UA81117C2 - Selective estrogen receptor modulators - Google Patents

Abstract

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

Description

Description of the invention

Leiomyoma(s) of the uterus (fibrous disease of the uterus) is a clinical problem known by 2 numerous names, including uterine fibrosis, uterine hypertrophy, uterine leiomyoma, myometrial hypertrophy, uterine fibrosis, and fibrotic metritis. In fact, uterine fibrosis is a painful condition in which there is an inappropriate deposition of fibrous tissue on the walls of the uterus. This condition is the cause of dysmenorrhea and infertility in women.

Endometritis is a condition of severe dysmenorrhea, which is accompanied by severe pain, bleeding into the endometrium or the peritoneal cavity and often leads to infertility. The causes of such symptoms are apparently ectopic endometrial tumors that respond inappropriately to normal hormonal regulation and are located in inappropriate tissues. As a result of this inappropriate location of endometrial tumors, local inflammatory-like reactions are apparently initiated in this tissue, causing macrophage infiltration and a sequence of events that lead to the initiation of a painful response. Available data 72 indicate that the cause of uterine fibrosis and endometritis is an inadequate response of fibrotic tissue and/or endometrial tissue to estrogens.

Over the past decade, numerous publications have appeared describing selective estrogen receptor modulators (SERMs), for example, US patents Мо5,484,795, Мо5,484,798, Мо5,510,358, Мо5,998,401 and international application UMO 96/09040). Generally speaking, it has been found that a significant number of these ZECMs exhibit beneficial activity as estrogen agonists in the bone and cardiovascular systems in combination with parallel beneficial activity as estrogen antagonists in the mammary glands. A small subset of such compounds that are particularly useful show activity as estrogen agonists in the uterus. Some compounds with this ZECM profile are particularly promising for the treatment of fibrotic uterine disease and/or endometritis.

However, the clinical application of such compounds with ZECM effect for the treatment of fibroid disease of the uterus and/or endometritis, in particular, in premenopausal women, is hindered by the ability of the mentioned compounds (3) to cause significant ovarian stimulation effects. Therefore, there is currently an urgent need for new compounds with the effect of ZEKM, which act as estrogen antagonists in the uterus, but do not significantly stimulate the ovaries.

This invention relates to a compound of formula I: in "-

SN.) -(sn-kh. - 2 "Fo I) (ee) in? 4 that p

OK "

WITH

. 8 » - ko U p th 0), (ee) where: - . t, 4 and r are independently 0, 1 or 2; - drinks or 1; pz E is M or SOBV?2;

BO independently in each case is OH, CE3, halogen, C4-C8-alkyl or C-Ce- alkoxy group; "m B and 2" independently of each other are Ci-Cv-alkyl, Ci-Cv-alkyl, ME, CEz or СНоСЕ"; or, if n and d are 0, then the group is -3022! can, in combination with the phenyl ring to which it is connected, form a fragment of formula (a) or formula (B):

Ф) име) 60 b5 cha and СН) 52о ( х ! , 2 Мо (СН), (a) (5), deitamM is 0, 1 or 2, provided that the sum of iiu should be equal to 2;

IN? is C-C-C alkyl; С--Св-Alkoxy group; ME"; a phenoxy group; or phenyl optionally substituted with halogen;

BZ is C1-C1-alkyl or phenyl;

Za and KE" are independently in each case H, Ci-Cv-alkyl or phenyl;

X is O, CH" or CO;

X is O or ME;

IN? is M or C-C6-alkyl;

BZ is M or methyl, provided that if r is 1 or 2, then KZ must be M and if r is 0, then KZ must be methyl; and sch

In is 5, СНоСН» or СН-СН; y y y y o or a pharmaceutically acceptable salt of such compound with an acid.

This invention also relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable acid salt of such a compound and a pharmaceutically acceptable carrier. Alternatively, the pharmaceutical composition of the present invention may be adapted for use in the treatment of endometritis and/or uterine fibrosis.

This invention also relates to methods of treating endometritis and/or uterine fibrosis using a compound (87 of formula I or a pharmaceutically acceptable salt of such a compound with an acid. "-

In addition, this invention relates to a compound of the formula | or a pharmaceutically acceptable acid salt of such compound for use in the treatment of endometritis and/or uterine fibrosis. Further, this invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt of such a compound with an acid for the manufacture of a medicament for the treatment of endometritis and/or uterine fibrosis.

In addition, this invention relates to the compound of formula I:

In p

Xx I so 4 o, - b - k-o x o shu 20 (Kk ) what ,

F) where: t, n, 4, r, o, c, B, 28 and X and Y correspond to the definitions given above for the compound of formula I; and is, 1 or 2; b is EZeHn, C.4-CeV-alkyl, benzyl or sova, and B2 corresponds to the definition given above for the compound of formula I;

X? is O or ME 7; and

B is H, C.-Cv-alkyl or SOZ(C.-Cv-alkyl); provided that y can be only 2, if K 9 is C.-Cv-alkyl. or 65 benzyl; or a pharmaceutically acceptable acid salt of such a compound; provided that the compound of formula I does not correspond to any of the following formulas:

"Snu S lnsnuyu ; "AH at "Ж at 54 or 5

C9-4-vme TI vm

Me-O 5 no 5 70 . ШЙ shk , useful, for example, as a chemical intermediate for the compound of formula I.

For purposes of the present invention disclosed and claimed herein, the following terms have the following definitions.

The term "halogen" means fluorine, chlorine, bromine and iodine. The term "C 1 -C 6 -alkyl" means a hydrocarbon radical of normal, branched or cyclic structure containing from one to six carbon atoms, for example, methyl, ethyl, n- propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, etc. Groups such as cyclobutylmethyleneyl are also covered by the term "Ci-Cv-alkyl". The term " C.--Cv-alkyl" specifically refers to the following groups: methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, cyclopropylmethyl and cyclobutyl. The term "C.-C- "Alkoxy(group)" means C1-C6-alkyl attached to the rest of the molecule through an oxygen bridge.

The term "pharmaceutically acceptable" as used herein as an adjective means "virtually harmless".

Compounds of the present invention (embodiments) which are preferred

Certain compounds of this invention are of particular interest and are preferred. Below are listed several groups of features of compounds that are preferred. It should be borne in mind that each feature from each group can be combined with other features of each group in order to form additional groups of compounds to which (8) is preferred. a) t is O or 2;

B) theo; there are 2 of them from s)t; a) peo; "- e)pe1; a is 0 or 1; t gives; "- n) d is 1; with

І)ге2;

Ken;

Yu V is a SOK?; 1) it is OH, methoxy group, CEz, fluorine, chlorine, methyl or ethyl; "t) BO is OH, CE", fluorine, chlorine, methyl or ethyl; - c n) KO is CEz or fluorine; z» o) the -5ХО2В group occupies the para-position in the phenyl to which it is attached; p) group -5028 does not combine with the phenyl to which it is attached to form a fragment of formula (a) or formula (B); so no 4) in is C.-Cu-alkyl or CE"; d) In! is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, - t-butyl, tert-butyl, cyclobutyl or CE"; - 8) VE! is methyl, ethyl, cyclopropyl or CE"; tsu 5 In is methyl, ethyl or CE"; tsu) B is methyl; "m M)! is ethyl; m) B! is cyclopropyl;

MIN! is SE";

C) B" is C, -C, -alkyl or CE"; (F) 73 B' is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,

GI cyclobutyl or CE"; aa) ВК" is methyl, ethyl, cyclopropyl or CE"; 60 б) БЕ" is methyl, ethyl or SEZ; cc) B" is methyl; 44) is ethyl; ee) B" is cyclopropyl;

TV" is CE"; 65 99) B is C4-C8-alkyl or phenyl;

n) B is C1-C1-alkyl, MNSN" or phenyl; iii) 22 is C1-C1-alkyl, MNH»3 or phenyl;

HER) VU is H, methyl or ethyl;

KK) VZ is H;

ShhX is; tt) X is 0; pp) X' is MV; oo) there are 5; then рр) ХУ is СНА-СН; cha) He SNІSN"; d) the compound of formula I is a hydrochloride.

Synthesis

Compounds of the formula | can be obtained as described in the following Schemes, Preparative Syntheses and Examples. s o cha "- "- "- d) shi s ;" (ee) - - - 50 what

F) name) 60 b5

Scheme (sn,

M(SNOH. same 4 - | "

Kk x BO U. Her!

X / unit

A B I; 0.

V'-o U -G(K

PI | IM

Y s (SN), I o - yin - v? х «о в 7 t y 1 -

OK

Z Y Sh

H o - ( zv he, U (Kk), y

Ka) « shi i . » p (SNU, I so 45 writes FI - 5 pe | r 7 E. H O.K yayu in "O.V.

AND; In (KH

F. I t According to Scheme 1, the compound of the formula IM is introduced into the reaction with the compound of the formula II under the usual conditions for carrying out the Suzuki (Zygiki) or Stille (Z(ШШШ)) reactions, that is, one of the substituents "A" or "0" is an ester group 60 boric acid or ethylstannane, and the other is a leaving group such as chlorine, bromine or iodine or a sulfonate such as trifluoromethyl sulfonate. If KZ is alkyl (predominantly methyl) or benzyl, then said KZ groups can be cleaved off under standard conditions (see , for example, the procedures described below or the latest edition of Greenie's monograph |Ogeepe, Rgogesiime Sgoimrz ip Ogdapis Zupipeviv, doyp UMPeu b Bopv, Mem/ Mogk, v5 M. M. I), It is possible to obtain a compound of formula I, where K is N. If and is 0 or 1, then the addition product can be oxidized under standard conditions (see the descriptions of preparatory syntheses below) to give the corresponding mono- or bis-sulfone of formula (a), where m is 2. From the compounds of formula I! or (a), where K is H, further derivatives can then be obtained in order to obtain the compound of formula I, d e B is JUICE.

Scheme 2 1! it (Ok, . od

HK,

Wo Wu (V

IN

"and a Mr

I: 8) 5O KI, o Od. iv, 1

F p 20-X, p 6 che 0 vo i o 2

Vo U (8, k), F)

M M cha t U st, -

M-(СНО); te UNI M- (CH 18 - 3 "-

Where in? d) then: VL (snu), td (SNO « 8 I. 8 I" - s E o (ZO ь, KE o OK b, r 50 F (5 50,8 0 y Vo 2 U E (V Vo y (8) (ee) - Kk) Tso) - According to Scheme 2, a compound of formula (B) is prepared by first reacting a compound of formula MI (obtained, -sh 20 |as described in US patent Mo5,929,090), incorporated herein by reference) with a compound of formula

MI under standard conditions of nucleophilic substitution, and the target compound is obtained, from which, by removing the "M" protecting groups and forming further derivatives, as described above, the compound of formula (B) can be obtained.

A compound of formula (c) can also be prepared from a compound of formula M as shown in Scheme 2. A compound of formula MI can be prepared by first reacting a compound of formula M with a base followed by addition of 4-fluorobenzaldehyde. The resulting aldehyde can be converted into the corresponding hydroxyl or sulfonyl compound of the formula MIII by reacting, for example, first with hydrogen peroxide, and

F) then with sodium perborate monohydrate. The resulting compound of formula MII can then be reacted with a compound of formula MI under standard conditions of nucleophilic substitution to obtain the target compound, from which, by removing the protecting groups and forming further derivatives, as described above, it is possible to obtain compound 60 of formula ((c). b5

Scheme 3 shshO: (sno (SN,); si ( sleeps in x in IF! bo-- stosu o o wo U (in ko-o U (Vo,

IX x (sn,), i (sN,), i ( me(snurgh: 2 in x (5058 " in Iv

Che Kk X 50, K 50,"

SO - with

In o ko (8, o i (Ko, sch o

This) tsa)

Scheme C illustrates an alternative method of preparing a compound of formula !, where K' and BK! are independently of each other C.-Cv-alkyl, CEz or СНоСЕ" and group 502B! does not combine with the KO group. The compound of the formula IX (obtained - analogously to the reaction of the compound of the formula I with the compound of the formula IM, as described in Scheme 1) can be introduced into - the reaction with the Tisalcoholate of the formula HB 72, where Ba is C.-Cv-alkyl, SEZ or СНоСЕ»z for example, with sodium methanethiolate, resulting in replacement of the "494" substituent(s). The group "Id" in the compound of formula IX is a substituent that activates the phenyl to which it is attached in relation to the nucleophilic aromatic substitution. h

The resulting simple thioether of formula X can then be oxidized to the corresponding sulfone or sulfoxide, from which, by removing the protecting groups and forming further derivatives, as described above, the compound of formula (4) can be obtained. If it is necessary to introduce more than one substituent I 9 into the compound of the formula IM, then the methodology

Schemes C can be applied, in particular, to obtain a compound of formula |(e), where n is 1 and t is 0 or 1.

Compounds of formula PI, formula IM, and formula MI can be prepared as shown below or by techniques similar to those known in the art. Compounds of formula M can be prepared by methods similar to those described in Chu Z (US Patent No. 5,929,090), or as described below. Compounds of the formula NUK 72, as a rule, are available on the market c or can be obtained by methods readily available to the average person skilled in the field of organic synthesis.

General features of experiments

Mass spectra with electrospray ionization are obtained, for example, on a Rippidap CO ХОцо device with CO 35 using a mixture of 5095 acetonitrile, 25956 methanol and 2595 2MM aqueous ammonium acetate solution as a mobile phase. - Preparative high-performance liquid chromatography (HPLC) is performed, for example, on the BioYop-Rgeragaime Zuviet system with the use of the Opiroipi Zoimage software and detection at two wavelengths (220nm and 254nm), as well as the Rippidap aba M5 mass spectrometer. As a stationary phase, you can use a column 005-АО 20mmх25Ωm with a sorbent particle size of 15μm. A binary system of solution A (0.195 trifluoroacetic acid (TEA), 190 isopropyl alcohol (IPA) in water) and solution B (0.0595 TPA, 195 IPA in acetonitrile) is used as an eluent. The standard way is to use a gradient of 30-9595 V, unless otherwise specified. Compounds purified in this way are isolated as salts with TEA.

Preparative RHPE can also be performed on the Violiade RagaiIeIRiIech system with appropriate detection at two wavelengths and software. A Hiegt column is used as a stationary phase

F) ZOmmx150mm or 19mmx250mm with a sorbent particle size of 10μm; as the mobile phase A-T0OMM MH." HSOOLOMM ko MH.OH and as the mobile phase B-100905 acetonitrile.

Preparatory synthesis of 1 in b-methoxy-1-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of trifluoromethanesulfonic acid

To dimethylformamide (OME, 250ml) at ambient temperature was added b-methoxynaphthalen-2-ol (20g, 114, mmol), and then M-bromosuccinimide (MV5, 21.5g, 120mmol) over 30 minutes.

In 45 minutes the mixture was diluted with water (800 ml), the precipitate was collected and dried, obtaining 25.5 g (87905) of 1-bromo-b-methoxy-naphthalene-2-ol.

1-Bromo-b-methoxy-naphthalen-2-ol (66.7g, 264mmol), potassium carbonate (K»CO3, 40.0g, 290mmol) and benzyl bromide (49.6g, 290mmol) were added to OME (800ml). The mixture was stirred at ambient temperature for an hour. Water (400 ml) was added to precipitate the product. The precipitate was separated and washed on a filter with heptane (3x125 ml), after which it was dried, obtaining 83.7 g of 2-benzyloxy-1-bromo-b6-methoxy-naphthalene (86.29).

Toluene (200 ml), 2-benzyloxy-1-bromo-6-methoxy-naphthalene (ZoOg, 87 4 mmol), 4-(2-piperidin-1-yl-ethoxy)phenol (23.2 g, 105 mmol) and cesium carbonate were mixed 34.4g, 105mmol), and the mixture was heated under reflux. Part of the toluene (100 ml) was removed. Ethyl acetate (390 mg, 4.37 mmol) and a complex of copper with benzene triflate (trifluoromethanesulfonate) (2.20 g, 4.37 mmol) were added to the reaction mixture, and the mixture was stirred for 70 min. The solvent was removed by distillation, and the residue was heated at 17422 for 1.5 hours.

The residue was dissolved in a mixture of ethyl acetate (200 ml) and an aqueous solution of NS (1-n., 30 ml). The organic layer was separated and concentrated to give a residue. The residue was chromatographed on a column and 12.4 g of 1-2-I(4-(-2-benzyloxy-6-methoxynaphthalene-1-yloxy)-phenoxy|ethyl)-piperidine (3090) was obtained.

1-(2-I4-(2-benzyloxy-6-methoxy-naphthalene-1-yloxy)-phenoxy|-ethyl)-piperidine (12.4 g, 25.5 mmol) 75 was added to a mixture of methanol and ethyl acetate (1:1 , 490 ml) and heated to form a solution. The heat source was removed and ammonium formate (4.83g, 76b,mmol) and RaY(OH)" on charcoal (2095 (wt), 1.58g, 1.12mmol) were added.

The mixture was heated under reflux for 50 minutes, after which it was filtered. The filtrate was concentrated, obtaining 9.9 g of b-methoxy-1-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol (98.596).

Dichloromethane (290 ml), triethylamine (3.08 g, 30.4 mmol) and b-methoxy-1-1-4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol (9.2 g, 234 mmol) to -502C and trifluoromethanesulfonic anhydride (7.26 bg, 25/mmol) was added. The resulting mixture was stirred at -5092C7 for 2 hours, after which the mixture was allowed to warm to room temperature, and then stirred for another 1 hour. Roseol (15 Oml) was added, and the organic layer was separated. The organic phase was washed with Manso solution, then dried and concentrated to obtain a residue. This residue was crystallized from diethyl ether-hexane, and C 11.2 g of the title compound (90.9965) was obtained. at

Preparatory synthesis of 2b-hydroxy-1-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of trifluoromethanesulfonic acid

To a solution of the compound obtained in Preparatory Synthesis 1 (1.07g, 2.04mmol) in dichloromethane (20ml) was added a 2M solution of hydrogen chloride in diethyl ether (1.5ml, 3mmol), and the solvent was removed in vacuo. The resulting hydrochloride was dissolved in dichloromethane (40 ml) and cooled in an ice bath. Boron tribromide (0.58 ml, 6.12 mmol) was added, stirred for 3.5 h, heated to ambient temperature and - stirred for 15 min., cooled in an ice bath and quenched with chilled ice saturated - sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane, the organic layers were combined and dried over magnesium sulfate, the solvent was removed in vacuo, and the residue was chromatographed on silica gel using dichloromethane/methanol as an eluent to give 99 mg of the title compound (9595).

Preparatory synthesis of β-benzyloxy-1-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of trifluoromethanesulfonic acid

b-Hydroxy-1-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester - with trifluoromethanesulfonic acid (247 mg, 0.48 mmol), triphenylphosphine (19 mg, 0.725 mmol) were mixed , benzyl alcohol (0.07 bml, 0.725 mmol) and tetrahydrofuran (ml) in a flask placed in an ice bath. Diisopropyl azodicarboxylate (0.14 ml, 0.725 mmol) was added, stirred for 1 h, warmed to room temperature and stirred for 3 h. The mixture was diluted with ethyl acetate and washed with 5095 saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over sulfate (ee ) magnesium, and the solvent was removed in vacuo.The residue was chromatographed on silica gel using dichloromethane/methanol as eluent to give 21 µg of the title compound (73905).

Example 1 - 1-(2-44--2--4-methanesulfonyl-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine - 50 o "I 7 o 57 " and sn o | with name) 60 sm,

4-(Methanesulfonyl)phenylboronic acid (6.8g, 34mmol), the compound from Preparatory Synthesis 1 (6.6g, 12.6mmol), cesium fluoride (17.2g, 113mmol) and acetonitrile (130ml) were mixed in a flame-dried well flask with a capacity of 65 B5O0Oml, equipped with a reflux condenser. Palladium (II) acetate (283 mg, 1.2 mmol) and tricyclohexylphosphine (53 mg, 1.9 mmol) were mixed in a separate flask. Acetonitrile (b5ml) was added, and the mixture was sonicated

10 minutes in a nitrogen atmosphere. A suspension of catalysts was added to the mixture of substrates and heated in an oil bath with a temperature of 902 for ЗОхв. The suspension was cooled to room temperature and filtered through a layer of celite. Celite was washed with ethyl acetate and the filtrate was washed with a mixture of water with a saturated aqueous solution of Ma»CO3 (50:50), a saturated aqueous solution of МНАС! and brine. The organic layer was dried (Ma»5O)), filtered and evaporated, obtaining 10 g of crude product. This crude product was treated with a solution of 195% methanol (MeOOnH) in NaOH and the resulting impurity was removed as a white solid (400 mg) by filtration. The filtrate was concentrated and the crude product was preadsorbed on silica gel.

The residue was chromatographed on a Bio column, eluting the product with methanol (from 090 to 1095) in dichloromethane, and 70 obtained 5.2 g of the title compound (7875). The crude fractions were concentrated, evaporated and recrystallized from ethyl acetate, obtaining an additional 1.2 g of the title compound (1895). Mass spectrum (ion sputtering): t/2-532.3 (MAN).

Example 2

Hydrochloride 1-(2-14-(2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine

The product from Example 1 (6b, 4g, 12.1mmol) was dissolved in a mixture of ethyl acetate, dichloromethane and methanol (300ml; 2.5:2.5:1). The obtained solution was cooled in an ice bath and treated with 2 M NOI in diethyl ether (9.Tml, 18.2 mmol). The solution was concentrated in a vacuum and dried at 502C (pressure "2 mm Hg (x266 Pa)) for 18 h, and 6.bg of the title compound (9695) was obtained. Mass spectrum (ion sputtering): t/2-532.3 (MAN-NSI).

Example C 6-(4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol

The product from Example 2 (6.45 g, 11.4 mmol) was dissolved in dichloromethane (200 ml) and cooled to 32C in an ice bath. Undiluted VVgz (5.4 ml, 57 mmol) was added to this solution dropwise over 5 minutes, and the mixture was stirred for 1 hour. at 0-102C. The reaction mixture was slowly poured into a separatory funnel with a capacity of 1 L, which contained a saturated aqueous Manso solution (30 Oml) and ice. The resulting biphasic mixture was diluted with a 7.595:CM solution of Meon in ethyl acetate (E(OAc, 400 ml) and brine (100 ml). The layers were separated and the aqueous phase (5) was extracted with 596 MeonN in EtOAc (2x150 ml). The combined organic layers were washed with brine (100 ml ), dried (Mazo)), filtered and evaporated, obtaining 5.3 g of crude product. The residue was chromatographed on a SiO2 column, eluting with methanol (2.595 to 1295) in dichloromethane to give 4.99 g of the title compound (85965). The product was dried at 459C (pressure "2mm Hg (x:266Pa) for 18 hours. Mass spectrum (ion sputtering): t/2-518.3 (M.N). "-

Example 4

Hydrochloride 6-(4-methanesulfonyl-phenyl)-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol --

The product from Example C (2.8 g, 5.4 mmol) was suspended in a mixture of ethyl acetate, diethyl ether and methanol "de (5 Oml; 5:1:4). The mixture was cooled in an ice bath and treated with 2M NOI in diethyl ether (4.1 ml , 8.2 mmol).

The resulting solid was collected on a paper filter, washed with diethyl ether and dried at 459°C (pressure of 2 mm Hg (266 Pa) for 18 hours, and 2.84 g of the title compound (9595) was obtained. Mass spectrum ( onne spraying): t/2-518.3 (MAN-NSII).

Example 5 "

Hydrochloride of 6-(4-methanesulfonyl-phenyl)-5-14-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of 2,2-dimethylpropionic acid. shchi o 57 so sin o x - sn, - o ayu not their ns o

CH,

HF) The product from Example C (220mg, 043mmol) was dissolved in pyridine (bml) and trimethylacetyl chloride (0.144ml, 1.17mmol) and dimethylaminopyridine (OMAR, catalytic amount) were added sequentially. It was stirred at ambient temperature for 18 hours, and the pyridine was evaporated. The residue was redissolved in ethyl acetate and washed with a saturated aqueous solution of MH, Cl, a saturated aqueous solution of 60 MansoOz, and brine. The organic layer was dried (Ma»5O4), filtered and evaporated, obtaining 277 mg of crude product. This crude product was preadsorbed on silica gel and the residue was chromatographed on a 5IO column eluting with methanol (095 to 6905) in dichloromethane to give 235 mg of 6-(4-methanesulfonyl-phenyl)-5-(4-(2- piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of 2,2-dimethylpropionic acid. The obtained free base was dissolved in a mixture of ethyl acetate and diethyl ether bo (20 ml; 1:1). It was cooled in an ice bath and treated with 2M HCI in diethyl ether (0.3ml, 0.bmmol).

The resulting precipitate was collected on a paper filter, washed with diethyl ether, and 22 Ωg of the title compound (80905) were obtained. Mass spectrum (ion sputtering): t/2-602.4 (MAN-NSII).

Example 6

Hydrochloride 6-(4-methanesulfonyl-phenyl)-5-14-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalene-2-yl ester of benzoic acid phe; yu F Phi 57

SIN 0 x H s Z

Y Y r X Ff

The compound from Example C (220 Ωg, 0.4 mmol) was dissolved in pyridine (ml) and benzoyl chloride (0.0–7 ml, 0.58 mmol) and OMAR (catalytic amount) were added sequentially. It was stirred at ambient temperature for 18 hours, and the pyridine was evaporated. The mixture was partitioned between a saturated aqueous solution of MH CI with ethyl acetate (with an admixture of 896 Meon). After separating the layers, the aqueous layer was extracted with ethyl acetate (with an impurity of 595 Meon) and both organic phases were combined. Washed with a saturated aqueous solution of ManNnsSoz and brine. The organic layer was dried (Ma»5O)), filtered and evaporated to give 276 mg of crude product as the free base. This crude product was previously adsorbed on silica gel and chromatographed on a column of SiO2 eluting with methanol (090 to 0.00) in dichloromethane to give 26000 mg of 6-(4-methanesulfonyl-phenyl)-5-I4-(2-piperidine- 1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester - benzoic acid. The obtained free base was dissolved in hot ethyl acetate (20 ml) and diluted with diethyl ether (20 ml). It was cooled in an ice bath and treated with 2M HCIII in diethyl ether (0.31 ml, 0.62 mmol). --

The resulting precipitate was collected on a paper filter, washed with diethyl ether, and 255 mg of the title compound (91905) was obtained. Mass spectrum (ion sputtering): t/2-622.3 (MAAN-NSI).

Example 7 (se) 6-(4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of 4-fluorobenzoic acid and From c to h - h» o F sn, so o - - o - 50 on E

The compound from Example C (11mg, 0.21mmol) was dissolved in dichloromethane (2ml). 4-Fluorobenzoyl chloride (30 ml, 0.25 mmol) was added dropwise. After stirring for 1 min. the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 ml) and extracted with dichloromethane (10 ml). Organic layer

HF) was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on a 10" column, eluting the product with methanol (from 090 to 395) in dichloromethane, and 99 mg of the title compound (73965) was obtained. Mass spectrum (ion sputtering): t/2-640.3 (M'-H).

Example 8 6o Hydrochloride 6-(4-methanesulfonyl-phenyl)-5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of 4-fluorobenzoic acid

The compound from Example 7 (9mg, 0.15mmol) was dissolved in dichloromethane (3ml) and 2M HCl in diethyl ether (400mg, 0.8mmol) was added. The solvent was removed in vacuo, and 111 mg of the title compound (10095) was obtained. Mass spectrum (ion sputtering): t/2-640.3 (MAN-NSI). because Example 9

6-(4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of isobutylcarboxylic acid o; "sn

Ki ate o o sleep,

The compound from Example C (120 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL), and isobutyl chloroformate (3 mL, 0.3 mmol) was added dropwise. After stirring for 1 min. the reaction mixture was poured with intensive stirring into diethyl ether (1 Oml) and filtered. The solid was dissolved in dichloromethane (1 Oml) and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on a column of ZIO0, eluting the product with methanol (4905) in dichloromethane, and 104 mg of the title compound (73905) was obtained. Mass spectrum (ion sputtering): t/727-618.4 (M'-H). at

Example 10

Isobutylcarboxylic acid 6-(4-methanesulfonyl-phenyl)-5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalene-2-yl ester hydrochloride

The compound from Example 9 (104mg, 0.17mmol) was dissolved in dichloromethane (3ml) and 2M HCl in diethyl ether (40µl, 0.dmmol) was added. The solvent was removed in vacuo, and 81 mg of the title compound (73905) was obtained. -

Mass spectrum (ion sputtering): pt/2-618.3 (MAN-NSI).

Example 11 h 6-(4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester - methylcarbamic acid g)

SU that « that about Sn Z with Z

The compound from Example C (201 mg, 0.3–8 mmol) was dissolved in dichloromethane (4 mL) and triethylamine (0.5 mL, 20–20 mmol) was added, followed by methyl isocyanate (500 mg, 8.7 mmol). After stirring for ЗОхв. the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a column of ZnO, eluting with methanol (095 to 495) in dichloromethane to give 133 mg of the title compound (60905). Mass spectrum ( ion sputtering): t/2-575.3 (MAN) and 518.3 (M-MeMcSO). 99 Example 12

HF) Hydrochloride 6-(4-methanesulfonyl-phenyl)-5-14-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of methylcarbamic acid of the Compound from Example 11 (130 mg, 0 .23 mmol) was dissolved in dichloromethane (3 mL) and 2M HCI in diethyl ether (40 µL, 0.8 mmol) was added. The solvent was removed in vacuo, and 81 mg of the title compound 60 (7395) was obtained. Mass spectrum (one sputtering): t/2-575.3 (M-N-NSI) and 518.3 (MAN-NSI-MeMSO).

Example 13

Hydrochloride 1-(2-14-(2-(4-ethanesulfonyl-phenyl)-b6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine b5 o 7 o o Mch

SIN SN, " v

Meow

4-(ethanesulfonyl)phenylboronic acid (1.83g, 8.bmmol), the compound from Preparatory Synthesis 1 (1.5g, 2.86bmmol), cesium fluoride (3.9g, 25.7mmol) and acetonitrile (32ml) were mixed in dried over a flame in a flask with a capacity of 100 Oml, equipped with a reflux condenser. Palladium (II) acetate (bbmg, 0.29 mmol) and tricyclohexylphosphine (120 mg, 0.4 mmol) were mixed in a separate dried flask. Acetonitrile (1 bml) was added and sonicated for 1 h. in a nitrogen atmosphere. A suspension of catalysts was added to the mixture of substrates, and 2o was heated in an oil bath with a temperature of 90 2C for 30 minutes. The suspension was cooled to room temperature and filtered through a layer of celite. The celite was washed with ethyl acetate and the filtrate was washed with a mixture of water with a saturated aqueous solution of Ma»CO»z (50:50), a saturated aqueous solution of MNaClI and brine.

The organic layer was dried (Ma»5O)), filtered and evaporated, obtaining 2 g of crude product. This crude product was previously adsorbed on silica gel and chromatographed on a Bio column, eluting with methanol (from 00 to 1096) in dichloromethane to give 1.5 g of 1-(2-44--2--(4-ethanesulfonyl-phenyl) )-6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine. The resulting free base was dissolved in a mixture of ethyl acetate and diethyl ether (bOml; 1:1). The solution was cooled in an ice bath and treated with 2M HCl in diethyl ether (2 ml, 4 mmol). The resulting solid was collected on a paper filter, washed with diethyl ether, and 1.5 g of the title compound (90905) was obtained. Mass spectrum (ion sputtering): t/2-546.3 (MNN).

Example 14 -

Hydrochloride 6-(4-ethanesulfonyl-phenyl)-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol "--

Using the product from Example 13 (1.5 g, 2.58 mmol) and the method described in Example C, 1.35 g of 6-(4-ethanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl- ethoxy)-phenoxy|-naphthalen-2-ol. The obtained free -

335 base in a mixture of ethyl acetate and diethyl ether (bOml; 1:1). Cooled in an ice bath and treated with 2M He)

NOI in diethyl ether (2 ml, 4 mmol). The resulting precipitate was collected on a paper filter, washed with diethyl ether and dried at 509 (pressure 2 mm Hg (266 Pa)) for 18 hours, obtaining 1.3 g of the title compound (89965). Mass spectrum (ion sputtering): t/2-532.3 (M'-H). "

Example 15 1-(2-44--2-(3-methanesulfonyl-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine - what about ;" Fi. ie IF so o - - 50 n.s. at; what

Palladium(II) acetate (17mg, 0.07bmmol), tricyclohexylphosphine (RSuZ, 32mg, 0.1Tmmol) and acetonitrile (4ml) were mixed. The mixture was treated with ultrasound for two minutes. The compound from Preparatory synthesis 1 25 (400mg, 0.7bmmol), cesium fluoride (1.00g, 6.62mmol), 3-(methanesulfonyl)phenylboronic acid (46Omg, 2.30mmol) was mixed

HF) and acetonitrile (12 ml). An ultrasonically treated suspension of Ra/PCu»z was added to the reaction vessel and heated at 902 for 30 minutes. The mixture was cooled to room temperature, filtered through a layer of celite, and the solvent was evaporated. The residue was dissolved in ethyl acetate (200 ml) and washed with a saturated aqueous solution

Manso" (1Oml). The layers were separated, the organic phase was washed with brine (1 ml), dried over Na95O, filtered and concentrated in vacuo. The residue was chromatographed on a column of Z 100 eluting with methanol (090 to 595) in dichloromethane to give 27 µg of the title compound (6790). Mass spectrum (ion sputtering): t/2-532.3 (M.N).

Example 16

Hydrochloride 6-(3-methanesulfonyl-phenyl)-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalene-2-ol) The product from Example 15 was dissolved in ethyl acetate (1 mL) and diethyl ether (bml). 2M CARRIER in diethyl ether (ml, 2.0mol) was added. The suspension was concentrated, and the residue was dried in vacuo. The residue was dissolved in dichloromethane (5.0ml) and placed under a nitrogen atmosphere. The solution was cooled to 092C in an ice bath , and added 1M BVgz in dichloromethane (1.0ml, 1.0mmol). After 20 minutes, the reaction mixture was diluted with ethyl acetate (25.0ml), and a saturated aqueous solution of MaHSO" (2x10ml) was added in portions. The layers were separated, the organic layer was washed with brine ( 10 ml), dried over M950, filtered and concentrated in vacuo. The residue was chromatographed on a Kk!zO column, eluting with 6-(3-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy )-phenoxy|-naphthalen-2-ol by a step gradient of methanol in dichloromethane (from 095 to 595). The resulting free base was dissolved in diethyl ether (5.Oml), 70 ethyl acetate (b.Oml) and methanol (1.O ml), and 2M HCl in diethyl ether (ml, 2.0 mmol) was added. The resulting precipitate was collected on a paper filter, washed with diethyl ether and dried in a vacuum (pressure of 2 mm Hg (266 Pa)) at 65923 for 48 hours, obtaining 7 mg of the title compound (2695). Mass spectrum (ion sputtering): t/2-518.5 (MIfree base|nt1).

Preparatory synthesis 4

C-fluoro-4-(methanesulfonyl)phenylboronic acid

4-bromo-2-fluorothioanisole (US patent Mob, 307,047|Y, 2.7g, 12mmol), oxone (38g, b2mmol) and methanol (200ml) were mixed and stirred for 12h. It was filtered through a layer of silica gel and eluted with ethyl acetate (5000 ml). The solvent was evaporated, and the residue was partitioned between dichloromethane (200 mL) and water (100 mL).

The layers were separated, the organic layer was washed with a saturated aqueous solution of Manso with (10ml), brine (10ml), dried over M950O, filtered and concentrated in vacuo. The crude solid was washed with hexane (20ml), diethyl ether (10ml) and dried under vacuum to give 2.4g of 4-bromo-2-fluoro-1-methanesulfonylbenzene (7896).

4-bromo-2-fluoro-1-methanesulfonylbenzene (1.7 g, b, /mmol), complex

I1,1-bis(diphenylphosphine)ferrocene|dichloropalladium (I) with dichloromethane (Ra(arrOsSiI».СНоСИ», 164mg, 0.200mmol), EM bis(pinacolato)diboron (1.79g, 7.0mmol), acetate potassium (2g, 2ommol) and dimethylsulfoxide (OM5O, 10Oml). (5)

The reaction mixture was heated at 902 for 1 hour. It was cooled to room temperature and diluted with ethyl acetate (20 ml). Washed with brine (1 Oml), dried over Mo95O), filtered and concentrated. in a vacuum The residue was chromatographed on a column of SiO, eluting with ethyl acetate (30905) in hexane, and 1.74 g (8095) were obtained. 2-(3-fluoro-4-methanesulfonyl-phenyl)-4,4,5,5-tetramethyl-y| 1,3,2|)dioxaborolane. in.

2-(3-fluoro-4-methanesulfonyl-phenyl)-4,4,5,5-tetramethyl-|1,3,2)dioxaborolane (222 mg, 0.74 mmol), "-

Ma, (474mg, 2.2mmol), tetrahydrofuran (TNE, 4ml) and water (ml). It was stirred for 2 hours, and 2M HCl in diethyl ether (0.2 ml) was added. It was stirred for another 12 hours, and the solid substance was removed by filtration. "--

The filtrate was washed with brine (1 Oml), dried over Mo95O, and the solvent was evaporated. The solid was washed with hexane (2x1Oml) and diethyl ether (1Oml). The solid product was dried in a vacuum, and b8mg was obtained

From the title compound (4290). co

Example 17 1-(2-44--2-(3-fluoro-4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy|-phenoxy)-ethyl)-piperidine o "

M o s "with ZO Me 1 F so E sh n.s. - o - oUu 70 Palladium (II) acetate (4.2 mg, 0.019 mmol), tricyclohexylphosphine (1 Ω, 0.033 mmol), a compound with

Preparative synthesis 1 (92 mg, 0.18 mmol), cesium fluoride (201 mg, 1.33 mmol), 3-fluoro-4-(methanesulfonyl)phenylboronic acid (8 mg, 0.33 mmol) and acetonitrile (1 mL). The mixture was heated at 9022 for 1 h. It was cooled to room temperature and the solution was diluted with ethyl acetate (20 ml) and washed with a saturated aqueous solution of MnSO" (1 ml). The layers were separated, the organic phase was washed with brine 22 (1 ml), dried over Mo5O, filtered and concentrated in vacuo. Chromatographed the balance on the column with

F! iO", eluting the product with methanol (from 295 to 4905) in dichloromethane to give bO9mg of the title compound (72965). Mass spectrum (ion sputtering): t/2-550.4 (M'-H). where Example 18

Hydrochloride 6-(3-fluoro-4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol 60 The product from Example 17 was dissolved in ethyl acetate (1 Oml ) and diethyl ether (bml). 2M CARRIER in diethyl ether (ml, 2.Omol) was added. The suspension was concentrated, and the residue was dried under vacuum. The residue was dissolved in dichloromethane (5.Oml) and placed under a nitrogen atmosphere. The solution was cooled to 02С in an ice bath. 1M BVgz in dichloromethane (0.1ml, 0.1mmol) was added and stirred for 1 hour. Water (1.00ml) and dichloromethane (10ml) were added. The layers were separated, the organic layer was washed with a saturated aqueous Manceau solution with (10ml) bo and brine (1 Oml), dried over MaO5O5, filtered and concentrated in vacuo. The residue was chromatographed on a Kk!io column, eluting with 6-(3-fluoro-4-methanesulfonyl-phenyl)-5-(4-(2-piperidine) -1-yl-ethoxy)-phenoxy|-naphthalen-2-ol by a stepwise gradient of methanol in dichloromethane (095 to 595). The resulting free base was dissolved in diethyl ether (5.0ml), ethyl acetate (b.0ml) and methanol ( 1 ,0ml), and added 2M HC in diethyl ether (Iml, 2.0mol).

The resulting precipitate was collected on a paper filter, washed with diethyl ether and dried in a vacuum (pressure "2 mm Hg (x:266 Pa)) at 6593 for 48 hours, obtaining 19 mg of the title compound (2690). Mass spectrum (ion sputtering): t/2-536.3 (MAN).

Preparatory synthesis 5 70 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 reflux flask. Meta-chloroperbenzoic acid (pSRBA, 6.1 g, 24.3 mmol, 6890) was added, and the reaction mixture was heated under reflux for 3 days. The reaction mixture was cooled to room temperature, and the organic layer 1-n was washed. aqueous Mahon solution (10 Oml). The 7/5 organic layer was separated and dried over sodium sulfate. It was filtered and concentrated in vacuo, obtaining 2.5 g of 1-bromo-4-trifluoromethanesulfonylbenzene (9096).

1-bromo-4-trifluoromethane-sulfonylbenzene (50 ΩgHg, 1.7 mmol), bis(pinacolato)diboron (523 ug, 2.07 mmol), |1,1"-bis(diphenylphosphine)ferrocene complex were charged into a flask dried over a flame |dichloropalladium (II) with dichloromethane (1:1) (42 mg, O0.05 mmol) and potassium acetate (467 mg, 5.2 mmol). The solids were dissolved in dimethyl sulfoxide (dml) and heated at 8093 under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled the mixture to room temperature and diluted with benzene (500ml).The organic layer was washed with water (20ml) and brine (20ml).The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.

The resulting oil was chromatographed on a 5000 column, eluting with ethyl acetate (2090) in hexane, to give 56 mg of the title compound (9695). with

Example 19 1-(2-14-(b-methoxy-2-(4--rifluoromethanesulfonyl-phenyl)-naphthalen-1-yloxy|-phenoxy)-ethyl)-piperidine and) (0) shi o sh

20 2-(4-trifluoromethanesulfonyl-phenyl)-4,4,5,5-tetramethyl-|1,3,2|dioxaborolane (56Omg, 1.67mmol) was mixed, with c the compound from Preparatory Synthesis 1 (30mg, 0.57mmol) and cesium fluoride (433mg, 2.85mmol) in a flask dried over a flame and equipped with a reflux condenser. Palladium (II) acetate (25 mg, 0.11 mmol) and tricyclohexylphosphine (48 mg, 0.17 mmol) were mixed in a separate dried flask. Dehydrated acetonitrile (bml) was added, and the mixture was sonicated for 1 h. in a nitrogen atmosphere. The catalyst mixture was added to solid Bechovyn, and the flask was placed in an oil bath with a temperature of 902C. After 25 minutes the black suspension was cooled to room temperature and filtered through celite, washing with dichloromethane. The filtrate was concentrated in vacuo. The residue was chromatographed on a column with 5iO, eluting the product with methanol (2.595) in dichloromethane with an admixture of 0.290 ammonium hydroxide, and 254 mg of the title compound (7695) was obtained. Mass spectrum (ion - sputtering): t/2-586 (MAN).

Example 20 - 5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-6-(4-riftormethanesulfonyl-phenyl)-naphthalen-2-ol

I Compound from Example 19 (25mg, 0.42mmol) was dissolved in dichloromethane (ml). 2M NOI in diethyl ether (0.42 ml, 0.84 mmol) was added and stirred for 1 h. The solvent was removed in vacuo and the residue was kept under high vacuum for 1 h. The obtained foam was dissolved in dehydrated dichloromethane (5 ml), cooled to 0°C, and BVg»z (0.20 ml, 2.1 mmol) was added dropwise. After 25 minutes the mixture was slowly poured into a saturated aqueous solution of sodium bicarbonate (1Oml) and extracted with dichloromethane (2x1Oml). Sushil united

F, organic phases over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a Coio column, eluting with methanol (395 to 590) in dichloromethane with 0.295 ammonium hydroxide to give 196 mg of the title compound (81905). Mass spectrum (on sputtering) t/2-572.3 (M'-H). in Example 21

5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy-1|-6--4--riftormethanesulfonyl-phenyl)-naphthalen-2-ol hydrochloride

The compound from Example 20 (196 mg, 0.34 mmol) was dissolved in ethyl acetate (1 ml) and diethyl ether (dml). 2M HCIII in diethyl ether (34 Ωcl, bvΩμmol) was added to the solution with stirring. The suspension was stirred for 10 minutes. The solid substance was separated by filtration on a Buchner funnel. This substance was dried overnight at 459C in a vacuum oven, and 98 mg of the title compound (4795) was obtained. Mass spectrum (ion sputtering) pt/2-572.3 (MAN-NSI).

Preparatory synthesis 6 2-(1,1-dioxo-2,3-dihydro-1H-1 24-benzo|b|giophen-5-yl)-4,4,5,5-tetramethyl-|(1/3, 2|dioxaborolane

5-Bromo-2,3-dihydro-benzo|Bithiophene (3. At. Spet. os, 1973, 1916-1925), 4.3g, 20mmol) was dissolved in MeOH (100ml) and oxone (36.9g, bbmmol) was added ). The reaction mixture was stirred at room temperature. overnight, after which the solid phase was removed by filtration. The filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 20-4090 EtOAc/hexane) to give 4.24 g of 5-bromo-2,3-dihydro-benzo[bithiophene-1,1-dioxide (8690).

5-Bromo-2,3-dihydro-benzo|b|thiophene-1,1-dioxide (2.0 g, 8.immol) was dissolved in OM5O (bOml). 70. Bis(pinacolato)diboron (2.26g, 8.0mmol), Rasi "(arruCH"cSi" (30mg, 0.41mmol) and potassium acetate (COAc, 2.38g, 24.3mmol) were added. Flask M was purged ", and then the reaction mixture was heated with stirring at 802C. Heating of the reaction mixture was continued, and then it was cooled to room temperature. Water (100ml) was added, and the aqueous layer was extracted with EtOAc (3x100ml). The combined organic layers were dried over Ma »zo,, was filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 10-5090 75 ethyl acetate in hexane) to give 1.4 g (5995) of the title compound.

Example 22 1-(2-44--2-(1,1-dioxo-2,3-dihydro-1H-125-benzo|bithiophen-5-yl)-6-methoxy-naphthalene-1-yloxy|- phenoxy)-ethyl)-piperidine 7 (o and C to ;

Ko Y vo - 30 "- meo - "-

2-(1,1-dioxo-2,3-dihydro-1H-1224-benzo|b|giophen-5-yl)-4,4,5,5-tetramethyl-|(1/3,2| dioxoborolane 35 (590mg, 2.02mmol) and the compound from Preparatory Synthesis 1 (350mg, 0.7mmol) in CH3SM (ml). Palladium(III) acetate (PI(OAc)", 15mg, 0.007mmol), tricyclohexylphosphine ( 28mg, O, Tmmol), and St (910Omg, bmmol).

The flask was purged with Mo and then the reaction mixture was heated to 902 with stirring. Heating of the reaction mixture was continued for 2 hours, and then it was cooled to room temperature. Water (5 Oml) was added, and the aqueous layer of СНоСиИ was extracted (Хх25 ml). The combined organic layers were dried over magnesium, filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0-496 Meon-MH.OnH (10/11 by volume)u/CH2Cl») , and 1bOmg of the title compound (4495) was obtained. Mass spectrum (ion sputtering): with t/2-544.3 (MN).

Example 23

Hydrochloride o 6-(1,1-dioxo-2,3-dihydro-1H-15,6-benzo|BIgiophen-b5-yl)-5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy |-naphthalene-2-ol-3z The compound from Example 22 (160mg, 0.29mmol) was dissolved in CHCl (5ml), and the solution was cooled to -7820.

NCI (0.2 ml, 2.0 M in diethyl ether (EBO)) was added, and the reaction mixture was stirred for 10 min. - The solvent was removed under reduced pressure, and then the solid was dissolved in CHCl (5 ml) in an M atmosphere. shu 20 The resulting solution was cooled to 02С, and VVgz (37Omg, 1.4 mmol) was added. The reaction mixture was stirred for 1 hour, and water (20 ml) was added. The aqueous layer of CH Si" (Zh2Oml) was extracted. The combined organic layers were dried over Ma»5O), filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 2-890 meon-Mmn. on (101, by volume)/SNeSi), obtaining 6-(1,1-dioxo-2,3-dihydro-1H-15,9-benzo|b)giophen-5-yl)-5-(4-(2-piperidin-1-yl-ethoxy) -phenoxy|-naphthalene-2-ol. 59 The obtained free base was dissolved in CH»-Si» (ml) and cooled to -782 C. HCl (0O.5 ml, 2.0 M in

HF) ESO), and the solution was stirred for 10 minutes. The solvent was removed under reduced pressure, and a solid was obtained

GF substance. This substance was dried in vacuo at 40927 overnight to give 42 mg of the title compound (27965). Mass spectrum (ion sputtering): t/27-530.3 (M'-H). in Preparatory synthesis of 7 (2,2-dioxo-2,3-dihydro-1H-2 75,6-benzo|sithiophen-5-yl)-trimethylstannane

4-bromo-1,2-bis-bromomethylbenzene was dissolved (3. Ogd. Spet., 1418-1421, 1985); 3.42g, 9.96mmol) in a mixture of ethanol (EUN) with TNE (21) (1196bml), and the solution was heated to 702 with stirring. The solution was added drop by drop

Ma25.9H2O (2.63g, 10.96bmmol) in water (40ml) for 1h using a syringe pump. Heating and stirring were continued for another 1 hour. It was cooled to room temperature, and the organic solvent was removed under reduced pressure. Water (200 ml) was added to the residue, and the aqueous layer was extracted

EUAs (3x200ml). The combined organic layers were dried over NaCl, filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, hexane) to give 1.27 g of 5-bromo-1,3-dihydro-benzo[sithiophene]

5-Bromo-1,3-dihydro-benzo|cthiophene (1.25g, 5.7U9mmol) was dissolved in methanol (25ml) and oxone (10.7g, 17.4mmol) was added. The reaction mixture was stirred for 2 hours. at 02С, and then a 1M aqueous solution of sodium bisulfite (100 ml) was added. The reaction mixture was stirred for 10 min., and a saturated Manso solution (200 ml) was added. The aqueous layer was extracted with СНоСИ» (Хх100 ml). The combined organic layers were dried over NaCl, filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 0-590 70 Meon/Snos) to give 900 mg of 5-bromo-1,3-dihydro-benzo of hyophene-2,2-dioxide (65905).

5-bromo-1,3-dihydro-benzo|c|thiophene (8 mg, 3.500 mmol) and hexamethyldiol (Zeq.) were dissolved in toluene, and tetrakis-triphenylphosphine)palladium(0) (RYA(PPNIz)4, Oh, Tekv.). Flask M" was purged, and then the mixture was heated to 1202 with stirring. The heating of the mixture was continued for 5 hours, and then it was cooled to room temperature. Water (50ml) was added, and the aqueous layer was extracted with EtOAc (3x50ml). The combined organic layers were dried over Na 2 O 5 4 , filtered, concentrated, and the residue was purified by flash chromatography (silica gel, 10-30956 Es in hexane) to give 1.22 g of the title compound (10095).

Example 24 1-(2-44--2-(2,2-dioxo-2,3-dihydro-13-2 25 -benzo|c|giophen-5-yl)-b-methoxy-naphthalene-1-yloxy |-phenoxy)-ethyl)-piperidine

Mo

S s o and SI zo i- 2 "- o -

Meo - d)

(2,2-dioxo-2,3-dihydro-1H-2,8-benzo|cIthiophen-5-yl)-trimethylstannane (1.19g, 3.bmol, 2.7eq.) and the compound from Preparatory synthesis 1 (6300mg , 1.2 mmol) in SNUSM. Ra(OAc)" (0/Eq.), tricyclohexylphosphine (0.15 eq.) and C5E (4 eq.) were added. Flask M" was purged, and then the reaction mixture was heated to 909" with stirring. Heating of the reaction mixture was continued for 1 hour, and then it was cooled to room temperature. Water (100 ml) was added, the layers were separated, and the aqueous layer was extracted with СНоСИ» (Хх10Омл). The combined organic layers were dried over NaCl5O, filtered, concentrated, and the residue was purified by flash chromatography on a column (silica gel, 0-590 Meon-MNAOH (10/1, by volume of CHClCl), obtaining 140 mg of the title compound (22905).

Example 25

Hydrochloride so 6-(2,2-dioxo-2,3-dihydro-1H-2 5,5-benzo|sithiophen-5-yl)-5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy |-naphthalen-2-ol - Demethylated - 1-(2-14-(2-(2,2-dioxo-2,3-dihydro-1H-75,9-benzo|sithiophen-5-yl)-b- methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperide 5ro Mn (140mg, 0.2bmmol) BVgz, and a salt was formed according to the procedure similar to that described in Example 23, obtaining - 13Omg (9495) of the title compound. Mass spectrum (ion sputtering): t/2-530.2 (MAN-NSI). "I Preparatory synthesis of 8 (4-methanesulfonyl-3-methoxy-phenyl)-trimethylstannane

b-Hydroxy-1,3-benzoxathiol-2-one (16.8 g, 0.1 mol) was dissolved in TNE (165 Oml) and the solution was cooled to 029C. Benzyl alcohol (16.2 g, 0.15 mol), triphenylphosphine (PPNH3, 39.3 g, 0.15 mol) and diisopropyl azodicarboxylate (30.3 g, 0.1 b mol) were added sequentially. The reaction mixture was stirred at room temperature and overnight. Water (1500 mL) was added, and the aqueous layer was extracted with EtOAc (3x1500 mL). The combined organic layers were dried over NaCl5O), filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 10-2595 EtOAc in hexane) to give 24.33 g of b-benzyloxy-benzo|1,3| oxathiol-2-one (9496). 60 b-benzyloxy-benzo|1,3|oxathiol-2-one (24.33g, 94.29mmol) was dissolved in dioxane (1000ml), and an aqueous KOH solution (94.29ml, 188mmol, 2M) was added with stirring. Flask M" was purged, and then the reaction mixture was heated at 802C for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The pH was set to 2 using an aqueous solution of HCl (200 ml, 1.0 M). The aqueous layer was extracted with EtOAc (3x500ml). The combined organic layers were dried over Na 2 O 2 , filtered and concentrated to give 17.8 g of 5-benzyloxy-2-mercapto-phenol (81.490).

5-Benzyloxy-2-mercaptophenol (17.8g, 76.72mmol) was dissolved in OME (300ml) and KCO3 (31.8Hg,

0.2Zmol) and Mei (32.7g, 0.2Z3mol). The reaction mixture was stirred at room temperature overnight.

Water (800 ml) was added, and the aqueous layer was extracted with EtOAc (3x80 ml). The combined organic layers were dried over

Ma»3O), was filtered, concentrated, and the residue was purified by flash column chromatography (silica, 9-2090 EOAc in hexane) to give 13.5 g of 4-benzyloxy-2-methoxy-1-methylsulfanylbenzene (6890).

4-Benzyloxy-2-methoxy-1-methylsulfanylbenzene (5.2 g, 2 mmol) was dissolved in CHCl (250 mL) and treated with t-SRBA (15.2 g, bbmmol, 6895). The reaction mixture was stirred at room temperature for 2 h.

A saturated solution of CoCO" (200 ml) was added, and the aqueous layer was extracted with EtOAc (3x200 ml). The combined organic layers were dried over NaCl5O, filtered, concentrated, and the residue was purified by flash chromatography on a 70 column (silica gel, 20-5095 EtOAc in hexane) to give 5.57 g of 4-benzyloxy-1-methanesulfonyl-2- methoxybenzene (96965).

4-Benzyloxy-1-methanesulfonyl-2-methoxybenzene (5.57g, 19.09mmol) was dissolved in Meon (200ml) under Mo, and 595 Ra-C (900mg) was added. The reaction vessel was evacuated and purged with gaseous hydrogen (three times). The reaction mixture was stirred at room temperature for under a hydrogen pressure of 1 atm.

The reaction mixture was filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 75 30-609565 EtOAc in hexane) to give 3.24 g of 4-methanesulfonyl-3-methoxyphenol (10096).

4-Methanesulfonyl-3-methoxyphenol (3.24g, 19.04mmol), 2,6-lutidine (4.08g, 38.08mmol) and OMAR (230mg, 1.9mmol) were dissolved in SiOCl (190ml). The solution was cooled to -782C, and then trifluoromethanesulfonic acid anhydride (120, 6.44g, 22.85mmol) was added dropwise. The reaction mixture was stirred for 2 h.

Water (200ml) was added, and the aqueous layer was extracted with EAs (3X200ml). The combined organic layers were dried over NaCl, filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 10-3090

EtOAc in hexane), obtaining 4.6 bg of 4-methanesulfonyl-3-methoxyphenyl ester of trifluoromethanesulfonic acid (72596).

4-methanesulfonyl-3-methoxyphenyl ester of trifluoromethanesulfonic acid (ZHg,

U9mmol) in toluene (180ml), and hexamethyltin (14.7g, 44.9mmol) and RY(PPH»z)4 (1.04g, 00mmol) were added. "is

The reaction mixture was heated at 1202C with stirring for 4 hours, after which it was cooled to room (5) temperature. Water (250 ml) was added, and the aqueous layer was extracted with EtOAc (3x25 ml). The combined organic layers were dried over NaCl 5 O), filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 5-4095 EtOAc in hexane) to afford 1.9 g of the title compound (61905).

Example 26 about 1-(2-44--2--4-methanesulfonyl-3-methoxy-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine «- «-

Mo -

IF so about 50, Me " - - OMe ;"

MeO (ee) - with (4-methanesulfonyl-3-methoxy-phenyl)-trimethylstannane (ZOOmg, 0.8 bmmol, 1.eq.) was added and the compound with

Preparatory synthesis 1 (ZOOmg, 0.57mmol) to a suspension of cesium fluoride (2.9eq) in acetonitrile (40ml). - Palladium (II) acetate (0.2 eq.) and tricyclohexylphosphine (0.Eq.) were mixed in acetonitrile (15 mL), and the mixture was sonicated for 10 min., after which it was added to the above mixture. The reaction mixture was heated at 9027 for 18 hours. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous Manso solution (500 mL). The organic layer was washed with a saturated aqueous solution of MNACI (5Oml) and brine (5Oml). They were dried over Na2O, filtered and concentrated in vacuo. The residue was chromatographed on a column of 500", eluting with a mixture of methanol and dichloromethane, and 180 mg of the title compound (56905) was obtained. Mass spectrum (ion sputtering): t/2-562.4 (M.N). o Example 27

6-(3-Hydroxy-4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol trifluoroacetate

Demethylated 60 0/0 1-(2--4--2--4-methanesulfonyl-3-methoxy-phenyl)-b-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine (24Omg, 0О ,4Zmmol) of VVgz according to a method similar to that described in Example 23, obtaining 220 mg of crude product in the form of a white solid (9595). This product was purified by preparative РХВЕ (biogop), and 120 mg of the title compound (4695) was obtained. Mass spectrum (ion sputtering): t/2-534.3 (M.AN-TEA).

Preparatory synthesis 9 65 4-bromo-2-chloro-1-methanesulfonylbenzene

2-Chloromethyl-benzenethiol (1Oml, 88mmol), potassium carbonate (25g, 180mmol), methyl iodide (11ml,

177 mmol) and OME (1000 ml). Stirred for 12 hours. The suspension was filtered through a layer of silica gel and eluted with ethyl acetate (500 ml). Half of the solvent was evaporated, and the remaining solution was washed with 1095 aqueous solution of GiCl (1000 ml). It was dried over Mo95O, and the solvent was evaporated. The residue was chromatographed on a column with

BIO" by elution with hexane, and 13g of 1-chloro-2-methylsulfanylbenzene (9396) were obtained.

1-Methylsulfanyl-2-chloromethylbenzene (3.7g, 233mmol), iron (13Omg, 2.3mmol), bromine (1.2ml, 238mmol) and dichloromethane (150ml) were mixed. Stirred for 2 hours. Water (100ml), saturated aqueous solution of sodium thiosulfate (100ml) and ethyl acetate (100ml) were added. The organic layer was separated, washed with brine, dried over NaOH, filtered and concentrated in vacuo. Chromatographed the residue on a column with 5iO»o with 7/0 elution with hexane, and obtained 4.8 g of 4-bromo-2-chloro-1-methylsulfanyl-benzene (87905).

4-Bromo-2-chloro-1-methylsulfanylbenzene (4.8g, 20mmol) and tSRBA (20g, vOmmol) were dissolved in dichloromethane (100ml). Stirred for 2 hours. The mixture was diluted with dichloromethane (30 Oml) and water (10 Oml). The organic layer was separated and washed with a saturated aqueous solution of MansSO" (2 x 100 ml) and brine (100 ml). It was dried over Mo95O, filtered and concentrated in vacuo. The solid residue was washed with diethyl ether (2x10ml) 75 and dichloromethane (10ml), and 1.7g of the title compound (31965) was obtained.

Example 28 1-(2-44--2-(3-chloro-4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy|-phenoxy)-ethyl)-piperidine at 20 C Fi at 50.Me s and si o n.s. o m 30 "-

Palladium(II) acetate (32mg, 0.14mmol), tricyclohexylphosphine (b7mg, 0.24mmol), cesium fluoride (1.3g, 8.bmmol) and acetonitrile (20ml) were mixed. It was stirred for 5 min., and the compound from the Preparatory synthesis - 1 (500 mg, 0.95 mmol) and bis(neopentyl glycol) diboron (322 mg, 1.442 mmol) were added. It was heated to 90 2C, and 4-bromo-2-chloro-1-methanesulfonylbenzene in acetonitrile (2 ml) was added. Stirred at 909 for 10 min. 35 It was cooled to room temperature, and the solution was diluted with ethyl acetate (20 ml) and washed with a saturated aqueous solution of MnSO" (1 ml). The layers were separated, the organic layer was washed with brine (1 Oml), dried over

Mao), filtered and concentrated under vacuum. The residue was chromatographed on a column of 500 g, eluting with methanol (0-595) in dichloromethane to give 18 mg of the title compound (3395). Mass spectrum (ion "20 sputtering): pt/2-566.2 (M'AN). with

Example 29 c 6-(3-chloro-4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol:c» The product from Example 28 was dissolved in ethyl acetate (10 mL) and diethyl ether (5 mL). 2M HCl in diethyl ether (0.5 mL, 1.2 mmol) was added. The suspension was concentrated and dried in vacuo. The residue was diluted with dichloromethane (5.00 mL) and placed under a nitrogen atmosphere. It was cooled. solution to 02°C in an ice bath. At 0.000 mL, 1.1 mmol, water (1.00 mL) and dichloromethane (10 mL) were added at 1 h. The layers were separated, and the organic layer was washed with saturated aqueous Manso solution (10 mL). , brine (10ml), dried over MAO5O, filtered - and concentrated in vacuo. The residue was chromatographed on a column with 500", eluting with a step gradient - methanol (0-595) in dichloromethane, and 120 mg of the title compound (6895) was obtained. Mass spectrum (ion sputtering): t/2- 552.2 (M'AN). -th Example 30 "m Hydrochloride 6-(3-chloro-4-methanesulfonyl-phenyl)-5-(4-(2- piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol

The product from Example 29 was dissolved in diethyl ether (5.0 mL), ethyl acetate (b.0 mL) and methanol (1.0 mL), and 2M HCl in diethyl ether (0.0 mL, 1.2 mmol) was added. The resulting precipitate was collected on a paper filter, washed with diethyl ether and dried in a vacuum (pressure "2 mm Hg (x:266 Pa)) at 2092C for 4 hours, obtaining 1 mg of the title compound (2695). Mass spectrum (ion sputtering): t/2-552.3 (MAN-NSI).

F) Preparatory synthesis of 10 ko 4-bromo-1-methanesulfonyl-2-trifluoromethylbenzene

2-trifluoromethyl-benzenethiol (10g, 5bmmol), potassium carbonate (25g, 140mmol) and methyl iodide (11ml, in 177mmol) were dissolved in OME (100b0ml). The solution was stirred for 12 hours. The obtained suspension was filtered through a layer of silica gel and eluted with ethyl acetate (500 ml). Half of the solvent was evaporated, and the remaining solution was washed with 1095 aqueous solution of GiSi (100 ml). They were dried over MazO, and the solvent was evaporated. The residue was chromatographed on a column with 10" eluting with hexane, and 9.5 g of 1-methylsulfanyl-2-trifluoromethylbenzene (88965) was obtained. 65 1-Methylsulfanyl-2-trifluoromethylbenzene (3.5g, 18mmol), iron (10Omg, 1.79mmol), bromine (0.95ml, 18mmol), aluminum chloride (242mg, 1.8mmol) and dichloromethane (5Oml) were mixed. and stirred for 2 hours.

Water (1Oml), a saturated aqueous solution of sodium thiosulfate (10Oml) and ethyl acetate (10Oml) were added. The organic layer was separated, washed with brine, dried over Mo95O), filtered and concentrated under vacuum.

The residue was chromatographed on a column with ZO" eluting with hexane, and 3Z,bg of 4-bromo-1-methylsulfanyl-2-trifluoromethylbenzene (83905) was obtained.

4-Bromo-1-methylsulfanyl-2-trifluoromethylbenzene (3.bg, 15mmol), tSRBA (7.7g, 30mmol) and dichloromethane (100ml) were mixed. Stirred for 2 hours. The mixture was diluted with dichloromethane (300 ml) and water (100 ml). The organic layer was separated and washed with a saturated aqueous solution of Manso with (2 x 100 ml) and brine (100 ml). They were dried over NaOH, filtered and concentrated in vacuo. The solid residue was washed with 7/0 diethyl ether (2x1Oml) and dichloromethane (1Oml), and 2.06g of the title compound (4490) was obtained.

Example 31 1-(2-44--2--4-methanesulfonyl-3-trifluoromethyl-phenyl)-1-(4-methoxyphenyl)-propenyloxy|-phenoxy)-ethyl)-piperidin mo o 5O,Me se, ns

From Mesch o

Palladium(II) acetate (bmg, 0.029mmol), tricyclohexylphosphine (1Zmg, 0.047mmol), cesium fluoride (258mg, 1./mmol) and acetonitrile (10ml) were mixed. Stirred for 5 minutes. The compound from Preparatory Synthesis 1 (92mg, 0.18mmol) and bis(neopentylglycolate)diboron (b4mg, 00.89mmol) were added and heated to 90°C. 4-bromo-1-methanesulfonyl-2-trifluoromethylbenzene in acetonitrile ( ml), and stirred at 9022 for 10 min.

It was cooled to room temperature, and the solution was diluted with ethyl acetate (20 ml) and washed with a saturated aqueous solution of ManSO 3 ManSO 3 (10 ml). The layers were separated, the organic layer was washed with brine (10 ml), dried over M950, filtered and concentrated in a vacuum. The residue was chromatographed on a 500 column, eluting with methanol (0-596) in dichloromethane to give 2 mg of the title compound (5495). Mass spectrum "7 (ion sputtering): t/2-600.3 (MNN). so

Example 32

Hydrochloride 6-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol

The product from Example 31 was dissolved in ethyl acetate (10 ml) and diethyl ether (5 ml). 2M HCl in diethyl ether (0.1 mL, 0.2 mmol) was added. The suspension was concentrated and dried in a vacuum. The residue was diluted with dichloromethane (5.00 ml) and placed under a nitrogen atmosphere. The solution was cooled to 02C in an ice bath. TsVVgz (0.1 ml, 1.1 mmol) was added and stirred for an hour. The mixture was diluted with water (1.0 ml) and dichloromethane (1 ml). The layers were separated, the organic layer was washed with a saturated aqueous solution of MnSO 2 (1 ml) and brine (1 ml). It was dried over MgSO, filtered and concentrated in vacuo. The residue was chromatographed on the column with

ZO", eluting (ee) 6-(4-methanesulfonyl-3-trifluoromethylphenyl)-5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol with a stepwise -3z gradient methanol/dichloromethane (0-5956). The obtained free base was dissolved in diethyl ether (5.0ml), ethyl acetate (b.0ml) and methanol (1.0ml) and 2M NOI in diethyl ether (0.1ml, 0.2mmol) was added. The obtained precipitate was collected on a paper filter, washed with diethyl ether and dried in a vacuum (pressure 2 mm Hg (266Pa)) at 65923 for 48 hours, obtaining Zamg of the title compound (5396).

Preparatory synthesis of 11 "and 1-bromo-2,3-dichloro-4-methanesulfonylbenzene

4-Bromo-2-chloro-1-methylsulfanylbenzene (1.9g, 200mmol) and tSRBA (5.0g, 10mmol) were mixed in dichloromethane (30ml). Stirred for 2 hours. It was diluted with dichloromethane (20 ml) and water (20 ml). The organic layer was separated, washed with a saturated aqueous solution of MansCO3 (2 x 100 ml) and brine (100 ml). It was dried over Na 5 O, filtered and concentrated in vacuo. The solid product was washed with diethyl ether (2x1Oml) and dichloromethane (1Oml), and 89Omg of the title compound (5296) was obtained. eat) Example 33 1-(2-44--2-(2,3-dichloro-4-methanesulfonyl-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine 60 b5

(at;

M

; C o i 50, Me b c

NS about this

Palladium(II) acetate (32mg, 0.14mmol), tricyclohexylphosphine (b7mg, 0.24mmol), cesium fluoride 75. (1.3g, 8.bmmol) and acetonitrile (200ml) were mixed. Stirred for 5 minutes. The compound from Preparative Synthesis 1 (500mg, 0.95mmol) and bis(neopentylglycolate)diboron (322mg, 1.442mmol) were added. It was heated to 90°C and 1-bromo-2,3-dichloro-4-methanesulfonylbenzene in acetonitrile (2 ml) was added. Stirred at 902C for 10 minutes.

It was cooled to room temperature, the solution was diluted with ethyl acetate (20 ml) and washed with a saturated aqueous solution of MansSO" (1 Oml). The layers were separated, the organic layer was washed with brine (1 Oml), dried over

Mo50O, was filtered and concentrated in vacuo. The residue was column chromatographed, eluting with methanol (0-595) in dichloromethane, to give 18mg of the title compound (3395). Mass spectrum (ion sputtering): t/2-566.2.

Example 34

Hydrochloride 6-(2,3-Dichloro-4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol with

The product from Example 33 was dissolved in ethyl acetate (1 mL) and diethyl ether (5 mL). 2M HCl in o diethyl ether (0.5 ml, 1.0 mmol) was added. The suspension was concentrated and dried under vacuum. The residue was diluted with dichloromethane (5.0 ml) and placed in a nitrogen atmosphere. The solution was cooled to 09C in an ice bath.

VVgz (0.1 ml, 1.1 mmol) was added and stirred for an hour. The mixture was quenched with water (1.Oml) and diluted with dichloromethane (1Oml). The layers were separated, the organic layer was washed with a saturated aqueous solution of Manso with - (10ml) and brine (1Oml). It was dried over Mao5ZO), filtered and concentrated in a vacuum. The residue was chromatographed on a io column, eluting with 6-(2,3-dichloro-4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalene-2 -ol by a stepwise gradient of methanol (from 095 to 5905) in dichloromethane. The obtained free base was dissolved in diethyl ether "- (5.0ml), ethyl acetate (b.0ml) and methanol (1.00ml) and 2M HCI in diethyl ether was added (0O.5ml, 1.O0mmol).

The precipitate was collected on a paper filter, washed with diethyl ether, and 38 mg of the title compound (3095) was obtained. Mass spectrum (on sputtering): t/27-586.2.

Preparatory synthesis of 12 4-bromo-1,2-bis-methanesulfonyl-benzene «

4-bromo-2-fluoro-1-methylsulfanylbenzene (4.8 g, 22 mmol) and sodium methanethiolate (1.6 g, 22 mmol) were mixed in

OME (BOml). Stirred for 48 hours. The reaction mass was poured onto ice (10 g). The layers were separated, and the organic layer was washed with a saturated aqueous solution of MnNsSOOz and brine. It was dried over Mo5O,), filtered and "» concentrated in a vacuum. The residue was chromatographed on a column of SiO, eluting with diethyl ether (0-5905) in " hexane, and 4.82 g of 4-bromo-1,2-bis-methylsulfanylbenzene ( 89905).

4-Bromo-1,2-bis-methylsulfanylbenzene (1.4 g, 5.5 mmol) and tCsPVA (8.6 g, 34 mmol) were mixed in dichloromethane (100 mL). Stirred for 2 hours. Dichloromethane (300ml) and water (100ml) were added. The organic layer was separated, washed with a saturated aqueous solution of MansCO3 (2 x 100 ml) and brine (100 ml). It was dried over - Ma5O, filtered and concentrated in a vacuum. The solid product was washed with diethyl ether (2x1Oml) and with dichloromethane (1Oml), and 800 mg of 4-bromo-1,2-bis-methanesulfonylbenzene (46965) was obtained.

Example 35 -k 70 1-(2-(4-(2-(3,4-bis-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy|-phenoxy)-ethyl)-piperidine "I ra re ,

M

C 5O, Me o o name)

And n.s. Zo 7

Kk Co:

Palladium(II) acetate (13mg, 0.058mmol), tricyclohexylphosphine (27mg, 0.09bmmol), cesium fluoride 65 (518mg, 34mmol) and acetonitrile (200ml) were mixed. The mixture was stirred for 1 h, and the compound from Preparative Synthesis 1 (200 mg, 0.3 mmol) and bis(neopentylglycol)diboron (13 mg, 0.58 mmol) were added. It was heated to 902C and added

4-bromo-1,2-bis-methanesulfonyl-benzene in acetonitrile (2 ml) and stirred for 10 min. It was cooled to room temperature, the solution was diluted with ethyl acetate (20 ml) and washed with a saturated aqueous solution

Manso" (10 ml). The layers were separated, the organic layer was washed with brine (1 Oml), dried over Mao), filtered and concentrated in vacuo. The residue was chromatographed on a column eluting with methanol (0-595) in dichloromethane to give 100 mg of the title compound (5695).

Example 36

Hydrochloride 6-(3,4-bis-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalene-2-ol

The product from Example 35 was dissolved in ethyl acetate (1 mL) and diethyl ether (5 mL). 2M HCl in 7/0 diethyl ether (0.uml, 0.2mmol) was added. The suspension was concentrated and dried under vacuum. The residue was diluted with dichloromethane (5.0 ml) and placed in a nitrogen atmosphere. The solution was cooled to 09C in an ice bath.

VVgz (0.1 ml, 1.1 mmol) was added and stirred for an hour. The mixture was quenched with water (1.Oml) and diluted with dichloromethane (1Oml). The layers were separated, the organic layer was washed with a saturated aqueous solution of Manso with (1Oml) and brine (1Oml). It was dried over NaSO), filtered and concentrated in vacuo. The residue 75 was chromatographed on a column, eluting 6-(3,4-bis-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol with a step gradient of methanol ( from 095 to 5905) in dichloromethane.The resulting free base was dissolved in diethyl ether (5.0 mL), ethyl acetate (b.0 mL), and methanol (1.0 mL), and 2M NOI in diethyl ether (0.0 mL, 0.2 mmol) was added ).

The precipitate was collected on a paper filter, washed with diethyl ether and dried in a vacuum (pressure 2 mm Hg (266Pa)) at 6593 for 48 hours, obtaining bimg of the title compound (4595). Mass spectrum (ion sputtering): pt/2: 594.9 (MAN-NSI).

Preparatory synthesis of 13 1-bromo-4-(2,2,2-trifluoroethanesulfonyl)-benzene

4-bromobenzenethiol (1.0g, 5.3mmol) was dissolved in dehydrated dimethylformamide (500ml) and cooled to 09C under a nitrogen atmosphere. Dry sodium hydride (152 mg, b4 mmol) was added in portions. After the cessation of intensive gas release, 2,2,2-trifluoroethyl ester of toluene-4-sulfonic acid (2.0 g, 8.0 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was slowly poured into water (400 ml) and extracted with ethyl acetate (2x15O0 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 was chromatographed on a SiO2 column, eluting with hexane, and 640 mg of 1-bromo-4-(2,2,2-trifluoroethylsulfanyl)-benzene (45960) was obtained.

1-Bromo-4-(2,2,2-trifluoroethylsulfanyl)-benzene (640mg, 2.4mmol) was dissolved in dichloromethane (25ml) and cooled to 02С. TSRBA (1.8 g, 7.immol, 6890) was added in portions, and the reaction mixture was stirred for 2 hours. at room temperature. The white precipitate was removed by filtration, and the filtrate was washed with 1-n. aqueous solution of Mahon. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 700 mg of the title compound (9896).

Example 37 1-(2-(4--6-methoxy-2-I(4-(2,2,2-trifluoroethanesulfonyl)-phenyl|-naphthalene-1-yloxy)-phenoxy)-ethyl|-piperidine « o shZ chiv oo ;" (ee) - - n.s.

In a flame-dried flask, palladium acetate (I) (b.4 mg, 0.029 mmol), tricyclohexylphosphine (13.3 mg, 0.048 mmol) and cesium fluoride (260 mg, 1.71 mmol) were added. Dehydrated acetonitrile ( 2ml), and stirred under a nitrogen atmosphere. The compound from Preparatory Synthesis 1 (10mg, 0.19mmol) was added, followed by bis(neopentylglycol)diboron (b4mg, 0.29mmol). The reaction mixture was placed in an oil

Gee! bath with a temperature of 802C. As soon as the reaction mixture turned black (after about 3-5 min.), 1-bromo-4-(2,2,2-trifluoroethanesulfonyl)-benzene (11 mg, 0.3 v8 mmol) was immediately added and heating was continued. After 45 minutes the mixture was cooled to room temperature and filtered through a layer of celite.

The filtrate was concentrated in vacuo and purified on a 5µO column, eluting with methanol (0-395) in dichloromethane to give 2 mg of the title compound (2390). Low-resolution mass spectrum (I EMB5) (electron impact ionization, positive ion) t/2-600.5 (MAN).

Example 38 5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-6-I(4-(2,2,2-trifluoro-ethanesulfonyl)-phenyl|-naphthalen-2-ol

The compound from Example 37 (2 mg, 0.043 mmol) was dissolved in dichloromethane (1 mL) and 2 M HCl in bo diethyl ether (4 mL, 0.08 mmol) was added. The solvent was removed under vacuum, and the residue was kept under high vacuum for 1 hour. The resulting foam was dissolved in dehydrated dichloromethane (ml) and cooled to 020.

VVgz (20 μl, 0.22 mmol) was added dropwise and stirred at 02С for an hour. The reaction mixture was poured into a cooled saturated aqueous solution of sodium bicarbonate (bml), and extracted with dichloromethane (2x5ml).

The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified on a column of ZIO0, eluting with methanol (0-895) in dichloromethane, and 1 mg of the title compound (64905) was obtained. Mass spectrum (ion sputtering) t/7-586.4 (M'-H).

Example 39

Hydrochloride 70... 5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy |-6-(4-(2,2,2-trifluoro-ethanesulfonyl)-phenyl|-naphthalene-2- alu

The compound from Example 38 (ZOmg, O0.051mmol) was dissolved in dehydrated dichloromethane (Iml) and added 2M

NOI in diethyl ether (0.1 Oml, 0.20 mmol). Stirred at room temperature during their The solvent was removed by passing a stream of nitrogen over the liquid. The residue was kept under high vacuum for 1 Th. The product was dried in a vacuum oven at 459C overnight, and 30 mg of the title compound 75 (9795) was obtained. Mass spectrum (ion sputtering) t/2-586.3 (M.-N-NSI).

Preparatory synthesis of 14 2-(4-isopropylsulfanyl-phenyl)-boronic acid

4-Bromo-benzenethiol (1.0g, 5.3mmol) was dissolved in dehydrated dimethylformamide (50ml) and cooled to 02С under a nitrogen atmosphere. Dry sodium hydride (153 mg, b, 4 mmol) was added in portions. After the cessation of intense gas evolution, 2-bromopropane (0.bOml, b.4mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was slowly poured into water (300 ml) and extracted with ethyl acetate (2x15000 ml). The combined organic layers were washed with water (10 Oml) and brine (10 Oml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The obtained residue was chromatographed on a column with 30%, eluting with 595 g of ethyl acetate in hexane, and 1 g (CM of 1-bromo-4-isopropylsulfanylbenzene (9290) was obtained.

1-Bromo-4-isopropylsulfanylbenzene (2.5g, 10.mmol) was dissolved in dehydrated tetrahydrofuran (10Oml) and the solution was cooled to -782С. A 2.5M solution of n-butyllithium in hexane (5.2ml, 12.9mmol) was added dropwise, the reaction mixture was allowed to warm to -402C and stirred for 30 minutes. The mixture was cooled to -785C, triisopropylborate (7.4 mL, 32.4 mmol) was added, and the reaction mixture was allowed to slowly warm to room temperature. 1095 aqueous sodium hydroxide solution (9 bml, 172 mmol) was added and stirred overnight. "-

The reaction mixture was slowly poured into a mixture of concentrated HCl and ice. The aqueous solution was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo to obtain 1.9 g of the title compound (9096). "-

Example 40 3o 1-(2-44-(2-(4-isopropylsulfanyl-phenyl)-6-methoxy-naphthalen-1-yloxy|-phenoxy)-ethyl)-piperidine so o » 8. СН щ с Со Я With and Ff sn

With about n.s. 2 o'clock -

2-(4-isopropylsulfanyl-phenyl)-boronic acid (223mg, 1.14mmol), the compound from Preparatory synthesis 1 (30mg, 0.57mmol) and cesium fluoride (43mg, 2.85mmol) were mixed in a flame-dried in a flask equipped with a reflux condenser and a nitrogen purge device. In a separate dried flask, palladium (II) acetate (1 mg, 0.00 mmol) and tricyclohexylphosphine (24 mg, 0.09 mmol) were mixed. Dehydrated acetonitrile (bml) was added, and the mixture was sonicated for 10 min. in a nitrogen atmosphere. A mixture of catalysts was added to the solids, and the flask was placed in an oil bath with a temperature of 902C. In 20 minutes. the black suspension was cooled to room temperature and filtered through celite, washing with dichloromethane. The filtrate was concentrated in (F) vacuum. The residue was chromatographed on a column of ZIO, eluting the product with methanol (390) in dichloromethane with 0.290 ammonium hydroxide, to give 300 mg of the title compound (95965). Mass spectrum (ion sputtering) t/2-528.3 (M.N). in Example 41 6-(4-isopropylsulfanyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol

The compound from Example 40 (300 mg, 0.57 mmol) was dissolved in dichloromethane (3 ml). 2M NOI in diethyl ether (0.51 ml, 1.14 mmol) was added and stirred for 1 h. The solvent was removed under vacuum and the residue was kept under high vacuum for 20 min. The obtained foam was dissolved in dehydrated dichloromethane (bml) and b5 was cooled to 02C. VVg»z (0.21 ml, 2.3 mmol) was added dropwise. It was stirred for 45 minutes, and the reaction was quenched by adding methanol (ml). The reaction mixture was slowly poured into a saturated aqueous solution of sodium bicarbonate (1Oml) and extracted with dichloromethane (2x1Oml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on a BIO column, eluting with methanol (5905) in dichloromethane with 0.295 ammonium hydroxide to give 23 mg of the title compound (8190). / Mass spectrum (ion sputtering) t/2-514.3 (INN).

Example 42 5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy1|-6-I4-(propane-2-sulfonyl)-phenyl|-naphthalen-2-ol

The compound from Example 41 (236 mg, 0.4 mmol) was dissolved in glacial acetic acid (ml), and sodium perborate (92 mg, 0.92 mmol) was added. The reaction mixture was stirred overnight and poured into a saturated aqueous solution of sodium bisulfite 70 (20 ml). It was extracted with dichloromethane (2 x 20 ml), and the combined organic phases were washed with a saturated aqueous solution of sodium bicarbonate (1 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on a column of SiO, eluting with methanol (495) in dichloromethane with 0.290 ammonium hydroxide, and 197 mg of the title compound (7990) was obtained. Mass spectrum (ion sputtering) t/27-546.3 (M'-H).

Example 43

Hydrochloride 5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy1|-6-(4-(propane-2-sulfonyl)-phenyl|-naphthalene-2-ol

The compound from Example 42 (123mg, O0.3bmmol) was dissolved in dehydrated dichloromethane (0.5ml). The solution was diluted with diethyl ether (4 ml), and 2M NOI in diethyl ether (0.3 bml, 0.72 mmol) was added. Stirred at room temperature for 10 minutes. The white precipitate was separated by filtration through filter paper and dried at 2° in a vacuum oven at 5023 overnight to give 102 mg of the title compound (78965). Mass spectrum (ion sputtering) pt/2-546.3 (MAN-NSI).

Preparatory synthesis of 15 2-methyl-4-methylthiophenylboronic acid

A 1M solution of 3-methyl-phenylmagnesium bromide in TNE (25ml, 25mmol) was added to diethyl ether (50ml), SU cooled to -302C. Dimethyldisulfide (1.8ml, 200mmol) was added to the reaction mixture over 30 minutes, allowing the mixture to warm to room temperature. The reaction mixture was diluted with H 20 (75 ml) and diethyl ether (5 ml). The layers were separated, and the cloudy aqueous layer was extracted with diethyl ether (25 ml). The combined organic layers were washed with HO (25 mL). The organic layer was dried over Ma»5O, (300g), filtered through a layer of celite-501 (10g) and concentrated in vacuo to give 3.0g of crude product. This product was mixed with their' second batch of the crude title compound, which would constitute 0g of the crude product. -

The total amount (9.00 g) of the crude product was chromatographed on a column of BiO, eluting with hexane to give 7.2 g (70905) of 1-methyl-3-methylsulfanylbenzene. --

Iron (25mg, 0.45mmol) and 1-methyl-3-methylsulfanylbenzene (204mg, 1.47mmol) were mixed in dichloromethane - (OSM, 2ml). The suspension was cooled to 32C, and Bg2 (74 μl, 1.44 mmol) was added over 5 min. It was stirred at 3°C for 1 hour, and the cooling bath was removed. It was stirred at room temperature d) for 4 hours, then the reaction was quenched with 1095 aqueous solution of Ma 55203. The reaction mixture was diluted with dichloromethane (1 Oml), and the layers were separated. The organic layer was washed with brine, concentrated and chromatographed, eluting with dichloromethane (0-596) in hexane, and 125 mg of 1-bromo-2-methyl-4-methylsulfanyl-benzene (53965) was obtained.

1-Bromo-2-methyl-4-methylsulfanylbenzene (bO8mg, 2.860mmol) was added to diethyl ether (bOml) and cooled to -782C in a nitrogen atmosphere. Ethylene glycol (3.4 ml, 5.78 mmol) was added for 15 min., stirred for 2 min., trimethylborate (Meo)53B, 34 ΩCl, 2.99 mmol) was added for 2 min., stirred for 15 min. at -782C, and then the mixture was allowed to warm to room temperature. The reaction was quenched with a saturated aqueous solution of MNACI (7 ml), stirred for 15 min., a 1 M aqueous solution of NS (bml) was added, stirred for another 2 min., and the layers were separated. It was dried over Ma 5503, filtered (the desiccant was washed with ethyl acetate SO (3x20 ml)) and concentrated. The crude product was chromatographed on a column with 5%, changing the composition of the eluent - from 2096 ethyl acetate in hexane to 59% methanol in ethyl acetate, and 267 mg of the title compound - (5296) was obtained.

Example 44 - 70 1-(2-44-(b-methoxy-2-(2-methyl-4-methylsulfanyl-phenyl)-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine hydrochloride

Ф) име) 60 b5 s С 70 SIN so and o ren

K o | sleep sleep

The compound from Preparatory Synthesis 1 (30mg, 0.57mmol), 2-methyl-4-methylthiophenylboronic acid (267mg, 1.47mmol) and cesium fluoride (672mg, 4.42mmol) were mixed with acetonitrile (3.0ml) in air-dried into a flask equipped with a reflux condenser. Palladium (II) acetate (14.5 mg,

0.0 mmol) and tricyclohexylphosphine (27.5 mg, 0.1 mmol). Dehydrated acetonitrile (2.5 ml) was added, and the mixture was sonicated for 1 h. in a nitrogen atmosphere. The flask was placed in an oil bath with a temperature of 909C. After 40 minutes the black suspension was cooled to room temperature, filtered and the solid was washed with acetonitrile (3x10ml). The filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (25 ml) and 596 with an aqueous solution of sodium carbonate (1 Oml). The layers were separated, and i) the organic layer was washed with a saturated aqueous solution of MNACI (1Oml) and brine (1Oml). The organic layer was concentrated in vacuo, and the residue was chromatographed on a column of ZnO, eluting with methanol (0-2.595) in dichloromethane, obtaining 331 mg of h- 1-(2-14-(β6-methoxy-2-(2-methyl-4-methylsulfanyl) -phenyl)-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine (9496).

The obtained free base was dissolved in ethyl acetate (10 ml), 2M HCl in diethyl ether (350 ml), and concentrated in vacuo to give the title compound. Mass spectrum (ion sputtering) t/2-514.3 (M.--N). --

Example 45 6-(2-methyl-4-methylsulfanyl-phenyl)-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol -

Ee 1-(2-44-(b-methoxy-2-(2-methyl-4-methylsulfanyl-phenyl)-naphthalen-1-yloxy|-phenoxy)-ethyl)-piperidine hydrochloride (3331mg, 0O.6b03mmol) was dissolved in dichloromethane (15 ml), and cooled to 5923. VVgz (285 μl, 3.02 mmol) was added to the light suspension over 5 min. Through the year quenched the reaction with a saturated aqueous Manso solution (15 ml). The layers were separated, and the aqueous layer was extracted with dichloromethane (2x1Oml). The solution was poured onto a layer of silica gel (20 g) and eluted with methanol (5-1595) in dichloromethane. The fractions were concentrated in a vacuum, and 301 mg of the compound (10095) specified in the title was obtained. Mass spectrum (ion sputtering) pt/2-500.3 (M'-H). and Example 46 is» Trifluoroacetate 6-(4-methanesulfonyl-2-methyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol

The compound from Example 45 (301 mg, 0.0 mmol) was dissolved in glacial acetic acid (5 mL), and Mavoz.nO (120 mmol, 1.20 mmol) was added. After 14 hours the reaction mixture was concentrated and distributed between 1095% aqueous solution of Manzo»z (30 ml), MeonH (3 ml) and dichloromethane (50 ml). The layers were separated, and the aqueous layer was extracted with dichloromethane (1 mL). The combined organic layers were washed with a saturated aqueous solution of MansSO" (1 Oml) and

BUT (1 Oml). They were dried over vacuum, filtered and concentrated in vacuo. The residue was chromatographed on a BIO column, eluting with methanol (0-1095) in dichloromethane, and the crude product was obtained. This product was purified by -shsh 20 preparative РХВЕ, and 97 mg of the title compound (2395) was obtained. Mass spectrum (one sputtering) t/2-532.3 (M.'A-N-TEA). "m Example 47 1-(2-44-(b-methoxy-2-(3-methyl-4-methylsulfanyl-phenyl)-naphthalen-1-yloxy|-phenoxy)-ethyl)-piperidine 7 nano,

FM from Me vo

And no. at

Palladium (II) acetate (21 mg, 0.094 mmol), tricyclohexylphosphine (5 mg, 0.19 mmol), a compound with

Preparatory synthesis 1 (500 mg, 0.95 mmol), cesium fluoride (1.009, 6.62 mmol), 3-methyl-4-(methylthio)phenylboronic acid (US patent Mob, 307,047); 52Omg, 2.8bmmol) and acetonitrile (40Oml). Heated at 902C for an hour. It was cooled to room temperature and the solution was diluted with ethyl acetate (20 ml) and washed with a saturated aqueous solution of MansSO" (1 ml). The layers were separated, the organic layer was washed with brine (1 Oml), dried over

Mao), filtered and concentrated under vacuum. The residue was chromatographed on a column of 500", eluting with methanol (2-495) in dichloromethane, and 371 mg of the title compound (7595) was obtained. Mass spectrum (ion sputtering): pt/2-514.3 (M'AN). 70 Example 48 6-(3-methyl-4-methylsulfanyl-phenyl)-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol

The product from Example 47 was dissolved in ethyl acetate (10 ml) and diethyl ether (bml). 2M NOSI in diethyl ether (ml, 10.00 mmol) was added. The suspension was concentrated, and the residue was dried under vacuum. The residue was diluted with dichloromethane (5.0 ml), and the solution was placed in a nitrogen atmosphere. The solution was cooled to 02C in an ice bath at 75°C, and VVgz (0.3ml, 3.2mmol) was added. After 1 hour water (1.0ml) and ethyl acetate (10ml) were added. The layers were separated, the organic layer was washed with a saturated aqueous Manso solution (1Oml) and brine (1Oml). Dried over

MazO,), was filtered and concentrated in vacuo. Column chromatographed the residue, eluting the product with a step gradient of methanol (0-0.595) in dichloromethane to give 30mg of the title compound (9290). Mass spectrum (ion sputtering): t/2-500.3 (M'N).

Example 49

Hydrochloride 6-(4-methanesulfonyl-3-methyl-phenyl)-5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol

The compound from Example 48 and sodium perborate (162mg, 1.62mmol) in acetic acid (4ml) were mixed. After 2 days, dichloromethane (20 ml) and water (bml) were added. The layers were separated, the organic layer was washed with a saturated aqueous solution of ManHSO 3 (1Oml), brine (1Oml), dried over Mo5O), filtered and concentrated in a vacuum. The residue was chromatographed on a column of zO", eluting with 6-(4-methanesulfonyl-3-methyl-phenyl)-5-14-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol stepwise i) gradient of methanol (0-595) in dichloromethane. The resulting free base was dissolved in diethyl ether (5.0 mL), ethyl acetate (b.0 mL), and methanol (1.0 mL), and 2M HCl in diethyl ether (mL, 2.0 mmol) was added. The precipitate was collected on a paper filter, washed with diethyl ether and dried in a vacuum (pressure 2 mm Hg (x266 Pa)) at 6590 °C for 48 hours, obtaining 4 mg of the title compound (1195). Mass spectrum (ion sputtering): t/2-537.0 (Man-NSI). -

Preparatory synthesis 16 h 2-benzo|B)giophen-5-yl-4,4,5,5-tetramethyl-|1,3,2|dioxaborolane

5-bromo-benzo|B|thiophene (U. Maieg. Spet., 10:2069-2081, 20001; 49g, 7.0 mmol) was dissolved in OM5O (4Oml). - Bis(pinacolato)diboron (7 mmol), Rasi "arrOsSNoSi" (0.3 mmol) and COAc (20 mmol) were added. The flask was purged with Mo, and then the reaction mixture was heated with stirring to 802. The reaction mixture was heated to 80° C. and then cooled to room temperature. Water (bbml) was added, and the aqueous layer was extracted with EtOAc (3xbbml). The combined organic layers were dried over NaCl 5 O, filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 0-5906 EPO in pentane) to afford 1.56 g of the title compound (8690). t c Example 50 h» 1-2-I4-(2-benzo|hiophen-5-yl-b6-methoxy-naphthalene-1-yloxy)-phenoxy|-ethyl)-piperidine p (uyu (ee) - - z yu o 5 "I y - Fe o My name)

2-benzo|b|giophen-5-yl-4,4,5,5-tetramethyl-|1,3,2)dioxaborolane (400 mg, 1.54 mmol) and the compound from Preparatory synthesis 1 (270, 0.5 mmol) were dissolved in SNUSM (24 ml). PaY(OAc)" (0.05 mmol), tricyclohexylphosphine (0.075 mmol) and C5E (4.5 mmol) were added. The flask was purged with Mo and then the reaction mixture was heated to 902 with stirring. Heating of the reaction mixture was continued for 2 hours, and then it was cooled to room temperature. Water (5 Oml) was added, and the aqueous layer of СНоСИ" (Хх25 ml) was extracted. The combined organic layers were dried over Ma»5O, filtered, concentrated, and the residue was purified by flash chromatography on a b5 column (silica gel, 0-495 MeOH-MNAOH (10/11 by volume) in СНоCl») to give 240 mg of the title compound (9396). "NN NMR (SOSIz) 5 7.99 (a, 9-1.2Hz, 1), 7.88 (a, 9-92Hz, 1), 7.82 (y, 9-84Hz, 1H), 7, 72 (9,

U-8.4Hz, 1), 7.58 (ad, 9-84, 1.2Hz, 71H), 7.41 (a, 9-5.6Hz, 1), 7.31 (a, 90-56Hz , 1), 7.21 (a, u-2.8Hz, 13, 7.11 (da, 0-9.2, 2.8Hz, 1), 6.73 (a, 9-56Hz, 1H), 6.60-6.63 (t, 4H), 4.04 (i 9-5.0Hz, 2H), 3.94 (in,

ZN), 2.93 (6, 9U-5.0Hz, 2H), 2.67-2.79 (t, 4H), 1.66-1.75 (t, 4H), 1.44-1, 55 (t, 2H).

Example 51

Trifluoroacetate b6-benzo|B|giophen-5-yl-5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol

The compound from Example 50 (240mg, 0.48mmol) was dissolved in dimethylformamide (OME, 7ml), sodium ethanethiolate (E(ZMa, 10Omg, 1.19mmol)) was added. Flask M" was purged, and then the reaction mixture was heated to 15020. Heating of the reaction the mixture was continued for 0.5 hours, after which it was cooled to room temperature. Water (7/0. A5Bml) was added, and the aqueous layer of SNSI" (Хх15ml) was extracted. The combined organic layers were dried over NaCl, filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 0-896o Meon-MnH.OnH (10/11 by volume) in СНоCl) to give 1400 mg of crude b-benzo|B)|huphen-5-yl-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol. This crude product was purified by preparative РХВЕ (bSiivop ) and gave 95 mg of the title compound (5590). Mass spectrum (75 ion sputtering): m/2-496.3 (M.'-H-TEA).

Example 52 6-(1,1-dioxo-1H-15,5-benzo|Bithiophen-5-yl)-5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl acetic acid ester

b-Benzo|b|giophen-5-yl-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol (56mg, 1.133mmol) was dissolved in CHClCl (20ml ), and the resulting solution was cooled to 02. OMAR (28 mmol), triethylamine (EBM, mmol) and acetic anhydride (AsoO, 1.0 mmol) were added. The reaction mixture was stirred for 1 h at 02 C, after which water (40 ml) was added. Extracted aqueous layer of СНоСИ" (Хх4Омл). The combined organic layers were dried over

Ma»zO), filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 0-590

Meon in СНоСИ»), obtaining Zbomg of the acylated product (5995); mass spectrum (ion sputtering): t/2-538.3 s (MN). The acylated product (110 mg, 0.2 mmol) was dissolved in acetic acid (ASON, 1.1 ml), and HO» g) (110 mg, 1.0 mmol, 3095 wt) was added. The reaction mixture was heated at 909 for 1 h, and then cooled to room temperature. A 1M aqueous solution of bisulfite (ml) was added, and the reaction mixture was stirred for 100 minutes. A saturated aqueous solution of MansCO3 (20 ml) was added, and the aqueous layer of CH2Cl3 (3x20 ml) was extracted.

The combined organic layers were dried over NaCl 5 O), filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 0-595 Meon in CHClCl) to give 5 mg of the title compound (44965). Mass spectrum (ion sputtering): t/2-570.3 (M'-H).

Example 53 --

Trifluoroacetate - 6-(1,1-dioxo-1H-15,6-benzo|B|thiophen-5-yl)-5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalene-2 -olu co

The compound from Example 52 (51 mg, O0.089 mmol) was dissolved in Meon (2 ml). Manso with (0.1Omol) was added, and the reaction mixture was stirred for 10 minutes. at room temperature. The solid was removed by filtration. The filtrate was concentrated, and the residue was purified by flash column chromatography (silica gel, 2-1096 Meon-Mmn.On (10/11 by volume) in SNSI"). The collected products were dried in vacuo at 402 overnight to give 7 mg of deprotected product (8595). Dissolve the product with the cleaved protecting group (b7 mg, 0.1 mmol) in СНоСИ» (1 Омл), and cool the solution to -782С. SEZSO5H (0.1 ml, 1.0 M and in CH2SiO5) was added, and the solvent was removed under reduced pressure to give a solid. This substance was dried in a vacuum at room temperature overnight, and 82 mg of the title compound (100905) was obtained.

Mass spectrum (ion sputtering): t/2-528.3 (M.-N-TEA).

Preparatory synthesis 17 6-(3,5-difluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol o The compound from Preparatory synthesis 1 (440mg, 0.84mmol), 3,5-difluorophenylboronic acid (40mg, 2.50mmol), palladium acetate (II) (19mg, 0.08mmol), tricyclohexylphosphine (35mg, 0.125mmol), cesium fluoride - (1.14g, 7, 52 mmol) and acetonitrile (1 Oml) and heated at 9020. After 10 minutes, the mixture was cooled to ambient temperature, diluted with dichloromethane, loaded into a cartridge with 10 g of CH, washed with 20 sh of dichloromethane, methanol, water, methanol, eluted with an ammonia solution (2- n. MNase in methanol, 8 Oml), and the solvent was removed in vacuo. The residue was dissolved in dichloromethane, chromatographed on silica gel eluting with dichloromethane/methanol mixtures, and a 1 M solution of hydrogen chloride in diethyl ether (0.8 ml) was added, obtaining A10 mg of hydrochloride 1 -(2-14-(2-(3,5-difluoro-phenyl)-6b-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine (9396).

1-(2-44--2-(3,5-difluoro-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine hydrochloride (410 mg, 0.7/bmmol) was dissolved in about dichloromethane (LOml) and cooled in an ice bath. Boron tribromide (0.22 ml, 2.28 mmol) was added and the mixture was stirred for 2.5 h. Methanol (5 mL) was added, heated to ambient temperature, diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution, dried over solid 60 magnesium sulfate, filtered, and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol mixtures, and 350 mg of the title compound (9695) was obtained.

Example 54 6-(3,5-bis-ethylsulfanyl-phenyl)-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol b5

(s o no

6-(3,5-difluoro-phenyl)-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol (ZOOmg, 0.bZmmol), sodium ethanethiolate ( 53Omg, 6.333mmol) and 1-methyl-2-pyrrolidinone (1Oml), and heated at 1309 for 4.5 hours.

The mixture was cooled to ambient temperature, diluted with dichloromethane, washed with brine and saturated sodium bicarbonate solution. The organic phase was loaded into a cartridge with 10 g of 5СХ, washed with dichloromethane, methanol, eluted with an ammonia solution (2N MH3 in methanol, 83 mL), and the solvent was removed under vacuum. The residue was dissolved in dichloromethane and chromatographed on silica gel eluting with dichloromethane/methanol to give 2 mg of the title compound (74905). Mass spectrum (ion sputtering): t/2-560 (MAN).

Example 55 sem 6-(3,5-bis-ethanesulfonyl-phenyl)-5-14-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol o

The compound from Example 54 (16mg, 0.29mmol) was dissolved in glacial acetic acid (ml). A solution of 77906 tSRBA (300 mg, theoretically 1.3 mmol) in acetic acid was added dropwise for 1 hour, and stirred at room temperature for an hour. The solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate, the organic phase was dried over solid magnesium sulfate, filtered, and the residue was chromatographed on silica gel eluting with dichloromethane/methanol mixtures, obtaining 13 mg of the title compound (7290). Mass spectrum (one sputtering): t/2-624 (M.N). "-

Example 56 "-

Hydrochloride 6-(3,5-bis-ethanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol

Dissolve the compound from Example 55 in dichloromethane and add 1-n. NSI in E2O (0.180 ml). Evaporated to dryness, 00 and the title compound was obtained.

Preparatory synthesis 18

Tert-butyl ether of t4-(2-4-methanesulfonyl-phenyl)-b-methoxy-naphthalene-1-yloxy|-phenyl)-carbamic acid

A mixture of b-methoxytetralone (9.6 g, 54 mmol), 4-bromothioanisole (25 ml, 1233 mmol), sodium tert-butylate (20.9 g, - with 217 mmol), palladium acetate (I) (6 b1Omg, 2.72 mmol), racemic 2 ,2'-bis(diphenylphosphino)-1,1-dinaphthyl h (1.8g, 2.72mmol) and toluene (1500ml) were heated under reflux for 18h, then cooled to ambient temperature and evaporated to dryness under reduced pressure .

The residue was dissolved in dichloromethane and washed with an aqueous solution of hydrochloric acid (1 N), filtered through a layer of celite and chromatographed twice on silica gel, eluting with hexane/ethyl acetate mixtures, (oh) obtaining 2.41 g of b-methoxy-2-(4-methylsulfanyl) -phenyl)-naphthalene-1-ol (1596). - A solution of b-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-ol (1.98 g, 6.8 mmol), 4-fluoro-nitrobenzene (0.78 ml, 7.34 mmol) and R.- tert-butylphosphazene base (6.7ml 1M in hexane, b.7mmol) in 1M,M-dimethylformamide (30ml) at ambient temperature for 4 hours. The reaction mixture was diluted to 20 with dichloromethane, washed with 1-n. with an aqueous solution of hydrochloric acid, water, dried over solid magnesium sulfate and chromatographed on silica gel, eluting with mixtures of hexane/ethyl acetate, obtaining 2.18 g of b-methoxy-2-(4-methylsulfanyl-phenyl)-1-(4-nitro- phenoxy)-naphthalene (7895).

779 tSRBA (34Omg, 2.00mmol) was added to a solution of b-methoxy-2-(4-methylsulfanyl-phenyl)-1-(4-nitro-phenoxy)-naphthalene (27Omg, 0.b6bmmol) in dichloromethane (1Oml).

The reaction mixture was stirred for 30 h, washed with saturated aqueous sodium bicarbonate solution, dried over solid magnesium sulfate, and filtered through a 1-inch (25 mm) pad of silica gel to give 290 mg of 2-(4-methanesulfonyl-phenyl)-β6-methoxy-1- (4-nitro-phenoxy)-naphthalene (9890). co Mixture of 2-(4-methanesulfonyl-phenyl)-6-methoxy-1-(4-nitro-phenoxy)-naphthalene (1.67g, 3/mmol), ammonium formate (4.7g, 74mmol), wet 2095 of palladium hydroxide on charcoal (420 mg, 2595 wt.) and absolute ethanol (8 Oml) was heated under reflux for an hour, then cooled to ambient temperature, filtered and evaporated to dryness under reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was dried over solid magnesium sulfate, and the residue was chromatographed on silica gel. eluting with dichloromethane/methanol mixtures, obtaining 115 g of 4-(2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenylamine (75965). 65 A solution of 4-(2-(4-methanesulfonyl-) was heated phenyl)-β6-methoxy-naphthalene-1-yloxy|-phenylamine (17Omg, 0.41mmol) and di-tert-butyldicarbonate (14O0mg, 0.bbmmol) in tetrahydrofuran (1Oml) under reflux for 4h, then cooled to ambient temperature and evaporated to dryness under reduced pressure.The residue was chromatographed on silica gel eluting with dichloromethane/methanol mixtures, obtaining 210 mg of 14-(2--4-methanesulfonyl-phenyl)-6-methoxy-naphthalene-1-yloxy tert-butyl ester |-phenyl)-carbamic acid (9790).

Example 57

Tert-butyl ester of t4-(2-4-methanesulfonyl-phenyl)-b-methoxy-naphthalene-1-yloxy|-phenyl)-(2-piperidin-1-yl-ethyl)-carbamic acid

N

From n.s. .sn, o o

OO An o o s 25

Fi o ns. . - zo Solution of tert-butyl complex ester of t4-(2--4-methanesulfonyl-phenyl)-b-methoxy-naphthalene-1-yloxy|-phenyl)-carbamic acid (20mg, 0.38mmol), g: hydrochloride 2 -chloroethyl-i-piperidine (1O00mg, 0.57mmol) and sodium borohydride (38mg, 0.94mmol) in

M,M-dimethylformamide was heated to 602C and stirred for 18 hours. Sodium tert-butylate (7bOmg,

0.b7mmol) and 2-chloroethyl-1-piperidine hydrochloride (4bmg, 0.25mmol), and stirred additionally for - from 2 hours, and then cooled to room temperature. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and chromatographed on silica gel eluting with dichloromethane/methanol mixtures, obtaining 12 mg of the title compound (5090).

Mass spectrum (ion sputtering): pp/2-631.3 (MAN).

Example 58 "

Dihydrochloride 6-(4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethylamino)-phenoxy|-naphthalen-2-ol) was added to a 4M solution of HCIII in dioxane (3 ml, 12 mmol) to a solution of the compound from Example 57 (11 mg, 0.17 mmol) in dichloromethane (3 ml), and the reaction mass was stirred for 40 min., after which it was evaporated under reduced pressure. :z» The residue was dissolved in dichloromethane (4 ml), and boron tribromide ( 0.068 ml, 0.72 mmol). The reaction mass was stirred for 3.5 hours, then a saturated aqueous solution of sodium bicarbonate (Bbml) was added, and the phases were separated. The organic layer was dried over solid magnesium sulfate and chromatographed on silica gel, eluting with mixtures of dichloromethane/ methanol. Fractions containing the product were evaporated to dryness and redissolved in a mixture of methanol (595) with dichloromethane (3ml). A 1M solution of hydrogen chloride in diethyl ether (0.28ml) was added, and then the solution was evaporated under reduced pressure to give 82 mg of the title compound (779605).- Mass spectrum (ion sputtering): n/2-517.5 (M Academy of Sciences).

Example 59 Dihydrochloride 5-I4-(2-azepin-1-yl-ethylamino)-phenoxy)|-6-(4-methanesulfonyl-phenyl)-naphthalen-2-ol "I H

M o schi -CH,

F) Z yu o F o

I and Febo According to methods similar to those described in Preparatory Synthesis 18 and Example 58, t4-(2--4-methanesulfonyl-phenyl)-b-methoxy-naphthalene-1-yloxy|-phenyl) was obtained from tert-butyl ester -carbamic acid (200 mg, 0.39 mmol) and 2-(hexamethyleneimino)ethyl chloride hydrochloride (140 mg, 0.7 mmol) and 77 mg of the title compound (3790).

Mass spectrum (ion sputtering): pt/2-531 (M.--N).

Preparatory synthesis of 19 4-(2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenol

To a solution of b-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-ol (3.0 g, 10.1 mmol) and 6095 sodium hydride (400 mg, 10.1 mmol) in 1-methyl-2-pyrrolidinone ( 30 ml) was added 4-fluorobenzaldehyde (2.20 ml, 20.33 mmol). 7/0. The reaction mixture was heated to 1702 for 7 hours, and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate (200 ml) and washed twice with 596 aqueous solution of lithium chloride (500 ml), brine, 1-N aqueous solution of hydrochloric acid, dried over solid magnesium sulfate and chromatographed on silica gel eluting with dichloromethane/hexane mixtures, obtaining 1.29 g of 4 -(b-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalene-1-yloxy|-benzaldehyde (32905).

4-1b-Methoxy-2-(4-methylsulfanyl-phenyl)-naphthalene-1-yloxy|-benzaldehyde (97Omg, 2.49mmol), sodium perborate monohydrate (2.5mmol) and glacial acetic acid (1bml) were mixed. Stirred for 4 hours. at ambient temperature, after which it was evaporated to dryness under reduced pressure. The residue was partitioned between dichloromethane and 5095 saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over solid magnesium sulfate and chromatographed on silica gel eluting with dichloromethane/methanol mixtures, obtaining 280 mg of the title compound (2795). Mass spectrum (ion sputtering): pt/2-419 (M-1).

Example 60

Hydrochloride 1-(2-14-(2-(4-methanesulfonyl-phenyl)-b6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-azepine c

M fiercely c) o

S An o F me im- o "- sho ns FFf -

C - h - o d)

A mixture of 4-(2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenol (16Omg,

O.ZOmmol), 2-(hexamethyleneimino)-ethyl chloride hydrochloride (140mg, O.bOmmol), 6095 sodium hydride (47mg, 1.18mmol) and

of M,M-dimethylformamide (2 ml) for 18 hours. at ambient temperature, after which it was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed with water, dried over solid magnesium sulfate and chromatographed on silica gel eluting with dichloromethane/methanol mixtures. The h fractions containing the product were mixed and 1-n. solution of hydrogen chloride in diethyl ether (0.3 Oml). The resulting solution was concentrated under reduced pressure, and 10 mg of the title compound (69905) was obtained. Mass spectrum (on sputtering): t/2-546 (M'-H).

Example 61 (ee) Hydrochloride 5-(4-(2-azepin-1-yl-ethoxy)-phenoxy)|-6-(4-methanesulfonyl-phenyl)-naphthalen-2-ol - The compound from Example bo (16Omg , 0.27 mmol) in 5-(4-(2-azepin-1-yl-ethoxy)-phenoxy|-6-(4-methanesulfonyl-phenyl)-naphthalen-2-ol, using a method similar to that described in Preparative synthesis 15 (85965). The obtained free base was dissolved in dichloromethane, 90% was added to 1N HCl in EBO (0.250ml), and then concentrated to give 140mg of the title compound.

Mass spectrum (ion sputtering): pt/2-532 (M.N). that Preparatory synthesis 20

M-Tert-butyl-4-(4,4,5,5-tetramethyl-|1,3,2|dioxaborolan-2-yl)-benzenesulfamide

Tert-butylamine (4.32 mL, 41.1 mmol), triethylamine (8.15 mL, 58.7 mmol) and dichloromethane (75 mL) were charged to a three-neck round-bottom flask. The resulting solution was cooled with stirring to 02C, and a solution of 4-bromobenzenesulfonyl chloride (10.0g, 39.1mmol) in dichloromethane (50ml) was added. An additional amount of dichloromethane (25 mL) was added, and the reaction mixture was stirred overnight, allowing it to warm to ambient temperature. The mixture was evaporated under vacuum. The resulting white solid was suspended in ethyl acetate and separated by filtration. The filtrate was concentrated in vacuo. The obtained residue was purified by flash chromatography (silica gel; gradient СНоСИ» (5095-8095) in hexane), obtaining -9.85 g of 4-bromo-M-tert-butyl-benzenesulfamide (8696).

4-bromo-M-tert-butyl-benzenesulfamide (2.00g, 6.84mmol), bis(pinacolato)diboron (2.09g, 8.21mmol), RasSi "(arr)"-SNoSi" ( 175mg, 0.24mmol), potassium acetate (2.02g, 20.5mmol) and anhydrous dimethylsulfoxide (25ml). The reaction mixture was placed in an oil bath and stirred at 902C for 7.5 hours. The purple reaction mixture was cooled to ambient temperature, quenched with a large amount of water, and the resulting aqueous mixture was extracted with dichloromethane. The combined extracts were washed with water and brine, dried (sodium sulfate) and evaporated in vacuo. The obtained dark solid was purified by flash chromatography (silica gel; gradient 090-590 EAs in

СНоСИ»), and 2.00 g of the title compound (8696) were obtained.

Example 62

M-tert-butyl-4-yl6-methoxy-1-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl)-benzenesulfamide o o 5. -OH, o o "M dream

ON from " in ns. Fr

The compound from Preparatory Synthesis 1 (335mg, 0.b4immol) was loaded,

N-tert-butyl-4-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)-benzenesulfamide (65mg, 1.92mmol) and acetonitrile (bml) into a round-bottomed flask, which contained cesium fluoride (875mg, 5.79U9mmol) and acetonitrile (bml). To this mixture was added an sonicated suspension of palladium (I) acetate (14 mg, 0.06 b4 mmol) and tricyclohexylphosphine (27 mg, 0.09 b mmol) in acetonitrile (2 mL). An additional amount of acetonitrile (2 ml) was added, and the reaction mixture was placed in an oil bath with a temperature of 902. The reaction mixture was stirred EM for 20 min. at 902C. The reaction mixture was cooled to room temperature and filtered through a layer of (3) celite (washed with a large amount of hot ethyl acetate). The filtrate was washed with 5095 aqueous sodium carbonate solution, saturated aqueous ammonium chloride solution, water and brine, dried (sodium sulfate) and evaporated in vacuo. The obtained solid was purified on a 25M silicon dioxide column (gradient 295-490 meon in СНеСИ»), and 315 mg of the title compound (8495) was obtained.

Example 63 h

Hydrochloride

M-tert-butyl-4-/6-hydroxy-1-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl)y-benzenesulfamide -

The product from Example 62 (30mg, 0.051mmol), sodium ethanethiolate (43mg, 0.5mmol) and -- dimethylformamide (2ml) were charged to a round bottom flask at room temperature. The reaction mixture was placed in an oil bath with a temperature of 902C, and stirred for 10 minutes, and then cooled to room temperature. co

The reaction mixture was quenched at room temperature with brine and extracted with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate, water and brine; dried (sodium sulfate) and concentrated in vacuo. The obtained crude product was purified on a SPphotayogop device (silica gel; gradient 6906-1090 MeOH in СНоСИ). The purified solid was dissolved in methanol (4 ml), and 70% of a 1.0 M solution of hydrogen chloride in diethyl ether (0.1 ml) was added. The resulting solution was shaken for 2 minutes. at room temperature and then evaporated in vacuo to give 25 mg of the title compound (8095). MO with (IZ'YU) t/e 575 (M.-1-NSI).

Preparatory synthesis 21

M,M-dimethyl-4-(4,4,5,5-tetramethyl-|(1,3,2|dioxaborolan-2-yl)-benzenesulfamide 395 Dimethylamine (5.25 ml of a 2.0 M solution in TNE, 10.4 mmol), triethylamine (ee) I and Y (2.04 ml, 14.68 mmol) and dichloromethane (30 ml). This solution was cooled with stirring to 02С, and a solution of 4-bromobenzenesulfonyl chloride (2.5 g, 9.78mmol) in dichloromethane (30ml). Additional dichloromethane (10ml) was added and the reaction mixture was stirred overnight, allowing it to warm to ambient temperature. The mixture was concentrated in vacuo. The resulting solid was dissolved in - ethyl acetate and filtered. filtrate in vacuo, and the resulting solid was dried in vacuo to give 2.50 g of 4-bromo-M,M-dimethyl-benzenesulfamide (9790).

4-bromo-M,M-dimethyl-benzenesulfamide (1.00g, 3.77mmol), bis(pinacolato)diboron (1.15g, 4.53mmol), RasSi "(drrO"-SNoSi) (97mg . medium, quenched with copious amounts of water, and the resulting aqueous mixture was extracted with dichloromethane. The combined extracts were washed with water and brine, dried (sodium sulfate), and evaporated in vacuo. The resulting solid was purified by flash chromatography (silica gel; gradient 290-590 EUAc in in СНоСи», loading material in СНоСИ»), and obtained 90 Омг of the compound indicated in the title (77905).

Example 64 4-(6-Methoxy-1-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl)-M,M-dimethyl-benzenesulfamide b5 o m IF o "; b dream about them with

Oh!

SN, "Zh

WELL

The compound from Preparatory synthesis 1 (175 mg, 0.3 mmol), t M,M-dimethyl-4-(4,4,5,5-tetramethyl-|1,3,2|dioxaborolan-2-yl) was loaded into a round-bottom flask -benzenesulfamide (311mg, 0.99mmol), acetonitrile (7ml) and cesium fluoride (455mg, 2.99mmol). To this mixture was added an sonicated suspension of palladium (II) acetate (8 mg, Ф0.03 mmol) and tricyclohexylphosphine (14 mg, О0.050 mmol) in acetonitrile (ml), followed by an additional amount of acetonitrile (3 ml). The reaction mixture was placed in an oil bath with a temperature of 902C and stirred for 10 minutes, after which acetonitrile (3 ml) was added. The reaction mixture was heated at 902C with stirring for an additional 10 minutes. The reaction mixture was cooled to ambient temperature, and it was filtered through a layer of celite (washed with a large amount of hot ethyl acetate). The filtrate 50956 was washed with an aqueous solution of sodium carbonate, a saturated aqueous solution of ammonium chloride, water and brine, dried (sodium sulfate) and evaporated in vacuo. The obtained solid substance was purified on the device

Spgotai(hop (silica gel; gradient 390-896 Meon in СНоСИи"), and 1 mg of the title compound (8790) was obtained. M5 (IZ'YU) t/e 561 (M'-1).

Example 65

Hydrochloride 4-(6β-hydroxy-1-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl)-M,M-dimethyl-benzenesulfamide chn zo The product was loaded into a round-bottomed flask from Preparatory Synthesis 64 (12mg, 0.214mmol), dichloromethane (bBml), and a 1.0M solution of hydrogen chloride in diethyl ether (0.43ml, 0.433mmol). in vacuum. After drying in vacuum, dichloromethane (1 Oml) was added to the residue, and the resulting solution was mixed in an ice bath with stirring. A 1.0 M solution of boron tribromide in dichloromethane (0.75 Oml, 0.750 mmol) was added, and the reaction mass was stirred 7 for 3-4 hours, maintaining the temperature in the range of 0-102 C. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried (sodium sulfate) and concentrated in vacuum

The obtained crude product was purified on a Spgothayogop device (silica gel; gradient 5956-1196 MeOH in

SNOSI"; loading in the mixture 796 Meon/SNei5). The purified solid was dissolved in methanol (5 ml), and a 1.0 M solution of hydrogen chloride in diethyl ether (0.4 ml) was added to the mixture. The resulting solution was shaken for 2 minutes. pt) s at room temperature and then evaporated in vacuo to give 9 mg of the title compound (779605).

M (IZYU) t/e 547 (M.--1-NSI). :z» Preparatory synthesis 22 2,2-dimethyl-propyl ether of 4-(4,4,5,5-tetramethyl-1/1,3,2)dioxaborolan-2-yl)-benzenesulfonic acid

A round-bottomed flask was charged with 4-bromobenzenesulfonyl chloride (2.20 g, 8.61 mmol) and pyridine (3 mL). At ambient temperature and stirring, neopentyl alcohol (1.39 ml, 12.91 mmol) was added. After stirring the reaction mixture overnight at ambient temperature, the mixture was quenched with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. Washed - combined extracts with a saturated aqueous solution of sodium bicarbonate, 0.05-n. aqueous solution of hydrogen chloride

Acids and brine, dried (sodium sulfate) and concentrated in vacuo. The obtained crude product was purified by flash chromatography on a column (silica gel; gradient 3090-5096 СНоSiO»о in hexane), and obtained

And 2.24 g of 2,2-dimethyl-propyl ester of 4-bromo-benzenesulfonic acid (8590).

2,2-dimethyl-propyl ester of 4-bromo-benzenesulfonic acid (1.00g, 3.2bmmol), bis(pinacolato)diboron (1.07g, 4.2mmol), Rasi "(darrOd"- SNiCl" (9mg, 0.12mmol), potassium acetate (1.04g, 10.bmmol) and anhydrous dimethylsulfoxide (12ml). The reaction mixture was placed in an oil bath and stirred at 909C for 1-1.5 hours. The reaction mixture was cooled to ambient temperature, quenched with copious amounts of water, and the resulting aqueous mixture was extracted with dichloromethane. The combined extracts were washed with water and brine, dried (sodium sulfate), and evaporated in vacuo. The resulting solid was purified by flash chromatography (silica gel; gradient from 1095 of hexane in 6o /CHnCl» to 10095 CHnCl» and further to 590 EAs/CHnCl»), and 950 mg of the title compound (8290) were obtained.

Example 66 2,2-dimethyl-propyl ether-4--6-benzyloxy-1-4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl/y"benzenesulfonic acid b5 o

M o

TSI and F Z. sia, about the UN

SN. at 10 o'clock at 15 Fa

The compound from Preparatory synthesis C (5mg, 0.078mmol), 2,2-dimethyl-propyl ester 4-(4,4,5,5-tetramethyl-|/1,3,2)dioxaborolan-2- yl)-benzenesulfonic acid (8 mg, 0.24 mmol) and acetonitrile (2 ml). To the resulting solution was added an ultrasonically treated suspension of palladium (II) acetate (2 mg, 0.008 mmol), tricyclohexylphosphine (Zmg, 0.012 mmol) and cesium fluoride (107 mg, 0.7 mmol) in acetonitrile (1 mL). The reaction mixture was placed in an oil bath with a temperature of 902C and stirred for 20 minutes. Then the reaction mixture was cooled to ambient temperature and filtered through a layer of celite (washed with a large amount of hot ethyl acetate). The filtrate was washed with 5095 aqueous sodium carbonate solution, saturated aqueous ammonium chloride solution, and brine; with 25 dried (sodium sulfate) and evaporated in a vacuum. The obtained solid was purified on a Spgothaigop device (3 (silica gel; gradient 2906-6906 MeonH in CH»eSi»), and received 320mg of the title compound (6095). M5 (IZ'U) t/e 680 (M'1) .

Example 67

Hydrochloride of 2,2-dimethyl-propyl ester - 30 4-(6b-hydroxy-1-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl/u)benzenesulfonic acid "-- mae, m

Mon - Fri, Sun 5. Sat, Sat, Sun 9 St.

From " і і і s і no

The product from Example 66 (42mg, 0.062mmol), ammonium formate (29mg, 45O.46b4mmol), 10965 Ra/C (bmg, 715905 (wt)) and MeonH (5ml) were charged to a round bottom flask. The mixture was heated under reflux for 5 minutes. The mixture was cooled to ambient temperature, filtered through a pad of celite, and the celite was washed with hot ethyl acetate and hot methanol. The filtrate was evaporated in a vacuum, and the obtained residue was purified by radial chromatography on silicon dioxide (gradient 2-595 MeonN in СНоСИи), - obtaining 27 mg of 2,2-dimethyl-propyl ester 50 4-(6-hydroxy-1-( 4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl"benzenesulfonic acid (7496) .02 ml (2 eq.) of a 1.0 M solution of hydrogen chloride in diethyl ether. This solution was shaken for 1-2 minutes at ambient temperature and evaporated in a vacuum, obtaining 7.1 mg of the title compound. M5 (IZ'U) t /e 590 (M'-1-NSI).

Example 68

N-tert-butyl-4-yl-methoxy-1-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl)"N-methyl-benzenesulfamide

To a solution of the product from Example 62 (79mg, 0.013mmol) in dimethylformamide (5ml) at room temperature (F) was added with stirring 6095 sodium hydride (bmg, 0.15mmol). The mixture was stirred at temperature

ambient He for 10 min., and then methyl iodide (0.014 ml, 0.15 mmol) was added. The reaction mixture was stirred for 30 minutes. at ambient temperature, and then quenched with brine. The resulting aqueous mixture was extracted with ethyl acetate. The combined extracts were washed with brine; dried (sodium sulfate) and concentrated in vacuo. The obtained substance was purified on a Spgothaiogop device (silica gel; gradient 3906-1095 MeOnH in СНеСИ"), and 47 mg of the title compound (68905) was obtained. M5 (IZ'YU) t/e 603 (M'-1).

Example 69 4-(6-methoxy-1-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl)-H-methyl-benzenesulfamide b5

AND

5.,-СН, at 5 M

NS at

The product from Example 68 (8Omg, O0.1Zmmol) and trifluoroacetic acid (5ml) were loaded into a round-bottomed flask. The mixture was heated under reflux for 15-20 minutes, and then cooled to ambient temperature. The reaction mixture was quenched by pouring it into a saturated aqueous solution of sodium bicarbonate, after which it was extracted with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate, water and brine; dried (sodium sulfate) and evaporated in vacuo. The obtained substance was purified on a Spgotaiggop device (silica gel; gradient 495-896 Meon in СНоСИ»), and bZmg of the title compound (8995) was obtained. M (IZ'YU) t/e 547 (M'-1).

Example 70

Hydrochloride of 4-/6-hydroxy-1-4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl)-M-methyl-benzenesulfamide c

The product from Example 69 (85mg, 0.14bmmol), dichloromethane (bml) and a 1.0M solution of hydrogen chloride in diethyl ether (0.15Oml, O0.150mmol) were loaded into a round-bottomed flask. The resulting solution was shaken at ambient temperature for 2 min., and then evaporated in a vacuum. After drying in a vacuum, dichloromethane (bml) was added, and the resulting solution was placed in an ice bath with stirring. A 1.0 M solution of boron tribromide in dichloromethane (0.32 ml, 0.32 mmol) was added, and the reaction mass was stirred for 2 hours, maintaining the temperature in the range of 0-10. The reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate, water and brine; dried (sodium sulfate) and evaporated in vacuo. The resulting crude "7 product" was purified on a Spgothayoggop apparatus (silica gel; 6906-1096 Meon gradient in SNOSi). The purified solid was dissolved in methanol (bml), and a 1.0 M solution of hydrogen chloride in diethyl ether (0.4 ml) was added. The resulting solution was shaken for 2 minutes. at room temperature and then evaporated in vacuo to give 71 mg (ee) of the title compound (8595). M (IZ'U) t/e 533 (M.-1-NSI).

Example 71

Hydrochloride « 6-(4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of isobutyric acid - c g SIN o

M water so We - o o sn, - - 50 o

In ns

With o o SN, o !

To a solution of the compound from Example C (10 µg, 0.18 bmmol) in TNE (bml) was added triethylamine (8 µg, in 0.574 mmol). The obtained solution was cooled to 0°C, and 4-dimethylaminopyridine (1 Ωg, 0.082 mmol) was added, after which isobutyric anhydride (4 Ωg, 0.241 mmol) was added dropwise. The mixture was allowed to warm to room temperature for 2 hours. An additional amount of isobutyric anhydride (200 μl, 1.20 mmol) was added and stirred overnight at room temperature. The mixture was diluted with E(Ac (2 Oml) and washed with 1N. SOHC, saturated solution of MnSO" and brine. The organic layer was dried over Ma"5O, filtered and concentrated in vacuo. The resulting residue was purified by radial chromatography (8095 СНСи):189560 EUAs: 295 EN), and 82 mg of 6-(4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of isobutyric acid was obtained. Dissolved this free base in TNE (5ml) and added to a solution of NOSI (1.0M in EBO, 04ml, 04mmol). The resulting solution was concentrated in vacuo and the residue from the mixture was crystallized

ESO/EUN, yielding 5 µg of the title compound. Mass spectrum (ion sputtering): 588 (M.--N-NSII).

Example 72

Methanesulfonate 6-(4-methanesulfonyl-phenyl)-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol

Approximately 1.0 g of the compound from Example C was heated in a solvent mixture containing 3 ml of denatured ethanol grade ZA and 5 ml of ethyl acetate, obtaining a finely dispersed suspension. Methanesulfonic acid (185 mg) in one ml of grade ZA ethanol was added to the hot suspension. Cooled and stirred for about 7/0 h. after reaching room temperature. The suspension was filtered, and the sediment on the filter was washed with ethyl acetate. The precipitate was dried on a filter in a vacuum at 459 for 2-3 days, and approximately 1.11 g of the title compound was obtained.

Example 73

6-(4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol succinate

Approximately 1.0 g of the compound from Example C was heated in a solvent mixture containing 100 ml of ethyl acetate and 1 ml of denatured ethanol grade ZA. Succinic acid (228 mg) was added to the hot suspension, and a finely dispersed suspension was obtained. An additional 2 ml of grade ZA ethanol was added. The suspension was briefly heated under reflux, cooled to room temperature and stirred for 15-3 hours, after which it was filtered. The precipitate on the filter was washed with ethyl acetate and dried under vacuum at 4597 for 2-3 days, yielding approximately 1.23 g of the title compound.

Preparatory synthesis of 23 b-methoxy-1-I4-(2-piperidin-1-yl-ethoxy)-benzoyl|-naphthalen-2-yl ester of trifluoromethanesulfonic acid

In a dried round-bottomed flask equipped with a mechanical stirrer, a temperature sensor and a supply line M", 2,6-dimethoxynaphthalene (1.Eq.) was dissolved in СНоСІ" (eq. by volume) at ambient temperature. The resulting solution was cooled to 09С in an ice bath, and 4-(2-piperidin-1-yl-ethoxy)-benzoyl chloride (1.1 eq.) was added. Aluminum chloride (2.00 equiv.) was added. After determining the moment of completion of the reaction, the reaction mixture was slowly quenched with 1-N. Mahon and diluted with an additional amount of water and SNSI." The aqueous layer was washed with SNOCI" (20 ml). The combined organic extracts were washed with brine and dried over (Ma»3O),). The crude product was recrystallized from methanol to give (2,6-dimethoxy-naphthalen-1-yl)-I(4-2-piperidin-1-yl-ethoxy)-phenyl|-methanone. -

(2,6-dimethoxy-naphthalen-1-yl)-(4-(2-piperidin-1-yl-ethoxy )-phenyl|-methanone in СНоСИ" (1 Oeeq. by volume). -

The flask was cooled in an ice-brine bath, and a 1.0 M solution of ALL with SNOCl (1.2 equiv.) was added dropwise. (oo)

The reaction mixture changed color to dark red, and the temperature initially increased to 59C. About 1 hour later. the reaction mixture was quenched with methanol (5 eq.) and allowed to warm to room temperature. An organic solution of СНоСи" (Teq. by volume) was diluted, a 1.0 M solution of МаНсСО"z (teq. by volume) was added, and "stirred for an hour. The aqueous and organic layers were separated. The aqueous layer was washed with CH 2Si» (1 volume), | combined organic layers. It was washed with a saturated solution of Mn.Si and dried over Ma»5O,;. The product was purified - with column chromatography (silica gel 50/1) eluting with a mixture of CH oxy" with hexane (3/1), and (2-hydroxy-6-methoxy-naphthalen-1-yl)-I4-(2 -piperidin-1-yl-ethoxy)-phenyl|-methanone. "» In a three-necked round-bottom flask equipped with a mechanical stirrer and connected to a source of Mo, (2-hydroxy-6-methoxy-naphthalen-1-yl)-(4-(2-piperidin-1-yl-ethoxy)-phenyl -"methanone in СНоСИ" (10 volumes) and cooled to 0 in an ice-brine bath. Pyridine (1.Eq.) was added. Trifluoromethanesulfonyl chloride (1.2 Eq.) was added via syringe over 15 min. After 15 minutes, the reaction mixture was quenched with HO (10 volumes), washed with a 1 N aqueous solution of HCl (5 volumes) and a 1.0 N aqueous solution

Manso" and dried over Ma"5O). 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,

M o, sn shchi o o Z Z cha » Fe: 60 no

65 b-methoxy-1-I4-(2-piperidin-1-yl-ethoxy)-benzoyl|-naphthalen-2-yl ester of trifluoromethanesulfonic acid (555 mg, 1.0 mmol), 4-methanesulfonylphenylboronic acid ( C310mg,

1.55 mmol), Pa(OAc)" (23.9 mg, 0.1 mmol), RizR (54.2 mg, 0.21 mmol) and Ma"CO3 (2.5 ml, 2 M in water) in ethylene glycol dimethyl ether (OME , ZOml). The mixture was heated under reflux for 2 hours, and an additional amount of RYAA(OAc) (25.2 mg) and PI1ZR (58.9 mg) was added. They heated with the reverse

In the refrigerator for 2 hours, after which the reaction mixture was diluted with water and extracted with chloroform.

The organic phase was dried over NaCl, filtered and concentrated. The crude product was purified by loading it onto a BHPLC column and eluting with 2M MNU3/Meon to give 56b9mg of the title compound (10196).

ISM5: t/2-544 (MAN).

Example 75 70 Hydrochloride

1b-hydroxy-2-(4-methanesulfonyl-phenyl)-naphthalen-1-ylI-(4-(2-piperidin-1-yl-ethoxy)-phenyl|-methanone

Pyridine hydrochloride (4.0 g) was added to the compound from Example 74 (100 mg, 0.18 mmol). The reaction vessel was purged with nitrogen, closed and heated at 200927 for 4 hours. The mixture was cooled to room temperature and diluted with a saturated aqueous solution of MansSoOz. A mixture of 2595 isopropanol (I-RHOH) 75% was extracted into CHCl3, dried over Ma»3O, and concentrated in a vacuum. The residue was purified using a 5CX column (eluting with 2M MH with/Meon) followed by flash chromatography (0-10965 Meon/snNeCl5). The product was dissolved in the mixture

CHZSMIM aqueous solution of HC (1:1) and lyophilized, obtaining 70.Zmg of the title compound (6895). | CM: t/2-530 (MAN).

Example 76 (2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yl-1-(4-(2-piperidin-1-yl-ethoxy)-phenyl|-methanol)

The compound from Example 74 (200 mg, 0.37 mmol) was dissolved in TNE (3 mL). Lithium aluminum hydride (GAN, 70, Zmg) was added. The reaction mixture was quenched with ice and water. It was acidified with a 1M aqueous solution of HCIII and the solution was brought to a weakly basic reaction with an aqueous solution of MansSoOz. Extracted 2595 -RGON in SNSIzh. The crude product was purified using a ZX column (eluting with 2M MH 3z/Meon), and 185 mg of the title C compound (9290) was obtained. at

Example 77 (2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalen-1-yl|-(4--2-piperidin-1-yl-ethoxy)-phenyl|-methane

The compound from Example 76 (185.2 mg, 0.3 mmol), E(Z3H (0.3 mL, 1.88 mmol) and TEA (0.3 mL, 3.8 mmol) was dissolved in CHClCl (3 mL). The solution was stirred at room temperature for an hour. Quenched with a saturated aqueous solution of Manso" and extracted 25965 I-RHOH in СНоСиИ". Dried over Ma»5О54, filtered and concentrated. "-

The crude product was purified by flash chromatography (0-595 Meon/SnHsSiI), and 1.18 g of the title compound (6395) was obtained. Y SM: t/2-530 (MN). --

Example 78 "--

Hydrochloride 6-(4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-benzyl|-naphthalen-2-ol

Pyridine hydrochloride (4 g) was added to the compound from Example 77 (1100 mg, 0.21 mmol). The reaction vessel was purged with nitrogen, closed and heated at 2002 for 2 hours. The reaction mixture was cooled and diluted with a saturated aqueous solution of MnNsCO3. The mixture was extracted with CHClCl, dried over MaCl5O), filtered and concentrated. The crude product was purified by flash chromatography (0-1095 Meon/snNs). The product was dissolved in a mixture of SNUSM/1M aqueous solution of HCIII (1:1) and lyophilized, obtaining 92 mg of the compound (8096) indicated in the title C 70. And SM: t/2-516 (MAN) - NSI. c Preparatory synthesis 24; with" 5-bromo-1,3-difluoro-2-methanesulfonyl-benzene

1,3-Difluorobenzene (3.5g, 30O.7mmol) was dissolved in TNE (100ml). The mixture was cooled to -782C, and 415 n-butyllithium (19ml, 30.7mmol) was added. It was stirred for 20 minutes, and dimethyl disulfide (3 mL, 3.38 mmol) was added. o The cooling bath was removed, and the mixture was allowed to warm 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). It was dried over NaOH, filtered and concentrated in vacuo to obtain 4.3 g of 1,3-difluoro-2-methylsulfanylbenzene (88965).

1,3-difluoro-2-methylsulfanylbenzene (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) at 02C. The reaction mixture was stirred

And at room temperature for 2 hours. A saturated solution of sodium thiosulfate (200 ml) and diethyl ether (100 ml) were added. The layers were separated, and the organic layer was washed with brine (20 ml). It was dried over M950O, filtered and concentrated in a vacuum. The residue was chromatographed on a column, eluting the product with diethyl ether (0-5905) in hexane, and 1.1 g of 5-bromo-1,3-difluoro-2-methylsulfanyl-benzene (179605) was obtained.

5-Bromo-1,3-difluoro-2-methylsulfanylbenzene (1.1 g, 4.bmmol), oxone (11 g, 18.4 mmol) and methanol (F) (20 mL) were mixed. The mixture was stirred for 12 hours. The obtained suspension was filtered, and the filtrate was evaporated. The residue was dissolved in dichloromethane (100 ml) and water (100 ml) was added. The layers were separated, and the organic layer was washed with brine (5 Oml). It was dried over NaOH, filtered and concentrated in vacuo. Chromatographed the residue on a column, eluting the product with diethyl ether (0-595) in hexane, and obtained 497 mg of the title compound (4096).

Example 79 1-(2-44-2-(3,5-difluoro-4-methanesulfonyl-phenyl)-b6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine b5 o ; with o and 50, Me

Us. at

Palladium acetate (II) (13 mg, 0.00 mmol), tricyclohexylphosphine (27 mg, 0.1 mmol), cesium fluoride 75 (518 mg, 34 mmol) and acetonitrile (10 mL) were mixed. The mixture was stirred for 5 minutes. The compound from Preparative Synthesis 1 (200 mg, 0.3 mmol) and bis(neopentylglycol) diboron (129 mg, 0.57 mmol) were added. It was heated to 902C for 1 min, and 5-bromo-1,3-difluoro-2-methanesulfonylbenzene (11 mg, 0.42 mmol) in acetonitrile (4 mL) was added. Stirred at 902 for 1 min. It was cooled to room temperature, the resulting solution was diluted with ethyl acetate (20 ml) and washed with a saturated aqueous solution of MnSO" (10 ml). The layers were separated, the organic layer was washed with brine (20 ml), dried over NaCl, filtered and concentrated in vacuo. The residue was column chromatographed, eluting the product with methanol (0-595) in dichloromethane to give 15mg of the title compound (69905). Mass spectrum (ion sputtering): t/2-568.3 (M'-H).

Example 80

Hydrochloride 6-(3,5-difluoro-4-methanesulfonyl-phenyl)-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol c

The compound from Example 79 was dissolved in ethyl acetate (1 mL) and diethyl ether (mL). A 2M solution of NOSI in diethyl ether (0.1 mL, 0.2 mmol) was added. The resulting suspension was concentrated and dried in a vacuum. The residue was diluted with dichloromethane (5.0ml) and placed in a nitrogen atmosphere. The resulting solution was cooled to 02C in an ice bath. VVgas (0.1 ml, 1.1 mmol) was added and stirred for 1 hour. The mixture was quenched with water (1.Oml) and diluted with dichloromethane (1Oml). The layers were separated, the organic layer was washed with a saturated aqueous solution -

Mansoz (10ml) and brine (1Oml). It was dried over MobBoO, filtered and concentrated in vacuo. "-

The residue was chromatographed on a column, eluting with 6-(3,5-difluoro-4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol. stepwise - gradient of methanol (0-57) in dichloromethane. The obtained free base was dissolved in diethyl ether (5.0 mL) and ethyl acetate (b, 0 mL). 2M NOI in diethyl ether (0.1 mL, O0.2 mmol) was added. The precipitate was collected on a paper filter and washed with diethyl ether to give 31mg of the title compound (2095).Mass spectrum (ion sputtering): pt/2: 554.3 (MAN-HCI).

Preparatory synthesis of 25 5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-b-trifluoromethanesulfonyloxy-naphthalene-2-yl ester of acetic acid

The compound from Preparatory synthesis 2 (800 mg, 1.33 mmol) was dissolved in CH 2 Si» (20 ml) in an atmosphere of Mo and cooled to 09С. EbZM (67Omg, b.bZmmol) and Aso»O (20Omg, "» 1.99mmol) were added dropwise to the reaction mixture. The resulting solution was stirred for 1 hour. Water (100ml) was added, and the aqueous layer was extracted with "СНоСИБ" (3x10Oml). The combined organic layers were dried over NaCl 5 O, filtered and concentrated to give 8 mg of the title compound as a colorless oil (10096).

Example 81 with 6-(4-methanesulfonyl-3-methoxy-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-yl ester of acetic acid - -o 70 zho and IF and at 5O, Me

F)

GF OMe 60 "

Pa(OAc)" (4 mg, 0.2 mmol), tricyclohexylphosphine (95 mg, 0.34 mmol), and Sv (1.85 g, 12.26 mmol) were mixed in SNUSM (20 mL) under Mo atmosphere. The reaction mixture was stirred for 5 min. 5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy|-b-trifluoromethanesulfonyloxy-naphthalen-2-yl ester of acetic acid (730 mg, 1.3 mmol) and bis-"(neopentylglycol )diboron (46bOmg, 2.04mmol).

The mixture was heated to 902 and stirred for about 5 minutes. 4-methanesulfonyl-3-methoxy-phenyl ester of trifluoromethanesulfonic acid (500 µg, 1.5 mmol) was added, and heating of the mixture was continued for 2 hours. The mixture was cooled to room temperature, water (10 Oml) was added, and the aqueous layer was extracted with СНоСИ» (3x100 Oml). The combined organic layers were dried over NaCl, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0-5906 MeOnH/CH2Cl), and 260 mg of the title compound (33965) was obtained. Mass spectrum (ion sputtering): t/27-590.4 (M'-H).

Example 82

Hydrochloride 6-(4-methanesulfonyl-3-methoxy-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol 70 The compound from Example 81 was dissolved (21Omg, O0 .3bmmol) in MeonH (4mL). Manceau Z (bOmg, 0.72mmol) was added, and the reaction mixture was stirred for 12h at room temperature. The mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel . -yl-ethoxy)-phenoxy|-naphthalen-2-ol (75965). 75 This free base (150mg, 0.27mmol) was dissolved in CH2Cl2 (5ml) and cooled to -782C. 2M HCl in diethyl ether (O0 .2ml), and the resulting solution was stirred for 2 h. The solvent was removed under reduced pressure to give a solid. This material was dried overnight under vacuum at room temperature to give 14 ug of the title compound (8795). Mass spectrum (one sputtering ): t/2-548.1 (MAN-NSI ).

Preparatory synthesis of 26 2-(4-propylsulfanyl-phenyl)-boronic acid

4-bromo-benzenethiol (2.0 g, 10.bmmol) was dissolved in anhydrous dimethylformamide (5 Oml), and the solution was cooled to 02С under a nitrogen atmosphere. Sodium hydride (SO5 mg, 12.7 mmol) was added in portions. After cessation of intense gas evolution, 1-bromo-propane (1.4 mL, 15.9 mmol) was added and stirred overnight at room temperature. The reaction mixture was slowly poured into water (40 Oml) and extracted with He diethyl ether (2x150 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-propylsulfanylbenzene (quantitative yield).

1-Bromo-4-propylsulfanylbenzene (2.7g, 11.bmol) was dissolved in anhydrous tetrahydrofuran (1000ml), and the solution was cooled to -782С. A 2.5 M solution of butyllithium in hexane (5.1 mL, 12.8 mmol) was added dropwise, and the reaction mixture was allowed to warm to -402C. The mixture was stirred for 30 minutes. and cooled to -782C. Triisopropylborate (8.0 mL, 34.8 mmol) was added, and the reaction mixture was allowed to slowly warm to room temperature. 1095 aqueous sodium hydroxide solution (100 ml, 17 µmol) was added and stirred overnight.

The reaction mixture was slowly poured into a mixture of concentrated NOSI and ice. The aqueous solution (87) was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo, obtaining 1.9 g of the title compound (8696).

From Example 83 with 1-(2-44--2-(4-propylsulfanyl-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine

WITH -

And" With . in - Meo -

In a flask dried over a flame, equipped with a reflux condenser and a device for purging with nitrogen, 2-(4-propylsulfanyl-phenyl)-boronic acid (168 mg, 0.85 mmol), a compound from Preparatory synthesis 1 was mixed

I (15mg, 0.28mmol) and cesium fluoride (214mg, 1.4mmol). In a separate dried flask, palladium (II) acetate (6b, 2 mg, 0.0 mmol) and tricyclohexylphosphine (12 mg, 0.04 mmol) were mixed. Anhydrous acetonitrile (Zml) was added and treated with ultrasound for 10 min. in a nitrogen atmosphere. A mixture of catalysts was added to the mixture of solid reagents, and the flask was placed in an oil bath with a temperature of 902. Through ZOkhv. the resulting suspension was cooled to room temperature and filtered through a layer of celite. The filtrate was concentrated in vacuo. (F, The resulting residue was chromatographed on a BIO column eluting with methanol (295) in dichloromethane, and 77 mg of the title compound (51965) was obtained. Mass spectrum (ion sputtering): t/2-528.3 (M. N).

Example 84 60 6-(4-propylsulfanyl-phenyl)-5-14-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol

The compound from Example 83 (77 mg, 0.15 mmol) was dissolved in dichloromethane (2 ml). 2M NH in diethyl ether (0.15 ml, 0.29 mmol) was added and stirred for 1 min. The solvent was removed under vacuum, and the residue was kept under high vacuum for 20 min. The obtained foam was dissolved in anhydrous dichloromethane (2 ml), and the solution was cooled to 02. VVgz (7 Oml, 0.7 mmol) was added dropwise. The mixture was stirred for 30 minutes, quenched by pouring into 65% saturated sodium bicarbonate solution (100 ml), and extracted with dichloromethane (2x100 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed on a BIO column eluting with methanol (595) in dichloromethane to give 58 mg of the title compound (7890). Mass spectrum (ion sputtering): t/2-514.3 (M'-H).

Example 85 5-I4-(2-piperidin-1-yl-ethoxy)-phenoxy1|-6-I4-(propane-1-sulfonyl)-phenyl|-naphthalen-2-ol

The compound from Example 84 (58 mg, 0.1 mmol) was dissolved in glacial acetic acid (1.1 ml), and sodium perborate (33 mg, 0.3 mmol) was added. The reaction mixture was stirred overnight and poured into a saturated aqueous solution of sodium bisulfite (1 Oml). It was extracted with dichloromethane (2x1Oml), and the combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (1Oml). The organic layer was dried over 7/0 sodium sulfate, filtered and concentrated in vacuo. The obtained residue was chromatographed on a column with 5iO" eluting with methanol (595) in dichloromethane, and 28 mg of the title compound (4795) was obtained. Mass spectrum (on sputtering) t/2-546.3 (M'-H).

Example 86

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

The compound from Example 85 (28mg, 0.05mmol) was dissolved in anhydrous dichloromethane (1ml), and 2M NOSI in diethyl ether (0.10ml, 0.20mmol) was added. The mixture was stirred at room temperature for 10 minutes. The solvent was removed by blowing with nitrogen, and the solid residue was dried in a vacuum oven at 502C overnight to give 27.9 mg of the title compound (93965). Mass spectrum (ion sputtering) t/2-546.3 (M.AN-NSI).

Preparatory synthesis 27 1-2-I4-(6-benzyloxy-2-bromo-benzo|b|giophen-3-yloxy)-phenoxy)|-ethyl)-piperidine

They dissolved b-methoxy-benzo|rigiophene (M. Med. Spet. 32:2548, 19891); 26.1g, 14bmmol) in OME (50Oml).

Sodium ethanethiolate (37g, 44 mmol) was added, and the reaction mixture was heated at 1502 with stirring overnight. An additional amount of sodium ethanethiolate (12.8g, 152mmol) was added, and heating was continued at 15020 overnight. The mixture was concentrated in a vacuum to 1/4 of the initial volume. The reaction mixture was partitioned between He ethyl acetate (500 ml) and water (500 ml), the layers were separated, the organic layer was washed with water (2 x 500 ml), (5) brine (500 ml) and dried over magnesium sulfate. The mixture was filtered, and it was concentrated in a vacuum, obtaining 8 g of benzo|b)giophen-b6-ol. The aqueous layers were extracted with ethyl acetate (3Xx100Oml), the organic extracts were washed with brine and dried over magnesium sulfate. It was concentrated in a vacuum, and an additional 15 g of benzo|bhiiophen-b6-ol was obtained. Residual OME was removed, and 22.7 g (10095) of benzo|b|hiophene-b-ol were obtained. -

Benzo|bithiophen-b-ol (10 g, b/mmol) was dissolved in pyridine (30 mL). 2,2-dimethyl-propionyl chloride (Zvml, Zovmmol) was added dropwise, and the mixture was stirred at room temperature for 8 hours.

The mixture was concentrated in a vacuum to 1/4 of the initial volume, distributed between ethyl acetate (250 ml) and water -- (250 ml). The layers were separated, the organic layer was washed with water (250 ml) and brine (200 ml). It was dried over magnesium sulfate, filtered and concentrated in a vacuum, obtaining 15 g of benzo|(b)hyophen-b-yl complex

From 2,2-dimethyl-propionic acid ether (98960). co

2,2-dimethyl-propionic acid benzo|b|hyophen-b-yl ester (22.0 g, 94.0 mmol) was dissolved in dichloromethane (500 ml). Bromine (12.bml, 244 mmol) was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of sodium thiosulfate (50 Oml). The layers were separated, and the aqueous layer was extracted with dichloromethane (5000 ml). The combined organic layers were washed with brine 40. (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude solid o) c product. This solid was washed with hexane (20 mL), diethyl ether (20 mL), and dichloromethane (20 mL). It was dried in a vacuum, and 3g (8195) of 2,3-dibromo-benzo|B|giophen-b-yl ester of 2,2-dimethyl-propionic acid was obtained.

2,3-dibromo-benzo|bithiophen-b-yl ester of 2,2-dimethyl-propionic acid (32 g, B82 mmol) was dissolved in ethanol (725 ml), 5095 aqueous potassium hydroxide solution (30 ml, 328 mmol) was added, and the mixture was heated because with a reflux refrigerator for 4 hours. The mixture was concentrated in a vacuum to 1/2 volume, distributed between - ethyl acetate (500 ml) and saturated aqueous ammonium chloride solution (50 Oml), the layers were separated, the organic layer was washed with saturated aqueous ammonium chloride solution (2x500 ml) and brine (3000 ml). It was dried over - sodium sulfate, filtered and concentrated in a vacuum, obtaining 25.5 g of 2,3-dibromo-benzo|b|hiophene-b-ol - 20 (10095),

A solution of 2,3-dibromo-benzo|bithiophene-b-ol (43.9 g, 143 mmol) in OME (1000 ml) was added dropwise to a suspension of 1 m of sodium hydride in OME (1.5 L) at 02C. Stirred for 20 min., added benzyl bromide (17 ml, 143 mmol).

The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (1L) and ethyl acetate (4L) and stirred overnight. The layers were separated, and the 29th organic layer was washed with water (3x80000ml) and brine (800ml). It was dried over sodium sulfate, filtered and

HF) was concentrated in a vacuum, obtaining 52.4 g of b-benzyloxy-2,3-dibromo-benzo|bithiophene (92905). b-Benzyloxy-2,3-dibromo-benzo|rhithiophene (20g, bbmmol) was dissolved in dichloromethane (88ml), and trifluoroacetic acid (88ml) was added. The mixture was stirred for 1 hour, after which 3095 aqueous solution of hydrogen peroxide (5.1 ml, 5 mmol) was added and stirred for 4 hours. Solid sodium bisulfite (2.2 g, 60 21 mmol) was added, the mixture was diluted with water (30 ml), stirred for 15 minutes, and then concentrated in vacuo.

The residue was partitioned between dichloromethane (150 ml) and a saturated aqueous solution of sodium bicarbonate (15 Oml), the layers were separated, and the organic layer was washed with an additional saturated aqueous solution of sodium bicarbonate (150 ml) and brine (10 Oml). It was dried over sodium sulfate, filtered and concentrated in a vacuum. The obtained residue was chromatographed on a column with BO" eluting with 10095 dichloromethane, and 12.8 g of b-benzyloxy-2,3-dibromo-benzo|bithiophene-1-oxide (62905) were obtained.

b-Benzyloxy-2,3-dibromo-benzo|b|giophene-1-oxide (5.9g, 14.2mmol) was dissolved in TNE (120ml). A suspension of 4-(2-piperidin-1-yl-ethoxy)-phenol (3.14g, 14.2mmol) and potassium tert-butylate (1.75g, 15.mmol) was added in

TNE (12O0ml), and stirred at 452C for an hour. The reaction mixture was partitioned between dichloromethane (400 mL) and a saturated aqueous solution of MNACI (400 mL), and the layers were separated. The organic layer was washed with a saturated aqueous solution of МН.СИ (4000 ml) and brine. It was dried over sodium sulfate, filtered and concentrated in a vacuum.

The resulting residue was chromatographed on a io column eluting with methanol (0-5905) in dichloromethane, and 6.9 g of 1-022-14-(6-benzyloxy-2-bromo-1-oxo-1H-15,-benzo| BIHIOphen-3-yloxy)-phenoxy|-ethyl)-piperidine (88965).

1-22-I4-(6-benzyloxy-2-bromo-1-oxo-1H-15-benzo|bithiophene-3-yloxy)-phenoxy)|-ethyl)-piperidine (22.36 g, 40.3 mmol) was dissolved ) in methanol (1ppm) and chloroform (8Oml). A 3095 solution of titanium trichloride in an aqueous solution of NOSI (31.4 ml, 80 mmol) was added and stirred at ambient temperature for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (50 Oml) and diluted with dichloromethane (500 ml). The layers were separated, and the organic layer was washed with a saturated aqueous solution of 75 sodium bicarbonate (BbOml), water (50Oml) and brine (50O0ml). It was dried over sodium sulfate, filtered and concentrated in a vacuum. The obtained residue was chromatographed on a column of ZiOo eluting with methanol (0-295) (with an impurity of 1095 MH.OH) in dichloromethane, and 19.2 g of the title compound (88965) was obtained.

Example 87 1-(2-4-(b-benzyloxy-2-(4-ethanesulfonyl-phenyl)-benzo|b|thiophen-3-yloxy|-phenoxy)-ethyl)-piperidine o, c / o 8) x o iy dany not iy b o so

1-42-I(4-(6-benzyloxy-2-bromo-benzo|bithiophen-3-yloxy)-phenoxy|-ethyl)-piperidine (700 mg, 1.3 mmol) was dissolved in dioxane (13 ml) and 1095 aqueous solution sodium carbonate (b.9ml, b.5mmol), and 4-(ethanesulfonyl)phenylboronic acid (430mg, 2mmol) and RI(PP3)4 (15mg, 0.1mmol) were added. It was heated at 702C and stirred overnight. The mixture was diluted with diethyl ether (25 ml) and water (25 ml), filtered through - c layer of celite, and the layers were separated. The aqueous layer was extracted with diethyl ether (5 Oml). The combined organic layers were washed with water (50 ml) and brine (500 ml). It was dried over sodium sulfate, filtered and concentrated under vacuum. The obtained residue was chromatographed on a column with 50% eluting with methanol (0-590) in dichloromethane to give 40 mg of the title compound (4995). Mass spectrum (ion sputtering): t/2-628.3 (MN). (ee) Example 88 - 2-(4-ethanesulfonyl-phenyl)-3-(4-(2-piperidin-1-yl-ethoxy)-phenoxy)|-benzo|(b|giophen-6b-ol

The compound from Example 87 (400 mg, 0.54 mmol) was dissolved in methanol (Uml) and ethyl acetate (/ml). Ammonium formate (521 mg, 8.3 mmol) and palladium hydroxide (24 mg) were added, and heated under reflux at 90°C for 5 hours. The reaction mixture was filtered and concentrated in vacuo to give Zb0Omg of the title compound (86965). Mass spectrum (ion sputtering): t/2-538 (M.N). "and Example 89

Hydrochloride 2-(4-ethanesulfonyl-phenyl)-3-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-benzo|BIgiophen-b-ol

The compound from Example 88 (30 mg, 0.5 mmol) was dissolved in dichloromethane (1 ml) and methanol (0.5 ml). 2M NOI in diethyl ether (0.4 ml) was added and stirred for 1 hour. The mixture was concentrated in vacuo and the solid product was dried in a vacuum oven at 502C overnight to give 224 mg of the title compound (71965).

Ohm and as spectrum (on sputtering): t/2-538 (MAN). Example 90

Trifluoroacetate 60 0/01-(2--A-(b-bsensyloxy-2-(4-methanesulfonyl-phenyl)-benzo|bithiophen-3-yloxy|-phenoxy)-ethyl)-piperidine b5 i 9 e )

E - fi i Ge HSN,

A suspension of palladium acetate (II) (10 mg, 0.4 mmol) and tricyclohexylphosphine (193 mg, 0.8 mmol) in acetonitrile (3 mL) was sonicated for 17 h. In a separate flask, a solution of 1-2-ID-(6-benzyloxy-2-bromo-benzo|B|giophen-3-yloxy)-phenoxy|-ethyl)-piperidine (with an admixture of 2,7-dibromo derivative; 25O0mg, 0 .4bmmol) and 4-(methanesulfonyl)-phenylboronic acid (27bmg, 1.38mmol) in acetonitrile (bml) to cesium fluoride (629mg, 4.14mmol). The sonicated mixture of catalysts was added and heated at 902 for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (20 mL). The organic layer was washed. "M with a saturated aqueous solution of ammonium chloride (30 ml) and brine (20 ml). Dried over sodium sulfate, concentrated in vacuo, and the resulting residue was chromatographed on a Bio column eluting with methanol (0-5905) in dichloromethane to give 220 mg of the title compound, contaminated with a by-product resulting from coupling at both positions of 2 and 7. This mixture was separated by preparative PHVE, and 85 mg of the title compound (3090) was obtained. Mass spectrum (one sputtering): t/2-614 (M.N). -

Example 91 "- 2-(4-methanesulfonyl-phenyl)-3-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-benzo|bigiophen-6b-ol

The compound from Example 90 (85 mg, 0.14 mmol) was dissolved in methanol (14 mL) and ethyl acetate (14 mL). Ammonium formate (262mg, 4.2mmol) and palladium hydroxide (OOmg) were added and heated under reflux for 1h. The reaction mixture was filtered and concentrated in vacuo. The residue was partitioned between a mixture of ethyl acetate and methanol (5:11, bml) and a mixture of a saturated aqueous solution of sodium bicarbonate and brine (1:11, bml). with

The organic layer was washed with brine and dried over sodium sulfate. Concentrated in vacuum, and obtained

BOmg of the title compound (68965). "H NMR (SOSIv): 5 7.85 (v, 4H), 7.18 (a, 9U-8.2 Hz, 1H), 7.14-7.12 (t, 1H), 6.78-6 .74 (t, ZN), 6.59-6.55 (t, 2H), 4.07 (5 9-5.4Hz, 2H), 3.05 (in, ZN), 2.92-2 88 (t, 2H), 2.69 (r, "Zh

AN), 1.74-1.68 (t, 4H), 1.50 (vv, 2H).

Example 92 c c Hydrochloride 2-(4-methanesulfonyl-phenyl)-3-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-benzo|bithiophen-b-ol"c The compound from Example 91 was dissolved ( 5mg, 0.09mmol) in ethyl acetate (ml), diluted with diethyl ether " (5ml) and immediately placed in an ice bath, and 2M HCl in diethyl ether (0.07ml) was added. The solid product was collected on a paper filter and washed with diethyl ether . The solid product was dried in a vacuum oven at 80° overnight to give 19 mg of the title compound (3895). Mass spectrum (ion sputtering): m/2-524 (M'-H). - Example 93 from 1- (2-4-(b-benzyloxy-2-(3-fluoro-4-methanesulfonyl-phenyl)-benzo|B)giophen-3-yloxy|-phenoxy)-ethyl)-piperidine - 50 -4 MOM o o o и о и З 5-сН о З 0

And S

1-2-I4-(6-benzyloxy-2-bromo-benzo|b|giophen-3-yloxy)-phenoxy)|-ethyl)-piperidine (335Omg, 0O,b5mmol) and 3-fluoro-4-methanesulfonyl were dissolved -phenylboric acid (213mg, 0.98mmol) in dioxane (1Oml), and 10956 aqueous solution of sodium carbonate (OUml) and Pa(PPNIz) were added; (75mg, 0.0b5mmol). They heated with the reverse

Refrigerator during the Agreement. The reaction mixture was partitioned between dichloromethane (20 ml) and a saturated aqueous solution of ammonium chloride (20 ml). The organic layer was washed with brine (3 mL), dried over sodium sulfate, and concentrated in vacuo. The obtained residue was chromatographed on a column of ZiOo eluting with methanol (0-595) in dichloromethane, and 150 mg of the title compound contaminated with the reduction by-product (2-H) was obtained. This mixture was used in the next step without further purification. 70 Example 94

Trifluoroacetate 2-(3-fluoro-4-methanesulfonyl-phenyl)-3-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-benzo|BIgiophen-b-ol

The compound from Example 93 (150 mg, O0.24 mmol) was dissolved in methanol (2 ml) and ethyl acetate (2 ml). Ammonium formate (30mg, 4.8mmol) and palladium hydroxide (15mg) were added and heated under reflux for 7/5 hours. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was chromatographed on a Bio column eluting with methanol (0-1095) in dichloromethane to give 8mg of the title compound contaminated with the debenzylation product of the reduced (2-H) by-product from the previous step. This mixture was separated by preparative HCBE, and 1 mg of the title compound (8905) was obtained. Mass spectrum (ion sputtering): t/2-542 (M.N).

Example 95 1--2-(4-(6-benzyloxy-2-(4-trifluoromethanesulfonyl-phenyl)-benzo|B|Hyiophen-3-yloxy|-phenoxy)-ethyl)-piperidine

FI o cha o o h- vh i -

With that, -

With c, o d)

A suspension of palladium acetate (II) (14 mg, 0.5 mmol) and tricyclohexylphosphine (273 mg, 0.98 mmol) in acetonitrile (4 mL) was sonicated for 10 h. In a separate flask, a solution of C with 1-2-I(4-(6-benzyloxy-2-bromo-benzo|B|giophen-3-yloxy)-phenoxy|-ethyl)-piperidine (335Omg, 0.ppmmol) and "» 4,4,5,5-tetramethyl-2-(4-trifluoromethanesulfonyl-phenyl)-(1,3,2|dioxaborolane (531 mg, 2.00 mmol) in acetonitrile " (dFml) to cesium fluoride (889 mg, 5 .9 mmol). The sonicated catalyst mixture was added and heated at 902 for 2 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (20 mL). The organic layer was mixed with saturated aqueous ammonium chloride (20 ml) and filtered. The organic layer was washed with brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed on a 50" column eluting with methanol (0-3956) in dichloromethane to give 240 mg of the title compound (5595), contaminated with tricyclohexylphosphine oxide. "H NMR (SOCIv): 5 8.03-7.95 (t, 4H), 7.45-7.33 (t, 5H), 7.32-70 (a , 9-2.3Hz, 1), 7.29 (a, 9-8.9Hz, 71H), 6.96 (aa, 9-90, 2.2Hz, 71H), 6.89-6.79 (t, 4H), 5, 13 (in, 2H), 4.03 -h (6 9U-6.0Hz, 2H), 2.73 (i, 9U-6.0Hz, 2H), 2.48 (rve, 4H), 1.96 -1.18 (complex multiplet masked by P(O)SU»z, bH).

Example 96 3-I4-(2-piperidin-1-yl-ethoxy)-phenoxy1|-2-(4-trifluoromethanesulfonyl-phenyl)-benzo|b|giophen-6b-ol 59 The compound from Example 95 (contaminated by P( O)Su with; 240mg, 0.3bmmol) in methanol (4ml) and ethyl acetate

GF) (Aml). Ammonium formate (11 µg, 1.9 mmol) and palladium hydroxide (bOmg) were added and heated under reflux

HF refrigerator during the Agreement. The reaction mixture was filtered and concentrated in vacuo. The obtained residue was chromatographed on a column with 5iOo eluting with methanol (0-495) in dichloromethane, and 100 mg of the title compound (4795) was obtained. "H NMR (SOCI3): 5 7.94 (b, 4H), 7.20 (a, 9-8.8Hz, 1H), 7.14 (49, 9-2.2Hz, 1H), 6.79 -6.76 (t, 2H), 6.75 (ad, 9-88, 2.2Hz, 1H), 6.63-6.58 (t, 2H), 4.03 (5 9-5.8Hz , 2H), 2.80 (i, -5.8Hz, 2H), 2.57 (rev, 4H), 1.68-1.61 (t, 4H), 1.49-1.44 (t, 2H).

Example 97

B0/3-4-(2-piperidin-1-yl-ethoxy)-phenoxy)-2-(4-trifluoromethanesulfonyl-phenyl)-benzo|bithiophen-b-ol trifluoroacetate

The compound from Example 96 (100 mg, 0.17 mmol) was dissolved in ethyl acetate (2 ml), diluted with diethyl ether

(1 Oml) and placed in an ice bath. 2M MEDIA in diethyl ether (0.1 mL) was immediately added, and the solid product was collected on a paper filter. The product was purified by preparative РХВЕ, and 37 mg of the title compound (29965) was obtained. Mass spectrum (ion sputtering): t/2-578 (M'-H).

Preparatory synthesis of 28 b-methoxy-2-(4-methanesulfonylphenyl)-1-(4-iodophenoxy)naphthalene

A three-necked flask equipped with a mechanical stirrer, a reflux condenser, a nitrogen purge device, and a temperature sensor was charged with b-methoxy-1-tetralone (Teq.), 4-bromothioanisole (2.5 eq.), palladium acetate (0.01 eq.) , 2-dicyclohexylphosphino-2'-(M,M-dimethylamino)biphenyl (0.02 equiv.) and toluene. 70 sodium tert-butylate (4 eq.) was added, and the suspension was heated to reflux. After about 2-4 hours. the reaction mixture was cooled to room temperature, and 3M aqueous solution of NCI was added together with tetrahydrofuran. The two-phase reaction mixture was stirred for 30 minutes, after which it was filtered and the layers were separated. The organic layer was concentrated, and b-methoxy-2-(4-methylthiophenyl)naphthalen-1-ol was separated by filtration.

Sodium hydride (1.05 equiv.) in anhydrous dimethylformamide was charged under a nitrogen atmosphere into a three-necked flask equipped with a mechanical stirrer, a dropping funnel with nitrogen purging, and a temperature sensor. b-Methoxy-2-(4-methylthiophenyl)naphthalen-1-ol (Teq.), dissolved in anhydrous dimethylformamide, was loaded into the dropping funnel. This solution was added dropwise with stirring to the sodium hydride solution at such a rate that the temperature was maintained below 35923. The reaction mixture was stirred for 30 minutes, after which 4-fluoronitrobenzene was added with an additional amount of anhydrous dimethylformamide. The resulting solution was heated at 602. After completion of the reaction, the flask was cooled, and water was slowly added to precipitate the product. The crude product was filtered and washed with water and then with methyl tert-butyl ether. The precipitate was dried on a filter in a vacuum cabinet, and b-methoxy-2-(4-methylthiophenyl)-1-(4-nitrophenoxy)naphthalene was obtained. Ha

Meta-chloroperbenzoic acid (2.eq.) and methylene chloride were charged into a three-necked flask equipped with a mechanical stirrer, a dropping funnel with nitrogen purging, and a temperature sensor. b-Methoxy-2-(4-methylthiophenyl)-1-(4-nitrophenoxy)naphthalene (Tekv.), dissolved in methylene chloride, was loaded into the dropping funnel. This solution was added dropwise with stirring to a suspension of perbenzoic acid at 102C. After completion of the addition, the resulting solution was stirred for 30 minutes. After the completion of the reaction, slowly added 1-n. aqueous Mahon solution, maintaining the temperature no higher than 2520. The layers were separated, and the organic layer was concentrated. The crude concentrate was purified on silica gel eluting with methyl chloride, and b-methoxy-2-(4-methanesulfonylphenyl)-1-(4-nitrophenoxy)naphthalene was obtained. -

b-Methoxy-2-(4-methanesulfonylphenyl)-1-(4-nitrophenoxy)-naphthalene was loaded into the reactor for hydrogenation - along with 3 volumes of dimethylformamide and a catalyst of 595 Pa/C. A hydrogen atmosphere under pressure was created in the reactor, and after the reaction was completed, the catalyst was immediately removed by filtering through Nuyot material. To (ee) filtrate was added 1-n. aqueous solution of NSI for precipitation of crude product. The sediment was separated by filtration, washed with 1-n. with an aqueous solution of NOSI, and the precipitate was dried on a filter in a vacuum cabinet, obtaining b-methoxy-2-(4-methanesulfonylphenyl)-1-(4-aminophenoxy)naphthalene hydrochloride. "

6b-Methoxy-2-(4-methanesulfonylphenyl)-1-(4-aminophenoxy)naphthalene hydrochloride (Eq.), iodine (0.eq.), copper iodide (1.05 eq.) and acetonitrile were charged into a three-necked flask equipped with a mechanical stirrer, dropper - with a watering can, a device for blowing with nitrogen and a temperature sensor. A solution of isoamyl nitrite (1.Eq.) in acetonitrile was loaded into a dropping funnel, and this mixture was added dropwise at a temperature not higher than 2090. After the addition was completed, the mixture was stirred for 10 minutes. After completion of the reaction, a saturated solution of sodium thiosulfate and methylene chloride were added to the mixture and stirred for an hour. The reaction mixture was filtered, and the layers were separated. The organic layer was concentrated to give a solid. It was purified on silica gel and the title compound was obtained. - An alternative method of obtaining the compound from Example 1

b-Methoxy-2-(4-methanesulfonylphenyl)-1-(4-iodophenoxy)-naphthalene (Teq.), cesium carbonate - (2 eq.), 1,10-phenanthroline (0.2 eq.), copper iodide ( О0, Текв.) and 1-piperidinethanol (5 volumes) in a three-necked flask equipped with a mechanical stirrer, a reflux condenser with a dephlegmator and a temperature sensor.

The system was evacuated and filled with nitrogen, repeating this operation three times, after which the mixture was heated at "m 17026. After the completion of the reaction, the flask was cooled to 80 2C, and a vacuum was created in the system to remove piperidinethanol by distillation. Then the vacuum was removed, and the flask was cooled to 502C, at this time, 0.5 N aqueous Masson solution was added. The flask was cooled below 359C, and methylene chloride was added. 29 The layers were separated, and methyl tert-butyl ether was added to the organic layer. The organic was concentrated

GF) layer, receiving sediment. This precipitate was separated by filtration, washed with methyl tert-butyl ether and dried in a vacuum cabinet. The mentioned precipitate was dissolved in methylene chloride and purified on silica gel, obtaining the title compound.

Preparatory synthesis 29 60 5-bromo-2-methanesulfonyl-1,3-dimethylbenzene

5-bromo-2-fluoro-1,3-dimethylbenzene (3.5 g, 17.2 mmol) was added to dimethylformamide (OME, ZOml) at ambient temperature, followed by sodium thiomethylate (1.32 g, 17.9 mmol). The mixture was heated at 502C for 8 hours, then diluted with water (10 ml) and diethyl ether (100 ml). The layers were separated, the organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a residue. This 62 residue was chromatographed on a 5102 column eluting with diethyl ether (20905) in hexane to give

56bmg (1495) 5-bromo-1,3-dimethyl-2-methylsulfanyl-benzene.

5-Bromo-1,3-dimethyl-2-methylsulfanylbenzene (555mg, 2.42mmol) was dissolved in methanol (30ml), and oxone (6.0g, 9.mmol) was added. The mixture was stirred at room temperature for an hour. The obtained suspension was filtered through a layer of silica gel eluting with CH»-SiO (10 Oml). The filtrate was evaporated, and Z1bmg (50

Fo) of the title compound.

Example 98 1-(2-44--2-(3,5-dimethyl-4-methylsulfonyl-phenyl)-6-methoxy-naphthalen-1-yloxy|-phenoxy)-ethyl)-piperidine 70 a re,

M sn, o zOMe sn, zo

Palladium(II) acetate (13 mg, 0.00 mmol), tricyclohexylphosphine (27 mg, 0.1 mmol), cesium fluoride (518 mg, 3, 4 mmol) and acetonitrile (10 mL) were mixed. Stirred for 5 minutes. The compound from Preparatory Synthesis 1 (200mg, 0.33mmol) and bis(neopentylglycol) diboron (129mg, 0.57mmol) were added. It was heated to 902C for 1 min, and 5-bromo-2-methanesulfonyl-1,3-dimethylbenzene (110 mg, 0.42 mmol) in acetonitrile (4 ml) was added. Stirred at 902 for 10 min. It was cooled to room temperature, the solution was diluted with ethyl acetate (20 Oml) and washed with a saturated aqueous solution of ManSO" (10 ml). The layers were separated, the organic layer was washed with brine, dried over M95O, filtered and concentrated in vacuo. The residue was chromatographed on a column of SiO 5 , eluting with methanol (490) in dichloromethane to give 180 mg (76905) of the title compound. in.

Mass spectrum (one sputtering): pt/2-560.3 (M'-H). "-

Example 99

Hydrochloride 6-(3,5-dimethyl-4-methylsulfonyl-phenyl)-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol z7

The compound from Example 98 (180 mg, 0.32 mmol) was dissolved in dichloromethane (bml), and a 2.0 M solution of hydrogen chloride in diethyl ether (0.4 ml, 0.0 mmol) was added. The mixture was stirred at room temperature for a while

For 2 min., after which it was evaporated in a vacuum. After drying in a vacuum, dichloromethane (5 ml) was added to the residue, and (2.0) the solution was placed in an ice bath with stirring. Boron tribromide (0.ml, 1.1 mmol) was added, and the reaction mixture was stirred for 1 h. at room temperature. A saturated aqueous solution of sodium bicarbonate (ml) was added, and the mixture was diluted with CH 5Si" (20 ml). The layers were separated, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on a Bio column eluting with methanol (495) in dichloromethane to give the free base (40 mg) of the title compound. Mass spectrum (on sputtering): t/2-560.3 (MAN). This free base was dissolved in EtOAc (2ml) and ESO (2ml), and 2M NOSI in ESO (0.40ml, 0.800mmol) was added. Stirred at room temperature for 10 min. The solvent was removed in vacuo and the resulting solid was dried in vacuo to give ZOmg (1895) of the title compound. Mass spectrum (ion sputtering) t/27-546.4 (MaN-NSY). co Preparative synthesis of 30 - 4-bromo-1-methanesulfonyl-2-methylsulfanyl-benzene and 4-bromo-2-fluoro-1-methanesulfonyl-benzene (340 mg, 1.34 mmol) was dissolved in OME (8 ml), and sodium thiomethylate was added (10 Zmg, 9, mmol). The mixture was stirred at room temperature for 2 days. Water (1 mL) and CHCl (20 mL) were added. The layers were separated, and the organic layer was washed 20 times with an aqueous solution of lithium chloride (1095), dried (magnesium sulfate) and evaporated under vacuum.

The residue was chromatographed on a Bio column eluting with EtOAc (2095) in hexane to give 286 mg (76,905) m of the title compound.

Example 100 1-(2-44--2--4-methanesulfonyl-3-methylsulfanyl-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine n

F) ime) 60 b5 o ; F o and 502Me v7 7o

Palladium acetate (II) (13 mg, 0.0 mmol), tricyclohexylphosphine (27 mg, 0.1 mmol), cesium fluoride 75. (518 mg, 3.4 mmol) and acetonitrile (100 ml) were mixed. Stirred for 5 minutes. The compound from Preparatory Synthesis 1 (200mg, 0.33mmol) and bis(neopentylglycol) diboron (129mg, 0.57mmol) were added. It was heated to 902C for 1 min, and 4-bromo-1-methanesulfonyl-2-methylsulfanylbenzene (118 mg, 0.42 mmol) in acetonitrile (4 mL) was added.

The mixture was stirred at 902 for 10 min. Cooled to room temperature, diluted the solution

EUDAs (20ml) and washed with a saturated aqueous solution of ManHsSoO»z (1Oml). The layers were separated, the organic layer was washed with brine (1 Oml), dried over MozO), filtered and concentrated in vacuo. The residue was chromatographed on a column of 5 µg eluting with methanol (495) in dichloromethane to give 15 µg (6495) of the title compound. Mass spectrum (ion sputtering): t/2-578.3 (M.--H).

Example 101

6-(4-methanesulfonyl-3-methylsulfanyl-phenyl)-5-I(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol) hydrochloride

The compound from Example 100 (15O0mg, 0.2bmmol) was dissolved in dichloromethane (3ml), and a 2.0M solution of i) hydrogen chloride in diethyl ether (0.2ml, 04mmol) was added. The solution was stirred at ambient temperature for 2 min., after which it was evaporated in a vacuum. After drying in a vacuum, dichloromethane (5 ml) was added, and the solution was placed in an ice bath with stirring. Boron tribromide (0.Tml, h-1.mmol) was added, and the reaction mixture was stirred for an hour. at room temperature. A saturated aqueous solution of sodium bicarbonate (ml) was added, and the mixture was diluted with CHCl (20 ml). The layers were separated, the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried (magnesium sulfate) and evaporated under vacuum. The residue was chromatographed on a ZIO column eluting with methanol (495) in dichloromethane to give the free base (40 mg) of the title compound. Mass spectrum (ion sputtering): - t/2-564.2 (MAN). This free base was dissolved in EtOAc (2ml) and ESO (2ml), and 2M HCl in EBO (04Oml, so 0O, vOmmol) was added. Stirred at room temperature for 10 minutes. The solvent was removed in vacuo and the resulting solid was dried in vacuo to give ZOmg (19965905) of the title compound. Mass spectrum (ion sputtering) pt/2-564.3 (MAAN-NSI). "

Preparatory synthesis 31 2-(4-cyclopropanesulfonyl-phenyl)-4,4,5,5-tetramethyl-|1,3,2)dioxaborolane - c 4-bromo-benzenethiol (2.00 g, 10.bmmol) was dissolved in anhydrous OM5O (5Oml) in a nitrogen atmosphere. Potassium tert-butylate (1.30 g, 11.7 mmol) was added and stirred until dissolved. Cyclopropyl bromide (2.bml, "» 31.vmmol) was added, and the reaction mixture was heated at 802C for 2 days. The reaction mixture was cooled to room temperature and poured into water (500ml). The aqueous layer was extracted with EBO (2x200ml) and washed combined organic layers with water (100 ml). Dried over sodium sulfate and concentrated in vacuo. Chromatographed (ee) the obtained residue on a column of ZO" eluting the product with hexane, and obtained 1.7 g of 1-bromo-4-cyclopropylsulfanylbenzene (72965).

1-Bromo-4-cyclopropylsulfanylbenzene (1.73g, 7.55mmol) was dissolved in anhydrous methylene chloride (75ml). tsRBA (4.8g, 18.8mmol, 6895) was added slowly in portions, controlling the release of heat of reaction. - l 20 After stirring for 1 hour. the precipitate formed was removed by filtration. The filtrate was washed with 1-n. Mann (BOml), and the organic layer was dried over sodium sulfate. It was concentrated in a vacuum, and 2.0 g of 1-bromo-4-cyclopropanesulfonylbenzene (100905) was obtained.

1-Bromo-4-dichloropropanesulfonylbenzene (50mg, 1.9mmol), bis(pinacolato)diboron (577mg, 2.29mmol), potassium acetate (513mg, 5.7/00mmol) and RasSi(arroSnNsiI) (46mg, 0.057 mmol) in anhydrous OMBO (1 Oml) in a nitrogen atmosphere. The mixture was heated at 802C for 4 hours. The reaction mixture was cooled to room temperature

Gee! temperature, and poured it into water (10 Oml). The aqueous phase was extracted with EBO (2x5Oml), and the combined organic layers were washed with water (5Oml). It was dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed on a column with ZO" eluting with the product E(UAs in hexane (10-4095), and 200 mg of the compound indicated in the title (34905) was obtained. 60 Example 102 1--4-(2-(piperidine-1- yl)ethoxy)phenoxy)-2-(4-diclopropanesulfonylphenyl)-6-methoxy-naphthalene b5 o a ; Fo og 8 to

In a dried flask equipped with a reflux condenser, 79 2-(4-cyclopropanesulfonyl-phenyl)-4,4,5,5-tetramethyl-|1,3,2| dioxaborolane (200 mg, 0.6 mmol), a compound with

Preparatory synthesis 1 (15Omg, 0.28mmol) and cesium fluoride (214mg, 1.4mmol). In a separate flask, palladium (II) acetate (b.2 mg, O0.028 mmol) and tricyclohexylphosphine (11.7 mg, O0.042 mmol) were mixed. Acetonitrile (3.0ml) was added and sonicated for 1 hour. in a nitrogen atmosphere. A mixture of catalysts was added to the solid reagents and heated in an oil bath with a temperature of 802 for 20 minutes. The obtained suspension was cooled to room temperature, and it was filtered through a compacted layer of celite. Celite was washed with acetonitrile, and the filtrate was evaporated. The resulting residue was chromatographed on a Bio column eluting with methanol (0-595) in dichloromethane to give 12 ug of the title compound (7790). Mass spectrum (ion sputtering): t/2-558.3 (M.N).

Example 103 p

Hydrochloride 6-(4-cyclopropanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-naphthalen-2-ol H0)

1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)-2-(4-cdcyclopropane-sulfonylphenyl)-6-methoxy-naphthalene (120 mg, 0.21 mmol) was dissolved in methylene chloride (2 ml), added 2M NOSI in EBO (21 Ωcl, 0.42 mmol), and concentrated.

The obtained foam was dissolved in anhydrous methylene chloride (Zml) and cooled to 02C in a nitrogen atmosphere.

VVg»z (9 Омкл, 1.05 mmol) was added dropwise and stirred for 20 min. The reaction mass was poured into t saturated sodium bicarbonate solution (1Oml) and extracted with methylene chloride (2x1Oml). The combined organic layers were dried over sodium sulfate and concentrated to give a yellow solid.

The resulting residue was chromatographed on a column of 50% eluting with methanol (2-1095) in dichloromethane to give 9mg of the free base of the title compound (8790). This free base was dissolved in methylene chloride, and 2M NSI in BBO (20 Ωcl, 0.40 mmol) was added. The solvent was evaporated, and the residue was dried at 452C (pressure "2 mm Hg (x266 Pa)) for 18 hours, obtaining 84 mg of the title compound (69905). Mass spectrum (ion sputtering): t/2-544.3 (MA-N-NSI).

Preparatory synthesis 32 4-bromo-3-(4-methanesulfonyl-phenyl)-7-methoxy-1,2-dihydro-naphthalene « 20 b-Methoxytetralone (1.0 eq.), 4-bromophenyl-methylsulfone (1.02 eq. .), RY(OAc)" (0.025 equiv.), with the ligands ORErNose Coxyde-2,1-phenylene)-bis(diphenylphosphine)) (0.02 equiv.) and toluene (12 volumes) in a three-necked flask, with equipped with a return cooler and a device for nitrogen purging. Then sodium tert-butylate (2.5 eq.) was added in one portion. The reaction mixture was heated due to the heat of the reaction to approximately 402C, while a heterogeneous mixture of yellow color was formed. This yellow heterogeneous reaction mixture was heated at 75-802С7 for 1-2 hours. The yellow suspension was cooled to room temperature, and the reaction was slowly quenched with water (12 volumes), keeping the temperature below 402C. The aqueous suspension was cooled to room temperature and stirred for 2 hours. The suspension was filtered through a polypropylene filter, and - the solid was washed with water (3x2 volumes). The resulting precipitate was dried on a filter in a vacuum overnight at -502C, and crude 2-(4-methanesulfonyl-phenyl)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (9196) was obtained. tsu 5 Loaded 2-(4-methanesulfonyl-phenyl)-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (1.00 equiv.), material. Nuyo (2095 wt.) and toluene (7.5 volumes) in a three-necked flask equipped with a reflux condenser and a device for "| purging with nitrogen. While stirring, РВг»z (1.75 Beq.) was added at room temperature in one portion.

The reaction mixture was heated to reflux (1102) overnight, allowing the gas to escape through a wash beaker with alkali. After heating with reflux for 15 hours. the yellow solution was cooled to 452C, and TNE (20 volumes) was slowly added. The resulting mixture was stirred for 30 minutes. at 455, and about it was filtered in a warm state through the Nuyo layer. The filter layer was washed with TNE heated to 452C (2x2 volumes). The filtrate was concentrated under reduced pressure until TNE was completely removed. Water (7.5 volumes) was carefully added to the residue, maintaining the temperature below 402C. The resulting suspension was cooled to room temperature and stirred for 2 hours. The suspension was filtered through a polypropylene 60" filter and washed with water (2 x 2 volumes). The resulting precipitate was dried on a filter in a vacuum overnight at 502C, and the title compound (74905) was obtained.

Example 104 1-(2-44--2--4-methanesulfonyl-phenyl)-6-methoxy-3,4-dihydro-naphthalene-1-yloxy|-phenoxy)-ethyl)-piperidine b5

0.

Shchy s o, y b y t su " S

Me

The compound from the Preparatory Synthesis 32 (1.Eq.), 4-(2-piperidinylethoxy)phenol (1.5Eq.), SZ»CO»z 75 (2.Eq.) and SiCl (0.2Eq.) were loaded into the three-neck flask equipped with a mechanical stirrer and a reflux condenser.

Toluene (7.5 volumes) was added, and the reaction mixture was degassed, alternating vacuuming and nitrogen purging four times. The reaction mixture was heated under reflux for 4-5 hours. Then the reaction mixture was cooled to room temperature, and it was poured into a mixture of concentrated ammonia solution (1.0 volume), 1-n. Mahon (5.0 volumes) and ethyl acetate (7.5 volumes). The mixture was vigorously shaken, after separation of the layers, the aqueous layer was discarded, and the organic layer was again washed with a mixture of ammonia solution (1.0 volume) and 1-N. mahogany (5.0 volumes) and then brine (5.0 volumes). The organic layer was dried over M950 and concentrated. The resulting solid was dissolved in acetone (2.0 volumes), and hexane (3.0 volumes) was added as a precipitant. After settling the mixture for 1-2 hours, the precipitated product was separated by filtration and dried in air, obtaining the compound indicated in the title (8095).

Example 105 about 6-(4-methanesulfonyl-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenoxy|-7,8-dihydro-naphthalen-2-ol

A three-necked flask was charged with the compound from Example 104 (5mg, 0.094mmol), sodium ethanethiolate (88mg, 1.05mmol) and dimethylformamide (4ml) at room temperature. The reaction mixture was placed in an oil bath with a temperature of 952C, stirred for 4 hours, and then cooled to ambient temperature. The mixture was quenched at room temperature with brine and extracted with ethyl acetate. The combined extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. The crude product was purified on a Spgotay device (hop (silica gel; gradient 5965-1296 Meon in SNeoCl)), and 7 mg of the title compound was obtained (1495). M (IZ'YU) t/e 520 (M'-1). "--

Preparatory synthesis of 33 1-bromo-2-(4-methanesulfonylphenyl)-b6-methoxynaphthalene so

In a three-necked flask equipped with a reflux condenser and a device for purging with nitrogen, b-methoxytetralone (1.0 equiv.), 4-bromophenyl-methylsulfone (1.0271.05 equiv.), RY(OAc)" (0.025 equiv.), ligand ORernose (0.02 beq.) and toluene (10712 volumes). Sodium tert-butylate (2.5 eq.), « 20, was added in one portion and the reaction mixture was allowed to heat up due to the heat of reaction to approximately 402C. The mixture was heated to 75-8020. -in

After completion of the reaction according to the analysis of РХВЕ, the mixture was cooled to room temperature. 12 volumes of water were slowly added, maintaining the temperature below 402C. Stirred for 2 hours. The suspension was filtered through a polypropylene filter, and the solid was washed with water (3x2 volumes). The resulting precipitate was dried on a filter in a vacuum overnight at 502C, and 2-(4-methanesulfonylphenyl)-6-methoxytetralone was obtained.

2-(4-Methanesulfonylphenyl)-b-methoxytetralone (1.Eq.), Nuyo's material (2095 wt.) and toluene (7.5 (ee) volumes) were mixed. With stirring, one portion of РВгз (1,571.7 beq.) was added at room temperature. The reaction mixture was heated under reflux (11022) overnight. After completion of the reaction according to the analysis of РХВЕ (usually after 15 h), the solution was cooled to 452С, and 20 volumes of TNE were slowly added. - Stirred during ZOkhv. at 452 and filtered the reaction mixture in a warm state through a layer of Nuyot. -sh 20 The filter layer was washed with TNE heated to 452С (2x2 volumes). The filtrate was concentrated to approximately 7 volumes. 7.5 volumes of water were added to the remaining mixture, keeping the temperature below 402C. (Note: On

That at the initial stage of adding water, a very exothermic reaction takes place with the release of a significant amount of HBg).

The resulting suspension was cooled to room temperature and stirred for 2 hours. The suspension was filtered through a polypropylene filter and washed with water (2x2 volumes). The resulting precipitate was dried on a filter 59 in a vacuum overnight at about

HF) 1-bromo-2-(4-methanesulfonylphenyl)-3,4-dihydro-6-methoxynaphthalene.

GF 1-bromo-2-(4-methanesulfonylphenyl)-3,4-dihydro-6-methoxy-naphthalene and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (00, 1, equiv. ) in 10 volumes of acetonitrile and 5 volumes of TNE. The reaction mixture was heated in a nitrogen atmosphere at 73-759C. The progress of the reaction was monitored using GC analysis until its completion. To complete the reaction, an additional amount of OR) (0.2-0.Seq.) may be required.

The mixture was cooled to ambient temperature, and 10 volumes of 1-n. sodium hydroxide solution. Stirred for about an hour. and filtered. The sediment on the filter was washed with 2 volumes of water,

Х5 volumes of 5095 acetonitrile and water mixture and, finally, C volumes of methanol. The precipitate was dried on a filter in a vacuum at 652C, and the title compound was obtained.

An alternative method of obtaining the compound from Example 2

1-Bromo-2-(4-methanesulfonylphenyl)-b-methoxynaphthalene, 4-(2-piperidinylethoxy)phenol (2.Eq.), cesium carbonate (2.0-2.1 eq.) and copper chloride (0. 1 beq.) to 12 volumes of diglyme. The flask was vacuumed for about 2 minutes, after which it was purged with nitrogen. The operations of vacuuming and purging with nitrogen were repeated three times. The mixture was heated at 1302 until the completion of the reaction according to the analysis of РХВЕ. After completion of the reaction, the mixture was cooled to almost ambient temperature, 12 volumes of ammonium hydroxide were added, and stirred for about 30 minutes. The mixture was filtered to remove the solid, and this material was washed with 9 volumes of 3095 Meon/MmN.OnH, suspending the solid on the filter. The solid product was washed with 2x9 volumes of 30965 MNAOH/MeonN, suspending the solid on the filter. Washed with 4 70 volumes of methanol. The precipitate was dried on a filter in a vacuum at 6b02C, and the free base of the title compound was obtained. This free base was suspended in 9 volumes of toluene, and the suspension was heated to 70-7590.

Dissolve 1.1 equiv. gaseous hydrogen chloride in 2 volumes of ethanol. An ethanol solution of NS was added to the hot suspension in toluene. The mixture was cooled to room temperature and stirred for 1-2 hours. The precipitate was filtered and washed with a small amount of toluene. The precipitate was dried on a filter in a vacuum at 6592C, and the title compound 75 was obtained.

An alternative method of obtaining the compound from Example 4

1-(2--4--2-(4-methanesulfonyl-phenyl)-6-methoxy-naphthalene-1-yloxy|-phenoxy)ethyl)-piperidine hydrochloride was mixed with 5 volumes of 1,2-dichloroethane (OSE ), and the mixture was cooled to a temperature below 102C. Added to the surface of the mixture

Backv. boron trichloride. The mixture was stirred at ambient temperature until the completion of the reaction according to the analysis of РХВЕ. The reaction mixture was quenched in 5.6 volumes of grade ZA ethanol (ethanol denatured at approximately 595 methanol), maintaining the temperature below 5020. Cooled to ambient temperature and stirred for 1-h. The solid substance was separated by filtration, and the sediment on the filter was washed with ethanol. The precipitate was dried on a filter in a vacuum at 652C, and the title compound was obtained. with

This product was optionally purified by dissolving the isolated product in 9.8 volumes of ethanol ZA and 1.5 Ge) volumes of deionized water at a temperature close to the boiling point of the mixture. The solution was heated under reflux for about 30 minutes and then allowed to cool to ambient temperature. At ambient temperature, the resulting suspension was stirred for 1-2 hours, then filtered and the sediment on the filter was washed with ethanol ZA. This product was optionally purified by dissolving the filter cake in 19 volumes of acetonitrile and 1.4 volumes of deionized water under reflux. Water was removed by azeotropic distillation to obtain a total of 12.1 volumes of distillate. The resulting suspension was cooled to ambient temperature, filtered, and the sediment on the filter was washed with acetonitrile. "--

Dosage forms (pharmaceutical compositions) 3o Since the compounds of formula I contain a basic group (i.e., an amino group), they can be introduced into a dosage form in the form of a pharmaceutically acceptable salt with an acid, for example, in the form of a hydrochloride or a salt (described in the reference "Napdrook o Rpagtaseciisa! Head: Rgoregpyev, ZeIesiop apa ve", MUeippeit, Mem Mogk:

MNeOA; UuPeu-MSN, 2002). Compounds of the formula | or their salts with acids, before introduction into the patient's body, according to the preferred option, they are given the form of dosage units, that is, dosage forms C for individual use, for example, tablets or capsules. The term "patient" includes human females and females of other mammals, such as domestic and domestic animals (dogs, cats, horses, etc.). Advantage

"Iz" among patients is given to people of the female sex. Another preferred patient is the premenopausal woman.

The pharmaceutical compositions of this invention are prepared by known methods using well-known and readily available ingredients. In the manufacture of pharmaceutical compositions according to the present invention, the active ingredient (a compound of formula I or a pharmaceutically acceptable salt thereof) is usually mixed with a carrier - either diluted with a carrier or placed in a carrier, which may be in the form of a capsule, wafer, paper bag or other container . If the carrier performs the function of a diluent, it can be a solid, semi-solid - or liquid material that can be a carrier, filler or medium for the active ingredient. Thus - in 70 ways, the mentioned compositions can be in the form of tablets, pills, powders, lozenges, wafers, packets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile solutions for injections and sterile packaged powders.

Some examples of suitable carriers, fillers and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starch varieties, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate 52, microcrystalline cellulose, polyvinylpyrrolidinone, cellulose, water-based syrup, methyl cellulose,

GF) methyl and propyl hydroxybenzoates, talc, magnesium stearate and mineral oil. The compositions may additionally contain lubricating agents, wetting agents, for example, polysorbate-80 or lauryl sulfate, emulsifiers and suspenders, preservatives, sweeteners or flavoring additives. The compositions of the present invention can be provided with properties that provide immediate, sustained or delayed release of the active ingredient after administration to the patient.

Examples of dosage forms

Capsules or tablets with 1Omg of the active ingredient

About 156 mg of filler (lactose, mannitol, or dextrose), about 20 mg of disintegrant (microcrystalline cellulose or starch), about 4 mg of disintegrator of enhanced BO efficiency (crospovidone or sodium starch glycolate), about 4 mg of binder -BO0- were loaded into the granulator.

(hydroxypropylmethylcellulose or hydroxypropyldelulose) and about 1Omg of the active ingredient (for example, the compound from Example 4), and mixed to obtain a homogeneous mixture of powders. During mixing, an aqueous granulation solution containing povidone, hydroxypropylmethylcellulose or hydroxypropylcellulose (in an amount sufficient to inject 2-495 (w/w) by weight of the dry powders) and a wetting agent such as polysorbate-80 or sodium lauryl sulfate was uniformly sprayed onto the powders. (in an amount sufficient to administer from 0.595 (wt.) to 395 (wt.)). The granulated material was passed in a wet state through a sieve to destroy large agglomerates. Sifted granulated powder was dried in a fluidized state or in a convection dryer. Grind the dried granular powder to a uniform 7/0 particle size by passing through a mill or other suitable device, and then transfer the resulting material to a mixer. The granulated powder was evenly mixed with a lubricating agent (magnesium stearate or sodium stearyl fumarate, approximately 195 of the total weight of the composition) and an additional disintegrant (approximately 2-495 of the weight of the powders excluding the weight of the active ingredient). The finished powder was packaged in hard gelatin capsules or pressed into tablets (with subsequent coating of the tablets with a film, as described below). The total mass of /5 Capsules or tablets made by the described method is approximately 2000 mg.

Capsules or tablets with 45 mg of active ingredient

Approximately 162 mg of filler (lactose, mannitol, or starch), approximately 1 mg of disintegrant (crospovidone or sodium starch glycolate), and approximately 45 mg of active ingredient (e.g., the compound from Example 4) were loaded into the granulator and mixed to obtain a homogeneous mixture of powders. An aqueous granulation solution containing povidone (approx. 35905 wt.) and polysorbate-80 (approx. 1095) was evenly sprayed onto the powders during 2 o of mixing. The granulated material was passed in a wet state through a sieve to destroy large agglomerates. Sifted granulated powder was dried in a fluidized state or in a convection dryer. The dried granulated powder was passed through a mill or other suitable device, and then the resulting material was transferred to a mixer. The granulated powder was evenly mixed with a lubricating agent (magnesium stearate, approximately 195% of the total weight of the composition) and an additional disintegrant (approximately 295% of the weight of the powders excluding the weight of the active ingredient). The finished powder i) was packaged in hard gelatin capsules or pressed into tablets (with subsequent coating of the tablets with a film, as described below). The total mass of a capsule or tablet made in the described way is approximately 23 Ω. M zo Alternatively, for the production of tablets, the filler, disintegrant and active ingredient were loaded into the mixer and mixed until a homogeneous mixture of powders was obtained. After achieving a uniform distribution of the powders, a lubricating agent was added and mixed again. The mixed "- material was transferred to a tablet press, and tablets were made, which were then coated with a film coating of the appropriate film-forming agent. --

Biological tests of co

Estrogen Receptor Binding Test: Representative compounds of the present invention were tested for binding affinity to both types of estrogen receptors (ECA and ECV). In this competitive binding test, the ability of compounds to displace 3H-estradiol is measured, and the values of IS 5) and K are determined; in relation to both types of receptors.

This competitive binding assay was performed in a buffer containing 50 mM Nerez, pH7.5, 1.5 mM EOTA, 150 mM Mass, 10965 glycerol, mg/ml egg albumin, and mM OTT, using 3H-estradiol (MEM and YAMET517 at 118Ci/mmol, 1mCi/ml) in the amount of 0.025mMCi per well and 1Ong/well of EKA or EKV receptor "" (Rapmega). The compound according to this invention was added in 10 different concentrations. Nonspecific binding was determined in the presence of iM 17-B -estradiol. The reaction mixture (1400 μl) was incubated for 4 hours at room temperature, then 7 μl of chilled OSS buffer was added to each mixture (OSS buffer contains 750 mg (ee) of activated carbon (Zidta) and 2500 mg of dextran (Rpagtasia) per 5 0 ml of test buffer). Tablets - were shaken on an orbital shaker for 8 minutes at 42 C. Then the tablets were centrifuged at 3000 rpm at 42 for 1 hour. An aliquot volume of the mixture (120 μl) was transferred to a second 96-well plate, white with - flat-bottomed wells (Soziag) , and added to each well 175 μl of scintillation fluid UMaijas Oriirnaze --3 20 "Level 3". The tablets were closed and intensively shaken on an orbital shaker. After incubation for 2.5 hours. the tablets were scanned using a U/aiias Misgoreg counter. The obtained data were used to calculate IC5O and the percentage of inhibition at a concentration of 10 µM. K 3 was determined for H-estradiol by binding to EKA and EKV receptors until saturation. IC values for the tested compounds were converted to K values using the Cheng-Prusoff equation (Spepd-Rtzoi edtsyop), and K was determined by 22 tests of binding to saturation.

GF) Ishikawa (Izpikaja) cell proliferation test. In this test, cell proliferation was measured (using the alkaline phosphatase indicator) both in an agonistic mode in the presence of only the compounds of this invention, and in an antagonistic mode, in which the ability of the compounds of this invention to block the stimulation of cell growth by estradiol was measured. 60 Human endometrial tumor Ishikawa cells were grown in MEM medium (minimum effective medium with Earle's salts (Eagie) and I-glutamine, Sibso VKI, Saipegerigo, MO), supplemented with 1095 (vol) fetal bovine serum (EB5) (Sibso VKI). One day before the experiment, the growth medium was replaced with the test medium UMEM/E-12 (3:1) (Egla's medium, modified according to Dulbecco: nutrient mixture E-12, 3:1, without phenol red (Birso VKI), supplemented with 1095 (vol. .) fetal bovine serum purified on activated carbon coated with 595 dextran (OSS-EV5) (Nusiope, Godep, OT), I-glutamine (2mm), MEM with sodium pyruvate (1mm), NEREZ (M-(2- hydroxyethyl|piperazine-M'-(2-ethanesulfonic acid), 2mm, all reagents manufactured by Sirso VKI). After overnight incubation, Ishikawa cells were washed with Dulbecco's phosphate-buffered saline (1X) (О-РВ5) without Ca" and Mao" (Sibso VE) and treated with trypsin

3-minute incubation with 0.2590 trypsin/EHUOTA without phenol red (Sibso VK). The cells were re-suspended in the test medium, and the concentration of the suspension was adjusted to 2500O0Ocells/ml.

Approximately 25,000 cells in 100 μl of medium were transferred to 96-well flat-bottom plates for microcultivation (Soviag 3596) and incubated at 379 in a humid atmosphere with 595 CO" for 24 hours.

The next day, serial dilutions of the test compounds were prepared in the test medium (at 70-8 times the final test concentration). The tests were performed in two modes - agonistic and antagonistic.

For the agonist mode, 25 μl/well of the test medium was applied to the plates, followed by 25 μl/well of the diluted compound of this invention (at a 6b final concentration). For the antagonist mode, 25 μl/well of bnm E2 (B-estradiol, Zidta, 51. I otsiv, MO) was used, and then 25 μl/well of the diluted 75 compound according to this invention (at a 6b-fold final concentration). After an additional 48-hour incubation at 372С in a humid atmosphere with 595 СО», the medium was aspirated from the wells, and 10 µl of fresh test medium was added to each microculture. Serial dilutions of compounds were prepared and added to the cells as described above. After an additional 72-hour incubation at 37 C in a humid atmosphere with 596 CO", the reaction was stopped by removing the media and washing the tablets twice with saline solution with phosphate buffer according to Dulbecco (1X) (0-РВ5) (Sibso VKI). Tablets were dried for 5 minutes. and frozen at -709С5 for at least 1 hour. Then the tablets were removed from the cooler and left to thaw at room temperature. 100 μl of the preparation 1-Zier RMRR (Riegse Spetis! Sotrapu,

Koskioga, I). After a 20-minute incubation, the plates were scanned on a spectrophotometer at a wavelength of 405 nm. with

The obtained data were processed by the method of linear interpolation, and EC 50 was determined (for the agonist mode) or about

ISvo (for antagonistic mode). For the antagonist mode, the relative efficiency (in percent) of each compound relative to the presence of only E2 (Inm) was calculated. For the agonist regimen, the relative efficacy (in percent) of each compound relative to the response to tamoxifen was calculated.

Compounds from Examples 3-6, 8, 10, 12, 14, 16, 18, 21, 23, 25, 27, c. were tested in the agonist mode. 29, 32, 34, 36, 39, 43, 46, 49, 53, 56, 58, 59, 61, 63, 65, 67, 70-73, 75, 78, 80, 82, 86, 89, 92, 94, 97, «- 99, 101, 103 and 105 and found that they have less stimulatory effect than tamoxifen. For example, the compound from Example 56 had an efficiency of 71.895. In the agonist mode, the inhibitory action of the same compounds exceeded at least 7095 the response to 1m of estradiol. For example, the compound from Example 16 had an IC of 35.2 nm and an efficiency of 106.7905.

MSE-7 proliferation test: The MSE-7 cell line is obtained from a human adenocarcinoma mammary gland and is used as an indicator of potential antiproliferative action in the mammary gland epithelium.

Cells of the MSE-7 human adenocarcinoma mammary gland line (ATSS NTV 22) were grown in MEM medium (minimum effective medium, without phenol red, Sbirso VKI) supplemented with 1095 (vol.) fetal bovine serum (EV5), Y-glutamine (2mm), with sodium pyruvate (mm), HERE5 (M-(2-hydroxyethyl|piperazine-M'-(2-ethanesulfonic acid), 2mm), substituted amino acids (0.mm) and Z with penicillin-streptomycin (1X). In 7 days before the experiment, MCE-7 cells were transferred to a test "" medium, which is similar to the growth medium, with the exception that it is supplemented with 1090 (vol.) " fetal bovine serum, purified on activated carbon, covered with 595 dextran (0ОСС-ЕВ5) instead of 1095 EV5.

MSE-7 cells were removed from the glasses using 10X trypsin-EOTA (without phenol red, Birso VK), and diluted to a concentration of 1X in HB5Z medium without phenol red (free from Ca""/Ma""7).

The concentration of cells in the test medium was brought up to 800OO cells/ml. Approximately 8,000 cells - (100 μl) were introduced into each well of 96-well scintillation plates Suiovziag T (AtegePpat) and incubated at 372C in a humid atmosphere with 596 CO" for 24 hours. to ensure adhesion and balancing of cells after - transfer. -k 70 Serial dilutions of compounds according to this invention were prepared in the test medium (at 4 times the desired final concentration). In the wells (for two parallel samples), aliquot volumes (5 Ωcl) of dilutions of the test compounds (at 4 times the final test concentration) were introduced, and then 5 Ωcl of the test medium for the agonistic mode or 5 Ωcl of 40 pM E2 for the antagonistic mode to the final volume 200 μl For each tablet of the agonist mode, the base level (in the medium) of 25 and the maximum stimulated level (with E2) were determined. The agonist mode was determined for each tablet

HF) the base level (in the medium) and the control level in the presence of only E2 (1O0pM). After an additional 48-hour incubation at 37 °C in a humid atmosphere with 595 °C, 20 μl of the test medium containing 0.0 μCi of C-thymidine (52 μCi/mmol, 5 μCi/μL, Ategepat) was added to each well. The tablets were incubated for nights under the same conditions, and then scintillations were counted on a counter

MUMaias Misgorega. The data were averaged, and the IC and percentage of inhibition were calculated relative to iMm in the antagonistic mode. For the agonist mode, ES 5o and the percentage of efficiency relative to E2 stimulation were calculated, as well as the concentration of maximum stimulation.

3-day test of antagonistic effects on rat uteri. This model of uterine β5 antagonism uses sexually immature (3-week-old) female rats, which show a very high sensitivity to estrogen stimulation of the uterus because circulating estrogen levels in their bodies are prepubertal. Maters of sexually immature rats are fully responsive to exogenous estrogen, being inactive in the absence of exogenous estrogen. Administration of exogenous estrogen to immature rats causes a significant increase in uterine mass, which can be used to investigate the antagonistic effect on the uterus.

Animals are injected with estradiol and a compound of this invention at 4 different concentrations for 3 days, and then wet uterine weight is determined.

Female rats aged 19 days to 21 days (or with a body weight of 45-50 g) were administered orally with E2 (0.1 mg/kg, an estrogenic stimulus that maximally stimulates a reliable increase in uterine mass) and 1Omg/kg, 1.Omg/ kg,

0.1mg/kg and 0.01mg/kg of the test compound for 3 days; each group included 6 animals. Tested 7/0 bpoluks were dissolved in 2095 solution of B-hydroxycyclodextrin and administered by feeding in a volume of 0.2 ml daily (15 minutes before feeding ethinyl estradiol). The vehicle, E2 and E2nraloxifene were used as controls.

After the administration of the last dose, the animals were kept without food overnight. The next morning, the animals were weighed, euthanized (with carbon dioxide), the uteri were quickly removed (via a midline peritoneal incision) and weighed.

The ratio of the weight of the uterus to the body weight (BWM) was calculated for each animal. Then the relative inhibition (in percent) of the estrogen-induced reaction was calculated according to the formula: to inhibition-100X(OM/Kestrogen- -OM/Kspoluka/OMuUKestrogen-OMUKkontrol).

By means of semi-log regression analysis of the linear portion of the dose-response curve, the value of EOvo was determined. Both the data from OMUK and the data from inhibition were statistically analyzed by one-way analysis of variance (ANOVA) followed by Fisher's test (RI 50) in cases where p<0.05 was indicated. Statistical analysis was performed using the Ziaimiem U 4.0 software package.

Compounds from 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 , 92, 99, 101 and 103 were tested as described above and were found to inhibit the estrogen-induced He response when administered at a dose of 1.00 mg/kg. For example, the compound from Example 92 had ЕЮОБо о

O.5Zmg/kg and 9o antagonistic influence 62.7905. A 4-day test of the agonist effect on the uterus of OMH rats. In order to confirm the absence of a partial agonistic effect of the tested compounds on the uterus, the compounds were administered to sexually mature ovariectomized rats. -

Rats were ovariectomized at the age of 75 days, and after 14 days, when the levels of circulating estradiol reached a minimum, the experiments began. After a 4-day treatment with doses of the compounds according to this invention (by rats per group), body weight, wet uterus weight and eosinophil peroxidase (EPO) activity were determined. what

Cholesterol levels were also determined to compare the relative cholesterol-lowering ability compared to other 5ECMs. In case of doubt about the presence or absence of uterine stimulation, the thickness of the epithelial layer was determined -

Cell histological examination. Ge

The compounds of Example 4 and Example 14 were tested and found not to cause a dose-dependent, statistically significant increase in EPO activity. 10-day test of hormonal status (ovarian stimulation) in rats. First, a primary test for ovarian toxicity was performed using a 10-day hormone assay to measure estradiol and luteinizing hormone (LH) levels after administration of the test compounds. This test was performed by oral administration of compounds with food for 10 days to sexually mature (age 9-10 weeks) E344 female rats. Blood was collected from the aorta by quickly cutting off the head for determination of IH and estradiol levels approximately 2 hours later. after the tenth dose. The blood serum obtained by centrifugation was removed and stored until the tests at a temperature below -60 C. The levels of IN and estradiol were determined by radioimmunoassay (IAA) methods. (ee) Primary rat IN antibody and controls (I H:KR-3) were obtained from Dr. Parlow (Og. A. RE. - Rapom/, Oigesiog, Rishyagu Nogtopez apa Apiizega Sepieg, Nagrog-OSI A Meadis! Sepieg , Togapse, SA). The upper limit of detection when determining IN was ZOng/ml, and the lower limit was 0O.Tng/ml for samples with a volume of 10 Ωcl. -l 20 Reagents for clinical analysis were obtained from the company OiazZogip 8.g.1, Zaishdia (Megseyii), Mau. The upper limit of detection was 100Opg/ml, and the lower limit was 5pg/ml. that compounds from Examples 4-6, 14, 21 and 103 were tested in this way; found that they did not cause a significant increase in circulating estradiol or IN levels.

A 5-day osteoporosis test in rats with healthy ovaries. Since known ACE inhibitors, including raloxifene, show efficacy in preventing osteoporosis in OMH rats, the possibility of an interaction with estrogen-regulated metabolism in ovariectomized rats should be considered.

This test was performed on sexually mature rats, the test concentrations were selected based on the results of the aforementioned three-day test. As a rule, at least three concentrations multiples of the obtained value of EbO 50 were chosen. These concentrations were, as a rule, 1x, 10x and ZOHEO5o. Compounds of this invention 60 were administered to OMH rats for 35 days and, for comparison, to control, ovariectomized, and/or rat gonadotropic hormone (RAH) animals. Femur bones, large tibia bones, uteri, ovaries and blood serum were used for further research.

Tubular bones were examined by X-ray X-ray absorption (X-ray absorption of two energies), CT (computed tomography) and histological analysis in order to detect any changes. The results of a 65-degree scan of the distal end of the femur were used to determine BMO (bone mineral density), cross-sectional area, and BMS (mineral content). Bone strength measurements (load to failure) can also be used to determine the effects of changes in bone mass or material.

Histological studies of the uterus and ovaries were used to confirm the effects of long-term use of the compounds on uterine function and potential ovarian stimulation. The serum was analyzed for the content of IN and E?2 as a possible indicator of the effect on the ovaries.

Utility

As estrogen antagonists in mammary and uterine tissues, the compounds of formula I or their pharmaceutically acceptable acid salts are useful in the treatment of conditions for which estrogens have been shown to be causative. As estrogen agonists in the skeletal and cardiovascular systems, compounds of the formula | or their 7/0 pharmaceutically acceptable acid salts are useful in the treatment of conditions for which estrogens have been shown to have a beneficial role.

The terms "treating" and "treating" as used herein include their common meanings, i.e. ameliorating, ameliorating, eliminating, preventing, preventing, limiting, retarding, terminating, or reversing the development or severity of a pathological condition or its effects , described in this document. The term "prophylaxis" means reducing the likelihood of the occurrence or development of any of the disease states or their complications described herein in an organism into which the compounds of formula I or their pharmaceutically acceptable acid salts are administered.

Diseases, disorders or pathological conditions for which the compounds of formula I or their pharmaceutically acceptable acid salts are useful include (but are not limited to) (1) uterine and/or breast cancer; (2) endometritis; (3) treatment and resolution of uterine leiomyoma(s) and associated symptoms; and (4) osteoporosis. The treatment for uterine leiomyoma (leiomyoma) described in this document may also provide relief from associated symptoms such as pain, frequent urination, and uterine bleeding.

Dosage

As used herein, the term "effective amount" means an amount of a compound of formula I or a pharmaceutically acceptable acid salt thereof that is capable of treating the pathological conditions or adverse effects thereof described herein. and)

The specific dose that is applied to the patient is determined in each case by specific circumstances.

These circumstances include the route of administration, the patient's medical history, the condition or symptom to be treated, the severity of the condition or symptom, and the age and gender of the patient. The patient's attending physician should determine the Mzo therapeutic dose taking into account these relevant circumstances.

Typically, the effective minimum daily dose of a compound of the present invention is greater than about 5 mg. In 07 typical cases, the effective maximum dose does not exceed approximately 350 mg. The exact dose can be determined - where according to the standard medical practice "dose titration" in relation to the patient, that is, the appointment of a small dose of sporluka at first and a gradual increase in the dose until the desired therapeutic effect is achieved. --

Ways of introducing co

Compounds of the formula | or their pharmaceutically acceptable acid salts can be administered by a variety of routes, including intramuscular, nasal, vaginal, intravenous, oral, rectal, subcutaneous, topical, and transdermal routes. Oral use is preferred. "

Complex therapy with c Compounds of formula I or their pharmaceutically acceptable salts with acids can be used in combination with other drugs that are used to treat diseases or conditions in which they are useful;" these compounds. Such other drugs may be administered by routes and in amounts conventionally used for this purpose, simultaneously or sequentially with the compounds or salts of this invention. In case

The use of a compound of the present invention simultaneously with one or more other medicinal products is an advantage

Go! given in dosage units of a dosage form that contains one or more other drugs in addition to the compound of the present invention. Accordingly, the pharmaceutical compositions of this invention include - compositions that contain one or more other active ingredients. Examples of other active ingredients that can be combined with the compounds of this invention and used alone or as part of the same pharmaceutical composition include agents used in hormone replacement therapy (HRT).

What

Claims (23)

The formula of the invention 1. The compound of formula I: o CH, I, K-sndu--x and 1 -y and Z, where: 65 t, 4 and g independently of each other are 0, 1 or 2; pe or 1; -B4- E is H or SOCU; BO independently in each case is OH, CE3, halogen, C4-C8-alkyl or C-Ce- alkoxy group; B and B" independently of each other are C1-C8-alkyl, C1-C8-alkyl, MA, CE3 or СНоСЕ"; or, if ptade is 0, then the group -5O28 can in combination with a phenyl ring, with which it is connected, form a fragment of formula (a) or formula (b): sn) (a), 50, and (Sni, o, (c), Mt ch-o and deitam is 0, 1 or 2, provided , that the sum of im should be equal to 2; B? is C4-Cv-alkyl; C-Cv-alkyl; ME"B"; phenoxy group; or phenyl, optionally substituted by halogen; BZ is C-C-alkyl or phenyl; Za and КЕ" independently in each case is H, C1-C8-alkyl or phenyl; X is O, СНо or СО; X' is O or ME; BZ is H or C-4-Ce-alkyl; c BZ is H or methyl , provided that if r is 1 or 2, then EZ must be H and if r is 0, then EZ must be methyl; and d) Y is CHNHCH" or CH-CH; or a pharmaceutically acceptable acid salt of such compound. 2. Compound according to claim 1, where t is 2 and g is 1 or 2; or a pharmaceutically acceptable acid salt of such compound. 3. Compound according to claim 1 or claim 2, where is BC? is C4-C8-alkyl, MNSNaz or phenyl and group -3028! does not combine with - phenyl, to which it is attached, with the formation of a fragment of formula (a) or formula (B); or a pharmaceutically acceptable salt of such a compound with an acid. 4. Compound according to any of claims 1-3, where n is 0; d is 0 or 1; group -3028E! occupies the lar position in the phenyl to which it is attached; K o is OH, CEz, fluorine, chlorine, methyl or ethyl; B" is methyl, ethyl, n-propyl, isopropyl, - C35 cyclopropyl, i-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl or C3; VC? is C4-C6-alkyl or phenyl; and MU is co SNASN; or a pharmaceutically acceptable salt of such compound with an acid. 5. A compound according to any one of claims 1-4, where X and X" are O; or a pharmaceutically acceptable salt of such a compound with an acid. " 6. Compound according to any of claims 1-5, the grandfather is 0; B is methyl, ethyl, cyclopropyl or CE"; and M is SNASN; or a pharmaceutically acceptable acid salt of such compound. - 7. The compound according to any of claims 1-6, selected from the group that includes: S IF She 52 SE, Y so 60 no b5 nak, ' no and so, s shshch 70 50 Me KA S st s ' o " vo or a pharmaceutically acceptable salt of such a compound with an acid. 8. A compound corresponding to the formula: nats) , c | - 502 Me about NO and | them- or a pharmaceutically acceptable salt of such a compound with an acid. - 9. A compound corresponding to the formula: or a pharmaceutically acceptable salt of such a compound with an acid. " 10. A compound that corresponds to the formula: s c ZO Me y Ci v ho (ee) - or a pharmaceutically acceptable salt of such a compound with an acid. - 11. A compound that corresponds to the formula: o ny ' - 50 Me i Ce KA i S F) ! - or a pharmaceutically acceptable salt of such a compound with an acid. where 12. A compound that corresponds to the formula: ek, ' i c z 50, but also b5 - y . or a pharmaceutically acceptable acid salt of such compound. -58c- 13. A compound corresponding to the formula: С st с ' o vo ШІ no . - or a pharmaceutically acceptable salt of such a compound with an acid. 70 14. A compound according to any one of claims 1-13, which is a hydrochloride. 15. A compound according to any one of claims 1-44 or a pharmaceutically acceptable salt of such a compound with an acid for use in the treatment of endometritis and/or uterine leiomyoma. 16. The compound of formula II: snu, I' 5 M-(sНni-х KE 5O Y y-o U (B, where: t, 4, r and y independently of each other are 0, 1 or 2; пе or 1 ; Ge BO independently in each case is OH, CEz, halogen, C-Cv-alkyl or C.-Cv-alkyl group; C 179426 17946 Ge) B' and KE" independently of each other are C.-Cv-alkyl, Si --Sn-Alkoxy group, mA a, CE3 or СНоСЕ"; or, if n and d are 0, then the group -ОВ! can, in combination with the phenyl ring to which it is connected, form a fragment of the formula (c) or the formula (9): SN. (c), - гy 5 -- х (CH - 50, (9, -- s MY deitam is 0, 1 or 2, provided that the sum of im should be equal to 2; « B? is C.-Cv-alkyl ; C--Cv-Alkoxy group; ME"; phenoxy group; or phenyl, optionally substituted by halogen; - t0 BZ is C-C-C-alkyl or phenyl; c Za and KE" are independently in each case H, C-C-C-alkyl or phenyl; :z" B is H, C1-C6-alkyl, benzyl or COC?; B is H, C4-C6-alkyl or CO5(C1-C6-alkyl); BZ is H or methyl, provided that that when r is 1 or 2, then 28 must be H; if r is 0, then C must be methyl; (ee) X is O, CH0 or CO; z X? is O or ME 7; Y is CHNHCH" or CH -CH; - or a pharmaceutically acceptable salt of such a compound with an acid; -oUu 70 with the proviso that y can only be 2 if B is C.4-Cv-alkyl or benzyl; or a salt of such a compound with an acid. 17. A compound according to claim 16 or a salt of such a compound with an acid, where r is 1 or 2; and "M a) if n is 0 and the group ZO and KO in combination with the phenyl ring to which they are connected form a fragment of formula (c) or formula (9), then i is 2; and p) if n is 1, then both t and y are 0, both are 1, or both are 2. 29 18. The compound according to claim 16 or claim 17, where the group -vOV! does not combine with the phenyl to which it is attached, with HF) to form a fragment of formula (c) or formula (4) and occupies the lara position in said phenyl to which it is attached; n is 0; d is 0 or 1; KO is OH, CE", fluorine, chlorine, methyl or ethyl; VE" is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, 4-butyl, isobutyl, t-butyl, tert-butyl, cyclobutyl or CE; VC? is C1-C6-alkyl or phenyl; X and X' is O; and M is СНеАСН; or a salt of such a compound with an acid. 19. The compound according to any of claims 16-18, grandparent; IN! is methyl, ethyl, cyclopropyl or CEz; and M is SNASN; or a salt of such a compound with an acid. 20. The compound according to any of claims 16-19, selected from the group consisting of: b5 ev. , 5O Me se Me -0 so su nk 70 50. Me -O s A 7 ZO SE, Me -0 С st s ' o " vo o o Me- a o or a salt of such a compound with an acid. 21. A compound corresponding to the formula: Ме , М нище) / М 3о | o - Ya Fo y y no - or a pharmaceutically acceptable salt of such a compound with an acid. with 22. The compound of formula I: SN, I, KE -(snu.-K « rev t OK, o) s zo, r» 9-0 " - y Z, , where: (ee) I . t, 4 and r independently of each other is 0, 1 or 2; -- pe or 1; - VE is H or SOC?; and y 29 independently in each case is OH, CE3, halogen, C4-C8-alkyl or C.-Ce -alkoxy group; B1 is methyl, ethyl, cyclopropyl or CE"; "and B" independently of each other is C1-C6-alkyl, C4-C6-alkyl, MA, CE3 or SNOCE"; or, if n and 4 is 0, then the -302K! group can, in combination with the phenyl ring to which it is connected, form a fragment of formula (a) or formula (B): сн) (а), Ф) 5, and d) (СН (In (c), because kh Mk 7 and -o because the deities are 0, 1 or 2, provided that the sum of them should be equal to 2; IN? is C4-C6-alkyl; Ci-Cv-Alkoxy group; ME "V"; phenoxy group; or phenyl optionally substituted with halogen; BZ is C.4-Cv-alkyl or phenyl; Za and KE" are independently in each case H, C1-C8-alkyl or phenyl; X is O, СНо or СО; X' is O or ME; BZ is H or C1-Cr-alkyl; BZ is H or methyl , provided that if r is 1 or 2 then EZ is H and if r is 0 then EZ is methyl; and M is 5; then either a pharmaceutically acceptable salt of such compound with an acid. 23. Compound of formula II: n-sn-vol or OA 1 y-o U (KE n where: t, 4, r and y independently of each other are 0, 1 or 2; pye 0 or 1; VO independently in each case is OH, CE3, halogen, C4-C8-alkyl or C.-C6-alkyl group; He!B! is methyl, ethyl, cyclopropyl or CE"; o БЕ" independently of each other is C.-Cv- Alkyl, C4-C6-Alkoxy group, MAza, CEz or SNYOSE"; or, if n and 4 are 0, then the group -ZO.K! can, in combination with the phenyl ring to which it is connected, form a fragment of the formula ( c) or formula (a): сн, (o, te gr 5 -- 50, (9), - MY d) deitam is 0, 1 or 2, provided that the sum of imu should be equal to 2; "V? is C.-Ci-alkyl; C--Ci-alkyl; ME"; phenoxy group; or phenyl, optionally substituted by halogen; t0 BZ is C.-Ci-alkyl or phenyl; 8 c Za and KE" independently in each case is H , C1-C8-alkyl or phenyl; :z" B is H, C1-C8-alkyl, benzyl or COC?; B is H, C4-C8-alkyl or CO5(C1-C8-alkyl); BZ is H or methyl, provided that when r is 1 or 2, 28 is H; when r is 0, C is methyl; o X is O, CH 2 or C AT; with X? is O or ME 7; M is 5; - or a pharmaceutically acceptable salt of such a compound with an acid; -oUu 70, provided that y can be only 2, if K5 is C.-Cv-alkyl or benzyl; or a salt of such a compound with an acid; and under the additional condition that the compound of formula II does not correspond to any of the following formulas: "m - or /-- ! ; Me -O0 5 no 5 6o Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 20, 10.12.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. b5