refers to fluoro, chloro, bromo and iodo. The term “C ₁ -C ₆ alkyl” denotes a straight, branched or cyclic hydrocarbon moiety having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl , Isobutyl, sec-butyl, t-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, etc.). Residues such as cyclobutylmethylenyl are also included within the scope of C ₁ -C ₆ alkyl groups. The term “C ₁ -C ₄ alkyl” specifically refers to methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclopropylmethyl and cyclobutyl . A "C ₁ -C ₆ alkoxy" group is a C ₁ -C ₆ alkyl residue linked via an oxy bond.

The term "medicament" as used herein means substantially harmless as an adjective.

Preferred Compounds of the Invention (Embodiments)

Particular compounds of the invention are of particular interest and preference. The following list describes some groups of preferred compounds. It is to be understood that each list can be combined with another list to form another group of the desired compounds.

a) m is 0 or 2;

b) m is 0;

c) m is 2;

d) n is 0;

e) n is 1;

f) q is O or 1;

g) q is 0;

h) r is 1;

i) r is 2;

j) R is H;

k) R is COR ² ;

l) R ^O is OH, methoxy, CF ₃ , fluoro, chloro, methyl or ethyl;

m) R ^O is OH, CF ₃ , fluoro, chloro, methyl or ethyl;

n) R ⁰ is CF ₃ or fluoro;

o) -SO ₂ R ¹ residue is attached at the para position of the phenyl ring;

p) the —SO ₂ R ¹ residue does not bond with the phenyl ring attached to form a residue of formula (a) or (b);

q) R ¹ is C ₁ -C ₄ alkyl or CF ₃ ;

r) R ¹ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl or CF ₃ ;

s) R ¹ is methyl, ethyl, cyclopropyl or CF ₃ ;

t) R ¹ is methyl, ethyl or CF ₃ ;

u) R ¹ is methyl;

v) R ¹ is ethyl;

w) R ¹ is cyclopropyl;

x) R ¹ is CF ₃ ;

y) R ^{1 ′} is C ₁ -C ₄ alkyl or CF ₃ ;

z) R ^{1 ′} is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl or CF ₃ ;

aa) R ^{1 ′} is methyl, ethyl, cyclopropyl or CF ₃ ;

bb) R ^{1 ′} is methyl, ethyl or CF ₃ ;

cc) R ^{1 ′} is methyl;

dd) R ^{1 ′} is ethyl;

ee) R ^{1 ′} is cyclopropyl;

ff) R ^{1 ′} is CF ₃ ;

gg) R ² is C ₁ -C ₆ alkyl or phenyl;

hh) R ² is C ₁ -C ₆ alkyl, NHCH ₃ or phenyl;

ii) R ² is C ₁ -C ₄ alkyl, NHCH ₃ or phenyl;

jj) R ⁵ is H, methyl or ethyl;

kk) R ⁵ is H;

ll) X is 0;

mm) X ¹ is O;

nn) X ¹ is NR ⁵ ;

oo) Y is S;

pp) Y is CH = CH;

qq) Y is CH ₂ CH ₂ ;

rr) The compound of formula I is a hydrochloride salt.

synthesis

Compounds of formula (I) can be prepared as described in the following schemes, preparations, and examples.

The compound of formula IV in Scheme 1 is reacted with the compound of formula III under conventional "Suzuki" or "Stille" reaction conditions, ie either substituent "A" or "D" is boric acid / ester or alkyl And a tin residue and the other is a leaving group (eg, a sulfonate group such as chloro, bromo, iodine or trifluoromethyl sulfonate). When R ⁶ is alkyl (preferably methyl) or benzyl, the R ⁶ group can be removed under standard conditions to give a compound of formula (R = H) (the latest edition of Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, NY]). When u is 0 or 1, the coupled product can be oxidized under standard conditions (see preparation below) to produce the corresponding mono or bis-sulfone of formula (I) (m = 2). Compounds of formula (I) or formula (I) may be further derivatized to produce compounds of formula (R = COR ² ).

In Scheme 2, a compound of formula VI, prepared essentially as disclosed in U.S. Patent 5,929,090, incorporated herein by reference, is reacted with a compound of formula VIII under standard nucleophilic substitution conditions to give a product compound that can be deprotected. Can be obtained, deprotected and further derivatized as described above to afford the compound of formula I (b).

Compounds of formula (I) can also be prepared from compounds of formula (V) as shown in Scheme 2. Compounds of formula (VII) may be prepared by reacting a compound of formula (V) with a base followed by addition of 4-fluoro-benzaldehyde. The product aldehyde can be converted to the corresponding hydroxy / sulfonyl compound of formula VII by reaction, such as with hydrogen peroxide and then with sodium perborate monohydrate. The compound of formula (VII) can then be reacted with a compound of formula (VIII) under standard nucleophilic substitution conditions to afford the product compound, which is deprotected and further derivatized as described above to give the compound of formula (I).

In Scheme 3, another method for preparing a compound of Formula I, wherein R ¹ and R ^{1 ′} are independently C ₁ -C ₆ alkyl, CF ₃ or CH ₂ CF ₃ and the SO ₂ R ¹ residue does not bind to the R ⁰ residue Is shown. Compounds of formula IX (prepared in a manner similar to the reaction of compounds of formula III and IV described in Scheme 1) with thiolates of compounds of formula HSR ^la (R ^1a is C ₁ -C ₆ alkyl), CF ₃ CH ₂ CF ₃ , such as sodium methanethiolate, causing a displacement of the “Lg” substituent. “Lg” residues found in compounds of Formula (IX) are substituents that activate attached phenyl groups for nucleophilic aromatic substitution. The thioether formula X product can then be oxidized to form the corresponding sulfone (or sulfoxide) compound which can be deprotected and further derivatized as described above to afford the compound of formula I (d). When more than Lg substituents can be introduced into the compound of formula IV, the methodology of scheme 3 may be particularly suitable for preparing compounds of formula I (e) (n = 1, m = 0 or 1).

Compounds of formulas (III), (IV) and (VIII) can be prepared as shown below or by similar steps as those known in the art. Compounds of Formula (V) may be prepared by similar steps as those described in US Pat. No. 5,929,090 or as described below. Compounds of formula HSR ^la are generally commercially available or can be prepared by procedures readily available to those of ordinary skill in the art synthetic organic chemists.

General experimental details

Electrospray mass spectra were obtained, for example, on a Finnigan LCQ Duo instrument using a mobile phase of 50% acetonitrile, 25% methanol, and 25% 2 mM water soluble ammonium acetate.

Preparative HPLC was run, for example, on Finnigan aQa MS, as well as Unipoint software and Gilson preferential systems with dual detection wavelengths of 220 and 254 nm. A 20-mm x 250-mm ODS-AQ column with a particle size of 15 microns was used as the stationary phase. Eluent is a binary system of bottle A (0.1% trifluoroacetic acid (TFA), 1% isopropyl alcohol (IPA) (in water)) and bottle B (0.05% TFA, in 1% IPA acetonitrile). Standard methods are gradients of 30-95% B, unless otherwise indicated. Compounds purified by this method were isolated as TFA salts.

Preparative HPLC can also be performed on Biotage ParallelPlex systems with proprietary dual detection wavelengths and software. Using a 30-mm x 150-mm or 19-mm x 250 mm Xterra (Xterra) column having a particle size of 10 microns as the stationary phase _{^{and, 1OmM NH 4 + HCOO - 100}} % a / 1OmM NH ₄ OH as mobile phase A Acetonitrile was used as mobile phase B.

Preparation method 1

Trifluoro-methanesulfonic acid 6-methoxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester

6-methoxynaphthalen-2-ol (20 g, 114.8 mmol) was added to dimethylformamide (DMF, 250 mL) at room temperature, followed by N-bromosuccinimide (NBS, 21.5. G over 30 minutes). , 120 mmol) was added. After 45 minutes, diluted with water (800 mL) and collected, the precipitate was dried to give 25.5 g (87%) of 1-bromo-6-methoxy-naphthalen-2-ol.

1-bromo-6-methoxy-naphthalen-2-ol (66.7 g, 264 mmol), potassium carbonate (K ₂ CO ₃ , 40.0 g, 290 mmol) and benzyl bromide (49.6 g, 290 mmol) were added to DMF ( 800 mL). The mixture was stirred at rt for 1 h. Water (400 mL) was added to precipitate the product. A precipitate was collected and the filter cake was washed with heptane (3 × 125 mL) and dried to give 83.7 g of 2-benzyloxy-1-bromo-6-methoxy-naphthalene (86.2%).

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) were mixed and the mixture was heated to reflux. A portion of toluene (100 mL) was removed. Ethyl acetate (390 mg, 4.37 mmol) and copper triflate benzene complex (2.20 g, 4.37 mmol) were added to the reaction mixture and stirred for 5 minutes. The solvent was distilled off and the residue obtained was heated to 174 ° C. for 1.5 h. The residue was dissolved in a mixture of ethyl acetate (200 mL) and aqueous HCl solution (IN, 90 mL). The organics were separated and concentrated to residue. The residue was column chromatographed to give 12.4 g of 1- {2- [4- (2-benzyloxy-6-methoxy-naphthalen-1-yloxy) -phenoxy] -ethyl} -piperidine (30 %) Was obtained.

1- {2- [4- (2-benzyloxy-6-methoxy-naphthalen-1-yloxy) -phenoxy] -ethyl} -piperidine (12.4 g, 25.5 mmol) was mixed with methanol / ethyl acetate (1: 1, 490 mL) and heated to form a solution. Heat was removed and ammonium formate (4.83 g, 76.6 mmol) and Pd (OH) ₂ on carbon (20% ww, 1.58 g, 1.12 mmol) were added. It was refluxed for 50 minutes and the mixture was filtered. The filtrate was concentrated to give 9.9 g of 6-methoxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol (98.5%).

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) was cooled to -50 ° C and trifluoromethanesulfonic anhydride (7.26 g, 25.7 mmol) was added. The resulting mixture was stirred at −50 ° C. for 2 hours and then the mixture was heated to room temperature and then stirred for an additional 1 hour. Brine (150 mL) was added and the organics were separated. The organics were washed with NaHCO ₃ , dried and concentrated to give a residue. The residue was crystallized with ethyl ether-hexane to give 11.2 g (90.9%) of the title compound.

Preparation method 2

Trifluoro-methanesulfonic acid 6-hydroxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester

2M hydrogen chloride / ether (1.5 mL, 3 mmol) was added to the solution of the compound of Preparation 1 (1.07 g, 2.04 mmol) / dichloromethane (20 mL) and the solvent was removed in vacuo. Hydrochloride was dissolved in dichloromethane (40 mL) and cooled in an ice bath. Boron tribromide (0.58 mL, 6.12 mmol) was added and stirred for 3.5 hours, then heated to room temperature and stirred for 15 minutes, cooled in an ice bath and quenched with ice-cooled saturated aqueous sodium bicarbonate solution. Extract the aqueous layer with dichloromethane, combine the organic layers, dry with magnesium sulfate, remove the solvent in vacuo, and chromatograph with dichloromethane / methanol mixture on silica gel to give 990 mg of the title compound (95%). Got it.

Preparation method 3

Trifluoro-methanesulfonic acid 6-benzyloxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester

Trifluoromethanesulfonic acid 6-hydroxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester (247 mg, 0.48 mmol), triphenyl Phosphine (190 mg, 0.725 mmol), benzyl alcohol (0.075 mL, 0.725 mmol) and tetrahydrofuran (5 mL) were mixed in a flask placed in an ice bath. Diisopropyl azodicarboxylate (0.14 mL, 0.725 mmol) was added and stirred for 1 hour, then heated to room temperature and stirred for 30 minutes. Diluted with ethyl acetate and washed with 50% saturated sodium bicarbonate saturated aqueous / saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent removed in vacuo. Chromatography with dichloromethane / methanol mixture on silica gel gave 213 mg of the title compound (73%).

Example 1

1- (2-4- [2- (4-methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenoxy} -ethyl) -piperidine

500 mL of 4- (methanesulfonyl) phenylboronic acid (6.8 g, 34 mmol), compound of Preparation 1 (6.6 g, 12.6 mmol), cesium fluoride (17.2 g, 113 mmol) and acetonitrile (130 mL) Mix in a flame-dried flask with reflux condenser. In a separate flask, palladium (II) acetate (283 mg, 1.26 mmol) and tricyclohexylphosphine (530 mg, 1.9 mmol) were mixed. Acetonitrile (65 mL) was added and sonicated under nitrogen for 10 minutes. The catalyst slurry was added to the substrate mixture and heated in an oil bath at 90 ° C. for 30 minutes. The suspension was cooled to room temperature and filtered through packed celite. The celite was rinsed with ethyl acetate and the filtrate was washed with a 50:50 mixture of water, saturated Na ₂ CO ₃ aqueous solution, saturated NH ₄ Cl aqueous solution and brine. The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated to afford 10 g of crude material. This crude was treated with 1% methanol / CH ₂ Cl ₂ solution and the resulting white solid impurity (400 mg) was removed by filtration. The filtrate was concentrated and the crude product was pre-adsorbed on silica gel. Chromatography eluting the residue with methanol / dichloromethane (0-10%) on a SiO ₂ column gave 5.2 g (78%) of the title compound. The crude fraction was concentrated, evaporated and then recrystallized from ethyl acetate to further give 1.2 g (18%) of the title compound: mass spectrum (ion spray): m / z = 532.3 (M + H).

Example 2

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

Example 1 (6.4 g, 12.1 mmol) of the product was dissolved in a mixture of ethyl acetate, dichloromethane, and methanol (300 mL; 2.5: 2.5: 1). The resulting solution was cooled in an ice bath and treated with 2M HCl / diethyl ether (9.1 mL, 18.2 mmol). The solution was concentrated in vacuo (<2 mmHg) and dried at 50 ° C. for 18 hours to give 6.6 g of the title compound (96%): mass spectrum (ion spray): m / z = 532.3 (M + H-HCl). ).

Example 3

6- (4-Methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol

Example 2 (6.45 g, 11.4 mmol) of the product was dissolved in dichloromethane (200 mL) and cooled to 3 ° C. in an ice bath. The solution was treated by dropwise addition of pure BBr ₃ (5.4 mL, 57 mmol) for 5 minutes and stirred at 0-10 ° C. for 3 hours. The reaction mixture was slowly poured into a 1 liter separatory funnel containing saturated aqueous NaHCO ₃ (300 mL) and ice. The two-phase mixture was diluted with a solution of 7.5% MeOH / ethyl acetate (EtOAc, 400 mL) and brine (100 mL). The layers were separated and the aqueous layer was back extracted with 5% MeOH / EtOAc (2 × 150 mL). The combined organic layers were washed with brine (100 mL), dried (Na ₂ SO ₄ ), filtered and evaporated to give 5.3 g of crude product. The residue was chromatographed on a SiO ₂ column with methanol / dichloromethane (2.5-12%), eluting the residue to give 4.99 g (85%) of the title compound. Dry at 45 ° C. for 18 h (<2 mmHg): Mass spectrum (ion spray): m / z = 518.3 (M + H).

Example 4

6- (4-Methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The product of Example 3 (2.8 g, 5.4 mmol) was slurried in a mixture of ethyl acetate, ethyl ether and methanol (50 mL; 5: 1: 4). The mixture was cooled in an ice bath and treated with 2M HCl / diethyl ether (4.1 mL, 8.2 mmol). The resulting solid was collected on filter paper, rinsed with diethyl ether and dried at 45 ° C. for 18 hours (<2 mmHg) to yield 2.84 g of the title compound (95%): mass spectrum (ion spray): m / z = 518.3 (M + H-HCl).

Example 5

2,2-Dimethyl-propionic acid 6- (4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester hydrochloride

The product of Example 3 (220 mg, 0.43 mmol) was dissolved in pyridine (5 mL) and subsequently treated with trimethylacetyl chloride (0.144 mL, 1.17 mmol) and dimethylaminopyridine (DMAP, catalytic amount). Stir at room temperature for 18 hours and evaporate pyridine. The residue was dissolved again in ethyl acetate and washed with saturated aqueous NH ₄ Cl, saturated aqueous NaHCO ₃ and brine. The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated to give 277 mg of crude material. Pre-adsorption on silica gel and chromatographing the material with methanol / dichloromethane (0-6%) on a SiO ₂ column to elute 2,2-dimethyl-propionic acid-6- (4-methanesulfonyl-phenyl) 235 mg of 5-5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester was obtained. The free base was dissolved in a mixture of ethyl acetate and diethyl ether (20 mL; 1: 1). Cool in ice bath and treat with 2M HCl / diethyl ether (0.3 mL, 0.6 mmol). The precipitate was collected on filter paper and rinsed with diethyl ether to give 220 mg of the title compound (80%): mass spectrum (ion spray): m / z = 602.4 (M + H-HCl).

Example 6

Benzoic acid 6- (4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester hydrochloride

The product of Example 3 was dissolved in (220 mg, 0.43 mmol) pyridine (5 mL) and subsequently treated with benzoyl chloride (0.067 mL, 0.58 mmol) and DMAP (catalyst amount). Stir for 18 hours at room temperature and evaporate pyridine. Fractionated between saturated aqueous NH ₄ Cl solution and ethyl acetate (containing 8% MeOH). After separating the layers, the aqueous layer was extracted with ethyl acetate (containing 5% MeOH) and the two organic layers were combined. Wash with saturated aqueous NaHCO ₃ and brine. The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated to give 276 mg of crude freebase material. Pre-adsorption on silica gel and chromatography of the material eluting with methanol / dichloromethane (0-6%) on a SiO ₂ column to give 260 mg of benzoic acid 6- (4-methanesulfonyl-phenyl) -5- [ 4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester was obtained. The free base was dissolved in hot ethyl acetate (20 mL) and then diluted with diethyl ether (20 mL). After cooling in an ice bath it was treated with 2M HCl / diethyl ether (0.31 mL, 0.62 mmol). The precipitate was collected on filter paper and rinsed with diethyl ether to give 255 mg of the title compound (91%): mass spectrum (ion spray): m / z = 622.3 (M + H-HCl).

Example 7

4-Fluoro-benzoic acid 6- (4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester

Example 3 (111 mg, 0.21 mmol) of the compound was dissolved in dichloromethane (2 mL). 4-fluorobenzoyl chloride (30 μL, 0.25 mmol) was added dropwise. After stirring for 10 minutes, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (10 mL) and extracted with dichloromethane (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography eluting the material with methanol / dichloromethane (0-3%) on a SiO ₂ column gave 99 mg of the title compound (73%): mass spectrum (ion spray): m / z = 640.3 (M + H).

Example 8

4-Fluoro-benzoic acid 6- (4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester hydrochloride

The compound of Example 7 (99 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL) and 2M HCl / ether (400 μl, 0.8 mmol) was added. The solvent was removed in vacuo to give 111 mg of the title compound (100%): mass spectrum (ion spray): m / z = 640.3 (M + H-HCl).

Example 9

Carbonic acid isobutyl ester 6- (4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester

The compound of Example 3 (120 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL) and then isobutylchloroformate (38 μl, 0.30 mmol) was added dropwise. After stirring for 10 minutes the reaction was poured into vigorously stirred ether (10 mL) and filtered. The solid was dissolved in dichloromethane (10 mL) and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column with methanol / dichloromethane (4%), eluting the material to afford 104 mg of the title compound (73%): mass spectrum (ion spray): m / z = 618.4 (M + H).

Example 10

Carbonic acid isobutyl ester 6- (4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester hydrochloride

The compound of Example 9 (104 mg, 0.17 mmol) was dissolved in dichloromethane (3 mL) and 2M HCl / ether (400 μl, 0.8 mmol) was added. The solvent was removed in vacuo to give 81 mg of the title compound (73%): mass spectrum (ion spray): m / z = 618.3 (M + H-HCl).

Example 11

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

The compound of Example 3 (201 mg, 0.38 mmol) was dissolved in dichloromethane (4 L), triethylamine (0.50 mL, 3.5 mmol) was added followed by methylisocyanate (500 mg, 8.7 mmol). After stirring for 30 minutes, the reaction mixture was added to saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography eluting the residue with methanol / dichloromethane (0-4%) on a SiO ₂ column gave 130 mg of the title compound (60%): mass spectrum (ion spray): m / z = 575.3 (M + H) and 518.3 (M-MeNCO).

Example 12

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

Example 11 (130 mg, 0.23 mmol) of the compound was dissolved in dichloromethane (3 mL), then 2M HCl / ether (400 μl, 0.8 mmol) was added. The solvent was removed under vacuum to give 81 mg of the title compound (73%): mass spectrum (ion spray): m / z = 575.3 (M + H-HCl) and 518.3 (M + H-HCl-MeNCO).

Example 13

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

4- (ethanesulfonyl) phenyl) boronic acid (1.83 g, 8.6 mmol), compound of Preparation 1 (1.5 g, 2.86 mmol), cesium fluoride (3.9 g, 25. 7 mmol) and acetonitrile (32 mL) Were mixed in a flame-dried flask with a 100 mL reflux condenser. In a separate dried flask, palladium (II) acetate (65 mg, 0.29 mmol) and tricyclohexylphosphine (120 mg, 0.43 mmol) were mixed. Acetonitrile (16 mL) was added and sonicated under nitrogen for 10 minutes. The catalyst slurry was added to the substrate mixture and heated in an oil bath at 90 ° C. for 30 minutes. The suspension was cooled to rt and filtered through compressed celite. Celite was rinsed with ethyl acetate and the filtrate was washed with a 50:50 mixture of water and saturated aqueous Na ₂ CO ₃ solution, saturated NH ₄ Cl solution and brine. The organic layer was dried (Na ₂ SO ₄ ), filtered and evaporated to afford 2 g of crude material. The crude material was pre-adsorbed onto silica gel and chromatographed with eluting methanol / dichloromethane (0 to 10%) on a SiO ₂ column to elute 1.5 g of 1- (2- {4- [2- ( 4-ethanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenoxy} -ethyl) 3-piperidine was obtained. The free base was dissolved in a mixture of ethyl acetate and diethyl ether (60 mL; 1: 1). Cool in ice bath and treat with 2M HCl / diethyl ether (2 mL, 4 mmol). The precipitate was collected on filter paper and rinsed with diethyl ether to give 1.5 g of the title compound (90%): mass spectrum (ion spray): m / z = 546.3 (M + H).

Example 14

6- (4-ethanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

Using the product of Example 13 (1.5 g, 2.58 mmol) and the steps described in Example 3, 1.35 g of 6- (4-ethanesulfonyl-phenyl) -5- [4- (2-piperidine- 1-yl-ethoxy) -phenoxy] -naphthalen-2-ol was prepared. The free base was dissolved in a mixture of ethyl acetate and diethyl ether (60 mL; 1: 1). Cool in an ice bath and treat with 2M HCl / diethyl ether (2 mL, 4 mmol). The precipitate was collected on filter paper, rinsed with diethyl ether and dried at 50 ° C. for 18 hours (<2 mmHg) to give 1.3 g of the title compound (89%): mass spectrum (ion spray): m / z = 532.3 (M + H).

Example 15

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

Palladium (II) acetate (17 mg, 0.076 mmol), tricyclohexylphosphine (PCy3, 32 mg, 0.11 mmol) and acetonitrile (4 mL) were mixed. The mixture was sonicated for 5 minutes. Compound 1 of Preparation 1 (400 mg, 0.76 mmol), cesium fluoride (1.00 g, 6.62 mmol), 3- (methanesulfonyl) phenylboronic acid (460 mg, 2.30 mmol) and acetonitrile (12 mL) were mixed. . Sonicated Pd / PCy3 suspension was added to the reaction vessel and heated to 90 ° C. for 30 minutes. Cool to room temperature, filter through a pad of celite and evaporate the solvent. The residue was dissolved in ethyl acetate (20 mL) and washed with saturated aqueous NaHCO ₃ (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. Chromatography eluting the residue with methanol / dichloromethane (0-5%) on a SiO ₂ column gave 270 mg of the title compound (67%): mass spectrum (ion spray): m / z = 532.3 (M + H).

Example 16

6- (3-Methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The product of Example 15 was dissolved in ethyl acetate (10 mL) and diethyl ether (5 mL). 2M HCl / diethyl ether (1 mL, 2.0 mmol) was added. The slurry was concentrated and dried under vacuum. The residue was diluted with dichloromethane (5.0 mL) and covered with nitrogen. The solution was cooled to 0 ° C. with an external ice bath and 1M BBr ₃ / dichloromethane (1.0 mL, 1.0 mmol) was added. After 20 minutes, the reaction mixture was diluted with ethyl acetate (25.0 mL) and portions of saturated aqueous NaHCO ₃ (2 × 10 mL) were added in portions. The layers were separated and the organic layer was washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was taken with 6- (3-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol as methanol / dichloro Chromatography on a SiO ₂ column eluting with a gradient of methane (0-5%). The free base was dissolved in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and 2M HCl / diethyl ether (1 mL, 2.0 mmol) was added.

The precipitate was collected on filter paper, rinsed with diethyl ether and dried for 48 hours at 65 ° C. in vacuo (<2 mmHg) to give 73 mg of the title compound (26%): mass spectrum (ion spray): m / z = 518.5 (M [free base] + 1).

Recipe 4

3-fluoro-4- (methanesulfonyl) phenylboronic acid

4-bromo-2-fluorothioanisole (US Pat. No. 6,307,047, 2.7 g, 12 mmol), oxone (38 g, 62 mmol) and methanol (200 mL) were mixed and stirred for 12 hours. Filter through a pad of silica gel and elute with ethyl acetate (500 mL). The solvent was evaporated and partitioned between dichloromethane (200 mL) and water (100 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (10 mL) and brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude solid was washed with hexane (20 mL) and ether (10 mL) and dried under vacuum to give 2.4 g 4-bromo-2-fluoro-1-methanesulfonyl-benzene (78%).

4-Bromo-2-fluoro-1-methanesulfonyl-benzene (1.7 g, 6.7 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) with dichloromethane Complex (Pd (dppf) Cl ₂ ˙CH ₂ Cl ₂ , 164 mg, 0.20 mmol), bis (pinacolato) diboron (1.79 g, 7.0 mmol), potassium acetate (2 g, 20 mmol) and dimethylsulfoxide (DMSO, 100 mL) was mixed. The reaction mixture was heated at 90 ° C. for 1 hour. Cool to room temperature and dilute with ethyl acetate (20 mL). Washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. Chromatography of the residue on an SiO ₂ column eluting with ethyl acetate / hexanes (30%) gave 1.74 g (80%) of 2- (3-fluoro-4-methanesulfonyl-phenyl) -4 , 4,5,5-tetramethyl- [1,3,2] dioxaborolane was obtained.

2- (3-fluoro-4-methanesulfonyl-phenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane (222 mg, 0.74 mmol), NaIO 4 (474 mg, 2.2 mmol), tetrahydrofuran (THF, 4 mL) and water (1 mL) were mixed. Stir for 2 hours and add 2M HCl / diethyl ether (0.2 mL). It was stirred for another 12 hours and filtered to remove solids. The filtrate was washed with brine (10 mL), dried over MgSO ₄ and the solvent was evaporated. The solid was washed with hexane (2 x 10 mL) and ether (10 mL). The solid was dried under vacuum to give 68 mg of the title compound (42%).

Example 17

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

Palladium (II) acetate (4.2 mg, 0.019 mmol), tricyclohexylphosphine (10 mg, 0.036 mmol), compound of Preparation 1 (92 mg, 0.18 mmol), cesium fluoride (201 mg, 1.33 mmol), 3 -Fluoro-4- (methanesulfonyl) phenyl boronic acid (68 mg, 0.31 mmol) and acetonitrile (10 mL) were mixed. Heated to 90 ° C. for 1 hour. Cool to room temperature, dilute the solution with ethyl acetate (20 mL) and wash with saturated aqueous NaHCO ₃ (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed by elution with methanol / dichloromethane (2-4%) on SiO ₂ column to give 69 mg of the title compound (72%): mass spectrum (ion spray): m / z = 550.4 (M + H).

Example 18

6- (3-Fluoro-4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The product of Example 17 was dissolved in ethyl acetate (10 mL) and diethyl ether (5 mL). 2M HCl / diethyl ether (1 mL, 2.0 mmol) was added. The slurry was concentrated and dried in vacuo. The residue was diluted with dichloromethane (5.0 mL) and covered with nitrogen. The solution was cooled to 0 ° C. with an external ice bath. 1M BBr ₃ / dichloromethane (0.1mL, 1.1 mmol) was added and stirred for 1 hour. Water (1.0 mL) and dichloromethane (10 mL) were added. The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (10 mL) and brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. 6- (3-Fluoro-4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol over SiO ₂ column The residue was chromatographed, eluting with a gradient of methanol / dichloromethane (0-5%). Freebase was dissolved in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and 2M HCl / diethyl ether (1 mL, 2.0 mmol) was added. The precipitate was collected on filter paper and dried for 48 hours at 65 ° C. under vacuum (<2 mmHg) to give 19 mg of the title compound (26%): mass spectrum (ion spray): m / z = 536.3 (M + H).

Recipe 5

2- (4-trifluoromethanesulfonyl-phenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

1-Bromo-4-trifluoromethyl sulfide (2.5 g, 9.7 mmol) was dissolved in dichloromethane (100 mL) in a 250 mL flask equipped with a reflux condenser. Meta-chloroperbenzoic acid (mCPBA, 6.1 g, 24.3 mmol, 68%) was added and the reaction heated to reflux for 3 days. The reaction was cooled to room temperature and the organic layer was washed with 1N aqueous NaOH solution (100 mL). The organic layer was separated and dried over sodium sulfate. Filtration and concentration in vacuo gave 2.5 g of 1-bromo-4-trifluoromethanesulfonyl-benzene (90%).

The flame-dried flask was charged with 1-bromo-4-trifluoromethanesulfonyl-benzene (500 mg, 1.73 mmol), bis (pinacolato) diboron (523 mg, 2.07 mmol), [1,1 ' -A bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (1: 1) (42 mg, 0.05 mmol) and potassium acetate (467 mg, 5.2 mmol). The solid was dissolved in dimethylsulfoxide (9 mL) and heated to 80 ° C. for 4 h under nitrogen. The reaction was cooled to rt and diluted with benzene (50 mL). The organic layer was washed with water (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The oil obtained on a SiO ₂ column was chromatographed by eluting with ethyl acetate (20%) in hexanes to give 560 mg of the title compound (96%).

Example 19

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

2- (4-trifluoromethanesulfonyl-phenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane (560 mg, 1.67 mmol), the compound of Preparation 1 ( 300 mg, 0.57 mmol) and cesium fluoride (433 mg, 2.85 mmol) were mixed in a flame-dried flask with reflux condenser. In a separate dried flask, palladium (II) acetate (25 mg, 0.11 mmol) and tricyclohexylphosphine (48 mg, 0.17 mmol) were mixed. Dry acetonitrile (6 mL) was added and sonicated under nitrogen for 10 minutes. A catalyst mixture was added to the solid and the flask was dropped into a 90 ° C. oil bath. After 25 minutes, the black suspension was cooled to room temperature and filtered through celite with dichloromethane. The filtrate was concentrated in vacuo. The residue obtained by eluting with 0.2% ammonium hydroxide and methanol / dichloromethane (2.5%) was chromatographed on a SiO ₂ column to give 254 mg of the title compound (76%): mass spectrum (ion spray): m / z = 586 (M + H).

Example 20

5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -6- (4-trifluoromethanesulfonyl-phenyl) -naphthalen-2-ol

The compound of Example 19 (250 mg, 0.42 mmol) was dissolved in dichloromethane (5 mL). 2M HCl / ether (0.42 mL, 0.84 mmol) was added and stirred for 1 minute. The solvent was removed in vacuo and placed on a high vacuum pump for 10 minutes. The foam was dissolved in dry dichloromethane (5 mL), cooled to 0 ° C. and then BBr ₃ (0.20 mL, 2.1 mmol) was added dropwise. After 25 minutes, poured slowly into saturated aqueous sodium bicarbonate solution (10 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column, eluting with 0.2% ammonium hydroxide and methanol / dichloromethane (3-5%) to give 196 mg of the title compound (81%): mass spectrum (ion spray) m / z = 572.3 (M + H).

Example 21

5- [4- (2-Piperidin-1-yl-ethoxy) -phenoxy] -6- (4-trifluoromethanesulfonyl-phenyl) -naphthalen-2-ol hydrochloride

The compound of Example 20 (196 mg, 0.34 mmol) was dissolved in ethyl acetate (1 mL) and diethyl ether (9 mL). 2M HCl / diethyl ether (340 μl, 680 μmol) was added to the stirred solution. The suspension was stirred for 10 minutes. The solid was filtered through a Buchner funnel. The solid was dried in vacuo at 45 ° C. overnight to give 98 mg of the title compound (47%): mass spectrum (ion spray) m / z = 572.3 (M + H-HCl).

Preparation method 6

2- (1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [b] thiophen-5-yl) -4,4,5,5-tetramethyl- [1,3, 2] dioxaborolane

5-bromo-2,3-dihydro-benzo [b] thiophene (J. Am. Chem. Soc, 1973, 1916-1925), 4.3 g, 20 mmol) was dissolved in MeOH (100 mL) and , Oxone (36.9 g, 60 mmol) was added. The reaction mixture was stirred at rt overnight, then the solids were removed by filtration. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 20-40% EtOAc / hexanes) to 4.24 g of 5-bromo-2,3-dihydro-benzo [b] thiophene 1 , 1-dioxide (86%) was obtained.

5-Bromo-2,3-dihydro-benzo [b] thiophene 1,1-dioxide (2.0 g, 8.1 mmol) was dissolved in DMSO (60 mL). Bis (pinacolato) diboron (2.26 g, 8.9 mmol), PdCl ₂ (dppf) .CH ₂ Cl ₂ (330 mg, 0.41 mmol), and potassium acetate (KOAc, 2.38 g, 24.3 mmol) were added. The flask was flushed with N ₂ and then the reaction mixture was heated to 80 ° C. with stirring. The reaction mixture was further heated for 3 hours and then cooled to room temperature. Water (100 mL) was added and the aqueous layer was extracted with EtOAc (3 x 100 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash column chromatography (silica gel, 10-50% ethyl acetate / hexanes) to give 1.4 g (59%) of the title compound. .

Example 22

1- (2- {4- [2- (1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [b] thiophen-5-yl) -6-methoxy-naphthalene- 1-yloxy] -phenoxy} -ethyl) -piperidine

2- (1,1-dioxo-2,3-dihydro-1H-1λ6-benzo [b] thiophen-5-yl) -4,4,5,5-tetramethyl- [1,3,2 Dioxaborolane (590 mg, 2.02 mmol) and the compound of Preparation 1 (350 mg, 0.67 mmol) were dissolved in CH ₃ CN (8 mL). Palladium (II) acetate (Pd (OAc) 2, 15 mg, 0.007 mmol), tricyclohexylphosphine (28 mg, 0.1 mmol) and CsF (910 mg, 6 mmol) were added. The flask was flushed with N ₂ and the reaction mixture was heated to 90 ° C. with stirring. The reaction mixture was further heated for 6 hours and then cooled to room temperature. Water (50 mL) was added and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 25 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated and flash flash chromatography (silica gel, 0-4% MeOH-NH 4 OH (10/1, v / v) / CH ₂ Cl ₂ ) Purification gave 160 mg of the title compound (44%): Mass spectrum (ion spray): m / z = 544.3 (M + H).

Example 23

6- (1,1-dioxo-2,3-dihydro-1H-1λ ⁶ -benzo [b] thiophen-5-yl) -5- [4- (2-piperidin-1-yl- Ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The compound of Example 22 (160 mg, 0.29 mmol) was dissolved in CH ₂ Cl ₂ (5 mL) and the solution was cooled to -78 ° C. HCl (0.2 mL, 2.0 M / diethyl ether (Et ₂ O)) was added and the reaction mixture was stirred for 10 minutes. The solvent was removed under reduced pressure, then the solid was dissolved in CH ₂ Cl ₂ (5 mL) under nitrogen. The solution was cooled to 0 ° C and BBr ₃ (370 mg, 1.46 mmol) was added. The reaction was stirred for 1 hour and water (20 mL) was added. The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 20 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash column chromatography (silica gel, 2-8% MeOH-NH 4 OH (10/1, v / v) / CH ₂ Cl ₂ ). 6- (1,1-dioxo-2,3-dihydro-1H-1λ6-benzo [b] thiophen-5-yl) -5- [4- (2-piperidin-1-yl- Ethoxy) -phenoxy] -naphthalen-2-ol was obtained. The free base was dissolved in CH ₂ Cl ₂ (5 mL) and cooled to -78 ° C. HCl (0.5 mL, 2.0 M / Et ₂₀ ) was added and the solution stirred for 10 minutes. The solvent was removed under reduced pressure to give a solid. The solid was dried at 40 ° C. under vacuum overnight to give 42 mg of the title compound (27%): mass spectrum (ion spray): m / z = 530.3 (M + H).

Preparation method 7

(2,2-dioxo-2,3-dihydro-1H-2λ6-benzo [c] thiophen-5-yl) -trimethyl-tin

4-bromo-1,2-bis-bromomethyl-benzene (J. Org. Chem., 1418-1421, 1985; 3.42 g, 9.96 mmol) was converted to ethanol (EtOH) and THF (1196 mL). Dissolved in a 2: 1 mixture and heated to 70 ° C. while stirring. Na2S.9H2O (2.63 g, 10.96 mmol) / water (40 mL) solution was added dropwise over 10 hours using a syringe pump. Heated with stirring for an additional 10 hours. Cool to room temperature and remove the organic solvent under reduced pressure. Water (200 mL) was added to the residue and the aqueous layer was extracted with EtOAc (3 x 200 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash column chromatography (silica gel, hexane) to give 1.27 g of 5-bromo-1,3-dihydro-benzo [ c] thiophene (59%).

5-bromo-1,3-dihydro-benzo [c] thiophene (1.25 g, 5.79 mmol) was dissolved in methanol (25 mL) and oxone (10.7 g, 17.4 mmol) was added. The reaction mixture was stirred for 2 h at 0 ° C. and then 1M aqueous sodium bisulfite solution (100 mL) was added. The reaction mixture was stirred for 10 minutes and saturated NaHCO ₃ solution (200 mL) was added. The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 100 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash column chromatography (silica gel, 0-5% MeOH / CH ₂ Cl ₂ ) to give 930 mg of 5-bromo- 1,3-dihydro-benzo [c] thiophene 2, 2-dioxide (65%) was obtained.

5-bromo-1,3-dihydro-benzo [c] thiophene (860 mg, 3.50 mmol) and hexamethylditin (3 eq.) Were dissolved in toluene and tetrakis (triphenylphosphine) palladium ( 0) (Pd (PPh 3) 4, 0.1 eq.) Was added. The flask was flushed with N ₂ and then the mixture was heated to 120 ° C. with stirring. The mixture continued to heat for 5 hours and then cooled to room temperature. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na ₂ S0 ₄ , filtered and concentrated and purified by flash column chromatography (silica gel, 10-30% EtOAc / hexanes) to give 1.22 g of the title compound (100%). .

Example 24

1- (2- {4- [2- (2,2-dioxo-2,3-dihydro-1H-2λ ⁶ -benzo [c] thiophen-5-yl) -6-methoxy-naphthalene- 1-yloxy] -phenoxy} -ethyl) -piperidine

(2,2-dioxo-2,3-dihydro-1H-2λ6-benzo [c] thiophen-5-yl) -trimethyl-tin (1.19 g, 3.6 mmol, 2.7 eq.) And compound of Preparation 1 (630 mg, 1.2 mmol) was dissolved in CH ₃ CN. Pd (OAc) 2 (0.1 eq.), Tricyclohexylphosphine (0.15 eq.), And CsF (4 eq.) Were added. The flask was flushed with N ₂ and then the reaction mixture was heated to 90 ° C. with stirring. The reaction mixture was continued to heat for 1 hour and then cooled to room temperature. Water (100 mL) was added and separated, then the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 100 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated, then flash column chromatography (silica gel, 0-5% MeOH-NH ₄ OH (10/1, v / v) / CH ₂ Cl ₂ Purification) yielded 140 mg of the title compound (22%): mass spectrum (ion spray): m / z = 544.2 (M + H).

Example 25

6- (2,2-dioxo-2,3-dihydro-1H-2λ ⁶ -benzo [c] thiophen-5-yl) -5- [4- (2-piperidin-1-yl- Ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

1- (2- {4- [2- (2,2-dioxo-2,3-dihydro-1H-2λ ⁶ -benzo [c] thiophen-5-yl) -6-methoxy-naphthalene- l-yloxy] -phenoxy} -ethyl) -piperidine (140 mg, 0.26 mmol) was demethylated with BBr ₃ and chlorided in a procedure similar to that used in Example 23 to 130 mg (94%) The title compound was obtained: Mass spectrum (ion spray): m / z = 530.2 (M + H-HCl).

Preparation Method 8

(4-Methanesulfonyl-3-methoxy-phenyl) -trimethyl-tin

6-hydroxy-1,3-benzoxathiol-2-one (16.8 g, 0.1 mol) was dissolved in THF (1650 mL) and cooled to 0 ° C. Sequentially benzyl alcohol (16.2 g, 0.15 mol), triphenylphosphine (PPh 3, 39.3 g, 0.15 mol), and diisopropylazodicarboxylate (30.3 g, 0.15 mol) were added. The reaction mixture was stirred at rt overnight. Water (1500 mL) was added and the aqueous layer was extracted with EtOAc (3 x 1500 mL). The organic layers were combined, dried over Na ₂ S0 ₄ , filtered, concentrated and purified by flash column chromatography (silica gel, 10-25% EtOAc / hexanes) to give 24.33 g of 6-benzyloxy-benzo [ 1,3] oxathiol-2-one (94%) was obtained.

6-benzyloxy-benzo [1,3] oxathiol-2-one (24.33 g, 94.29 mmol) is dissolved in dioxane (1000 mL) and KOH solution (94.29 mL, 188 mmol, 2M aqueous solution) is added with stirring It was. The flask was flushed with N ₂ and the reaction mixture was then heated to 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The pH was adjusted to less than 2 with HCl (200 mL, 1.0 M aqueous solution). The aqueous layer was extracted with EtOAc (3 x 500 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated to give 17.8 g of 5-benzyloxy-2-mercapto-phenol (81.4%).

5-benzyloxy-2-mercapto-phenol (17.8 g, 76.72 mmol) was dissolved in DMF (300 mL) and K ₂ CO ₃ (31.8 g, 0.23 mol) and MeI (32.7 g, 0.23 mol) were added. . The reaction mixture was stirred at rt overnight. Water (800 mL) was added and the aqueous layer was extracted with EtOAc (3 x 800 mL). The organic layers were combined, dried over Na ₂ S0 ₄ , filtered, concentrated and purified by flash column chromatography (silica, 5-20% EtOAc / hexanes) to 13.5 g of 4-benzyloxy-2-meth Toxy-1-methylsulfanyl-benzene (68%) was obtained.

4-benzyloxy-2-methoxy-1-methylsulfanyl-benzene (5.2 g, 20 mmol) is dissolved in CH ₂ Cl ₂ (250 mL) and m-CPBA (15.2 g, 60 mmol, 68%) Treated as. The reaction mixture was stirred at rt for 6 h. Saturated K ₂ CO ₃ solution (200 mL) was added and the aqueous layer was extracted with EtOAc (3 × 200 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash column chromatography (silica gel, 20-50% EtOAc / hexanes) to 5.57 g of 4-benzyloxy-1- Methanesulfonyl-2-methoxy-benzene (96%) was obtained.

4-benzyloxy-1-methanesulfonyl-2-methoxy-benzene (5.57 g, 19.09 mmol) was dissolved in MeOH (200 mL) under N ₂ and 5% Pd-C (900 mg) was added. The reaction vessel was evacuated and flushed with hydrogen gas (three times). The reaction mixture was stirred at room temperature under 1 atmosphere of hydrogen gas for 3 hours. After filtration and concentration, the reaction mixture was purified by flash column chromatography (silica gel, 30-60% EtOAc / hexanes) to afford 3.24 g of 4-methanesulfonyl-3-methoxy-phenol (100%). Got it.

4-methanesulfonyl-3-methoxy-phenol (3.24 g, 19.04 mmol), 2,6-lutidine (4.08 g, 38.08 mmol) and DMAP (230 mg, 1.9 mmol) were added to CH ₂ Cl ₂ (190 mL). )). The solution was cooled to −78 ° C. and then trifluoromethanesulfonic anhydride (Tf ₂ O, 6.44 g, 22.85 mmol) was added dropwise. The reaction mixture was stirred for 6 hours. Water (200 mL) was added and the aqueous layer was extracted with EtOAc (3x 200 mL). The organic layers were combined, dried over Na ₂ S0 ₄ , filtered and concentrated and purified by flash column chromatography (silica gel, 10-30% EtOAc / hexanes) to 4.6 g of trifluoro-methanesulfonic acid 4 Methanesulfonyl-3-methoxy-phenyl ester (72%) was obtained.

Trifluoro-methanesulfonic acid 4-methanesulfonyl-3-methoxy-phenyl ester (3 g, 9 mmol) is dissolved in toluene (180 mL), hexamethylditin (14.7 g, 44.9 mmol) and Pd (PPh3 ) 4 (1.04 g, 0.9 mmol) was added. The reaction mixture was heated to 120 ° C. for 4 hours with stirring. Water (250 mL) was added and the aqueous layer was extracted with EtOAc (3 x 250 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated and purified by flash column chromatography (silica gel, 5-40% EtOAc / hexanes) to give 1.9 g of the title compound (61%). Got it.

Example 26

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

(4-methanesulfonyl-3-methoxy-phenyl) -trimethyl-tin (300 mg, .0.86 mmol, 1.5 eq.) And the compound of Preparation 1 (300 mg, 0.57 mmol) were cesium fluoride (2.9 eq.) / To a suspension of acetonitrile (40 mL) was added. Palladium (II) acetate (0.2 eq.) And tricyclohexylphosphine (0.3 eq.) Were mixed in acetonitrile (15 mL) and sonicated for 10 minutes before adding to the mixture. The reaction mixture was heated to 90 ° C for 18 h. Concentrate in vacuo and partition the residue between ethyl acetate (50 mL) and saturated aqueous NaHCO ₃ (50 mL). The organic layer was washed with saturated aqueous NH ₄ Cl (50 mL) and brine (50 mL). Dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column eluting with methanol / dichloromethane to give 180 mg of the title compound (56%): mass spectrum (ion spray): m / z = 562.4 (M + H).

Example 27

6- (3-hydroxy-4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol trifluoroacetate

1- (2- {4- [2- (4-Methanesulfonyl-3-methoxy-phenyl) -6-methoxy-naphthalene-l-yloxy] -phenoxy} -ethyl) -piperidine ( 240 mg, 0.43 mmol) was demethylated with BBr ₃ in a similar procedure to that used in Example 23 to give 220 mg (95%) of the crude product as a white solid. The resulting impure product was purified by preparative HPLC (Gilson) to give 120 mg of the title compound (46%): mass spectrum (ion spray): m / z = 534.3 (M + H-TFA).

Recipe 9

4-Bromo-2-chloro-1-methanesulfonyl-benzene

2-chloromethyl-benzenethiol (10 mL, 88 mmol), potassium carbonate (25 g, 180 mmol), iodomethane (11 mL, 177 mmol) and DMF (100 mL) were mixed. Stir for 12 hours. The suspension was filtered through a pad of silica gel and eluted with ethyl acetate (500 mL). Half of the solvent was evaporated and the remaining solution was washed with 10% aqueous LiCl solution (100 mL). Dry with MgSO ₄ and evaporate the solvent. The residue was chromatographed on the SiO ₂ column, eluting with hexanes to give 13 g of 1-chloro-2-methylsulfanyl-benzene (93%).

1-methylsulfanyl-2-chloromethyl-benzene (3.7 g, 23 mmol), iron (130 mg, 2.3 mmol), bromine (1.2 mL, 238 mmol), and dichloromethane (150 mL) were mixed. Stir for 2 hours. Water (10 mL), saturated aqueous sodium thiosulfate solution (100 mL) and ethyl acetate (100 mL) were added. The organic layer was separated, washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column, eluting with hexanes to afford 4.8 g of 4-bromo-2-chloro-1-methylsulfanyl-benzene (87%).

4-bromo-2-chloro-1-methylsulfanyl-benzene (4.8 g, 20 mmol) and mCPBA (20 g, 80 mmol) were dissolved in dichloromethane (100 mL). Stir for 2 hours. Dilute with dichloromethane (300 mL) and water (100 mL). The organic layer was separated and washed with saturated aqueous NaHCO ₃ (2 × 100 mL) and brine (100 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo. The solid was washed with ether (2 x 10 mL) and dichloromethane (10 mL) to give 1.7 g of the title compound (31%).

Example 28

1- (2- {4- [2- (3-Chloro-4-methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenoxy} -ethyl) -piperidine

Palladium (II) acetate (32 mg, 0.14 mmol), tricyclohexylphosphine (67 mg, 0.24 mmol), cesium fluoride (1.3 g, 8.6 mmol) and acetonitrile (20 mL) were mixed. Stirred for 5 minutes, and the compound of Preparation 1 (500 mg, 0.95 mmol) and bis (neopentyl glycolato) diboron (322 mg, 1.42 mmol) were added. Heat to 90 ° C. and 4-bromo-2-chloro-1-methanesulfonyl-benzene / acetonitrile (2 mL) was added. Stir at 90 ° C. for 10 minutes. Cool to room temperature, dilute the solution with ethyl acetate (20 mL) and wash with saturated aqueous NaHCO ₃ (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. Chromatography of the residue eluting with methanol / dichloromethane (0-5%) on a SiO ₂ column gave 180 mg of the title compound (33%): mass spectrum (ion spray): m / z = 566.2 (M + H).

Example 29

6- (3-Chloro-4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol

The product of Example 28 was dissolved in ethyl acetate (10 mL) and diethyl ether (5 mL). 2M HCl / diethyl ether (0.6 mL, 1.2 mmol) was added. The slurry was concentrated and dried under vacuum. The residue was diluted in dichloromethane (5.0 mL) and covered with nitrogen. The solution was cooled to 0 ° C. with an external ice bath. BBr ₃ (0.1 mL, 1.1 mmol) was added. After 1 h, water (1.0 mL) and dichloromethane (10 mL) were added. The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (10 mL) and brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column, eluting with a gradient of methanol / dichloromethane (0-5%) to afford 120 mg of the title compound (68%): mass spectrum (ion spray): m / z = 552.2 (M + H).

Example 30

6- (3-Chloro-4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The product of Example 29 was dissolved in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and 2M HCl / diethyl ether (0.6 mL, 1.2 mmol) was added. The precipitate was collected on filter paper, rinsed with diethyl ether and dried at 20 ° C. in vacuo (<2 mmHg) for 4 hours to give 16 mg of the title compound (26%): mass spectrum (ion spray): m / z = 552.3 (M + H-HCl).

Preparation Method 10

4-bromo-1-methanesulfonyl-2-trifluoromethyl-benzene

2-trifluoromethyl-benzenethiol (10 g, 56 mmol), potassium carbonate (25 g, 180 mmol) and iodomethane (11 mL, 177 mmol) were dissolved in DMF (100 mL). Stir for 12 hours. The suspension was filtered through a pad of silica gel and eluted with ethyl acetate (500 mL). Half of the solvent was evaporated and the remaining solution was washed with 10% aqueous LiCl solution (100 mL). Dry with MgSO ₄ and evaporate the solvent. The residue was chromatographed on the SiO ₂ column, eluting with hexanes to afford 9.5 g of 1-methylsulfanyl-2-trifluoromethyl-benzene (88%).

1-methylsulfanyl-2-trifluoromethyl-benzene (3.5 g, 18 mmol), iron (100 mg, 1.79 mmol), bromine (0.95 mL, 18 mmol), aluminum chloride (242 mg, 1.8 mmol) and Dichloromethane (50 mL) was mixed and stirred for 2 hours. Water (10 mL), saturated aqueous sodium thiosulfate solution (100 mL) and ethyl acetate (100 mL) were added. The organic layer was separated, washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on the SiO ₂ column, eluting with hexanes to afford 3.6 g of 4-bromo-1-methylsulfanyl-2-trifluoromethyl-benzene (83%).

4-bromo-1-methylsulfanyl-2-trifluoromethyl-benzene (3.6 g, 15 mmol), mCPBA (7.7 g, 30 mmol) and dichloromethane (100 mL) were mixed. Stir for 2 hours. Dilute with dichloromethane (300 mL) and water (100 mL). The organic layer was separated and washed with saturated aqueous NaHC03 (2x 100 mL) and brine (100 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo. The solid was washed with diethyl ether (2 x 10 mL) and dichloromethane (10 mL) to give 2.06 g of the title compound (44%).

Example 31

1- (2- {4- [2- (4-methanesulfonyl-3-trifluoromethyl-phenyl) -1- (4-methoxy-phenyl) -propenyloxy] -phenoxy} -ethyl) Piperidine

Palladium (II) acetate (6 mg, 0.029 mmol), tricyclohexylphosphine (13 mg, 0.047 mmol), cesium fluoride (258 mg, 1.7 mmol), and acetonitrile (10 mL) were mixed. Stir for 5 minutes. Compound of Preparation 1 (92 mg, 0.18 mmol) and bis (neopentylglycolato) diboron (64 mg, 0.89 mmol) were added and heated to 90 ° C. 4-bromo-1-methanesulfonyl-2-trifluoromethyl-benzene / acetonitrile (1 mL) was added and stirred at 90 ° C. for 10 minutes. Cool to room temperature, dilute the solution with ethyl acetate (20 mL) and wash with saturated aqueous NaHCO ₃ (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column eluting with methanol / dichloromethane (0-5%) to give 62 mg of the title compound (54%): mass spectrum (ion spray): m / z = 600.3 ( M + H).

Example 32

6- (4-Methanesulfonyl-3-trifluoromethyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The product of Example 31 was dissolved in ethyl acetate (10 mL) and diethyl ether (5 mL). 2M HCl / diethyl ether (0.1 mL, 0.2 mmol) was added. The slurry was concentrated and dried under vacuum. The residue was diluted with dichloromethane (5.0 mL) and covered with nitrogen. The solution was cooled to 0 ° C. with an external ice bath. BBr ₃ (0.1 mL, 1.1 mmol) was added and stirred for 1 h. Dilute with water (1.0 mL) and dichloromethane (10 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (10 mL) and brine (10 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo. 6- (4-methanesulfonyl-3-trifluoromethyl-phenyl) -5- [4- (2-piperidine- in a stepped gradient of methanol / dichloromethane (0-5%) on a SiO ₂ column The residue was chromatographed, eluting 1-yl-ethoxy) -phenoxy] -naphthalen-2-ol. The free base was dissolved in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and 2M HCl / diethyl ether (0.1 mL, 0.2 mmol) was added. The precipitate was collected on filter paper, rinsed with diethyl ether and dried for 48 h at 65 ° C. in vacuo (<2 mmHg) to give 34 mg of the title compound (53%).

Preparation Method 11

1-Bromo-2,3-dichloro-4-methanesulfonyl-benzene

4-bromo-2-chloro-1-methylsulfanyl-benzene (1.9 g, 20 mmol) and mCPBA (5.0 g, 80 mmol) were dissolved in dichloromethane (30 mL). Stir for 2 hours. Dilute with dichloromethane (20 mL) and water (20 mL). The organic layer was separated and washed with saturated aqueous NaHCO ₃ (2 × 100 mL) and brine (100 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo. The solid was washed with diethyl ether (2x 10 mL) and dichloromethane (10 mL) to give 890 mg of the title compound (52%).

Example 33

1- (2- {4- [2- (2,3-Dichloro-4-methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenoxy} -ethyl) -piperidine

Palladium (II) acetate (32 mg, 0.14 mmol), tricyclohexylphosphine (67 mg, 0.24 mmol), cesium fluoride (1.3 g, 8.6 mmol) and acetonitrile (20 mL) were mixed. Stir for 5 minutes. Compound of Preparation 1 (500 mg, 0.95 mmol) and bis (neopentylglycolato) diboron (322 mg, 1.42 mmol) were added. Heat to 90 ° C. and add 1-bromo-2,3-dichloro-4-methanesulfonyl-benzene / acetonitrile (2 mL). Stir at 90 ° C. for 10 minutes. Cool to room temperature, dilute the solution with ethyl acetate (20 mL) and wash with saturated aqueous NaHCO ₃ (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a column eluting with methanol / dichloromethane (0-5%) to afford 180 mg of the title compound (33%): mass spectrum (ion spray): m / z = 566.2.

Example 34

6- (2,3-Dichloro-4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The product of Example 33 was dissolved in ethyl acetate (10 mL) and diethyl ether (5 mL). 2M HCl / diethyl ether (0.5 mL, 1.0 mmol) was added. The slurry was concentrated and dried in vacuo. The residue was diluted in dichloromethane (5.0 mL) and covered with nitrogen. The solution was cooled to 0 ° C. with an external ice bath. BBr ₃ (0.1 mL, 1.1 mmol) was added and stirred for 1 h. Quench with water (1.0 mL) and dilute with dichloromethane (10 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (10 mL) and brine (10 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo. To 6- (2,3-dichloro-4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-l-yl- with a stepwise gradient of methanol / dichloromethane (0-5%) The residue was chromatographed on an SiO ₂ column eluting methoxy) -phenoxy] -naphthalen-2-ol. The free base was dissolved in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and 2M HCl / diethyl ether (0.5 mL, 1.0 mmol) was added. The precipitate was collected on filter paper and rinsed with diethyl ether to give 38 mg of the title compound (30%): mass spectrum (ion spray): m / z = 586.2.

Preparation 12

4-Bromo-1,2-bis-methanesulfonyl-benzene

4-bromo-2-fluoro-1-methylsulfanyl-benzene (4.8 g, 22 mmol) and sodium methanethiolate (1.6 g, 22 mmol) were mixed in DMF (50 mL). Stir for 48 hours. The reaction mixture was poured into ice (10 g). The layers were separated and the organic layer was washed with saturated aqueous NaHC03 solution and brine. Dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a column eluting with diethyl ether / hexane (0-5%) to afford 4.82 g of 4-bromo-1,2-bis-methylsulfanylbenzene (89%).

4-bromo-1,2-bis-methylsulfanylbenzene (1.4 g, 5.5 mmol) and mCPBA (8.6 g, 34 mmol) were mixed in dichloromethane (100 mL). Stir for 2 hours. Dichloromethane (300 mL) and water (100 mL) were added. The organic layer was separated and washed with saturated aqueous NaHCO ₃ (2 × 100 mL) and brine (100 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo. The solid was washed with ether (2 × 10 mL) and dichloromethane (10 mL) to afford 800 mg of 4-bromo-1,2-bis-methanesulfonylbenzene (46%).

Example 35

1- (2- {4- [2- (3,4-Bis-methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenoxy} -ethyl) -piperidine

Palladium (II) acetate (13 mg, 0.058 mmol), tricyclohexylphosphine (27 mg, 0.096 mmol), cesium fluoride (518 mg, 3.4 mmol), and acetonitrile (20 mL) were mixed. Stir for 5 minutes and add compound of Preparation 1 (200 mg, 0.38 mmol) and bis (neopentyl glycolato) diboron (130 mg, 0.58 mmol). Heated to 90 ° C., 4-bromo-1,2-bis-methanesulfonyl-benzene / acetonitrile (2 mL) was added and stirred for 10 minutes. Cool to room temperature, dilute the solution with ethyl acetate (20 mL) and wash with saturated aqueous NaHCO ₃ (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a column eluting with methanol / dichloromethane (0-5%) to give 130 mg of the title compound (56%).

Example 36

6- (3,4-bis-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The product of Example 35 was dissolved in ethyl acetate (10 mL) and diethyl ether (5 mL). 2M HCl / diethyl ether (0.1 mL, 0.2 mmol) was added. The slurry was concentrated and dried in vacuo. The residue was diluted in dichloromethane (5.0 mL) and covered with nitrogen. The solution was cooled to 0 ° C. with an external ice bath. BBr ₃ (0.1 mL, 1.1 mmol) was added and stirred for 1 h. Quench with water (1.0 mL) and dilute with dichloromethane (10 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (10 mL) and brine (10 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo. 6- (3,4-bis-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) with a stepwise gradient of methanol / dichloromethane (O-5%) The residue was chromatographed on a column eluting -phenoxy] -naphthalen-2-ol. The free base was dissolved in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and 2M HCl / diethyl ether (0.1 mL, 0.2 mmol) was added. The precipitate was collected on filter paper, rinsed with diethyl ether and dried for 48 hours at 65 ° C. under vacuum (<2 mmHg) to give 61 mg of the title compound (45%): mass spectrum (ion spray): m / z: 594.9 (M + H-HCl).

Preparation 13

1-Bromo-4- (2,2,2-trifluoro-ethanesulfonyl) -benzene

4-bromo-benzenethiol (1.0 g, 5.3 mmol) was dissolved in dry dimethylformamide (50 mL) and cooled to 0 ° C under nitrogen. Dry sodium hydride (152 mg, 6.4 mmol) was added in portions. After vigorous gas evolution ceased, toluene-4-sulfonic acid 2,2,2-trifluoro-ethyl ester (2.0 g, 8.0 mmol) was added and the reaction was stirred at rt overnight. The reaction was poured into water (400 mL) and extracted with ethyl acetate (2x150 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue obtained on a SiO ₂ column with hexane was chromatographed to give 640 mg of 1-bromo-4- (2,2,2-trifluoro-ethylsulfanyl) -benzene (45%).

1-Bromo-4- (2,2,2-trifluoro-ethylsulfanyl) -benzene (640 mg, 2.4 mmol) was dissolved in dichloromethane (25 mL) and cooled to 0 ° C. mCPBA (1.8 g, 7.1 mmol, 68%) was added portionwise and the reaction was stirred for 2 hours at room temperature. The white precipitate was filtered off and the filtrate was washed with 1N aqueous NaOH solution. The organic layer was washed with sodium sulfate, filtered and concentrated in vacuo to give 700 mg of the title compound (98%).

Example 37

1- [2- (4- {6-methoxy-2- [4- (2,2,2-trifluoro-ethanesulfonyl) -phenyl] -naphthalen-1-yloxy} -phenoxy)- Ethyl] -piperidine

The flame-dried flask was charged with palladium (II) acetate (6.4 mg, 0.029 mmol), tricyclohexylphosphine (13.3 mg, 0.048 mmol) and cesium fluoride (260 mg, 1.71 mmol). Dry acetonitrile (2 mL) was added and stirred under nitrogen. Compound of Preparation 1 (100 mg, 0.19 mmol) was added followed by bis (neopentylglycolato) diboron (64 mg, 0.29 mmol). The reaction was placed in an 80 ° C oil bath. As long as the reaction turned black (~ 3-5 minutes), immediately add 1-bromo-4- (2,2,2-trifluoro-ethanesulfonyl) -benzene (116 mg, 0.38 mmol) Heating continued. After 45 minutes, the reaction was cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo and purified on a SiO ₂ column with methanol / dichloromethane (0-3%) to give 26 mg of the title compound (23%): LRMS (ESI, zwitterion) m / z = 600.5 (M + H).

Example 38

5- [4- (2-Piperidin-1-yl-ethoxy) -phenoxy] -6- [4- (2,2,2-trifluoro-ethanesulfonyl) -phenyl] -naphthalene- 2-ol

The compound of Example 37 (26 mg, 0.043 mmol) was dissolved in dichloromethane (1 mL) and 2M HCl / diethyl ether (43 μl, 0.086 mmol) was added. The solvent was removed in vacuo and placed on a high vacuum pump for 10 minutes. The resulting foam was dissolved in dry dichloromethane (1 mL) and cooled to 0 ° C. BBr ₃ (20 μl, 0.22 mmol) was added dropwise and stirred at 0 ° C. for 1 h. The reaction was poured into cold saturated aqueous sodium bicarbonate solution (5 mL) and extracted with dichloromethane (2 x 5 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified with methanol / dichloromethane (0 to 8%) on SiO ₂ column to give 16 mg of the title compound (64%): mass spectrum (ion spray) m / z = 586. 4 (M + H).

Example 39

5- [4- (2-Piperidin-1-yl-ethoxy) -phenoxy] -6- [4- (2,2,2-trifluoro-ethanesulfonyl) -phenyl] -naphthalene- 2-ol hydrochloride

The compound of Example 38 (30 mg, 0.051 mmol) was dissolved in dry dichloromethane (1 mL) and 2M HCl / diethyl ether (0.10 mL, 0.20 mmol) was added. Stir at room temperature for 1 minute. The solvent was removed by blowing nitrogen over the liquid. The residue was placed on a high vacuum pump for 1 hour. The product was dried overnight in a vacuum oven at 45 ° C. to give 30 mg of the title compound (97%): mass spectrum (ion spray) m / z = 586.3 (M + H-HCl).

Preparation 14

2- (4-Isopropylsulfanyl-phenyl) -boronic acid

4-bromo-benzenethiol (1.0 g, 5.3 mmol) was dissolved in dry dimethylformamide (50 mL) and cooled to 0 ° C under nitrogen. Dry sodium hydride (153 mg, 6.4 mmol) was added in portions. After vigorous gas evolution ceased, 2-bromo-propane (0.60 mL, 6.4 mmol) was added and the reaction stirred overnight at room temperature. The reaction was slowly poured into water (300 mL) and extracted with ethyl acetate (2x150 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue obtained was chromatographed with 5% ethyl acetate / hexanes on a SiO ₂ column to give 1.1 g of 1-bromo-4-isopropylsulfanyl-benzene (92%).

1-Bromo-4-isopropylsulfanyl-benzene (2.5 g, 10.8 mmol) was dissolved in dry tetrahydrofuran (100 mL) and the solution was cooled to -78 ° C. 2.5M n-butyllithium / hexane (5.2 mL, 12.9 mmol) was added dropwise and the reaction was allowed to warm to -40 ° C and stirred for 30 minutes. The reaction was cooled to -78 ° C and triisopropyl borate (7.4 mL, 32.4 mmol) was added and then the reaction was allowed to slowly warm to room temperature. 10% aqueous potassium hydroxide solution (96 mL, 172 mmol) was added and stirred overnight. The reaction was slowly poured into a mixture of concentrated HCl solution and ice. The aqueous solution was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo to give 1.9 g of the title compound (90%).

Example 40

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

2- (4-isopropylsulfanyl-phenyl) -boronic acid (223 mg, 1.14 mmol), the compound of Preparation 1 (300 mg, 0.57 mmol) and cesium fluoride (433 mg, 2.85 mmol) with a reflux condenser Mix in a flame-dried flask and purge with nitrogen. In a separate dried flask, palladium (II) acetate (13 mg, 0.06 mmol) and tricyclohexylphosphine (24 mg, 0.09 mmol) were mixed. Dry acetonitrile (5 mL) was added and sonicated under nitrogen for 10 minutes. Catalyst slurry was added to the solid and the flask was placed in a 90 ° C. oil bath. After 20 minutes the black suspension was cooled to room temperature, filtered through celite and rinsed with dichloromethane. The filtrate was concentrated in vacuo. The residue obtained was chromatographed with 0.2% ammonium hydroxide and 3% methanol / dichloromethane on SiO ₂ column to give 300 mg of the title compound (95%): mass spectrum (ion spray) m / z = 528.3 (M + H ).

Example 41

6- (4-Isopropylsulfanyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol

Example 43 (300 mg, 0.57 mmol) of the compound was dissolved in dichloromethane (3 mL). 2M HCl / diethyl ether (0.51 mL, 1.14 mmol) was added and stirred for 1 minute. The solvent was removed in vacuo and placed on a high vacuum pump for 20 minutes. The foam was dissolved in dry dichloromethane (6 mL) and cooled to 0 ° C. BBr ₃ (0.21 mL, 2.3 mmol) was added dropwise. Stir for 45 minutes and quench by adding methanol (1 mL). The reaction mixture was slowly poured into saturated aqueous sodium bicarbonate solution (10 mL) and extracted with dichloromethane (2 x 10 mL). The combined organic layers were dried over sodium sulfate, concentrated in vacuo and the residue was chromatographed with 0.2% ammonium hydroxide and 5% methanol / dichloromethane on SiO2 column to give 236 mg of the title compound (81%): mass spectrum (Ion spray) m / z = 514.3 (M + H).

Example 42

5- [4- (2-Piperidin-1-yl-ethoxy) -phenoxy] -6- [4- (propane-2-sulfonyl) -phenyl] -naphthalen-2-ol

The compound of Example 41 (236 mg, 0.46 mmol) was dissolved in glacial acetic acid (5 mL) and sodium perborate (92 mg, 0.92 mmol) was added. The reaction was stirred overnight and the mixture was poured into saturated aqueous sodium bisulfite solution (20 mL). Extract with dichloromethane (2x20 mL) and wash the combined organic layers with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed with 4% methanol / dichloromethane with 0.2% ammonium hydroxide on SiO ₂ column to give 197 mg of the title compound (79%): mass spectrum (ion spray) m / z = 546.3 (M + H).

Example 43

5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -6- [4- (propane-2-sulfonyl) -phenyl] -naphthalen-2-ol hydrochloride

The compound of Example 42 (123 mg, 0.36 mmol) was dissolved in dry dichloromethane (0.5 mL). The solution was diluted with diethyl ether (4 mL) and 2M HCl / diethyl ether (0.36 mL, 0.72 mmol) was added. Stir at room temperature for 10 minutes. The white precipitate was filtered through filter paper and the solid was dried overnight in a vacuum oven at 50 ° C. to give 102 mg of the title compound (78%): mass spectrum (ion spray) m / z = 546.3 (M + H-HCl). ).

Preparation 15

2-Methyl-4-methylthiophenylboronic acid

1M 3-methyl-phenylmagnesium bromide / THF (25 mL, 25 mmol) was added to -30 ° C diethyl ether (50 mL). Dimethyl disulfide (1.8 mL, 20 mmol) was added to the reaction over 3 minutes and the reaction was allowed to warm to room temperature. The reaction was diluted with H ₂ 0 (75 mL) and diethyl ether (50 mL). The hazy water soluble layer was separated and extracted with diethyl ether (25 mL). The organic layers were combined and washed with H ₂ 0 (25 mL). The organic layer was dried over Na ₂ SO ₄ (30 g), filtered over Celite 501 (10 g) and concentrated in vacuo to yield 3.0 g of crude material. Another batch of crude title compound (6.0 g of crude compound obtained) was combined. A total of 9.0 g of crude compound was chromatographed with hexanes on a SiO ₂ column to give 7.2 g (70%) of 1-methyl-3-methylsulfanyl-benzene.

Iron (25 mg, 0.45 mmol) and 1-methyl-3-methylsulfanyl-benzene (204 mg, 1.47 mmol) were mixed in dichloromethane (DCM, 2 mL). The slurry was cooled to 3 ° C. and Br ₂ (74 μl, 1.44 mmol) was added over 5 minutes. Stir at 3 ° C. for 10 minutes and remove the external cooling bath. Stir at room temperature for 4 hours and quench with 10% Na ₂ S ₂ O ₃ aqueous solution. The reaction was diluted with dichloromethane (10 mL) and separated. The organic layer was washed with brine, concentrated and chromatographed with dichloromethane / hexanes (0-5%) to give 125 mg of 1-bromo-2-methyl-4-methylsulfanyl-benzene (53%).

1-Bromo-2-methyl-4-methylsulfanyl-benzene (608 mg, 2.80 mmol) was added to diethyl ether (60 mL) and cooled to -78 ° C under nitrogen flow. t-BuLi (3.4 mL, 5.78 mmol) was added over 15 minutes, stirred for 2 minutes, trimethyl borate ((MeO) ₃ B, 340 μl, 2.99 mmol) was added over 2 minutes and for 15 minutes After stirring at -78 ° C, it was allowed to warm to room temperature. The reaction was quenched with saturated aqueous NH ₄ Cl solution (7 mL), stirred for 15 minutes, then 1M HCl aqueous solution (6 mL) was added, stirred for another 2 minutes, and then separated. Dry over Na ₂ S0 ₄ , filter (wash the desiccant with ethyl acetate (3 x 20 mL)) and concentrate. The crude material was chromatographed with 20% ethyl acetate / hexanes to 5% methanol / ethyl acetate on SiO ₂ column to give 267 mg of the title compound (52%).

Example 44

1- (2- {4- [6-methoxy-2- (2-methyl-4-methylsulfanyl-phenyl) -naphthalen-1-yloxy] -phenoxy} -ethyl) -piperidine hydrochloride

Compound (300 mg, 0.57 mmol), 2-methyl-4-methylthiophenylboronic acid (267 mg, 1.47 mmol) and cesium fluoride (672 mg, 4.42 mmol) in a flame-dried flask with a reflux condenser ) Was added with acetonitrile (3.0 mL). In a separate dried flask, palladium (II) acetate (14.5 mg, 0.06 mmol) and tricyclohexylphosphine (27.5 mg, 0.10 mmol) were mixed. Dry acetonitrile (2.5 mL) was added and sonicated under nitrogen for 10 minutes. The catalyst suspension was added to the reaction slurry and the flask was placed in a 90 ° C oil bath. After 40 minutes, the black suspension was cooled to room temperature, filtered and the solid washed with acetonitrile (3 x 10 mL). The filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (25 mL) and 5% aqueous sodium carbonate solution (10 mL). The layers were separated and the organic layer was washed with NH ₄ Cl (10 mL) and brine (10 mL). The organic layer was concentrated in vacuo and the residue was chromatographed on a SiO ₂ column with methanol / dichloromethane (0 to 2.5%) to give 331 mg of 1- (2- {4- [6-methoxy-2- (2). -Methyl-4-methylsulfanyl-phenyl) -naphthalen-1-yloxy] -phenoxy} -ethyl) -piperidine (94%) was obtained. The freebase material was dissolved in ethyl acetate (10 mL), 2M HCl / diethyl ether (350 μl) was added and concentrated in vacuo to give the title compound: mass spectrum (ion spray) m / z = 514.3 (M + H).

Example 45

6- (2-Methyl-4-methylsulfanyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol

1- (2- {4- [6-methoxy-2- (2-methyl-4-methylsulfanyl-phenyl) -naphthalen-1-yloxy] -phenoxy} -ethyl) -piperidine hydrochloride ( 331 mg, 0.603 mmol) was dissolved in dichloromethane (15 mL) and cooled to 5 ° C. BBr ₃ (285 μl, 3.02 mmol) was added to the light suspension over 5 minutes. After 1 hour the reaction was quenched with saturated aqueous NaHCO ₃ (15 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 10 mL). The solution was poured onto a Si02 plug (20 g) and eluted with methanol / dichloromethane (5-15%). Fractions were concentrated in vacuo to afford 301 mg of the title compound (100%): mass spectrum (ion spray) m / z = 500.3 (M + H).

Example 46

6- (4-Methanesulfonyl-2-methyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol trifluoroacetate

The compound of Example 45 (301 mg, 0.060 mmol) was dissolved in glacial acetic acid (5 mL) and NaBO 3 .H 2 O (120 mg, 1.20 mmol) was added. After 14 hours the reaction was concentrated and partitioned between 10% aqueous NaHSO ₃ (30 mL), MeOH (3 mL) and dichloromethane (50 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (10 mL). The organic layers were combined and washed with saturated aqueous NaHCO ₃ (10 mL) and H ₂ O (10 mL). Dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. Chromatography with methanol / dichloromethane (0 to 10%) on an SiO ₂ column gave an impure product. This crude material was purified by preparative HPLC to give 97 mg of the title compound (23%): mass spectrum (ion spray) m / z = 532.3 (M + H-TFA).

Example 47

1- (2- {4- [6-methoxy-2- (3-methyl-4-methylsulfanyl-phenyl) -naphthalen-1-yloxy] -phenoxy} -ethyl) -piperidine

Palladium (II) acetate (21 mg, 0.094 mmol), tricyclohexylphosphine (53 mg, 0.19 mmol), compound of Preparation 1 (500 mg, 0.95 mmol), cesium fluoride (1.OOg, 6.62 mmol), 3-methyl-4- (methylthio) benzeneboronic acid (US Pat. No. 6,307,047; 520 mg, 2.86 mmol) and acetonitrile (40 mL) were combined. Heated to 90 ° C. for 1 hour. After cooling to room temperature, the solution was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO ₃ (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column eluting the material with methanol / dichloromethane (2-4%) to give 371 mg of the title compound (75%): mass spectrum (ion spray): m / z = 514.3 (M + H).

Example 48

6- (3-Methyl-4-methylsulfanyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol

The product of Example 47 was combined in ethyl acetate (10 mL) and diethyl ether (5 mL). 2M HCl / diethyl ether (5 mL, 10.0 mmol) was added. The slurry was concentrated and dried under vacuum. The residue was diluted in dichloromethane (5.0 mL) and covered with nitrogen. The solution was cooled to 0 ° C. with an external ice bath and BBr ₃ (0.3 mL, 3.2 mmol) was added. After 1 hour, water (1.0 mL) and ethyl acetate (10 mL) were added. The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (10 mL) and brine (10 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a column eluting the material with a gradient of methanol / dichloromethane (0 to 0.5%) to give 330 mg of the title compound (92%): mass spectrum (ion spray): m / z = 500.3 (M + H).

Example 49

6- (4-Methanesulfonyl-3-methyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The compound of example 48 and sodium perborate (162 mg, 1.62 mmol) were combined in acetic acid (4 mL). After 2 days, dichloromethane (20 mL) and water (5 mL) were added. The layers were separated and the organic layer was washed with saturated aqueous NaHC03 (10 mL) and brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. 6- (4-methanesulfonyl-3-methyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) with a gradient of methanol / dichloromethane (0 to 5%) The residue was chromatographed on an SiO 2 column eluting -phenoxy] -naphthalen-2-ol. The free base was dissolved in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and 2M HCl / diethyl ether (1 mL, 2.0 mmol) was added. The precipitate was collected on filter paper, rinsed with diethyl ether and dried for 48 hours at 65 ° C. in vacuo (<2 mmHg) to give 40 mg of the title compound (11%): mass spectrum (ion spray): m / z = 537.0 (M + H-HCl).

Preparation 16

2-benzo [b] thiophen-5-yl-4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

5-bromo-benzo [b] thiophene (J. Mater. Chem., 10: 2069-2081, 2000; 49 g, 7.0 mmol) was dissolved in DMSO (40 mL). Bis (pinacolato) diboron (7 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ (0.33 mmol), and KOAc (20 mmol) were added. After the flask was flushed with N ₂ , the reaction mixture was heated to 80 ° C. with stirring. The reaction mixture was continued to heat for 3 hours and then cooled to room temperature. Water (66 mL) was added and the aqueous layer was extracted with EtOAc (3 x 66 mL). The organic layers were combined, dried over Na ₂ S0 ₄ , filtered, concentrated and purified by flash column chromatography (silica gel, 0-5% Et ₂ 0 / pentane) to afford 1.56 g of the title compound (86%). Got it.

Example 50

1- {2- [4- (2-Benzo [b] thiophen-5-yl-6-methoxy-naphthalen-1-yloxy) -phenoxy] -ethyl} -piperidine

2-benzo [b] thiophen-5-yl-4,4,5,5-tetramethyl- [1,3,2] dioxaborolane (400 mg, 1.54 mmol) and the compound of Preparation 1 (270 g) , 0.51 mmol) was dissolved in CH ₃ CN (24 mL). Pd (OAc) 2 (0.05 mmol), tricyclohexylphosphine (0.075 mmol), and CsF (4.5 mmol) were added. After the flask was flushed with N ₂ , the reaction mixture was heated to 90 ° C. with stirring. The reaction mixture was continued to heat for 6 hours and then cooled to room temperature. Water (50 mL) was added and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 25 mL). Combine organic layers, dry over Na ₂ SO ₄ , filter, concentrate and flash column chromatography (silica gel, 0-4% MeOH-NH ₄ OH (10/1, v / v) / CH ₂ Cl ₂ ) Purification by gave 240 mg of the title compound (93%): 1 H NMR (CDCl ₃ ) δ 7.99 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.82 (d , J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.4, 1.2 Hz, 1H), 7.41 (d, J = 5.6 Hz, 1H), 7.31 (d , J = 5.6 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 7.11. (dd, J = 9.2, 2.8 Hz, 1H), 6.73 (d, J = 5.6 Hz, 1H), 6.60-6.63 (m, 4H), 4.04 (t, J = 5.0 Hz, 2H), 3.94 (s, 3H), 2.93 (t, J = 5.0 Hz, 2H), 2.67-2.79 (m, 4H), 1.66-1.75 (m, 4H), 1.44-1.55 (m, 2H).

Example 51

6-benzo [b] thiophen-5-yl-5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol trifluoroacetate

The compound of Example 50 (240 mg, 0.48 mmol) was dissolved in dimethylformamide (DMF, 7 mL) and sodium ethanethiolate (EtSNa, 100 mg, 1.19 mmol) was added. The flask was flushed with N ₂ and then heated to 150 ° C. The reaction mixture was continued to heat for 0.5 h and then cooled to room temperature. Water (15 mL) was added and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 15 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated, then flash column chromatography (silica gel, 0-8% MeOH-NH ₄ OH (10/1, v / v) / CH ₂ Cl ₂ 140 mg of crude 6-benzo [b] thiophen-5-yl-5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalene-2- Got the ol. The resulting impure product was purified by preparative HPLC (Gilson) to give 95 mg of the title compound (55%): mass spectrum (ion spray): m / z = 496.3 (M + H-TFA).

Example 52

Acetic acid 6- (1,1-dioxo-1H-1λ ⁶ -benzo [b] thiophen-5-yl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy ] -Naphthalen-2-yl ester

6-benzo [b] thiophen-5-yl-5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol (560 mg, 1.13 mmol) Was dissolved in CH ₂ Cl ₂ (20 mL) and the solution was cooled to 0 ° C. DMAP (28 mmol), triethylamine (Et3N, 8 mmol) and acetic anhydride (Ac ₂ 0, 1.9 mmol) were added. The reaction mixture was stirred for 3 h at 0 ° C. and then water (40 mL) was added. The aqueous layer was extracted with CH ₂ Cl ₂ (3 × 40 mL). The organic layers were combined, dried over Na ₂ S0 ₄ , filtered, concentrated and purified by flash column chromatography (silica gel, 0-5% MeOH / CH ₂ Cl ₂ ) to 360 mg of acylation product (59% ): Mass spectrum (ion spray): m / z = 538.3 (M + H). Acylation product (110 mg, 0.2 mmol) was dissolved in acetic acid (AcOH, 1.1 mL) and H ₂ 0 ₂ (110 mg, 1.0 mmol, 30% wt) was added. The reaction mixture was heated to 90 ° C. for 1 hour and cooled to room temperature. 1M aqueous bisulfite solution (1 mL) was added and the reaction mixture was stirred for 10 minutes. NaHCO ₃ saturated aqueous solution (20 mL) was added and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 20 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash column chromatography (silica gel, 0-5% MeOH / CH ₂ Cl ₂ ) to 51 mg of the title compound (44%). Obtained: Mass spectrum (ion spray): m / z = 570.3 (M + H).

Example 53

6- (1,1-Dioxo-1H-lλ ⁶ -benzo [b] thiophen-5-yl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] Naphthalen-2-ol trifluoroacetate

The compound of Example 52 (51 mg, 0.089 mmol) was dissolved in MeOH (2 mL). NaHCO ₃ (0.10 mmol) was added and the reaction mixture was stirred for 3 hours at room temperature. The solid was removed by filtration. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 2-10% MeOH-NH 4 OH (10/1, v / v) / CH ₂ Cl ₂ ). The collected material was dried in vacuo at 40 ° C. overnight to give 67 mg of deprotected product (85%). Deprotected product (67 mg, 0.13 mmol) was dissolved in CH ₂ Cl ₂ (10 mL) and cooled to -78 ° C. After addition of CF ₃ CO ₂ H (0.13 mL, 1.0 M / CH ₂ Cl ₂ ), the solvent was removed under reduced pressure to give a solid. The solid was dried under vacuum overnight at room temperature to give 82 mg of the title compound (100%): mass spectrum (ion spray): m / z = 528.3 (M + H-TFA).

Preparation 17

6- (3,5-Difluoro-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol

Compound of Preparation 1 (440 mg, 0.84 mmol), 3,5-difluoro-benzeneboronic acid (400 mg, 2.50 mmol), palladium (II) acetate (19 mg, 0.083 mmol), tricyclohexylphosphine ( 35 mg, 0.125 mmol), cesium fluoride (1.14 g, 7.52 mmol), and acetonitrile (10 mL) were combined and heated at 90 ° C. After 10 minutes, cooled to ambient temperature, diluted with dichloromethane, loaded on a 10 g SCX cartridge, washed with dichloromethane, methanol, water and methanol, with ammonia solution (2N NH ₃ / methanol, 80 mL) Elution and solvent removed under vacuum. Dissolved in dichloromethane, chromatographed with a dichloromethane / methanol mixture on silica gel, and 1M hydrogen chloride / diethyl ether (0.8 mL) was added to give 410 mg of 1- (2- {4- [2- (3, 5-Difluoro-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenoxy} -ethyl) -piperidine hydrochloride (93%) was obtained.

1- (2- {4- [2- (3,5-Difluoro-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenoxy} -ethyl) -piperidine hydrochloride (410 mg , 0.76 mmol) was dissolved in dichloromethane (10 mL) and cooled in an ice bath. Boron tribromide (0.22 mL, 2.28 mmol) was added and stirred for 2.5 h. Methanol (5 mL) was added and allowed to warm to room temperature, diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, dried over solid magnesium sulfate, filtered and the solvent removed under vacuum. Chromatography with dichloromethane / methanol mixture on silica gel gave 350 mg of the title compound (96%).

Example 54

6- (3,5-Bis-ethylsulfanyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol

6- (3,5-Difluoro-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol (300 mg, 0.63 mmol) , Sodium ethane thiol (530 mg, 6.33 mmol) and 1-methyl-2-pyrrolidinone (10 mL) were combined and heated to 130 ° C. for 4.5 h. Cool to ambient temperature, dilute with dichloromethane and wash with brine and saturated aqueous sodium bicarbonate solution. The organic phase was loaded onto a 10 g SCX cartridge, washed with dichloromethane and methanol, eluted with ammonia solution (2N NH ₃ / methanol, 80 mL) and the solvent removed in vacuo. Dissolve in dichloromethane and chromatograph on a silica gel with a dichloromethane / methanol mixture to give 260 mg of the title compound (74%). Mass spectrum (ion spray): m / z = 560 (M + H).

Example 55

6- (3,5-Bis-ethanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol

The compound of Example 54 (160 mg, 0.29 mmol) was dissolved in glacial acetic acid (5 mL). An acetic acid solution of 77% mCPBA (300 mg, 1.31 mmol theory) was added dropwise over 10 minutes and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Fractionated between dichloromethane and saturated aqueous sodium bicarbonate solution, dried over solid magnesium sulfate, filtered and chromatographed on a dichloromethane / methanol mixture on silica gel to give 130 mg (72%) of the title compound. Mass spectrum (ion spray): m / z = 624 (M + H).

Example 56

6- (3,5-Bis-ethanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The compound of Example 55 was dissolved in dichloromethane and 1N HCl / Et ₂ 0 (0.180 mL) was added. Evaporation to dryness afforded the title compound.

Preparation 18

{4- [2- (4-Methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenyl} -carbamic acid tert-butyl ester

6-methoxytetralone (9.6 g, 54 mmol), 4-bromothioanisole (25 mL, 123 mmol), sodium tert-butoxide (20.9 g, 217 mmol), palladium (II) acetate (610 mg, 2.72 mmol), a solution of racemic 2,2'-bis (diphenylphosphino) -1,1'-binafthyl (1.8 g, 2.72 mmol) and toluene (150 mL) was refluxed for 18 hours. After heating, it was cooled to room temperature and evaporated under reduced pressure to dry. The residue was dissolved in dichloromethane and washed with aqueous hydrochloric acid solution (IN), filtered through celite and chromatographed twice with hexane / ethyl acetate mixture on silica gel to give 2.41 g of 6-methoxy-2- (4- Methylsulfanyl-phenyl) -naphthalen-1-ol (15%) was obtained.

6-methoxy-2- (4-methylsulfanyl-phenyl) -naphthalen-1-ol (1.98 g, 6.68 mmol), 4-fluoro-nitrobenzene (0.78 mL, 7.34 mmol) and phosphazene P ₄ A solution in -t-butyl (6.7 mL of 1M / hexane, 6.7 mmol) in N, N-dimethylformamide (30 mL) was stirred at rt for 4 h. The reaction was diluted with dichloromethane, washed with 1N aqueous hydrochloric acid solution, water, dried over solid magnesium sulfate and chromatographed with hexane / ethyl acetate mixture on silica gel to give 2.18 g of 6-methoxy-2- (4-methyl Sulfanyl-phenyl) -1- (4-nitro-phenoxy) -naphthalene (78%) was obtained.

77% mCPBA (340 mg, 2.00 mmol) was added to 6-methoxy-2- (4-methylsulfanyl-phenyl) -1- (4-nitro-phenoxy) -naphthalene (270 mg, 0.66 mmol) / dichloromethane (10 mL) was added to the solution. The reaction was stirred for 30 minutes, washed with saturated sodium carbonate solution, dried over solid magnesium sulfate and filtered through 1 inch pad of silica gel to give 290 mg of 2- (4-methanesulfonyl-phenyl) -6 -Methoxy-1- (4-nitro-phenoxy) -naphthalene (98%) was obtained.

2- (4-methanesulfonyl-phenyl) -6-methoxy-1- (4-nitro-phenoxy) -naphthalene (1.67 g, 3.7 mmol), ammonium formate (4.7 g, 74 mmol), wettability 20 The solution of% palladium hydroxide (420 mg, 25 wt%) and pure ethanol (80 mL) on carbon was heated to reflux for 1 hour, then cooled to room temperature, filtered and evaporated to dry under reduced pressure. The residue was partitioned with dichloromethane / water. The organic layer was dried over solid magnesium sulfate and chromatographed on a silica gel with a dichloromethane / methanol mixture to give 1.15 g of 4- [2- (4-methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yljade. C] -phenylamine (75%) was obtained.

4- [2- (4-methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenylamine (170 mg, 0.41 mmol) and di-tert-butyl dicarbonate (140 mg, 0.66 mmol) of the solution in tetrahydrofuran (10 mL) was heated to reflux for 4 hours, then cooled to room temperature and evaporated to dryness under reduced pressure. The residue was chromatographed on a silica gel with a dichloromethane / ethyl acetate mixture to give 210 mg of {4- [2- (4-methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenyl}. -Carbamic acid tert-butyl ester (97%) was obtained.

Example 57

{4- [2- (4-Methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenyl}-(2-piperidin-1-yl-ethyl) -carbamic acid tert- Butyl ester

{4- [2- (4-Methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenyl} -carbamic acid tert-butyl ester (200 mg, 0.38 mmol), 2-chloroethyl N, N-dimethylformamide solution of -1-piperidine hydrochloride (100 mg, 0.57 mmol) and 60% sodium hydride (38 mg, 0.94 mmol) was heated to 60 ° C. and stirred for 18 h. Potassium tert-butoxide (760 mg, 0.67 mmol) and 2-chloroethyl-1-piperidine hydrochloride (46 mg, 0.25 mmol) were added and stirred for a further 2 hours before cooling to room temperature. The reaction was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and chromatographed with a dichloromethane / methanol mixture on silica gel to give 120 mg of the title compound (50%). Mass spectrum (ion spray): m / z = 631.3 (M + H).

Example 58

6- (4-Methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethylamino) -phenoxy] -naphthalen-2-ol dihydrochloride

4M HCl / dioxane (3 mL, 12 mmol) was added to the solution of the compound of Example 57 (110 mg, 0.17 mmol) / dichloromethane (3 mL), the reaction was stirred for 40 minutes and then evaporated to dry under reduced pressure. I was. The residue was dissolved in dichloromethane (4 mL) and boron tribromide (0.068 mL, 0.72 mmol) was added. The reaction was stirred for 3.5 h, then saturated aqueous sodium bicarbonate solution (5 mL) was added and the phases allowed to separate. The organic layer was dried over solid magnesium sulfate and chromatographed with a dichloromethane / methanol mixture on silica gel. Fractions containing product were evaporated to dryness and redissolved in 5% methanol / dichloromethane (3 mL). After addition of 1M hydrogen chloride / diethyl ether (0.28 mL), the solution was evaporated under reduced pressure to give 82 mg of the title compound (77%). Mass spectrum (ion spray): m / z = 517.5 (M + H).

Example 59

5- [4- (2-Azepin-1-yl-ethylamino) -phenoxy] -6- (4-methanesulfonyl-phenyl) -naphthalen-2-ol dihydrochloride

Using a step similar to Preparation 18 and Example 58, 4- [2- (4-methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenyl} -carbamic acid tertbutyl ester ( 200 mg, 0.39 mmol) and 2- (hexamethyleneimino) -ethyl chloride hydrochloride (140 mg, 0.70 mmol) were converted to 77 mg of the title compound (37%). Mass spectrum (ion spray): m / z = 531 (M + H).

Preparation 19

4- [2- (4-methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenol

4-Fluoro-benzaldehyde (2.20 mL, 20.3 mmol) was added 6-methoxy-2- (4-methylsulfanyl-phenyl) -naphthalen-1-ol (3.0 g, 10.1 mmol) and 60% sodium hydride (400 mg, 10.1 mmol) in 1-methyl-2-pyrrolidinone (30 mL) solution. The reaction was heated to 170 ° C. for 70 minutes and then cooled to room temperature. Dilute the reaction with ethyl acetate (200 mL), wash twice with 5% aqueous lithium chloride solution (500 mL), brine, 1N aqueous hydrochloric acid solution, dry over solid magnesium sulfate, and dichloromethane / hexane mixtures on silica gel. Chromatography gave 1.29 g of 4- [6-methoxy-2- (4-methylsulfanyl-phenyl) -naphthalen-1-yloxy] -benzaldehyde (32%).

4- [6-methoxy-2- (4-methylsulfanyl-phenyl) -naphthalen-1-yloxy] -benzaldehyde (970 mg, 2.49 mmol), sodium perborate monohydrate (2.5 mmol) and glacial acetic acid (16 mL) was mixed. After stirring for 4 hours at room temperature, the solution was evaporated to dryness under reduced pressure. Fractionated with dichloromethane / 50% saturated sodium bicarbonate aqueous solution. The organic layer was washed with brine, dried over solid magnesium sulfate, filtered and chromatographed on a dichloromethane / methanol mixture on silica gel to give 280 mg of the title compound (27%). Mass spectrum (ion spray): m / z = 419 (M-1).

Example 60

1- (2- {4- [2- (4-Methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenoxy} -ethyl) -azepine hydrochloride

4- [2- (4-Methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenol (160 mg, 0.39 mmol), 2- (hexamethyleneimino) -ethyl chloride hydrochloride ( A solution of 140 mg, 0.69 mmol), 60% sodium hydride (47 mg, 1.18 mmol) and N, N-dimethylformamide (2 mL) was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed with water, dried over solid magnesium sulfate and chromatographed with a dichloromethane / methanol mixture on silica gel. Fractions containing product were combined and 1N hydrogen chloride / diethyl ether (0.30 mL) was added. The resulting solution was concentrated under reduced pressure to give 160 mg of the title compound (69%). Mass spectrum (ion spray): m / z = 546 (M + H).

Example 61

5- [4- (2-Azepin-1-yl-ethoxy) -phenoxy] -6- (4-methanesulfonyl-phenyl) -naphthalen-2-ol hydrochloride

Compound 60 (160 mg, 0.27 mmol) in Example 60 was added to 5- [4- (2-Azepin-1-yl-ethoxy) -phenoxy] -6- (4-methanesulfonyl-phenyl) -naphthalene- Conversion was carried out using a step analogous to Preparation 15 in 2-olo (85%). The free base was dissolved in dichloromethane, 1N HCl / Et ₂ 0 (0.250 mL) was added and then concentrated to give 140 mg of the title compound. Mass spectrum (ion spray): m / z = 532 (M + H).

Preparation 20

N-tert-butyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzenesulfonamide

t-butylamine (4.32 mL, 41.1 mmol), triethylamine (8.15 mL, 58.7 mmol) and dichloromethane (75 mL) were placed in a three-neck round bottom flask. The stirring solution was cooled to 0 ° C. and 4-bromobenzenesulfonyl chloride (10.0 g, 39.1 mmol) / dichloromethane (50 mL) solution was added. Additional dichloromethane (25 mL) was added and the reaction stirred overnight and allowed to warm to room temperature. The reaction was evaporated in vacuo. The white solid obtained was suspended in ethyl acetate and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by flash chromatography (silica gel; 50% -80% gradient CH ₂ Cl ₂ / hexanes) to 9.85 g of 4-bromo-N-tert-butyl-benzene Sulfonamide (86%) was obtained.

4-bromo-N-tert-butyl-benzenesulfonamide (2.00 g, 6.84 mmol), bis (pinacolato) diboron (2.09 g, 8.21 mmol), PdCl ₂ (dppf) ₂ CH ₂ Cl ₂ ( 175 mg, 0.24 mmol), potassium acetate (2.02 g, 20.5 mmol) and anhydrous dimethyl sulfoxide (25 mL) were placed in a round bottom flask. The reaction was placed in an oil bath and stirred at 90 ° C. for 7.5 h. The purple reaction was cooled to room temperature, quenched with sufficient water and the resulting aqueous mixture was extracted with dichloromethane. The combined extracts were washed with water and brine, then dried over sodium sulfate and evaporated in vacuo. The resulting dark solid was purified on flash column (silica gel; 0% -5% gradient EtOAc / CH ₂ Cl ₂ ) to give 2.00 g of the title compound (86%).

Example 62

N-tert-butyl-4- {6-methoxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl} -benzenesulfonamide

Compound of Preparation 1 (335 mg, 0.64 mmol), N-tert-butyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzene Sulfonamide (650 mg, 1.92 mmol) and acetonitrile (6 mL) were added to a round bottom flask containing cesium fluoride (875 mg, 5.79 mmol) and acetonitrile (6 mL). To this mixture, sonicated suspension in palladium (II) acetate (14 mg, 0.064 mmol) and tricyclohexylphosphine (27 mg, 0.096 mmol), acetonitrile (2 mL) was added. Additional acetonitrile (2 mL) was added and the reaction placed in an oil bath at 90 ° C. The reaction was stirred at 90 ° C. for 20 minutes. The reaction was cooled to room temperature and then filtered through a pad of celite (rinsed with plenty of hot ethyl acetate). The filtrate was washed with 50% aqueous sodium carbonate, saturated aqueous ammonium chloride solution, water and brine; Dry over sodium sulfate and evaporate the filtrate under vacuum. The resulting solid was purified on 25M silica column (2% -4% MeOH gradient / CH ₂ Cl ₂ ) to give 315 mg of the title compound (84%). MS (IS +) m / e 589 (M + 1).

Example 63

N-tert-butyl-4- {6-hydroxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl} -benzenesulfonamide hydrochloride

The product of Example 62 (30 mg, 0.051 mmol), sodium ethanethiolate (43 mg, 0.51 mmol) and dimethylformamide (2 mL) were placed in a round bottom flask at room temperature. The reaction was placed in a 90 ° C. oil bath, stirred for 3 hours and then cooled to room temperature. The room temperature reaction was quenched with brine and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution, water and brine; Dry over sodium sulfate and extract was concentrated in vacuo. The crude material was purified on chromatography (silica gel; 6% -10% MeOH gradient / CH ₂ Cl ₂ ). The purified solid was dissolved in methanol (4 mL) and 1.0M hydrochloric acid / diethyl ether solution (0.10 mL) was added. The resulting solution was stirred for 2 minutes at room temperature and then evaporated in vacuo to afford 25 mg of the title compound (80%). MS (IS +) m / e 575 (M + 1-HCl).

Preparation 21

N, N-dimethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzenesulfonamide

Dimethylamine (5.25 mL of 2.0M / THF solution, 10.4 mmol), triethylamine (2.04 mL, 14.68 mmol) and dichloromethane (30 mL) were placed in a round bottom flask. The solution was cooled to 0 ° C. with stirring and a 4-bromobenzenesulfonyl chloride (2.5 g, 9.78 mmol) / dichloromethane (30 mL) solution was added. Additional dichloromethane (10 mL) was added and the reaction stirred overnight and allowed to warm to room temperature. The reaction was concentrated in vacuo. The solid obtained was taken up in ethyl acetate and filtered. The filtrate was evaporated in vacuo and the solid obtained was dried in vacuo to give 2.50 g of 4-bromo-N, N-dimethyl-benzenesulfonamide (97%).

4-bromo-N, N-dimethyl-benzenesulfonamide (1.00 g, 3.77 mmol), bis (pinacolato) diboron (1.15 g, 4.53 mmol), PdCl ₂ (dppf) ₂ CH ₂ Cl ₂ ( 97 mg, 0.13 mmol), potassium acetate (1.11 g, 11.32 mmol) and anhydrous dimethyl sulfoxide (12 mL) were placed in a round bottom flask. The reaction was placed in an oil bath and stirred at 90 ° C. for 8 hours. The purple reaction was cooled to room temperature, quenched with sufficient amount of water and the resulting aqueous mixture was extracted with dichloromethane. The combined extracts were washed with water and brine, then dried over sodium sulfate and the extract was evaporated in vacuo. The solid obtained was purified on flash column (silica gel; 2% -5% gradient EtOAc / CH ₂ Cl ₂ , filler / CH ₂ Cl ₂ ) to give 900 mg of the title compound (77%).

Example 64

4- {6-methoxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl} -N, N-dimethyl-benzenesulfonamide

In a round bottom flask, compound 1 of formula 1 (175 mg, 0.33 mmol), N, N-dimethyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2 -Yl) -benzenesulfonamide (311 mg, 0.99 mmol), acetonitrile (7 mL) and cesium fluoride (455 mg, 2.99 mmol) were added. To this mixture, an sonicated suspension of palladium (II) acetate (8 mg, 0.033 mmol) and tricyclohexylphosphine (14 mg, 0.050 mmol) / acetonitrile (1 mL) solution was added, followed by further aceto Further nitrile (3 mL) was added. The reaction was placed in a 90 ° C. oil bath and stirred for 10 minutes before further acetonitrile (3 mL) was added. The reaction was heated to 90 ° C. for 10 more minutes while stirring. The reaction was cooled to room temperature and filtered through a pad of celite (sufficient amount of hot ethyl acetate rinsed). The filtrate was washed with 50% aqueous sodium carbonate aqueous solution, ammonium chloride aqueous solution and brine; Dry with sodium sulfate and evaporate in vacuo. The resulting solid was purified on chromatotron (silica gel; 3% -8% MeOH gradient / CH ₂ Cl ₂ ) to give 160 mg of the title compound (87%). MS (IS +) inle 561 (M + 1).

Example 65

4- {6-hydroxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl} -N, N-dimethyl- benzenesulfonamide hydrochloride

In a round bottom flask was placed the product of Example 64 (120 mg, 0.214 mmol), dichloromethane (5 mL) and 1.0 M hydrochloric acid / diethyl ether solution (0.43 mL, 0.43 mmol). The solution was stirred at room temperature for 2 minutes and then evaporated in vacuo. After drying in vacuo, dichloromethane (10 mL) was added and the solution was placed in an ice bath with stirring. 1.0 M boron tribromide / dichloromethane solution (0.750 mL, 0.750 mmol) was added and the reaction stirred for 3-4 hours while maintaining a temperature between 0-10 ° C. The reaction was quenched with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution, water and brine; Dry with sodium sulfate and evaporate in vacuo.

The crude solid was purified on chromatography (silica gel; 5% -11% MeOH gradient / CH ₂ Cl ₂ ; loaded with 7% MeOH / CHCl ₃ ). The purified material was dissolved in methanol (5 mL) and 1.0 M hydrochloric acid / diethyl ether solution (0.43 mL) was added. The resulting solution was stirred for 2 minutes at room temperature and then evaporated in vacuo to give 96 mg of the title compound (77%). MS (IS +) mle 547 (M + 1-cl).

Preparation 22

4- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzenesulfonic acid 2,2-dimethyl-propyl ester

4-bromobenzenesulfonyl chloride (2.20 g, 8.61 mmol) and pyridine (30 mL) were added to a round bottom flask. At room temperature, neopentyl alcohol (1.39 mL, 12.91 mmol) was added with stirring. After stirring the reaction overnight at room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution, 0.05 N aqueous hydrochloric acid solution and brine, then dried over sodium sulfate and concentrated in vacuo. The material obtained was purified on flash column (silica gel; 30% -50% gradient CH ₂ Cl ₂ / hexanes) to afford 2.24 g of 4-bromo-benzenesulfonic acid 2, 2-dimethyl-propyl ester (85%). .

4-bromo-benzenesulfonic acid 2,2-dimethyl-propyl ester (1.00 g, 3.26 mmol), bis (pinacolato) diboron (1.07 g, 4.23 mmol), PdCl ₂ (dppf) .CH ₂ Cl ₂ ( 90 mg, 0.12 mmol), potassium acetate (1.04 g, 10.6 mmol) and anhydrous dimethyl sulfoxide (12 mL) were placed in a round bottom flask. The reaction was placed in an oil bath and stirred at 90 ° C. for 1-1.5 hours. The reaction was cooled to room temperature, quenched with sufficient water and the resulting aqueous mixture was extracted with dichloromethane. The combined extracts were washed with water and brine; Dry with sodium sulfate and evaporate them under vacuum. The resulting solid was purified on flash column (silica gel; gradient 10% hexanes / CH ₂ Cl ₂ to 100% CH ₂ Cl ₂ to 5% EtOAc / CH ₂ Cl ₂ ) to give 950 mg of the title compound (82%).

Example 66

4- {6-Benzyloxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl} -benzenesulfonic acid 2,2-dimethyl-propyl ester

In a round bottom flask, Preparation 3 (50 mg, 0.078 mmol) of the compound, 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzenesulphonic acid , 2-dimethylpropyl ester (83 mg, 0.24 mmol) and acetonitrile (2 mL) were added. To this solution, sonication of palladium (II) acetate (2 mg, 0.008 mmol), tricyclohexylphosphine (3 mg, 0.012 mmol), cesium fluoride (107 mg, 0.71 mmol) / acetonitrile (1 mL) Added suspension. The reaction was placed in an oil bath at 90 ° C. and stirred for 20 minutes. The reaction was then cooled to room temperature and filtered through a pad of celite (rinsed with plenty of hot ethyl acetate).

The filtrate was washed with 50% aqueous sodium carbonate, saturated aqueous ammonium chloride solution and brine; Dry with sodium sulfate and evaporate in vacuo. The resulting solid was purified on chromatotron (silica gel; 2% -6% MeOH gradient / CH ₂ Cl ₂ ) to give 320 mg of the title compound (60%). MS (IS +) m / e 680 (M + 1).

Example 67

4- {6-hydroxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl} -benzenesulfonic acid 2,2-dimethyl-propyl ester hydrochloride

To the round bottom flask, the product of Example 66 (42 mg, 0.062 mmol), ammonium formate (29 mg, 0.464 mmol), 10% Pd / C (6 mg, -15 wt%) and MeOH (5 mL) were added It was. The mixture was heated to reflux for 35 minutes. The reaction was cooled to room temperature, filtered through a pad of celite and the celite was rinsed with hot ethyl acetate and hot methanol. The filtrate was evaporated under Gini pore and the resulting residue was purified by radial chromatography on radial chromatography over silica (2-5% MeOH gradient / CH ₂ Cl ₂ ) to 27 mg of 4- {6-hydroxy-. 1- [4- (2-Piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl} -benzenesulfonic acid 2,2-dimethyl-propyl ester (74%) was obtained. Freebase (6.7 mg) was dissolved in CH ₂ Cl ₂ (3 mL) and 0.023 mL (2 equiv) of 1.OM hydrochloric acid / diethyl ether solution was added. The solution was stirred for 1-2 minutes at room temperature and evaporated in vacuo to give 7.1 mg of the title compound. MS (IS +) mle 590 (M + 1-HCl).

Example 68

N-tert-butyl-4- {6-methoxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl} -N-methyl-benzene Sulfonamide

To the stirred product of Example 62 (79 mg, 0.013 mmol) / dimethylformamide (5 mL) room temperature solution was added 60% sodium hydride (6 mg, 0.15 mmol). The mixture was stirred at rt for 10 min before methane iodide (0.014 mL, 0.15 mmol) was added. The reaction was stirred for 30 minutes at room temperature and then quenched with brine. The resulting aqueous mixture was extracted with ethyl acetate. The combined extracts are washed with brine; Dried over sodium sulfate and concentrated in vacuo. The material obtained was purified on chromatography (silica gel; 3% -10% MeOH gradient / CH ₂ Cl ₂ ) to give 47 mg of the title compound (68%). MS (IS +) mule 603 (M +1).

Example 69

4- {6-methoxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl} -N-methyl- benzenesulfonamide

In a round bottom flask, the product of Example 68 (80 mg, 0.13 mmol) and trifluoroacetic acid (5 mL) were placed. The solution was heated to reflux for 15-20 minutes and then cooled to room temperature. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium bicarbonate solution, water and brine; Dry with sodium sulfate and evaporate in vacuo. The material obtained was purified on chromatography (silica gel; 4% -8% MeOH gradient / CH ₂ Cl ₂ ) to give 63 mg of the title compound (89%). MS (IS +) m / e 547 (M + 1).

Example 70

4- {6-hydroxy-1- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl} -N-methyl- benzenesulfonamide hydrochloride

In a round bottom flask, the product of Example 69 (85 mg, 0.146 mmol), dichloromethane (5 mL) and 1.0 M hydrochloric acid / diethyl ether (0.150 mL, 0.150 mmol) solution were placed. The solution was stirred at room temperature for 2 minutes and then evaporated in vacuo. After drying in vacuo, dichloromethane (6 mL) was added and the solution was placed in an ice bath with stirring. A 1.0 M boron tribromide / dichloromethane (0.32 mL, 0.32 mmol) solution was added and the reaction stirred for 2-3 hours while maintaining the temperature at 0-10 ° C. The reaction was quenched with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The combined extracts were extracted with saturated aqueous sodium bicarbonate solution, water and brine; Dry with sodium sulfate and evaporate in vacuo. The crude solid was purified on chromatography (silica gel; 6% -10% MeOH gradient / CH ₂ Cl ₂ ). The purified material was dissolved in methanol (5 mL) and 1.0 M hydrochloric acid / diethyl ether (0: 30 mL) solution was added. The resulting solution was stirred for 2 minutes at room temperature and then evaporated in vacuo to give 71 mg of the title compound (85%). MS (IS +) m / e 533 (M + l-HCl).

Example 71

Isobutyric acid 6- (4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester hydrochloride

Triethylamine (80 μl, 0.574 mmol) was added to the compound of Example 3 (103 mg, 0.186 mmol) / THF (5 mL). The solution was cooled to 0 ° C. and 4-dimethylaminopyridine (10 mg, 0.082 mmol) was added followed by the dropwise addition of isobutyric anhydride (40 μl, 0.241 mmol). The solution was allowed to heat to room temperature over 2 hours. Additional isobutyric anhydride (200 μl, 1.206 mmol) was added and stirred overnight at room temperature. The solution was diluted with EtOAc (20 mL) and washed with 1N HCl, NaHCO ₃ saturated solution, and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was purified by radial chromatography (80% CH ₂ Cl ₂ : 18% EtOAc: 2% EtOH) to 82 mg of isobutyric acid 6- (4-methanesulfonyl-phenyl) -5- [4- ( 2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester was obtained. The free base was dissolved in THF (5 mL) and HCl (1.OM/Et ₂ 0, 0.4 mL, 0.4 mmol) was added to the solution. The solution was concentrated in vacuo and the residue was crystallized from Et ₂ 0 / EtOH to give 53 mg of the title compound. MS (ion sprayed): 588 (M + H-HCl).

Example 72

6- (4-Methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol methanesulfonate

About 1.0 g of the compound of Example 3 was heated in a mixed solvent consisting of 3 mL of 3A-ethanol and 5 mL of ethyl acetate to obtain a thin slurry. Methanesulfonic acid (185 mg) / 1 mL 3A-ethanol was added to the hot slurry. Cool and stir for approximately 1 hour to reach room temperature. The slurry was filtered and rinsed with ethyl acetate. The filter cake was vacuum dried at 45 ° C. over 2-3 days to yield approximately 1.11 g of the title compound.

Example 73

6- (4-Methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol succinate

About 1.0 g of the compound of Example 3 was heated in a mixed solvent consisting of 10 mL of ethyl acetate and 1 mL 3A-ethanol. Succinic acid (228 mg) was added to the hot slurry to give a thin slurry. Further 2 mL 3A-ethanol was added. The slurry was briefly reheated to reflux, then cooled to room temperature, the mixture was stirred for 15-30 minutes and then filtered. The filter cake was rinsed with ethyl acetate and dried in vacuo at 45 ° C. over 2-3 days to afford about 1.23 g of the title compound.

Preparation 23

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

2,6-dimethoxynaphthalene (1.0 eq.) Was dissolved in CH ₂ Cl ₂ (5 vol. Eq.) At room temperature in a dry round bottom flask equipped with a stirring bar, a temperature probe and an N ₂ line. The solution was cooled to 0 ° C. with an ice bath and 4- (2-piperidin-1-yl-ethoxy) -benzoyl chloride (1.1 eq.) Was added. Aluminum chloride (2.0 eq.) Was added. Once the reaction is determined to be complete, the reaction is slowly quenched with 1 N NaOH solution and diluted with additional water and CH ₂ Cl ₂ . The aqueous layer was washed with CH ₂ Cl ₂ (20 mL). The organic extracts were combined, washed with brine and dried over Na ₂ S0 ₄ . The crude product was crystallized from methanol to give (2,6-dimethoxy-naphthalen-1-yl)-[4- (2-piperidin-1-yl-ethoxy) -phenyl] -methanone.

In a three-neck round bottom flask equipped with pressure equalization funnel, stir bar, and N ₂ source, (2,6-dimethoxy-naphthalen-1-yl)-[4- (2-piperidin-1-yl -Ethoxy) -phenyl] -methanone was dissolved in CH ₂ Cl ₂ (10 vol eq.). Cool in a flask ice / brine bath and add 1.0 M BC13 / CH ₂ Cl ₂ (1.2 eq.) Solution dropwise. The reaction solution turned dark red and the temperature initially increased to 5 ° C. After about 1 hour, the reaction is quenched with methanol (5 eq.) And allowed to heat to room temperature. The organic solution was diluted with CH ₂ Cl ₂ (1 volume eq.), 1.0M NaHC0 ₃ solution (5 volume eq.) Was added and stirred for 1 hour. The aqueous layer and the organic layer were separated. The aqueous layer was washed with CH ₂ Cl ₂ (1 vol) and the organic layers combined. Washed with saturated NH ₄ Cl solution and dried over Na ₂ SO ₄ . The product was purified via column chromatography (50/1 silica gel) eluting with CH ₂ Cl ₂ / hexanes (3/1) to give (2-hydroxy-6-methoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -methanone was obtained.

In a three necked round bottom flask equipped with a stirring bar and an N ₂ source, (2-hydroxy-6-methoxy-naphthalen-1-yl)-[4- (2-piperidin-1-yl-ethoxy ) -Phenyl] -methanone was dissolved in CH ₂ Cl ₂ (10 vol) and cooled to 0 ° C. in an ice / brine bath. Pyridine (1.3 eq.) Was added. Trifluoromethanesulfonyl chloride (1.2 eq.) Was added over 15 minutes via syringe. After about 15 minutes, the reaction was quenched with H20 (10 vol), washed with 1 N aqueous HCl solution (5 vol) and 1.0 N NaHCO ₃ aqueous solution, and dried over Na ₂ SO ₄ . After concentration, the title compound was obtained in quantitative yield.

Example 74

[2- (4-Methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yl]-[4- (2-piperidin-1-yl-ethoxy) -phenyl] -methanone

Trifluoro-methanesulfonic acid6-methoxy-1- {4- (2-piperidin-1-yl-ethoxy) -benzoyl] -naphthalen-2-yl ester (555 mg, 1.0mmol), 4- Methanesulfonylphenylboronic acid (310 mg, 1.55 mmol), Pd (OAc) ₂ (23.9 mg, 0.11 mmol), Ph ₃ P (54.2 mg, 0.21 mmol) and Na ₂ CO ₃ (2.5 mL, 2M / water) Was dissolved in ethylene glycol dimethyl ether (DME, 30 mL). The mixture was refluxed for 2 hours and additionally Pd (OAc) ₂ (25.2 mg) and Ph 3 P (58.9 mg) were added. After refluxing for 2 hours, the reaction mixture was diluted with water and extracted with chloroform. The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated. The crude material was loaded on an SCX column and purified by eluting with 2M NH ₃ / MeOH to give 569 mg of the title compound (101%). LCMS: m / z = 544 (M + H) &lt; + &gt;

Example 75

[6-hydroxy-2- (4-methanesulfonyl-phenyl) -naphthalen-1-yl]-[4- (2-piperidin-1-yl-ethoxy) -phenyl] -methanone hydrochloride

Pyridine hydrochloride (4.0 g) was added to the compound of Example 74 (100 mg, 0.18 mmol). The vessel was purged with nitrogen, sealed and heated to 200 ° C. for 4 hours. Cool to room temperature and dilute with saturated aqueous NaHCO ₃ . Extracted with 25% isopropanol (i-PrOH) / CHCl ₃ , dried over Na ₂ SO ₄ , and concentrated in vacuo. Purification using an SCX column (eluted with 2M NH3 / MeOH) followed by flash chromatography (0-10% MeOH / CHCl3). The product was dissolved in 1: 1 CH ₃ CN / 1M HCl aqueous solution and lyophilized to give 70.3 mg (68%) of the title compound. LCMS: m / z = 530 (M + H) &lt; + &gt;.

Example 76

[2- (4-Methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yl]-[4- (2-piperidin-1-yl-ethoxy) -phenyl] -methanol

The compound of Example 74 (200 mg, 0.37 mmol) was dissolved in THF (30 mL). Lithium aluminum hydride (LAH, 70.3 mg) was added. Quench with water and ice. Acidified with 1M aqueous HCl solution and made the solution slightly basic with aqueous NaHCO ₃ solution. Extracted with 25% i-PrOH / CHCl ₃ . The crude product was purified using SCX column eluting with 2MNH 3 / MeOH to give 185 mg of the title compound (92%). LCMS: m / z = 546 (M + H) &lt; + &gt;

Example 77

[2- (4-Methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yl]-[4- (2-piperidin-1-yl-ethoxy) -phenyl] -methane

The compound of Example 76 (185.2 mg, 0.33 mmol), Et 3 SiH (0.3 mL, 1.88 mmol) and TFA (0.3 mL, 3.8 mmol) were dissolved in CH ₂ Cl ₂ (30 mL). Stir at room temperature for 1 hour. Quenched with saturated aqueous NaHCO ₃ and extracted with 25% i-PrOH / CH ₂ Cl ₂ . Dry over Na ₂ S0 ₄ , filter and concentrate. The crude material was purified by flash chromatography (0-5% MeOH / CH ₂ Cl ₂ ) to give 1.18 g of the title compound (63%). LCMS: m / z = 530 (M + H) &lt; + &gt;.

Example 78

6- (4-Methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -naphthalen-2-ol hydrochloride

Pyridine hydrochloride (4 g) was added to the compound of Example 77 (110 mg, 0.21 mmol). Purged with nitrogen, the vessel was sealed and heated to 200 ° C. for 2 hours. The reaction mixture was cooled down and diluted with saturated aqueous NaHCO ₃ . Extracted with CH ₂ Cl ₂ , dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash chromatography (0-10% MeOH / CH ₂ Cl ₂ ). The product was dissolved in 1: 1 CH ₃ CN / 1M HCl aqueous solution and dried in vacuo to give 92 mg of the title compound (80%). LCMS: m / z = 516 (M + H) + -HCl.

Preparation 24

5-Bromo-1,3-difluoro-2-methanesulfonyl-benzene

1,3-difluorobenzene (3.5 g, 30.7 mmol) was dissolved in THF (100 mL). The mixture was cooled to -78 ° C and n-butyl lithium (19 mL, 30.7 mmol) was added. Stir for 20 minutes and add dimethyl disulfide (3 mL, 3.38 mmol). The cooling bath was removed and allowed to heat to room temperature. The reaction mixture was poured into ice (10 g) and diethyl ether (100 mL) was added. The layers were separated and the organic layer was washed with brine (20 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo to give 4.3 g of 1,3-difluoro-2-methylsulfanyl-benzene (88%).

1,3-difluoro-2-methylsulfanyl-benzene (4.3 g, 27 mmol), iron (300 mg, 5.4 mmol), bromine (1.4 mL, 27 mmol), aluminum chloride (400 mg, 3.0 mmol) And dichloromethane (100 mL) were mixed at 0 ° C. The reaction mixture was stirred at rt for 2 h. Saturated sodium thiosulfate solution (20 mL) and diethyl ether (100 mL) were added. The layers were separated and the organic layer was washed with brine (20 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo. The residue is chromatographed on a column eluting with diethyl ether / hexanes (0-5%) to give 1.1 g of 5-bromo-1,3-difluoro-2-methylsulfanyl-benzene (17%). Got it.

5-Bromo-1,3-difluoro-2-methylsulfanyl-benzene (1.1 g, 4.6 mmol), oxone (11 g, 18.4 mmol) and methanol (20 mL) were mixed. Stir for 12 hours. The suspension is filtered and the filtrate is evaporated. The residue was dissolved in dichloromethane (100 mL) and water (100 mL) was added. The organic layer was separated and washed with brine (50 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a column eluting the material with diethyl ether / hexane (0-5%) to give 497 mg of the title compound (40%).

Example 79

1- (2- {4- [2- (3,5-Difluoro-4-methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenoxy} -ethyl) -pi Ferridine

Palladium (II) acetate (13 mg, 0.06 mmol), tricyclohexylphosphine (27 mg, 0.10 mmol), cesium fluoride (518 mg, 3.4 mmol), and acetonitrile (10 mL) were mixed. Stir for 5 minutes. Compound of Preparation 1 (200 mg, 0.38 mmol) and bis (neopentyl glycolato) diboron (129 mg, 0.57 mmol) were added. Heat to 90 ° C. for 1 minute and add 5-bromo-1,3-difluoro-2-methanesulfonyl-benzene (113 mg, 0.42 mmol) / acetonitrile (4 mL) solution. Stir at 90 ° C. for 10 minutes. After cooling to room temperature, the solution was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO ₃ (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a column eluting the material with methanol / dichloromethane (0-5%) to give 150 mg of the title compound (69%): mass spectrum (ion spray): m / z = 568.3 (M + H).

Example 80

6- (3,5-Difluoro-4-methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The compound of Example 79 was dissolved in ethyl acetate (10 mL) and diethyl ether (5 mL). 2M HCl / diethyl ether (0.1 mL, 0.2 mmol) was added. The slurry was concentrated and dried in vacuo. The residue was diluted with dichloromethane (5.0 mL) and covered with nitrogen. The solution was cooled to 0 [deg.] C. with an external urine bath. BBr ₃ (0.1 mL, 1.1 mmol) was added and stirred for 1 h. Quench with water (1.0 mL) and dilute with dichloromethane (10 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHC03 (10 mL) and brine (10 mL). Dried over MgSO ₄ , filtered and concentrated in vacuo. Methanol / dichloromethane (0-5%) with stepped gradient 6- (3,5-difluoro-4-methanesulfonyl-phenyl) 5- [4- (2-piperidin-1-yl- Chromatography on a column eluting ethoxy) -phenoxy] -naphthalen-2-ol. The free base was dissolved in diethyl ether (5.0 mL) and ethyl acetate (6.0 mL). 2M HCl / diethyl ether (0.1 mL, 0.2 mmol) was added. The precipitate was collected on filter paper and rinsed with diethyl ether to give 31 mg of the title compound (20%): mass spectrum (ion spray): m / z: 554.3 (M + H-HCl).

Recipe 25

Acetic acid 5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -6-trifluoromethanesulfonyloxy-naphthalen-2-yl ester

The compound of Preparation 2 (800 mg, 1.33 mmol) was dissolved in CH ₂ Cl ₂ (20 mL) under nitrogen and cooled to 0 ° C. Et ₃ N (670 mg, 6.63 mmol) and Ac ₂ O (200 mg, 1.99 mmol) were added dropwise to the reaction mixture. The solution was stirred for 3 hours. Water (100 mL) was added and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 100 mL). The organic layers were combined and dried over Na ₂ SO ₄ . Filtration and concentration gave 860 mg of the title compound as a colorless oil (100%).

Example 81

Acetic acid 6- (4-methanesulfonyl-3-methoxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-yl ester

Pd (OAc) ₂ (46 mg, 0.20 mmol), tricyclohexylphosphine (95 mg, 0.34 mmol), and CsF (1.85 g, 12.26 mmol) were mixed under CH _{2 to} CH ₃ CN (20 mL). The reaction mixture was stirred for 5 minutes. Acetic acid 5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -6-trifluoromethanesulfonyloxy-naphthalen-2-yl ester (730 mg, 1.36 mmol) and bis (Neopentyl glycollato) diboron (460 mg, 2.04 mmol) was added to the reaction mixture. Heat to 90 ° C. and stir for about 5 minutes. Trifluoro-methanesulfonic acid 4-methanesulfonyl-3-methoxy-phenyl ester (500 mg, 1.5 mmol) was added and the mixture was continued to heat for 2 hours. Cool to room temperature, add water (100 mL) and extract the aqueous layer with CH ₂ Cl ₂ (3 × 100 mL). The organic layers were combined, dried over Na ₂ S0 ₄ , filtered and concentrated. Purification by flash column chromatography (silica gel, 0-5% MeOH / CH ₂ Cl ₂ ) gave 260 mg of the title compound (33%): mass spectrum (ion spray): m / z = 590.4 (M + H).

Example 82

6- (4-Methanesulfonyl-3-methoxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalene-2-ol hydrochloride

The compound of Example 81 (210 mg, 0.36 mmol) was dissolved in MeOH (4 mL). NaHCO ₃ (60 mg, 0.72 mmol) was added and the reaction mixture was stirred for 12 hours at room temperature. Filtration and the solvent removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, 2-10% MeOH-NH ₄ OH (10/1, v / v1 / CH ₂ Cl ₂ ) to 150 mg of 6- (4-methanesulfonyl-3 -Methoxy-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol (75%) was obtained Free base (150 mg, 0.27) mmol) was dissolved in CH ₂ Cl ₂ (5 mL) and cooled to −78 ° C. 2M HCl / diethyl ether (0.2 mL) was added and the solution stirred for 5 minutes The solvent was removed under reduced pressure The solid was dried overnight at room temperature in vacuo to afford 140 mg of the title compound (87%): mass spectrum (ion spray): m / z = 548.1 (M + H-HCl).

Preparation 26

2- (4-propylsulfanyl-phenyl) -boronic acid

4-bromo-benzenethiol (2.0 g, 10.6 mmol) was dissolved in dry dimethylformamide (50 mL) and cooled to 0 ° C under nitrogen. Sodium hydride (305 mg, 12. 7 mmol) was added in portions. After vigorous gas evolution ceased, 1-bromo-propane (1.4 mL, 15.9 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction was slowly poured into water (400 mL) and extracted with diethyl ether (2 x 150 mL). The combined organic layers were washed with water (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 2.7 g of 1-bromo-4-propylsulfanyl-benzene (quantitative yield).

1-bromo-4-propylsulfanyl-benzene (2.7 g, 11.6 mmol) was dissolved in dry tetrahydrofuran (100 mL) and the solution was cooled to -78 ° C. 2.5 M butyllithium / hexane (5.1 mL, 12.8 mmol) was added dropwise and the reaction mixture was allowed to heat to -4.0 ° C. Stir for 30 minutes and cool the reaction to -78 ° C. Triisopropyl borate (8.0 mL, 34.8 mmol) was added and the reaction mixture was allowed to slowly heat to room temperature. 10% water soluble potassium hydroxide (100 mL, 179 mmol) was added and stirred overnight. Slowly the reaction mixture was poured into a mixture of concentrated hydrochloric acid and ice. The aqueous solution was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo to give 1.9 g of the title compound (86%).

Example 83

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

2- (4-propylsulfanyl-phenyl) -boronic acid (168 mg, 0.85 mmol), the compound of Preparation 1 (150 mg, 0.28 mmol) and cesium fluoride (214 mg, 1.4 mmol) were refluxed in a condenser Mix in an excited flame-dried flask and purge with nitrogen. In a separate dried flask, palladium (II) acetate (6.2 mg, 0.03 mmol) and tricyclohexylphosphine (12 mg, 0.04 mmol) were mixed. Dry acetonitrile (3 mL) was added and sonicated under nitrogen for 10 minutes. The catalyst mixture was added to the solid and the flask was placed in a 90 ° C. oil bath. After 30 minutes, the suspension is cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo. The obtained residue was chromatographed on methanol ₂ column with methanol / dichloromethane (2%) to give 77 mg of the title compound (51%): mass spectrum (ion spray): m / z = 528.3 (M + H).

Example 84

6- (4-propylsulfanyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol

The compound of Example 83 (77 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL). 2M HCl / diethyl ether (0.15 mL, 0.29 mmol) was added and stirred for 1 minute. The solvent was removed in vacuo and placed on a high vacuum pump for 20 minutes. The foam was dissolved in dry dichloromethane (2 mL) and cooled to 0 ° C. BBr ₃ (70 μl, 0.73 mmol) was added dropwise. Stir for 30 minutes, pour into saturated aqueous sodium bicarbonate solution (10 mL), quench and extract with dichloromethane (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on methanol ₂ column with methanol / dichloromethane (5%) to give 58 mg of the title compound (78%): mass spectrum (ion spray): m / z = 514.3 (M + H).

Example 85

5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -6- [4- (propane-1-sulfonyl) -phenyl] -naphthalen-2-ol

The compound of Example 84 (58 mg, 0.11 mmol) was dissolved in glacial acetic acid (1.1 mL) and sodium perborate (33 mg, 0.33 mmol) was added. The reaction mixture was stirred overnight and poured into saturated aqueous sodium bisulfite solution (10 mL). Extract with dichloromethane (2 X 10 mL) and wash the combined organic layers with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on methanol ₂ column with methanol / dichloromethane (5%) to give 28 mg of the title compound (47%): mass spectrum (ion spray) m / z = 546.3 (M + H).

Example 86

5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -6- [4- (propane-1-sulfonyl) -phenyl] -naphthalen-2-ol hydrochloride

The compound of Example 85 (28 mg, 0.05 mmol) was dissolved in dry dichloromethane (1 mL) and 2M HCl. Diethyl ether (0.10 mL, 0.20 mmol) was added. Stir at room temperature for 10 minutes. The solvent was removed with a stream of nitrogen and the solid was dried overnight in a vacuum oven at 50 ° C. to give 27.9 mg of the title compound (93%): mass spectrum (ion spray) m / z = 546.3 (M + H-HCl).

Preparation 27

1- {2- [4- (6-benzyloxy-2-bromo-benzo [b] thiophen-3-yloxy) -phenoxy] -ethyl} -piperidine

6-methoxy-benzo [b] thiophene (J. Med. Chem. 32: 2548, 1989; 26.1 g, 146 mmol) was dissolved in DMF (500 mL). Ethane thiol sodium salt (37 g, 440 mmol) was added and stirred overnight while heating to 150 ° C. Further ethanethiol sodium salt (12.8 g, 152 mmol) was added and heating continued to 150 ° C. overnight. Concentrate to ¼ volume under vacuum. The reaction mixture was partitioned between ethyl acetate (500 mL) and water (500 mL), the layers separated and the organic layer washed with water (2 X 500 mL), brine (500 mL) and dried over magnesium sulfate. . Filtration and concentration in vacuo afforded 8 g of benzo [b] thiophen-6-ol. The aqueous layer was reextracted with ethyl acetate (3 × 1000 mL) and the organics washed with brine and dried over magnesium sulfate. Concentration in vacuo afforded an additional 15 g of benzo [b] thiophen-6-ol. Residual DMF was distilled off to give 22.7 g (100%) of benzo [b] thiophene-6-ol.

Benzo [b] thiophen-6-ol (10 g, 67 mmol) was dissolved in pyridine (300 mL). 2,2-dimethyl-propionyl chloride (38 mL, 308 mmol) was added dropwise and stirred at room temperature for 8 hours. Concentrated to ¼ volume under vacuum and partitioned between ethyl acetate (250 mL) and water (250 mL). The layers were separated and the organic layer was washed with water (250 mL) and brine (200 mL). Dried over magnesium sulfate, filtered and concentrated in vacuo to afford 15 g of 2,2-dimethyl-propionic acid benzo [b] thiophen-6-yl ester (98%).

2,2-Dimethyl-propionic acid benzo [b] thiophen-6-yl ester (22.0 g, 94.0 mmol) was dissolved in dichloromethane (500 mL). Bromine (12.6 mL, 244 mmol) was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was added to saturated aqueous sodium thiosulfate solution (500 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (500 mL). The organic layers were combined and washed with brine (100 mL). Dried over magnesium sulfate, filtered and concentrated in vacuo to afford a crude solid material. This solid was washed with hexane (20 mL), diethyl ether (20 mL) and dichloromethane (20 mL). Drying in vacuo afforded 30 g (81%) of 2,2-dimethyl-propionic acid 2,3-dibromo-benzo [b] thiophen-6-yl ester.

2,2-Dimethyl-propionic acid 2,3-dibromo-benzo [b] thiophen-6-yl ester (32 g, 82 mmol) was dissolved in ethanol (725 mL), and 50% aqueous solution of potassium hydroxide ( 39 mL, 328 mmol) was added and heated to reflux for 4 h. Concentrate to ½ volume in vacuo, fractionate between ethyl acetate (500 mL) and saturated aqueous ammonium chloride (500 mL), separate layers, and organics with saturated aqueous ammonium chloride solution (2x 500 mL) and brine (300 mL). Drying with sodium sulfate, filtration and concentration in vacuo afforded 25.5 g of 2,3-dibromo-benzo [b] thiophen-6-ol (100%).

A 2,3-dibromo-benzo [b] thiophene-6-ol (43.9 g, 143 mmol) / DMF (1000 mL) solution was added dropwise to a suspension of sodium hydride / DMF (1.5 L) at 0 ° C. Stir for 20 minutes and add benzyl bromide (17 mL, 143 mmol). The ice bath was removed and stirred at room temperature for 2 hours. The reaction mixture was poured into water (8 L) and ethyl acetate (4 L) and stirred overnight. The layers were separated and the organic layer was washed with water (3X 800 mL) and brine (800 mL). Drying with sodium sulfate, filtration and concentration in vacuo gave 52.4 g of 6-benzyloxy-2,3-dibromo-benzo [b] thiophene (92%).

6-benzyloxy-2,3-dibromo-benzo [b] thiophene (20 g, 50 mmol) was dissolved in dichloromethane (88 mL) and trifluoroacetic acid (88 mL) was added. After stirring for 10 minutes, 30% aqueous hydrogen peroxide solution (5.1 mL, 50 mmol) was added and stirred for 4 hours. Solid sodium bisulfite (2.2 g, 21 mmol) was added, diluted with water (30 mL), stirred for 15 minutes and then concentrated in vacuo. The residue was partitioned between dichloromethane (150 mL) and saturated aqueous sodium bicarbonate solution (150 mL), the layers separated and the organic layer washed with additional saturated aqueous sodium bicarbonate solution (150 mL) and brine (100 mL). Dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on a SiO ₂ column eluting with 100% dichloromethane gave 12.8 g of 6-benzyloxy-2,3-dibromo-benzo [b] thiophene1-oxide (62%).

6-benzyloxy-2,3-dibromo-benzo [b] thiophene-oxide (5.9 g, 14.2 mmol) was dissolved in THF (120 mL). 4- (2-piperidin-1-yl-ethoxy) -phenol (3.14 g, 14.2 mmol) and a suspension of potassium tert-butoxide (1.75 g, 15.6 mmol) and THF (120 mL) were added, 1 Stir at 45 ° C for hours. The reaction mixture was partitioned between dichloromethane (400 mL) and saturated aqueous NH ₄ Cl solution (400 mL) and separated. The organic layer was washed with saturated aqueous NH ₄ Cl solution (400 mL) and brine. Dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column eluting with methanol / dichloromethane (0-5%) to 6.9 g of 1- {2- [4- (6-benzyloxy-2-bromo-1-oxo-1H -1-benzo [b] thiophen-3-yloxy) -phenoxy] -ethyl} -piperidine (88%) was obtained.

1- {2- [4- (6-benzyloxy-2-bromo-1-oxo-1H-1λ4-benzo [b] thiophen-3-yloxy) -phenoxy] -ethyl} -piperidine (22.36 g, 40.3 mmol) was dissolved in methanol (160 mL) and chloroform (80 mL). Titanium trichloride / HCl 30% aqueous solution (31.4 mL, 80.6 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (500 mL) and diluted with dichloromethane (500 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (500 mL), water (500 mL), and brine (500 mL). Dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column eluting with methanol (containing 10% NH ₄ OH) / dichloromethane (0 to 2%) to give 19.2 g of the title compound (88%).

Example 87

1- (2- {4- [6-Benzyloxy-2- (4-ethanesulfonyl-phenyl) -benzo [b] thiophen-3-yloxy] -phenoxy} -ethyl) -piperidine

1- {2- [4- (6-benzyloxy-2-bromo-benzo [b] thiophen-3-yloxy) -phenoxy] -ethyl} -piperidine (700 mg, 1.3 mmol) Dissolved in dioxane (13 mL) and 10% aqueous sodium carbonate solution (6.9 mL, 6.5 mmol), 4- (ethanesulfonyl) benzene boronic acid (430 mg, 2 mmol) and Pd (PPh ₃ ) ₄ (150 mg, 0.13 mmol) was added. Heat to 70 ° C. and stir overnight. Dilute with diethyl ether (25 mL) and water (25 mL), filter through celite, and separate layers. The aqueous layer was extracted with diethyl ether (50 mL). The organic layers were combined and washed with water (50 mL) and brine (50 mL). Dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column eluting with methanol / dichloromethane (0-5%) to give 400 mg of the title compound (49%): mass spectrum (ion spray): m / z = 628.3 (M + H).

Example 88

2- (4-ethanesulfonyl-phenyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophene-6-ol

The compound of Example 87 (400 mg, 0.64 mmol) was dissolved in methanol (7 mL) and ethyl acetate (7 mL). Ammonium formate (521 mg, 8.3 mmol) and palladium hydroxide (240 mg) were added and heated to reflux for 5 hours. The reaction mixture was filtered and concentrated in vacuo to give 300 mg of the title compound (86%): mass spectrum (ion spray): m / z = 538 (M + H).

Example 89

2- (4-ethanesulfonyl-phenyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophene-6-ol hydrochloride

The compound of Example 88 (300 mg, 0.56 mmol) was dissolved in dichloromethane (10 mL) and methanol (0.5 mL). 2M HCl / diethyl ether (0.4 mL) was added and stirred for 10 minutes. Concentrated in vacuo and the solid was dried in a vacuum oven at 50 ° C. overnight to give 224 mg of the title compound (71%): mass spectrum (ion spray): m / z = 538 (M + H).

Example 90

1- (2- {4- [6-Benzyloxy-2- (4-methanesulfonyl-phenyl) -benzo [b] thiophen-3-yloxy] -phenoxy} -ethyl) -piperidine tri Fluoroacetate

A suspension of acetonitrile (3 mL) of palladium (II) acetate (103 mg, 0.46 mmol) and tricyclohexylphosphine (193 mg, 0.69 mmol) was sonicated for 10 minutes. In a separate flask, 1- {2- [4- (6-benzyloxy-2-bromo-benzo [b] thiophen-3-yloxy) -phenoxy] -ethyl} -piperidine solution (2 Containing, 7-dibrominated impurity; 250 mg, 0.46 mmol) and 4- (methanesulfonyl) benzeneboronic acid (276 mg, 1.38 mmol) / acetonitrile (6 mL) cesium fluoride (629 mg, 4.14 mmol) Was added. Sonicated catalyst mixture was added and heated at 90 ° C. for 1 hour. Concentrated in vacuo and the residue was partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (30 mL) and brine (20 mL). Dry with sodium sulfate, concentrate in vacuo and chromatograph on a SiO ₂ column eluting with methanol / dichloromethane (0-5%) to 220 mg of the title compound (cross-coupled at 2- and 7-positions). Contaminated with ring byproducts). This mixture was separated by preparative HPLC to give 85 mg of the title compound (30%): mass spectrum (ion spray): m / z = 614 (M + H).

Example 91

2- (4-Methanesulfonyl-phenyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophene-6-ol

The compound of Example 90 (85 mg, 0.14 mmol) was dissolved in methanol (14 mL) and ethyl acetate (14 mL). Ammonium formate (262 mg, 4.2 mmol) and palladium hydroxide (90 mg) were added and heated to reflux for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was partitioned between ethyl acetate: methanol (5: 1, 6 mL) and saturated aqueous sodium bicarbonate: brine (1: 1, 6 mL). The organic layer was washed with brine and dried over sodium sulfate. Concentration in vacuo gave 50 mg of the title compound (68%): 1 H NMR (CDCl 3): δ 7.85 (s, 4H), 7.18 (d, J = 8.2 Hz, 1H), 7.14-7.12 (m, 1H) , 6.78-6.74 (m, 3H), 6.59-6.55 (m, 2H), 4.07 (t, J = 5.4 Hz, 2H), 3.05 (s, 3H), 2.92-2.88 (m, 2H), 2.69 (bs , 4H), 1.74-1.68 (m, 4H), 1.50 (bs, 2H).

Example 92

2- (4-Methanesulfonyl-phenyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -benzo [b] thiophene-6-ol hydrochloride

The compound of Example 91 (50 mg, 0.09 mmol) was dissolved in ethyl acetate (1 mL), diluted with diethyl ether (5 mL) and immediately placed in an ice bath and 2M HCl / diethyl ether (0.07 mL) was added. Added. The precipitate was collected on filter paper and rinsed with diethyl ether. The solid was dried overnight in vacuo at 60 ° C. to give 19 mg of the title compound (38%): mass spectrum (ion spray): m / z = 524 (M + H).

Example 93

1- (2- {4- [6-benzyloxy-2- (3-fluoro-4-methanesulfonyl-phenyl) -benzo [b] thiophen-3-yloxy] -phenoxy} -ethyl) Piperidine

1- {2- [4- (6-benzyloxy-2-bromo-benzo [b] thiophen-3-yloxy) -phenoxy] -ethyl} -piperidine (350 mg, 0.65 mmol) 3-fluoro-4-methanesulfonyl-phenyl-boronic acid (213 mg, 0.98 mmol) is dissolved in dioxane (10 mL), aqueous 10% sodium carbonate solution (9 mL) and Pd (PPh ₃ ) ₄ (75 mg, 0.065 mmol) was added. Heated to reflux for 3 hours. The reaction mixture was partitioned between dichloromethane (20 mL) and saturated aqueous ammonium chloride solution (20 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column eluting with methanol / dichloromethane (0-5%) to afford 150 mg of the title compound (contaminated with 2-H reduced byproduct). The mixture was used in the next step without further purification.

Example 94

2- (3-Fluoro-4-methanesulfonyl-phenyl) -3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy]-benzo [b] thiophene-6- All trifluoroacetate

The compound of Example 93 (150 mg, 0.24 mmol) was dissolved in methanol (2 mL) and ethyl acetate (2 mL). Ammonium formate (300 mg, 4.8 mmol) and palladium hydroxide (150 mg) were added and heated to reflux overnight. The reaction mixture was filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column eluting with methanol / dichloromethane (0-10%) to afford 80 mg of the title compound (contaminated with debenzylated 2-H reduction byproduct from the previous step).

This mixture was separated by preparative HPLC to give 13 mg of the title compound (8%): mass spectrum (ion spray): m / z = 542 (M + H).

Example 95

1- (2- {4- [6-benzyloxy-2- (4-trifluoromethanesulfonyl-phenyl) -benzo [b] thiophen-3-yloxy] -phenoxy} -ethyl) -pi Ferridine

An acetonitrile suspension (4 mL) of palladium (II) acetate (146 mg, 0.65 mmol) and tricyclohexylphosphine (273 mg, 0.98 mmol) was sonicated for 10 minutes. In a separate flask 1- {2- [4- (6-benzyloxy-2-bromo-benzo [b] thiophen-3-yloxy) -phenoxy] -ethyl} -piperidine (350 mg, 0.65 mmol) and 4,4,5,5-tetramethyl-2- (4-trifluoromethanesulfonyl-phenyl)-[1,3,2] dioxaborolane (531 mg, 2.0 mmol) / aceto Nitrile (9 mL) solution was added to cesium fluoride (889 mg, 5.9 mmol). Sonicated catalyst mixture was added and heated to 90 ° C. for 2 hours. Concentrated in vacuo and the residue was partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was combined with saturated aqueous ammonium chloride solution (20 mL) and filtered. The organic layer was washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on an SiO ₂ column eluting with methanol / dichloromethane (0-3%) to afford 240 mg of the title compound (55%) (contaminated with tricyclohexylphosphineoxide). ¹ H NMR (CDCl ₃ ): δ 8.03-7.95 (m, 4H), 7.45-7.33 (m, 5H), 7.32 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H) , 6.96 (dd, J = 9.0, 2.2 Hz, 1H), 6.89-6.79 (m, 4H), 5.13 (s, 2H), 4.03 (t, J = 6.0 Hz, 2H), 2.73 (t, J = 6.0 Hz, 2H), 2.48 (bs, 4H), 1.96-1.18 (complex multiplet, obscured by P (O) Cy ₃ , 6H).

Example 96

3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -2- (4-trifluoromethanesulfonyl-phenyl) -benzo [b] thiophen-6-ol

The compound of Example 95 (contaminated with P (O) Cy 3; 240 mg, 0.36 mmol) was dissolved in methanol (4 mL) and ethyl acetate (4 mL). Ammonium formate (113 mg, 1.8 mmol) and palladium hydroxide (60 mg) were added and heated to reflux for 3 hours. Filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column eluting with methanol / dichloromethane (0-4%) to give 100 mg of the title compound (47%): ¹ H NMR (CDCl ₃ ): δ 7.94 (s, 4H) , 7.20 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.79-6.76 (m, 2H), 6.75 (dd, J = 8.8, 2.2 Hz, 1H), 6.63- 6.58 (m, 2H), 4.03 (t, J = 5.8 Hz, 2H), 2.80 (t, J = 5.8 Hz, 2H), 2.57 (bs, 4H), 1.68-1.61 (m, 4H), 1.49-1.44 (m, 2 H).

Example 97

3- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -2- (4-trifluoromethanesulfonyl-phenyl) -benzo [b] thiophene-6-ol tri Fluoroacetate

The compound of Example 96 (100 mg, 0.17 mmol) was dissolved in ethyl acetate (2 mL), diluted with diethyl ether (10 mL) and placed in an ice bath. Immediately 2M HCl / diethyl ether (0.13 mL) was added and the solid collected on filter paper. Purification by preparative HPLC gave 37 mg of the title compound (29%): mass spectrum (ion spray): m / z = 578 (M + H).

Preparation 28

6-methoxy-2- (4-methanesulfonylphenyl) -1- (4-iodophenoxy) naphthalene

6-methoxy-1-tetralon (1 eq.), 4-bromothioanisole (2.5 eq.), Palladium acetate (0.01eq.), 2-dicyclohexylphosphino-2 '-(N , N-dimethylamino) biphenyl (0.02 eq.) And toluene were placed in a three necked flask equipped with a mechanical stirrer, reflux condenser, nitrogen purge and temperature probe. Sodium tert-butoxide (4 eq.) Was added and the slurry was heated to reflux. After about 2-4 hours, the reaction was cooled to room temperature and 3M HCl aqueous solution was added with tetrahydrofuran. The two phase reaction mixtures were stirred for 30 minutes, then filtered and the layers separated. The organic layer was concentrated to separate 6-methoxy-2- (4-methylthiophenyl) naphthalen-1-ol by filtration.

Sodium hydride (1.05 eq.) / Dry dimethylformamide was placed under nitrogen in a three necked flask equipped with a mechanical stirrer, a dropping funnel with nitrogen purge, and a temperature probe. The dropping funnel was charged with 6-methoxy-2- (4-methylthiophenyl) naphthalen-1-ol (1 eq.) Dissolved in dimethylformamide. This solution was added dropwise to the stirring sodium hydride solution at a rate keeping the temperature below 35 ° C. After the reaction mixture was stirred for 30 minutes, 4-fluoronitrobenzene was added with additional dry dimethylformamide. The solution was heated to 60 ° C. Once the reaction was complete, the flask was cooled and water was added slowly to cause precipitation of the product. The crude product was filtered off, washed with water and then with methyl tert-butyl ether. The filter cake was dried in a vacuum oven to give 6-methoxy-2- (4-methylthiophenyl) -1- (4-nitrophenoxy) naphthalene.

Meta-chloroperbenzoic acid (2.5 eq.) And methylene chloride were placed in a three neck flask equipped with a mechanical stirrer, a dropping funnel with nitrogen purge, and a temperature probe. The dropping funnel was charged with 6-methoxy-2- (4-methylthiophenyl) -1- (4-nitrophenoxy) naphthalene (1 eq.) Dissolved in methylene chloride. This solution was added dropwise to the stirred slurry of perbenzoic acid at 10 ° C. Once the addition was complete, the solution was stirred for 30 minutes. Upon completion of the reaction, 1N NaOH aqueous solution was slowly added while maintaining the temperature below 25 ° C. The layers were separated and the organic layer was concentrated. The crude reaction concentrate was purified on silica gel eluting with methylene chloride to afford 6-methoxy-2- (4-methanesulfonylphenyl) -1- (4-nitrophenoxy) naphthalene.

6-methoxy-2- (4-methanesulfonylphenyl) -1- (4-nitrophenoxy) naphthalene was placed in a hydrogenation vessel with 3 volumes of dimethylformamide and 5% Pd / C catalyst. The vessel was pressurized with hydrogen and the catalyst was removed by filtration with Hyflo once the reaction was deemed complete. 1N HCl aqueous solution was added to the filtrate to precipitate the crude product. The precipitate was filtered off, washed with 1N HCl aqueous solution and the filter cake was placed in a vacuum drying oven to give 6-methoxy-2- (4-methanesulfonylphenyl) -1- (4-aminophenoxy) naphthalene hydrochloride .

6-methoxy-2- (4-methanesulfonylphenyl) -1- (4-aminophenoxy) naphthalene hydrochloride (1 eq.), Iodine (0.6 eq.), Copper iodide (1.05 eq.) And acetonitrile Was placed in a three necked flask equipped with a mechanical stirrer, dropping funnel, nitrogen purge and temperature probe. The dropping funnel was filled with isoamylnitrite (1.1 eq.) / Acetonitrile and the mixture was added dropwise at 20 占 폚 or lower. After addition, the mixture was stirred for 1 hour. After the reaction was completed, saturated sodium thiosulfate solution and methylene chloride were added to the mixture and stirred for 1 hour. The reaction mixture was filtered and the layers separated. The organic layer was concentrated to form a solid. The solid was purified on silica gel to give the title compound.

Another Alternative Preparation of the Compound of Example 1

6-methoxy-2- (4-methanesulfonylphenyl) -1- (4-iodophenoxy) naphthalene (1 eq.), Cesium carbonate (2 eq.), 1,10-phenanthroline (0.2 eq.), Copper iodide (0.1 eq.) And 1-piperidineethanol (5 vol) were placed in a three neck flask equipped with a mechanical stirrer, reflux distillation head, and a temperature probe. The system was evacuated and reinjected with nitrogen three times, then heated to 170 ° C. After the reaction was complete, the flask was cooled to 80 ° C. and the system was placed under vacuum to distill off piperidineethanol. The vacuum was removed, the flask was cooled to 50 ° C., and 0.5N NaOH aqueous solution was added. The flask was cooled to below 35 ° C. and methylene chloride was added. The layers were separated and methyltert-butyl ether was added to the organic layer. The organic layer was concentrated to form a precipitate. The precipitate was filtered off, washed with methyl tert-butyl ether and dried in a vacuum oven. The precipitate was dissolved in methylene chloride and purified on silica gel to give the title compound.

Preparation 29

5-bromo-2-methanesulfonyl-1,3-dimethyl-benzene

5-bromo-2-fluoro-1,3-dimethyl-benzene (3.5 g, 17.2 mmol) was added to dimethylformamide (DMF, 30 mL) at room temperature, followed by sodium thiomethoxide (1.32 g, 17.9 mmol) was added. Heated to 50 ° C. for 8 h and diluted with water (10 mL) and diethyl ether (100 mL). The layers were separated and the organics washed with brine, dried over magnesium sulfate and concentrated to the residue. The residue was chromatographed on a SiO ₂ column eluting with diethyl ether (20%) / hexanes to give 566 mg (14%) of 5-bromo-1,3-dimethyl-2-methylsulfanyl-benzene.

5-Bromo-1,3-dimethyl-2-methylsulfanyl-benzene (555 mg, 2.42 mmol) was dissolved in methanol (30 mL) and treated with oxone (6.0 g, 9.8 mmol). The mixture was stirred at rt for 1 h. The suspension was filtered through silica gel and eluted with CH ₂ Cl ₂ (100 mL). The filtrate was evaporated to give 316 mg (50%) of the title compound.

Example 98

1- (2- {4- [2- (3,5-Dimethyl-4-methylsulfonyl-phenyl) -6-methoxy-naphthalene-l-yloxy] -phenoxy} -ethyl) -piperidine

Palladium (II) acetate (13 mg, 0.06 mmol), tricyclohexylphosphine (27 mg, 0.10 mmol), cesium fluoride (518 mg, 3.4 mmol) and acetonitrile (10 mL) were combined. Stir for 5 minutes. Compound of Preparation 1 (200 mg, 0.38 mmol) and bis (neopentylglycolato) diboron (129 mg, 0.57 mmol) were added. Heat to 90 ° C. for 1 minute and add 5-bromo-2-methanesulfonyl-1,3-dimethyl-benzene (110 mg, 0.42 mmol) / acetonitrile (4 mL). Stir at 90 ° C. for 10 minutes. After cooling to room temperature, the solution was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO ₃ (10 mL). The layers were separated and the organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on an SiO ₂ column eluting with methanol (4%) / dichloromethane to afford 180 mg (76%) of the title compound. Mass spectrum (ion spray): m / z = 560.3 (M + H).

Example 99

6- (3,5-Dimethyl-4-methylsulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The compound of Example 98 (180 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL) and 2.0 M hydrochloric acid / diethyl ether solution (0.4 mL, 0.8 mmol) was added. The solution was stirred at room temperature for 2 minutes and then evaporated in vacuo. After drying under vacuum, dichloromethane (5 mL) was added and the solution was placed in an ice bath with stirring. Boron tribromide (0.1 mL, 1.1 mmol) was added and the reaction was stirred at rt for 1 h. Saturated aqueous sodium bicarbonate solution (1 mL) was added and diluted with CH ₂ Cl ₂ (20 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine; Dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on a SiO ₂ column eluting with methanol (4%) / dichloromethane to give the free base (40 mg) of the title compound: mass spectrum (ion spray): m / z = 560.3 (M + H) . The free base was dissolved in EtOAc (2 mL) and Et ₂ 0 (2 mL) and 2M HCl / Et ₂ 0 (0.40 mL, 0.80 mmol) was added. Stir at room temperature for 10 minutes. The solution was removed in vacuo and the solid was dried in vacuo to give 30 mg (18%) of the title compound. Mass spectrum (ion spray) m / z = 546.4 (M + H-HCl).

Preparation 30

4-bromo-1-methanesulfonyl-2-methylsulfanyl-benzene

4-bromo-2-fluoro-1-methanesulfonyl-benzene (340 mg, 1.34 mmol) was dissolved in DMF (8 mL) and treated with sodium thiomethoxide (103 mg, 9.8 mmol). Stir at room temperature for 2 days. Water (10 mL) and CH ₂ Cl ₂ (20 mL) were added. The layers were separated and the organic layer was washed with aqueous lithium chloride solution (10%), then dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on an SiO ₂ column eluting with EtOAc (20%) / hexanes to give 286 mg (76%) of the title compound.

Example 100

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

Palladium (II) acetate (13 mg, 0.06 mmol), tricyclohexylphosphine (27 mg, 0.10 mmol), cesium fluoride (518 mg, 3.4 mmol,) and acetonitrile (10 mL) were mixed. Stir for 5 minutes. Compound of Preparation 1 (200 mg, 0.38 mmol) and bis (neopentylglycolato) diboron (129 mg, 0.57 mmol) were added. Heat to 90 ° C. for 1 minute and add 4-bromo-1-methanesulfonyl-2-methylsulfanyl-benzene (118 mg, 0.42 mmol) / acetonitrile (4 mL). Stir at 90 ° C. for 10 minutes. Cool to room temperature, dilute the solution with EtOAc (20 mL) and wash with saturated aqueous NaHCO ₃ (10 mL). The layers were separated and the organic layer was washed with brine (10 mL), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on a SiO ₂ column eluting with methanol (4%) / dichloromethane to give 150 mg (64%) of the title compound. Mass spectrum (ion spray): m / z = 578.3 (M + H).

Example 101

6- (4-Methanesulfonyl-3-methylsulfanyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

The compound of Example 100 (150 mg, 0.26 mmol) was dissolved in dichloromethane (3 mL) and 2.0 M hydrochloric acid / diethyl ether (0.2 mL, 0.4 mmol) was added. The solution was stirred at room temperature for 2 minutes and then dried under vacuum. After drying in vacuo, dichloromethane (5 mL) was added and the solution was placed in an ice bath with stirring. Boron tribromide (0.1 mL, 1.1 mmol) was added and the reaction stirred at rt for 1 h. Saturated aqueous sodium bicarbonate solution (1 mL) was added and diluted with CH ₂ Cl ₂ (20 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, then dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on a SiO ₂ column eluting with methanol (4%) / dichloromethane to afford 40 mg of the title compound of free base. Mass spectrum (ion spray): m / z = 564.2 (M + H). The free base was dissolved in EtOAc (2 mL) and Et ₂ 0 (2 mL) and 2M HCl / Et ₂ O (0.40 mL, 0.80 mmol) was added. Stir at room temperature for 10 minutes. The solvent was removed in vacuo and the solid was dried in vacuo to give 30 mg (19%) of the title compound. Mass spectrum (ion spray) m / z = 564.3 (M + H-HCl).

Preparation 31

2- (4-cyclopropanesulfonyl-phenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane

4-bromo-benzenethiol (2.00 g, 10.6 mmol) was dissolved in dry DMSO (50 mL) under nitrogen atmosphere. Potassium tert-butoxide (1.30 g, 11.7 mmol) was added and stirred until dissolved. Cyclopropyl bromide (2.6 mL, 31.8 mmol) was added and the reaction heated at 80 ° C. for 2 days. Cool to room temperature and pour the reaction into water (500 mL). The aqueous layer was extracted with Et ₂ 0 (2 × 200 mL) and the combined organic layers were washed with water (100 mL). Dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on an SiO ₂ column eluting the material with hexanes to give 1.73 g of 1-bromo-4-cyclopropylsulfanyl-benzene (72%).

1-Bromo-4-cyclopropylsulfanyl-benzene (1.73 g, 7.55 mmol) was dissolved in dry methylene chloride (75 mL). mCPBA (4.8 g, 18.8 mmol, 68%) was added slowly in portions to gently control the exotherm. After stirring for 1 hour, the obtained precipitate was filtered off. The filtrate was washed with 1N NaOH (50 mL) and the organic layer was dried over sodium sulfate. Concentration in vacuo gave 2.0 g of 1-bromo-4-cyclopropanesulfonyl-benzene (100%).

1-bromo-4-cyclopropanesulfonyl-benzene (500 mg, 1.91 mmol), bis (pinacolato) diboron (577 mg, 2.29 mmol), potassium acetate (513 mg, 5.70 mmol) and PdCl ₂ ( dppf) .CH ₂ Cl ₂ (46 mg, 0.057 mmol) was dissolved in dry DMSO (10 mL) under nitrogen atmosphere. The mixture was heated to 80 ° C for 4 h. The reaction was cooled to rt and poured into water (100 mL). The aqueous phase was extracted with Et ₂ 0 (2 × 50 mL) and the combined organic layers were washed with water (50 mL). Dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on an SiO ₂ column eluting the material with EtOAc / hexanes (10-40%) to give 200 mg of the title compound (34%).

Example 102

1- (4- (2- (piperidin-1-yl) ethoxy) phenoxy) -2- (4-cyclopropanesulfonylphenyl) -6-methoxy-naphthalene

2- (4-cyclopropanesulfonyl-phenyl) -4,4,5,5-tetramethyl- [1,3,2] dioxaborolane (200 mg, 0.65 mmol), compound of Preparation 1 (150 mg , 0.28 mmol) and cesium fluoride (214 mg, 1.4 mmol) were mixed in a dried flask with reflux condenser. In a separate flask, palladium (II) acetate (6.2 mg, 0.028 mmol) and tricyclohexylphosphine (11.7 mg, 0.042 mmol) were mixed. Acetonitrile (3.0 mL) was added and sonicated under nitrogen for 10 minutes. The catalyst solution was added to the solid and heated in an 80 ° C. oil bath for 20 minutes. The suspension was cooled to rt and filtered through compressed celite. Celite was rinsed with acetonitrile and evaporated. The residue was chromatographed on a SiO ₂ column eluting the material with methanol / dichloromethane (0-5%) to afford 120 mg of the title compound (77%). Mass spectrum (ion spray): m / z = 558.3 (M + H).

Example 103

6- (4-Cyclopropanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -naphthalen-2-ol hydrochloride

1- (4- (2- (piperidin-1-yl) ethoxy) phenoxy) -2- (4-cyclopropanesulfonylphenyl) -6-methoxy-naphthalene (120 mg, 0.21 mmol) Dissolved in methylene chloride (2 mL), 2M HCl / Et ₂ O (210 μl, 0.42 mmol) was added and concentrated. The resulting foam was dissolved in dry methylene chloride (3 mL) and cooled to 0 ° C. under nitrogen. BBr ₃ (99 μl, 1.05 mmol) was added dropwise and stirred for 20 minutes. The reaction was poured into saturated sodium bicarbonate solution (10 mL) and extracted with methylene chloride (2 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated to give a yellow solid. The residue was chromatographed on an SiO ₂ column eluting the material with methanol / dichloromethane (2-10%) to give 99 mg of the title compound (87%) of free base. The free base was dissolved in methylene chloride and 2M HCl / Et ₂ 0 (200 μl, 0.40 mmol) was added. The solvent was evaporated and dried (<2 mmHg) at 45 ° C. for 18 h to give 84 mg of the title compound (69%): mass spectrum (ion spray): m / z = 544.3 (M + H-HCl).

Preparation 32

4-Bromo-3- (4-methanesulfonyl-phenyl) -7-methoxy-1,2-dihydro-naphthalene

6-methoxytetralone (1.0 eq.), 4-bromophenyl-methyl-sulfone (1.02 eq.), Pd (OAc) ₂ (0.025 eq.), DPE Force Ligand [(Oxydi-2,1 -Phenylene) bis (diphenylphosphine)] (0.026 eq.) And toluene (12 vol) were added to a three necked flask equipped with a reflux condenser and nitrogen vent purge. Then sodium t-butoxide (2.5 eq.) Was added in one portion. The reaction mixture exothermed to about 40 ° C., forming a heterogeneous yellow mixture. The heterogeneous yellow reaction mixture was heated to 75-80 ° C. for 1-2 hours. The yellow slurry was cooled to room temperature and the reaction was slowly quenched with water (12 vol) while maintaining a temperature below 40 ° C. The aqueous slurry was cooled to room temperature and stirred for 2-3 hours. The slurry was filtered with polypropylene and the solid was washed with water (3 × 2 volumes). The filter cake obtained was dried in vacuo at 50 ° C. overnight to afford crude 2- (4-methanesulfonyl-phenyl) -6-methoxy-3,4-dihydro-2H-naphthalen-1-one (91%). Got it.

2- (4-methanesulfonyl-phenyl) -6-methoxy-3,4-dihydro-2H-naphthalen-l-one (1.0eq.), Hyflo (20 wt%), and toluene (7.5 vol. ) Was added to a three necked flask equipped with a reflux condenser and nitrogen vent purge. While stirring at room temperature, PBr ₃ (1.75 eq.) Was added in one portion. The reaction was heated to reflux overnight (˜110 ° C.) and allowed to vent through a caustic scrubber. After refluxing for 15 hours, the yellow solution was cooled to 45 ° C. and slowly added THF (20 vol). The mixture was heated to 45 ° C. for 30 minutes and filtered with a hyflo pad while warming. The pad was washed with 45 ° C. THF (2 × 2 volumes). The filtrate was concentrated under reduced pressure to remove all THF. Water (7.5 vol) was carefully added to the residual mixture while maintaining the temperature below 40 ° C. The slurry was cooled to room temperature and stirred for 2-3 hours. The slurry was filtered through a polypropylene pad and washed with water (2 × 2 volumes). The filter cake obtained was dried at 50 ° C. overnight in a vacuum oven to give the title compound (74%).

Example 104

1- (2- {4- [2- (4-Methanesulfonyl-phenyl) -6-methoxy-3,4-dihydro-naphthalen-1-yloxy] -phenoxy} -ethyl) -piperi Dean

Compound (1.0 eq.), 4- (2-piperidinylethoxy) phenol (1.5 eq.), Cs ₂ CO ₃ (2.5 eq.) And CuCl (0.2 eq.) Of Preparation 32 were prepared by using a magnetic stirrer and a condenser. Placed in an RB flask equipped with. Toluene (7.5 vol) was added and the reaction mixture was subjected to four degassing-nitrogen charges by vacuum. The reaction was heated to reflux for 4-5 hours. The reaction was then cooled to room temperature and poured into a mixture of concentrated ammonia solution (1.0 vol), 1N NaOH (5.0 vol), and ethyl acetate (7.5 vol). The mixture was stirred vigorously, the layers separated and the aqueous layer was removed and the organic layer was washed again with a mixture of ammonia (1.0 vol), 1N NaOH (5.0 vol) and brine (5.0 vol). The organic layer was dried over MgSO ₄ and concentrated. The resulting solid was dissolved in acetone (2.0 vol) and hexane (3.0 vol) was added as non-solvent. After the mixture was allowed to stand for 1-2 hours, the precipitated material was collected by filtration and allowed to dry to give the title compound (80%). MS (ES &lt; ⁺ &gt;) m / e 534 (M + H) ⁺ .

Example 105

6- (4-Methanesulfonyl-phenyl) -5- [4- (2-piperidin-1-yl-ethoxy) -phenoxy] -7,8-dihydro-naphthalen-2-ol

In a round bottom flask, the compound of Example 104 (50 mg, 0.094 mmol), sodium ethanethiolate (88 mg, 1.05 mmol) and dimethylformamide (4 mL) were placed at room temperature. The reaction was placed in a 95 ° C. oil bath, stirred for 4 hours and then cooled to room temperature. The mixture at room temperature was quenched with brine and extracted with ethyl acetate. The combined extracts were washed with brine; Dried over sodium sulfate and concentrated in vacuo. The crude material was purified on chromatography (silica gel; 5% -12% MeOH gradient / CH ₂ Cl ₂ ) to give 7 mg of the title compound (14%). MS (IS +) m / e 520 (M + l).

Preparation 33

1-bromo-2- (4-methanesulfonylphenyl) -6-methoxynaphthalene

In a three-necked flask equipped with a reflux condenser and nitrogen vent purge, 6-methoxytetralone (1.0 eq.), 4-bromophenyl-methyl-sulfone (1.02- 1.05 eq.), Pd (OAc) ₂ ( 0.025 eq.), DPE force ligand (0.026 eq.) And 10-12 volumes of toluene were added. Sodium t-butoxide (2.5 eq.) Was added in one portion and the mixture was allowed to exotherm to ˜40 ° C. Heated to 75-80 ° C. Judging by HPLC analysis, the reaction was completed and then cooled to room temperature. 12 volumes of water were added slowly to maintain a temperature below 40 ° C. Stir for 2-3 hours. Filter with polypropylene pad and wash with water (3 × 2 volumes). The filter cake was dried at 50 ° C. overnight to give 2- (4-methanesulfonylphenyl) -6-methoxytetralone.

2- (4-methanesulfonylphenyl) -6-methoxytetralone (1.0 eq.), Hyflo (20% / weight), and toluene (7.5 vol) were mixed. PBr ₃ (1.5-1.75 eq.) Was added in one portion while stirring at room temperature. The contents were heated to reflux overnight (˜110 ° C.). After the reaction was complete as determined by HPLC analysis (usually 15 hours), the solution was cooled to 45 ° C. and slowly added 20 vol THF. Stir for 30 minutes at 45 ° C. and filter warm with a hyflo pad. The pad was washed at 45 ° C. with 2 × 2 volume THF. The filtrate was concentrated to approximately 7 volumes. 7.5 volumes of water were further added to the residual mixture while maintaining a temperature below 40 ° C. (initial addition of water is very exothermic with many occurrences of HBr). The slurry was cooled to room temperature and stirred for 2-3 hours. Filtered with a polypropylene pad and washed with 2 x 2 volumes of water. The filter cake was dried overnight at 60 ° C. under vacuum to afford 1-bromo-2- (4-methanesulfonylphenyl) -3,4-dihydro-6-methoxynaphthalene.

1-bromo-2- (4-methanesulfonylphenyl) -3,4-dihydro-6-methoxynaphthalene and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ , 1.8 equiv.) Were mixed in 10 volumes of acetonitrile and 5 volumes of THF. The reaction contents were heated to 73-75 ° C under nitrogen atmosphere. The progress of the reaction was monitored by GC analysis until the reaction was complete. Additional DDQ (0.2-0.3 equiv.) May be required to complete the reaction. The contents were cooled to room temperature and 10 volumes of 1N sodium hydroxide were added. Stir for approximately 1 hour and filter. The filter cake was rinsed with 2 volumes of water, 3 × 5 volumes of 50% acetonitrile / water, and finally with 3 volumes of methanol. The filter cake was dried in vacuo at 65 ° C. to afford the title compound.

Another Alternative Preparation of the Compound of Example 2

1-bromo-2- (4-methanesulfonylphenyl) -6-methoxynaphthalene, 4- (2-piperidinylethoxy) phenol (2.0 equiv), cesium carbonate (2.0-2.1 equiv.) And copper chloride (0.15 equiv.) Were charged to 12 volumes of diglyme. The flask was evacuated for ˜ 2 minutes and then purged with nitrogen. The evacuation / nitrogen purge was repeated three times. The contents were heated to 130 ° C. until completion of the reaction was judged by HPLC analysis. After the reaction was complete, the contents were cooled to near room temperature, 12 volumes of ammonium hydroxide were added and stirred for about 30 minutes. The solids were removed by filtration and the solids were washed with 9 volumes of 30% MeOH / NH ₄ OH while slurrying the solids on the filter support. The solid was washed with 2 X 9 volume of 30% NH ₄ OH / MeOH while slurrying the solid on the filter support. Washed with 4 volumes methanol. The filter cake was dried in vacuo at 60 ° C. to obtain the title compound as a free base. The free base was slurried in 9 volumes of toluene and the slurry was heated to 70-75 ° C. 1.1 equivalents of hydrogen chloride gas were dissolved in 2 volumes of ethanol. HCl ethanol solution was added to the hot toluene slurry. The solution was cooled to rt and stirred for 1-2 h. It was filtered and washed with a small amount of toluene. The filter cake was dried in vacuo at 65 ° C. to afford the title compound.

Another Alternative Preparation of the Compound of Example 4

1- (2- {4- [2- (4-methanesulfonyl-phenyl) -6-methoxy-naphthalen-1-yloxy] -phenoxy} -ethyl) -piperidine hydrochloride in 5 volumes of 1 Mix with, 2-dichloroethane (DCE) and cool the mixture to below 10 ° C. 5 equivalents of boron trichloride were added by subsurface addition. It was stirred at room temperature until judged by HPLC analysis until the reaction was complete. The reaction contents were quenched in 5.6 volumes of 3A-ethanol (ethanol modified with about 5% methanol) while maintaining the temperature of the contents below 50 ° C. Cool to room temperature and stir for 1-3 hours. The solid was filtered off and the filter cake was rinsed with 3A-ethanol. The filter cake was dried in vacuo at 65 ° C. to afford the title compound. This material can optionally be further purified by dissolving the isolated product in 9.8 volumes of 3A ethanol and 1.5 volumes of deionized water at the approximate reflux temperature of the mixture. After the solution was refluxed for about 30 minutes, the mixture was cooled to room temperature. After reaching room temperature, the resulting slurry was stirred for 1-2 hours at room temperature, then filtered, and the filter cake was rinsed with 3A ethanol. This material can optionally be further purified by dissolving the filter cake in reflux with 19 volumes of acetonitrile and 1.4 volumes of deionized water. Water was azeotropically removed by distillation until a total of 12.1 volumes of distillate were removed. The resulting slurry was cooled to room temperature, filtered and the filter cake was rinsed with acetonitrile.

Formulations (Pharmaceutical Compositions)

Since the compound of formula (I) contains a basic moiety (ie amino), the compound may be hydrochloride or described in "Handbook of Pharmaceutical Salts: Properties, Selection and Use", Weinheim, New York: VHCA; Wiley-VCH, 2002, such as salts of pharmaceutical acid addition salts. The compounds of formula (I), or pharmaceutical acid addition salts thereof, are preferably formulated in dosage unit form, ie in individual delivery vehicles (capsules or tablets) prior to administration to the recipient patient. The term "patient" includes non-human female animals such as human females and pets (dogs, cats, horses, etc.). Preferred patients for treatment are human females. Another preferred patient for treatment is a fertility female human.

Pharmaceutical compositions herein are prepared by known steps using known and readily available ingredients. In preparing the preparations of the invention, the active ingredient (compound I compound, or a pharmaceutical salt thereof) is typically mixed with the carrier, diluted by the carrier or contained in the carrier, which is a capsule, a sachet paper or It may be in another container form. When the carrier acts as a diluent, it may be a solid, semisolid or liquid substance which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions may be used in tablets, pills, powders, lozenges, cachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in liquid medium), soft and hard gelatin capsules, suppositories, sterile injections Solutions, and sterile packaged powders.

Examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrroly Don, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoate, talc, magnesium stearate and mineral oils. The formulations may further comprise lubricants, wetting agents (eg, polysorbate 80 or lauryl sulfate), emulsifying and suspending agents, preservatives, sweetening or flavoring agents. Compositions of the present invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a receiving patient.

Preparation Example

10 mg capsules or tablets

About 156 mg of bulking agent (lactose, mannitol, or dextrose), about 20 mg of disintegrant (microcrystalline cellulose, or starch), about 4 mg of superdisintegrant (crospovidone, or sodium starch glycolate), about 4 mg of binder (hydroxy propyl methyl cellulose or hydroxy propyl cellulose) and about 10 mg of active ingredient (such as the compound of Example 4) were added to the granulator and mixed to ensure a uniform distribution of the powder. Povidone, hydroxy propyl methyl cellulose or hydroxy propyl cellulose (sufficient to deliver about 2-4% by weight of the dry powder) and wetting agents such as polysorbate 80 or sodium lauryl sulfate (0.5-3% by weight) Sufficient to deliver), sprayed onto the powder at a uniform rate while mixing. The granulated material was wet sieved through the screen to break up large aggregates. The filtered granulated powder was dried by fluid bed processing or in a convection oven. The size of the dried granulated powder was uniformly reduced by passing it through a co-mill or other suitable device and transferring the material to the mixer. The granulated powder was uniformly blended with lubricant (about 1% by weight magnesium stearate, or sodium stearyl fumarate) of the total formulation and additional disintegrant (about 2-4% by weight in the outer powder). The final powder is filled into hard gelatin capsules or the powder is compressed to form tablets (the tablets are then film coated as described below). The total weight of the capsule or tablet produced by this manner is about 200 mg.

45 mg capsules or tablets

About 162 mg of bulking agent (lactose, mannitol or starch), about 10 mg of disintegrant (crospovidone or sodium starch glycolate), and about 45 mg of the active ingredient (such as the compound of Example 4) are added to the granulator The mixture was mixed to make the powder uniformly distributed. A granulating aqueous solution consisting of povidone (about 35% by weight) and polysorbate 80 (about 10% by weight) was sprayed onto the powder at a uniform rate while mixing. The granulated material was wet sieved through the screen to break up large aggregates. The filtered granulated powder was dried by fluid bed processing or in a convection oven. The dried granulated powder was passed through a co-mill or other suitable device and the material was transferred to a mixer. The granulated powder was uniformly blended with a lubricant (about 1% by weight magnesium stearate of the total formulation) and an additional disintegrant (about 2% by weight in the outer powder). The final powder is filled into hard gelatin capsules or the powder is compressed to form tablets (the tablets are then film coated as described below). The total weight of the capsule or tablet produced by this manner is about 230 mg.

Alternatively, to prepare tablets, bulking agent, disintegrant, and active ingredient were added to the mixer and blended to distribute the powder uniformly. After the powder was distributed evenly, lubricant was added and blended again. The blended material was transferred to a tablet compressor to make a tablet, which was then film coated with a suitable film former.

Biological efficacy test

Estrogen Receptor Avidity Assay: Representative compounds of the invention were examined for binding affinity for both estrogen receptor types (ERα and ERβ). This competitive binding assay measures the ability of a compound to replace 3H-estradiol and generates IC ₅₀ and K _i values for both receptor types.

Competitive binding assays were performed in buffer containing 50 mM Hepes, pH 7.5, 1.5 mM EDTA, 150 mM NaCl, 10% glycerol, 1 mg / mL Ovalbumin and 5 mM DTT, 0.025 μCi 3H-estradiol per well (118 Ci / mmol) , NEN # NET517 at 1 mCi / mL), 10 ng / well ERα or ERβ receptor (Pan Vera). Compounds of the invention were added at 10 different concentrations. Nonspecific binding is measured in the presence of 1 μM of 17-β estradiol. The binding reaction (140 μl) was incubated for 4 hours at room temperature, then 70 μl of cold DCC buffer was added to each reaction (DCC buffer was 750 mg Charcoal (Sigma) and 250 mg per 50 mL of assay buffer). Contains dextran (Pharmacia). The plates were mixed for 8 minutes on an orbital stirrer at 4 ° C. and then principle separated at 3,000 rpm at 4 ° C. for 10 minutes. An equivalent portion of 120 μl of the mixture was transferred to another 96-well, white flat bottom plate (Costar), and 175 μl of Wallac Optiface “Hisafe 3” scintillation fluid was added to each well. The plate was sealed and vigorously stirred on an orbital stirrer. After 2.5 hours of incubation, the plates were read at Wallac microbeta counter. Data was used to calculate% inhibition at IC ₅₀ and 10 μM. K _d for 3H-estradiol was determined by saturation binding to ERα and ERβ receptors. IC ₅₀ values for test compounds were converted to K _j using the cheng-Prusoff equation, and K _d was determined by saturation binding assay.

Ishikawa Cell Proliferation Assay: This assay determines cell proliferation (using alkaline phosphatase recordings) in the agonist mode in which only compounds of the invention are present or the ability of the compounds of the invention to block growth stimulation of estradiol is measured. Measure

MEM (Earle's salt and L-glutamine, Gibco, a minimum essential medium supplemented with 10% fetal bovine serum (FBS) (V / V), (Gibco BRL) of Ishikawa human endometrial tumor cells BRL, Geiderburg, MD). One day prior to assay, growth medium was added to 5% dextran coated charcoal, stripped fetal bovine serum (DCC-FBS) (Hyclone, Logen, UT), L-glutamine (2 mM), MEM sodium pyruvate (1 mM), assay medium supplemented with HEPES (N- [2-hydroxyethyl] piperazine-N '-[2-ethanesulfonic acid] 2 mM) (all from Gibco BRL), DMEM / F-12 (3: 1 (Dulbecco's modified Earl's medium: nutrient mixture F-12, 3: 1 mixture, phenol red-free, Gibco BRL). After overnight incubation, Ishikawa cells were rinsed with Dulbecco's Phosphate Buffered Saline (1X) (D-PBS) (Ca ²⁺ , without Mg ²⁺ ) (Gibco BRL), 0.25% Trypsin / EDTA, Phenolic Red-Free Trypsinization was incubated with (Gibco BRL) for 3 minutes. Cells were resuspended in assay medium and adjusted to 250,000 cells / mL. Approximately 25,000 cells in 100 μl medium were added to a flat bottom 96 well microculture plate (Costar 3596) and incubated for 24 hours in a 37 ° C., 5% CO ₂ humidified incubator. The next day, serial dilutions of the compounds were prepared in potency assay media (6 fold at final concentration in potency assay). Assays were performed in dual mode (agonist mode and antagonist mode).

In agonist mode, plates received 25 μl / well of assay medium followed by 25 μl / well of diluted compound of the invention (6 fold at final concentration). In antagonist mode, plates received 25 μl / well of 6 nM E ₂ (β-estradiol, Sigma, St. Louis, MO) followed by 25 μl / well of diluted compound of the invention. (6 times at final concentration). After an additional 48 hours of incubation at 37 ° C. in a 5% CO ₂ humidified incubator, the medium was aspirated from the wells and 100 μl of fresh assay medium was added to each microculture. Serial dilutions of the compound were prepared and added to the cells as described above. After an additional 72 hours of incubation at 37 ° C. in a 5% CO ₂ humidified incubator, the assay was performed by removing the medium and placing the plate twice with Dulbecco's phosphate buffered saline (1 ×) (D-PBS) (Gibco BRL). Quenched by rinsing. The plate was dried for 5 minutes and frozen at −70 ° C. for at least 1 hour. The plate was then removed from the freezer and allowed to thaw at room temperature. To each well, 100 μl of 1-Step TM PNPP (Pierce Chemical Company, Rockford, IL) was added. After 20 minutes of incubation, the plates were read spectroscopically at 405 nm.

Data was fitted by linear interpolation to derive EC50 (agonist mode) or IC50 (antagonist mode) values. For the antagonist mode, the% potency for each compound was calculated for E2 (1 nM) only. For agonist mode, the% potency of each compound was calculated for the response to tamoxifen.

In agonist mode, Examples 3-6, 8, 10, 12, 14, 16, 18, 21, 23, 25, 27, 29, 32, 34, 36, 39, 43, 46, 49, 53, 56, The compounds of 58, 59, 61, 63, 65, 67, 70-73, 75, 78, 80, 82, 86, 89, 92, 94, 97, 99, 101, 103 and 105 were tested and were less than tamoxifen. It has been found to be irritating. For example, the compound of Example 56 had a relative% potency of 71.8%. In antagonist mode, the same compound inhibited more than 70% of the 1 nM estradiol reaction. For example, the compound of Example 16 had an IC 50 value of 35.2 nM and a% potency of 106.7%.

MCF-7 Proliferative Potency Assay: MCF-7 cell lines are derived from human thoracic adenocarcinoma and are used as indicators of potential anti-proliferative activity in thoracic epithelium.

MCF-7 thoracic adenocarcinoma cells (ATCC HTB 22) were treated with 10% fetal bovine serum (FBS) (V / V), L-glutamine (2 mM), sodium pyruvate (1 mM), HEPES ((N- [2 -Hydroxyethyl] piperazine-N '-[2-ethanesulfonic acid] 10 mM}, MEM supplemented with non-essential amino acids (0.1 mM) and penicillin streptomycin (1X) (minimum essential medium, phenol red-free, Gibco BRL) Seven days prior to validation, MCF-7 cells were supplemented with 10% dextran-coated charcoal-stripped fetal bovine (DCC-FBS) assay medium instead of 10% FBS. Were switched to the same assay medium as the preservation medium except MCF-7 cells were removed from the flask using 10 × trypsin EDTA (phenol red-free, Gibco BRL) and Ca ++ / Mg ++ free HBSS (phenol red) -Free), cells were adjusted to 80,000 cells / mL in assay medium, approximately 8,000 cells (100 μl) were added to 96 well cytos T T scintillation plate. Each well of Amersham was added and incubated for 24 hours in a 37 ° C., 5% CO ₂ humidified incubator to allow cells to attach and equilibrate after transfer.

Serial dilutions of the compounds of the invention were prepared in assay media at 4 × final desired concentrations. Transfer 50 μl equivalents of test compound dilution (4 × final assay concentration) to two wells, and then transfer 50 μl of assay medium for agonist mode or 50 μl of 40 pM E2 for antagonist mode. The volume is 200 μl. For each agent plate, basal level (medium) and maximal stimulated level (with 1 μM E2) were measured. For each antagonist plate, controls at base level (medium) and E2 (10 μM) alone were measured. After further incubation at 37 ° C. for 48 hours in a 5% CO ₂ humidified incubator, 20 μl of assay medium containing 0.01 μCi of ¹⁴ C-thymidine (52 mCi / mmol, 50 μCi / μl, Amersham) was added. To each well. Plates were incubated overnight in the same incubator and then counted on Wallac microbeta counters. Data was averaged to calculate IC 50 and% inhibition (1 μM) for antagonist mode. For agonist mode, EC50, maximum E2 stimulation rate set and concentration of maximum stimulation were calculated.

3-Day Rat Uterine Antagonist Efficacy Test : This model for uterine antagonism was used in immature (3 week old) female rats whose uterus was highly sensitive to estrogen stimulation, assuming that circulating estrogen levels were before puberty. The uterus of immature rats is fully responsive to exogenous estrogens, but unresponsive in the absence of exogenous estrogens. Administration of exogenous estrogens to immature rats results in a reliable increase in uterine weight, which can be used to study the antagonist effects of the uterus. Rats were treated with both estradiol and four different concentrations of the compound of the invention for 3 days, after which the wet weight of the uterus was measured.

Female rats between 19 and 21 days of age (or 45-50 g) were treated with E2 (0.1 mg / kg, maximal stimulation of estrogen stimulant for increasing uterine weight) and 10, 1.0, 0.1 and 0.01 mg / kg The test compound was orally treated for 3 days with 6 rats in each group. Test compounds were dissolved in 20% β-hydroxycyclodextrin and administered daily via oral gavage in a volume of 0.2 mL (15 minutes before ethynyl estradiol gavage). Vehicle control, E2 alone and E2 + raloxifene were done as controls. Animals were fasted overnight and given final dose. The next morning the animals were weighed, then euthanized (by carbon dioxide asphyxiation), the uterus was collected quickly (via the abdominal central incision) and weighed.

Uterine weight / weight ratio (UWR) was calculated for each animal. Then, the estrogen-a% inhibition of the induced response was calculated by the following equation:% inhibition = 100 x (UWR _estrogen -UWR _{test compound} / UWR _estrogen - UWR _control). ED50 values were derived from semi-log regression analysis of the linear portion of the dose response curve. Both UWR data and% inhibition were statistically analyzed by Fisher's post-mortem analysis with PLSD and one-way ANOVA (ANOVA), as indicated by P <0.05. Statistical analysis was performed using Starview® 4.0 software package.

Examples 4-6, 12, 14, 18, 21, 23, 27, 29, 32, 34, 39, 43, 46, 53, 56, 58, 59, 61, 65, 70, 78, 86, 89, Compounds of 92, 99, 101 and 103 were tested in this potency assay and were found to inhibit estrogen-induced responses when administered at 1.0 mg / kg. For example, the compound of Example 92 had 0.53 mpk ED50 and 62.7%% antagonism.

4 Day OVX Rat Uterine Agonist Assay : To assure that the test compound does not have any partial uterine agonist activity, the compound was administered to mature ovarian rats.

75-day-old rats were ovarian resected and treatment started 14 days after circulating estradiol levels reached minimum levels. After 4 days of treatment with 3 doses of a compound of the present invention, body weight (6 rats / group), wet weight of the uterus and eosinophil peroxidase (EPO) activity of the uterus were measured. Cholesterol levels were also measured to compare the relative ability to lower cholesterol with other SERMs. If there is a question of irritation of the uterus, a biopsy will determine epithelial cell height.

The compounds of Examples 4 and 14 were tested in the above assays and they did not produce a dose-related statistically significant increase in EPO activity.

10-Day Rat Hormone (Ovary Stimulation) Investigation : An initial, initial test for ovarian toxicity was performed using a 10-day rat hormone study to determine estradiol and luteinizing hormone levels following compound administration. This investigation was performed by dosing the compound for 10 days with oral gavage in mature (9-10 week old) F344 female rats. Stem cells were collected by rapid head secretion two hours after the tenth dose for evaluation of LH and estradiol levels. Serum obtained by centrifugation was isolated and cryopreserved below -60 ° C until potency assay. Serum levels of LH and estradiol were measured using radioimmunoassay (RIA).

Rat LH major antibodies and reference preparations (rat LH: RP-3) A. F. Farlow (Director, Pituitary Hormones and Antisera Center, Harbor-UCLA Medical Center, Torrance, CA). The upper limit of detection of the LH assay was 30 ng / mL and the lower limit of detection was 0.1 ng / mL for a 100 µl sample.

E2 Clinical efficacy test. DiaSorin s.r.l., Saluggia, Vercelli, Italy. The upper detection limit is 1000 pg / mL, and the lower detection limit is 5 pg / mL.

The compounds of Examples 4-6, 14, 21 and 103 were tested in the above assays and did not significantly increase circulating estradiol or LH levels.

35-Day Ovarian-Uncontrolled Rat Bone Efficacy: Previous SERMs containing raloxifene have been shown to prevent bone loss in OVX rats, but to address the possibility of interfering with estrogen-regulated survival rate in ovary-uncontrolled rats. There is a need.

This potency assay was performed in mature rats at concentrations based on potency demonstrated in the 3-day potency assay. Generally, three or more concentrations are selected based on multiples of the ED 50 generated therein. This multiple is generally 1x, 10x and 30x ED50. Compounds of the invention were administered to OVX rats for 35 days and compared to control, ovarian, and / or GnRH-administered rats. Femur, tibia, uterus, ovary and serum were taken for further analysis. Dual Energy X-ray Absorptivity (DEXA), Computed Tomography (CT) and tissue analysis were performed on the iliac bone to investigate any changes. CT scans of the distal femur were performed to calculate bone mineral density (BMD), cross-sectional area and bone mineral content (BMC). Bone strength measurements (load to breakage) can also be performed to determine the results of changes in bone mass or material. Tissues of the uterus and ovaries were examined to determine the long-term effect of uterine efficacy and stimulation of latent ovaries. Serum was analyzed for LH and E2 levels as possible indicators of the effect of the ovary.

Availability

As antagonists of estrogen in the tissues of the chest and uterus, the compounds of formula (I) or pharmaceutical acid addition salts thereof are useful for treating conditions in which estrogen has been found to play a causal role therein. As agents of estrogens in the skeletal and cardiovascular systems, the compounds of formula (I) or pharmaceutical acid addition salts thereof are useful for treating conditions in which estrogens have been found to play a beneficial role therein.

The terms "treatment" and "treat", as used herein, alleviate, ameliorate, manage, prevent, inhibit, the general meaning of, the progression or severity of the pathological condition described herein, or its sequelae, Limiting, delaying, stopping, or reversing. The term "prevention" refers to reducing the likelihood that a recipient of a compound of formula (I), or a pharmaceutical acid addition salt thereof, causes or develops the pathological condition described herein or its sequelae.

Diseases, disorders, or conditions in which a compound of Formula (I) or a pharmaceutical acid addition salt thereof are useful for treating include, but are not limited to: (1) uterine and / or chest tumors; (2) endometriosis; (3) treatment and management of leiomyoma / leiomyoma and related symptoms of the uterus; And (4) osteoporosis. As described herein, treatment of leiomyoma / leiomyoma of the uterus may also reduce related symptoms such as pain, frequent urination, and bleeding of the uterus.

Dosage

As used herein, the term “effective amount” means the amount of a compound of formula (I) or a pharmaceutical acid addition salt thereof that can treat the condition described herein or treat its side effects.

The specific dosage administered is determined by the specific circumstances around each situation. Such circumstances include the route of administration, the previous history of the recipient, the pathological condition or condition to be treated, the severity of the condition / symptom to be treated and the age and gender of the recipient. The physician of the receiving patient should determine the therapeutic dose to be administered in view of the appropriate circumstances.

In general, the daily minimum effective dose of a compound of the present invention will exceed about 5 mg. Typically, the maximum effective dose per day will not exceed about 350 mg. The exact dosage can be determined according to standard practice of the medical community regarding the "dose titration" of the recipient. This is initially administered at a low dosage of the compound and gradually increasing the dosage until the desired therapeutic effect is observed.

Route of administration

The compounds of formula (I) or pharmaceutical acid addition salts thereof may be administered by various routes, such as intramuscular, intranasal, vaginal, intravenous, oral, rectal, subcutaneous, topical and transdermal routes. Preferred routes of administration are oral routes.

Combination therapy

The compounds of formula (I) or pharmaceutical acid addition salts thereof may be used with other drugs in which these compounds are used for the treatment of useful diseases or conditions. Such other drug (s) may be administered in the routes and amounts generally used concurrently or sequentially with the salts of the present invention. When the compound of the present invention is used simultaneously with one or more other drugs, pharmaceutical unit dosage forms containing such other drug in addition to the present compound are preferred. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients. One example of another active ingredient that may be used in combination with a compound of the present invention includes agents used in hormone replacement therapy (HRT), whether administered separately or in the same pharmaceutical composition.

Claims (22)

A compound of formula (I) or a pharmaceutical acid addition salt thereof. <Formula I> Where m, q and r are independently 0, 1 or 2; n is 0 or 1; R is H or COR ² ; R ^O is independently at each occurrence OH, CF ₃ , halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; R ¹ and R ^{1 ′} are independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ³ R ^3a , CF ₃ or CH ₂ CF ₃ ; Or when n and q are 0, the —SO ₂ R ¹ residue may be bonded to the attached phenyl ring to form a residue of formula (a) or (b) <Formula (a)> <Formula (b)> (Where t and v are 0, 1 or 2 provided that the sum of t + v is 2); R ² is C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; NR ⁴ R ⁴ ; Phenoxy; Or phenyl optionally substituted with halo; R ³ is C ₁ -C ₆ alkyl or phenyl; R ^3a and R ⁴ are independently at each occurrence H, C ₁ -C ₆ alkyl or phenyl; X is O, CH ₂ or CO; X ¹ is O or NR ⁵ ; R ⁵ is H or C ₁ -C ₆ alkyl; R ⁸ is H or methyl, provided that when R is 1 or 2 R ⁸ must be H and when r is 0 R ⁸ must be methyl; Y is S, CH ₂ CH ₂ or CH = CH. The compound of claim 1, wherein m is 2; or a pharmaceutical acid addition salt thereof, wherein r is 1 or 2. 3. The method of claim 1, wherein R ² is C ₁ -C ₆ alkyl, NHCH ₃ or phenyl and an —SO ₂ R ¹ residue is attached to the phenyl ring to form a residue of formula (a) or (b). Compounds or pharmaceutical acid addition salts thereof that do not bind to the phenyl ring. The process of claim 1, wherein n is 0; q is 0 or 1; The -SO ₂ R ¹ residue is attached at the para position of the phenyl ring; R ⁰ is OH, CF ₃ , fluoro, chloro, methyl or ethyl; R ¹ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl or CF ₃ ; R ² is C ₁ -C ₆ alkyl or phenyl; A compound wherein Y is S or CH = CH or a pharmaceutical acid addition salt thereof. The compound according to any one of claims 1 to 4, wherein X and X ¹ are 0, or a pharmaceutical acid addition salt thereof. 6. The compound of any one of claims 1 to 5, wherein q is 0; Or a pharmaceutical acid addition salt thereof, wherein R ¹ is methyl, ethyl, cyclopropyl or CF ₃ and Y is CH = CH. The method according to any one of claims 1 to 6, A compound selected from the group consisting of or a pharmaceutical acid addition salt thereof. Phosphorus compounds or pharmaceutical acid addition salts thereof. Phosphorus compounds or pharmaceutical acid addition salts thereof. Phosphorus compounds or pharmaceutical acid addition salts thereof. Phosphorus compounds or pharmaceutical acid addition salts thereof. Phosphorus compounds or pharmaceutical acid addition salts thereof. Phosphorus compounds or pharmaceutical acid addition salts thereof. The compound according to any one of claims 1 to 13, which is a hydrochloride salt. A method of treating endometriosis comprising administering to a patient in need thereof an effective amount of the compound of any one of claims 1 to 14 or a pharmaceutical acid addition salt thereof. A method of treating uterine leiomyoma comprising administering to a patient in need thereof an effective amount of the compound of any one of claims 1 to 14 or a pharmaceutical acid addition salt thereof. The compound of any one of claims 1 to 14 or a pharmaceutical acid addition salt thereof for use in treating endometriosis and / or leiomyoma of the uterus. A compound of formula II or an acid addition salt thereof. <Formula II> Where m, q, r and u are independently 0, 1 or 2; n is 0 or 1; R ⁰ is independently at each occurrence OH, CF ₃ , halo, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; R ¹ and R ^{1 ′} are independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ³ R ^3a , CF ₃ or CH ₂ CF ₃ ; Or when n and q are 0 the —SO _u R ¹ residue may be bonded to the attached phenyl ring to form the following formula (c) or (d) (Where t and v are 0, 1 or 2 provided the sum of t + v is 2); R ² is phenyl optionally substituted with C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁴ R ⁴ , phenoxy or halo; R ³ is C ₁ -C ₆ alkyl or phenyl; R ^3a and R ⁴ in each occurrence are independently H, C ₁ -C ₆ alkyl or phenyl; R ⁶ is H, C ₁ -C ₆ alkyl, benzyl or COR ² ; R ⁷ is H, C ₁ -C ₆ alkyl or CO ₂ (C ₁ -C ₆ alkyl); R ⁸ is H or methyl, provided that when R is 1 or 2 R ⁸ must be H and when r is 0 R ⁸ must be methyl; X is O, CH ₂ or CO; X ² is O or NR ⁷ ; Y is S, CH ₂ CH ₂ or CH = CH; Provided that when R ⁶ is C ₁ -C ₆ alkyl or benzyl u is only 2 and the compound of formula II is or This is not it. 19. The compound of claim 18, wherein r is 1 or 2; a) when n is 0 and -SO _u R ¹ residue and R ⁰ are both bonded to the phenyl ring to which they are attached to form a residue of formula (c) or (d) u is 2; b) A compound wherein n and 1 are both 0, all 1 or all 2, or acid addition salts thereof. The method of claim 18 or 19, The —SO _u R ¹ residue does not bond with the phenyl ring attached to form a residue of Formula (c) or Formula (d) and is attached at the para-position of the phenyl ring; n is 0; q is 0 or 1; R ⁰ is OH, CF ₃ , fluoro, chloro, methyl or ethyl; R ¹ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl or CF ₃ ; R ² is C ₁ -C ₆ alkyl or phenyl; X and X ¹ are O; Y is S or CH = CH, or its acid addition salt. The method according to any one of claims 18 to 20, q is 0; R ¹ is methyl, ethyl, cyclopropyl or CF ₃ ; Y is CH = CH, or its acid addition salt. The method according to any one of claims 18 to 21, A compound selected from the group consisting of, or acid addition salts thereof.