KR20150039705A - Novel arylalkene derivatives and use thereof as selective estrogen receptor modulators - Google Patents

Abstract

The present invention provides novel alkene-based compounds represented by formula I that are capable of preventing and / or treating estrogen dependent pathology or disease as selective estrogen receptor modulators (SERMs).

Description

NOVEL ARYLALKENE DERIVATIVES AND USE THEREOF AS SELECTIVE ESTROGEN RECEPTOR MODULATORS FIELD OF THE INVENTION [0001] The present invention relates to novel arylalkene derivatives,

The present invention relates to a series of substituted arylalkenyl compound derivatives used as selective estrogen receptor modulators (SERMs), pharmaceutical compositions thereof, uses in pharmaceuticals, and methods of preventing and / or preventing estrogen-dependent diseases of mammals ≪ / RTI >

The estrogen receptor (ER) is an important nuclear transcription factor and plays an important physiological role in the reproductive system, bone tissue, cardiovascular and central nervous system. More than 400 tissues or organs, including the uterus, the vagina, the breast, the pelvic girdles (ligaments and connective tissue), the skin, the bladder, the urinary tract, the skeleton and the cerebrum, etc., contain receptors for estrogen in the female body. As women enter the menopausal world and estrogen is massively reduced, all the tissues, organs, and systems in which estrogen-related receptors are present undergo corresponding changes. Thus, older women generally exhibit a series of menopausal symptoms, including facial flushing, fever, face lift, depression, headache, vaginal dryness, cardiovascular symptoms, urinary incontinence, swelling, breast tenderness and fatigue (Payer, L: The menopause in various cultures. In: A portrait of the menopause Expert reports on medical and therapeutic strategies for the 1990s Ed. Burger H & Boulet M, Parthenon Publishing, Park Ridge, NJ, 22, and Rekers H: Mastering the menopause. In: A portrait of the menopause. Expert reports on medical and therapeutic strategies for the 1990s. Ed. Burger H & Boulet M, Parthenon Publishing, Park Ridge, NJ, USA, 1991. pp. 23-43) strategies for the 1990s. Ed. Burger H & Boulet M, Parthenon Publishing, Park Ridge, NJ, USA, 1991. pp. 23-43). Prolonged estrogen deficiency can lead to osteoporosis, senile dementia and cardiovascular disease.

Estrogen replacement therapy is increasingly being used in women with menopausal allergy. At the same time, estrogen replacement therapy reduces osteoporotic fractures and is effective in the prevention of Alzheimer's disease (Henderson VW: Estrogen, cognition, and as a woman's risk of Alzheimer's disease . Am J Med 103 (3A): 11S-18S, It has been reported that LDL-cholesterol levels can be reduced to prevent cardiovascular disease (Grodstein F, Stampfer, MJ: Estrogen for women at varying risk of coronary disease . Maturitas 30: 19-26, 1998). However, the use of estrogen replacement therapy may increase the risk of breast and endometrial cancer (Lobo RA, Am J Obstet Gynecol 173: 982-990, 1995).

Selective estrogen receptor modulators (SERMs) exhibit different activities against estrogen receptors in different tissues. They mimic estrogen in some tissues, and some have anti-estrogenic effects in some tissues. Using these properties of SERMs, it is possible to develop an ideal drug that causes agonists to the estrogen receptor in the bone tissue, the cardiovascular system and the central nervous system, but in the mammary gland and the uterus such as the estrogen receptor, Side effects of therapy can be avoided.

Raloxifene, a SERMs drug approved for the treatment of osteoporosis for the first time, exhibits ER antagonism in mammary gland and uterine cells and ER immunoreactivity in bone tissue and cardiovascular system. However, raloxifene is not superior to tamoxifen in the clinical treatment of breast cancer and also causes adverse reactions such as facial flushing, spasms, headache and weight gain (Davies GC et al., Obstet Gyneco l93: 558-565 1999).

Therefore, there is a need to prevent and treat estrogen-dependent diseases and conditions with more effective and safe drugs.

In one aspect, the present invention provides a compound represented by the general formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

here,

R ⁰ and R ¹ are each independently selected from hydrogen, a halogen, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, And independently may be substituted by one or more substituents selected from halogen, -OH, -NH ₂ , -SH, an alkyl group, a halogenated alkyl group and an alkoxy group, and the carbon atoms of said cycloalkyl, heterocyclyl and heteroaryl groups Lt; / RTI > may optionally be oxidized;

The A ring and the B ring are each independently selected from an aryl group, a heteroaryl group and a heterocyclyl group; the carbon atoms of the heterocyclyl group and the heteroaryl group may be optionally oxidized;

R ² and R ³ are each independently selected from the group consisting of halogen, -OH, -NH ₂ , -CN, -SH, -COOH, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy, alkylsulfanyl A cycloalkyloxy group, a heterocyclyloxy group, a monoalkylamino group, a dialkylamino group, a -S (O) -alkyl group and a -S (O) ₂ -alkyl group, and the alkyl group, alkenyl group (O) -alkyl group and -S (O) ₂ -alkyl group may be substituted with at least one substituent selected from the group consisting of an alkyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an alkoxy group, a cycloalkoxy group, a heterocycloalkoxy group, a monoalkylamino group, a dialkylamino group, R ⁴ and R ⁵ are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, or R ⁴ and R ⁵ are each independently selected from the group consisting of halogen, -OH, heterocyclyl or -NR ⁴ R ⁵ , form a heterocyclyl with the nitrogen source connected to the ^fifth and these Number, and said heterocyclic group may optionally be substituted by an alkyl group;

m and n each represent the number of R ² in ring A and the number of R ³ in ring B, and m and n are each independently selected from 0, 1, 2 or 3.

In another aspect, the invention provides a compound represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof, for use in the modulation of estrogenic activity.

In another aspect, the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of estrogen- Isomer or prodrug thereof.

In another aspect, the invention provides a pharmaceutical composition comprising a compound represented by Formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof, and a pharmaceutically acceptable carrier A pharmaceutical composition is provided.

In another aspect, the invention relates to the use of a compound represented by the general formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof in the manufacture of a medicament for the modulation of estrogenic activity .

In another aspect, the present invention relates to the use of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof for the prevention and / or treatment of an estrogen-dependent disease or condition, Or for the manufacture of a medicament for treatment.

In another aspect, the present invention provides a method of preventing and / or treating estrogen-dependent diseases and conditions in a mammal, particularly a human, comprising administering to a mammal, particularly a human, in need thereof a therapeutically effective amount of a compound of formula I Includes administering the indicated compound or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof.

Figure 1 shows the nude mouse weight change in the anti-cancer (MCF-7) test.

Unless otherwise defined, the meaning of all technical terms in the text is identical to those understood by those of ordinary skill in the art to which the claimed subject matter belongs. Unless otherwise stated, all patents, patent applications, and publicly available material cited in the entire text are incorporated by reference in the text.

The foregoing summary and the following detailed description are exemplary and, for illustrative purposes only, and are not to be construed as limiting the subject matter of the invention. In the present invention, plural numbers are included when a single number is used, unless otherwise specified. It should be noted that, unless the context clearly dictates otherwise, the singular forms used in this specification and the appended claims include plural forms of specified objects. It should also be noted that unless otherwise stated, the terms " or " or " used " mean " and / or ". In addition, the terms " inclusive " and other forms of use, such as " including, " " inclusive, "

Definitions of standard chemical terms can be found in the references (Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 ^TH ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise specified, conventional methods of the art are used, such as mass spectrometry, NMR, IR and UV / Vis spectroscopy spectroscopy and pharmacological methods. The terms used in the description of analytical chemistry, organic synthetic chemistry, and drug and drug chemistry in the text are well known in the art, unless the specific definition is presented. Standard techniques can be used in chemical synthesis, chemical analysis, drug manufacturing, formulation and delivery, and treatment of patients. For example, reactions are carried out and purification proceeded using the instructions of the manufacturer's kit, or in a manner known in the art or described herein. Conventionally, the techniques and methods may be practiced in accordance with conventional techniques well known in the art by reference to a plurality of abstracts and specific literature references cited and discussed herein. In the present specification, radical groups and substituents thereof may be selected by those skilled in the art to provide stable structural moieties and compounds.

When describing a substituent through a conventional chemical formula written from left to right, the substituent includes a chemically equivalent substituent which is obtained when a structural formula is written from right to left. For example, CH ₂ O is the same as OCH ₂ .

The paragraph headings used in the present invention are merely indicative of sentence organization, and do not limit the matters to be described. All documents or subdocuments cited in this application include, but are not limited to, patents, patent applications, sentences, books, instruction manuals and articles, and the documents are cited in the text as quoted.

In some of the chemical radicals (substituents) named here, the number of carbon atoms can be displayed using the abbreviation. For example, the C ₁ -C ₆ alkyl group represents an alkyl group group and indicates that the total of 1 to 6 carbon atoms is contained. The total number of carbon atoms indicated by the abbreviated symbol does not include the number of carbon atoms present in the substituent.

Further, unless expressly stated otherwise, the following terms used in the above description or in the description of the invention and in the claims shall have the implications specified therein.

The term "halogen", "halogenated" or "halide" refers to bromine, chlorine, fluorine and iodine.

The term " aromatic ring, " " aromatic ", " aromatic ", and " aromatic ring " used in the present specification mean a ring part of one or plural rings in planar form, Lt; RTI ID = 0.0 > n < / RTI > is an integer. An aromatic ring may be formed from 5, 6, 7, 8, 9, or 9 or more atoms. The aromatic compound may be optionally substituted and may be monocyclic or fused ring polycyclic. The term aromatic compound includes all carbon containing rings (for example benzene rings) and rings containing one or more heteroatoms (for example pyridine).

The term " heteroatom " or " hetero, " as used herein alone or as part of another component means an atom other than carbon and hydrogen. Hetero atoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments where there are two or more heteroatoms, the two or more heteroatoms may be identical to each other, or some or all of the two or more atoms may be different from each other.

The term " fused " or " fused ring ", as used herein alone or in combination, means a ring structure in which two or more rings together share one or more bonds.

The term " alkyl group " used alone or as part of another component, such as a halogenated alkyl group, means an optionally substituted straight or optionally substituted side chain monovalent saturated hydrocarbon, which has from 1 to 12 carbon atoms, Preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms. May be connected to other part of the molecule by a single bond and may be bonded to other part of the molecule by a single bond such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec- n-pentyl group, n-hexyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, n-octyl group, .

As used herein, the term " alkoxy group " refers to the group -OR _a where R _a is an alkyl group as defined above. Specific examples of the alkoxy group include a methoxy group, ethoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group and tert-butoxy group.

As used herein, the term " alkylthio group " refers to the group -SR _a , wherein R _a is an alkyl group as defined above. Specific examples of alkylthio groups include methylthio group, ethylthio group, isopropylthio group and the like.

The term " monoalkylamino group " as used herein refers to the group -NHR _a , wherein R _a is an alkyl group as defined above. Specific examples of the monoalkylamino group include a methylamino group, an ethylamino group, and an isopropylamino group.

The terms " dialkylamino group "," bisalkylamino group ", as used herein, refers to the group -NR _a R _b , wherein R _a and R _b represent independent alkyl groups as defined above. Specific examples of the "dialkylamino group" and "bisalkylamino group" include a dimethylamino group, a diethylamino group, a dipropylamino group, and a methylethylamino group.

The term " alkenyl group " used alone or as part of another component in the context means a straight or branched monovalent hydrocarbon group, which has only carbon and hydrogen atoms, contains at least one double bond, Containing from 2 to 14 carbon atoms, preferably from 2 to 10 carbon atoms, more preferably from 2 to 6 carbon atoms. This may be connected to other parts of the molecule by a single bond and may be, for example, an ether group, a 1-propenyl group, an allyl group, a 1-butenyl group, a 2-butenyl group, And Nilki.

The term " alkynyl group " used alone or as part of another component in the context refers to a straight or branched monovalent hydrocarbon group, which contains only carbon and hydrogen atoms, contains at least one triple bond, More triple bonds or more double bonds. Also, it includes 2 to 14 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. This may be linked to other moieties of the molecule by a single bond and may include, for example, ethynyl, 1-propynyl, 1-butynyl, pent- ynyl).

The term " cycloalkyl group " used alone or as part of another component in the text refers to a stable mono-valent non-aromatic monocyclic or polycyclic hydrocarbon group and includes only carbon and hydrogen atoms And may include fused rings or bridged ring systems, including 3-15 ring carbon atoms, preferably 3-10 ring carbon atoms, and 3-8 rings More preferably a saturated carbon atom, and may be saturated or unsaturated and may be connected to other moieties of the molecule by a single bond. Specific examples of the "cycloalkyl group" include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclohexanonyl group, cycloheptyl group, cyclooctyl group, 1H-indenyl group, Dihydroindenyl group, 1,2,3,4-tetrahydronaphthyl group, 5,6,7,8-tetrahydronaphthyl group, 8,9 dihydro-7H-benzocyclohepten-6-yl (8 , 9-dihydro-7H-benzocyclohepten-6-yl), 6,7,8,9-tetrahydro-5H-benzocycloheptenyl (6,7,8,9- 7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, dicyclo [2.2.1] heptene, 7, Dimethyl-dicyclo [2.2.1] heptyl, dicyclo [2.2.1] heptyl group, dicyclo [2.2.2] octyl group, Dicyclo [2.2.1] octenyl, dicyclo [3.2.1] octenyl, adamantyl, Tetahydro-4,7-methylene-1H-indenyl, octahydro-2,5-methylene-pentalinyl, Norbornyl, decalinyl, and the like. In the present invention, the heterocyclyl preferably contains 3-8 carbon atoms, and is more preferably a cyclopentyl group, a cyclohexyl group, a cyclohexanonyl group, or a cycloheptyl group.

As used herein the term " cycloalkoxy group " refers to the group -OR _b , wherein R _b is a cycloalkyl group as described above.

The term " heterocyclyl group "," heterocyclyl group / heterocyclic ", as used herein alone or as part of another component, refers to a stable 3-18 membered mono-valent non-aromatic ring, 2-12 carbon atoms, 1-6 nitrogen, oxygen and sulfur. Unless otherwise indicated, a heterocyclyl group may be a single ring, a bicyclic ring, a tricyclic ring, or a quaternary ring system, which may include a fused ring or bridged ring system, The nitrogen, carbon or sulfur may optionally be oxidized, the nitrogen atom may optionally be quaternized, and the heterocyclyl group may be partially or fully saturated. The carbon atom of the heterocyclyl group may be connected to the rest of the molecule by a single bond and the heteroatom of the heterocyclyl group may be connected to the remainder of the molecule by a single bond. Heterocyclyl groups including fused rings may include one or more aromatic rings or heteroaromatic rings, and the remaining part of the molecule And an atom on the non-aromatic ring may be connected. In the present application, it is preferred that the heterocyclyl group is a stable 4-11 mono-valent non-aromatic monocyclic ring or dicyclo which contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, More preferred are stable 4- to 8-membered mono-valent non-aromatic monocyclic rings containing heteroatoms selected from 1-3 nitrogen, oxygen and sulfur. Specific examples of the heterocyclyl group include a nitrogen heterocycyclobutyl group, a morpholinyl group, a piperazinyl group, a piperidyl group, a pyrrolidine group, and a thienyl group.

As used herein the term " heterocycloalkoxy group " refers to the group -OR _c , wherein R _c is a heterocyclyl group as described above.

The term " aromatic ring, "" aromatic cyclic group, "" aromatic group / aryl group " or " Refers to a hydrocarbon ring system comprising hydrogen, 6-18 ring carbon atoms, with 6-10 ring carbon atoms and at least one aromatic ring being preferred. In the present invention, the aromatic ring may be a single ring, a bicyclic ring, a tricyclic ring or a quaternary ring system, which may include a fused ring or a bridged ring system. The aryl carbon atoms can be linked to other moieties of the molecule by a single bond. Specific examples of the aryl group include a phenyl group, a naphthyl group, and an anthracenyl group. In the present invention, the aryl group is preferably an aryl group having _{6 to 10} carbon atoms, more preferably a phenyl group.

The term " heteroaryl group ", used alone or as part of another moiety in the text, refers to a 5-16 membered ring system containing 1-15 carbon atoms, 1-10 carbon atoms, 1-4 nitrogen , A heteroatom selected from oxygen and sulfur, and at least one aromatic ring. Unless otherwise indicated, a heteroaryl group can be a single ring, a bicyclic ring, a tricyclic ring, or a quaternary ring system, which can include a fused ring or bridged ring system, Is an aromatic ring atom. The nitrogen atom, the carbon atom and the sulfur atom on the heteroaromatic ring may be selectively oxidized, and the nitrogen atom may be optionally quaternized. In the present invention, a stable 4-11 membered (mono) aromatic ring is preferred as the heteroaryl group, which contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur and is a stable 5-8 membered (mono) More preferred are aromatic rings, which contain 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of non-limiting examples of heteroaryl groups include benzimidazolyl, benzothiazolyl, benzoxazolyl, carbazolyl, indazolyl, isoindazolyl, isoquinolyl, quinolyl, isothiazolyl Yl, pyridyl-2-ketone group-4-yl, pyridyl group, pyridyl group, pyrimidinyl group, pyrimidinyl group, A pyrimidine pyrrolyl group, a quinolyl group, a quinine group, a thiazolyl group, and a tetrazolyl group. In the present application, the heteroaryl group is preferably a 5- to 8-membered heteroaryl group, which contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and is selected from pyridyl, pyrimidinyl, thiazolyl, oxopyridyl , 1H-pyridine-2-ketone group-4-yl or thienyl group.

The terms " optional ", " optional ", " selectively ", as used herein, mean that a later matter or circumstance occurs or does not occur and that the statement or circumstance occurs, It is not included. For example, an "optionally substituted aryl group" indicates that the aryl group is substituted or unsubstituted, and the description also includes unsubstituted aryl groups including substituted aryl groups.

The terms " substituent ", " radical group ", and " chemical radical group (substituent) " used in the present text refer to a specified moiety or functional group in the molecule. Chemical radicals are usually recognized as chemical entities inserted or added to the molecule.

&Quot; Stereoisomer " refers to a compound that has the same atoms bonded to the same bond but has a different three-dimensional structure. In the present invention, various stereoisomers and mixtures thereof will be considered.

In addition to the separate designations, the compounds described in the present invention have olefinic double bonds and include E and Z isomers.

&Quot; Tautomeric " refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All compounds of the present invention encompass any tautomer of the compound.

The term " crystalline polymorph "or" crystalline polymorph (phenomenon) " used in the present invention indicates that the compound of the present invention has various crystal lattice forms. Some of the compounds of the present invention may have one or more crystalline forms, and the present invention encompasses all polymorphic forms or mixtures thereof.

Also included within the scope of the present invention are the intermediate compounds of formula (I), all crystalline polymorphs of this kind and the properties of their crystals. Likewise, all of the transitional property types are also encompassed within the scope of the present invention.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, can have one or more asymmetric centers and are capable of producing enantiomers, non-enantiomers, and other stereoisomeric forms, Configuration is indicated by (R) - or (S) -. The present invention includes all possible isomers, and their racemates and optically pure forms. Optically active (+) and (-), or (R) - and (S) -isomers can be separated by chiral reactant source or by chiral reagent, And can be prepared, for example, by column chromatography and fractional crystallization.

Conventional techniques for preparing / separating enantiomeric monomers include proceeding or using chiral synthesis from optically pure precursors, for example by chiral high performance liquid chromatography (HPLC) There is a method of separating a semi-body (or a racemate of a salt or a derivative). You can refer to the following data. Gerald Giibitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A.M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3: 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

The term " pharmaceutically acceptable salts " as used herein includes acid addition salts and also includes base addition salts.

&Quot; Pharmaceutically acceptable acid addition salt " refers to salts formed with inorganic or organic acids, while maintaining the biological effectiveness and properties of the free base of the compound, without side effects in the biological or other aspects, , Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, but not limited thereto, and examples of the organic acid include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, , Camphoric acid, caproic acid, caprylic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2- But are not limited to, disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 1,5-di-tert-butylanthraquinone, maleic acid, maleic acid, malonic acid, methanesulfonic acid, acetic acid, naphthalene-1,5-di But are not limited to, sulfonic acid, sulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, auroic acid, oxalic acid, palmitic acid, fumaric acid, propionic acid, pyroglutamic acid, pyruvic acid, , Stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like, but are not limited thereto.

A " pharmaceutically acceptable base addition salt " refers to a salt that retains the biological effectiveness and properties of the free acid of the compound, while at the same time without side effects on the biological side or otherwise. Such salts are prepared by reacting the free acid with inorganic or organic salts. Salts formed by reaction with inorganic salts include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts and aluminum salts . As inorganic salts, ammonium salts, sodium salts, potassium salts, calcium salts and manganese salts are preferable.

Organic salts which form salts include, but are not limited to, primary amines, secondary amines, tertiary amines, substituted amines (including amines with substitution in nature), cyclic amines and basic ion exchange resins, For example, there may be mentioned ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylaminoethanol, 2-dimethylethanolamine, But are not limited to, hexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, venetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, deobromine, Tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. As organic salts, isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine are particularly preferred.

In the present invention, a solvate of the compound is frequently generated by crystallization. The term " solvate " as used herein refers to an aggregate composed of one or more molecules of the compound of the present invention combined with one or more solvent molecules.

Water may be used as the solvent, in which case the solvate is a hydrate. An organic solvent may also be used. Accordingly, the compounds of the present invention may exist as hydrates and include monohydrates, dihydrates, hemihydrates, trihydrates, tetra-hydrates and the like, including the corresponding solvated forms. The compounds of the present invention may be pure solvates, but under some other circumstances, the compounds of the present invention may possess adventitious water or may have a mixture of water and other solvents mixed. The compound of the present invention can be reacted in a kind of solvent or precipitated or crystallized in a kind of solvent. Solvates of the compounds of the present invention are also encompassed within the scope of the present invention.

The present invention also relates to prodrugs of the compounds of the present invention. &Quot; Prodrug " refers to a compound of the present invention in which a compound can be converted to have a biologically active action under physiological conditions or under solvation. Thus, the term " prodrug " refers to a pharmaceutically acceptable metabolizable sphere of the compound of the present invention, which may be inactive when administered to a subject in need of such prodrug, Can be switched. Prodrugs are generally hydrolyzed in the body, e. G., In the blood, and rapidly converted to the parent compound of the present invention. Prodrugs are typically excellent in solubility, tissue compatibility, or delayed release in organisms of mammals. Prodrugs include protecting groups for amino groups and protecting groups for carboxy groups, all of which are self-evident to those of ordinary skill in the art. Methods for preparing prodrugs include, for example, those described by Saulnier, M. G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R. B., et al., J. Med. Chem. 2000, 43, 475, incorporated herein by reference.

The term " pharmaceutical composition " as used herein refers to a preparation in which the compound of the present invention is usually admixed with media acceptable in the art, wherein the medium contains a biologically active compound to a mammal (e. G., A human) It acts to transmit. Such a medium includes all pharmaceutically acceptable carriers.

The term " acceptable " with respect to the formulation, composition or ingredient used in the text indicates that there is no persistent adverse effect on the overall health of the subject.

The term " pharmaceutically acceptable " as used herein refers to a relatively non-toxic substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the invention, i.e., Indicates that there is no poor biological response or does not interact with any of the components contained in the composition in a poor manner.

"Pharmaceutically acceptable carrier" means an adjuvant, carrier, excipient, accelerator, deodorant, diluent, preservative, dye / colorant, seasoning, surfactant, wetting agent, But are not limited to, dispersants, suspensions, stabilizers, isotonic agents, solvents or emulsifiers.

The term " SERM " as used herein refers to a selective estrogen receptor modulator, which exhibits estrogen receptor antagonism in one or more target tissues and may exhibit estrogen receptor control in one or more other target tissues.

The term " subject, " " patient, " or " subject " used in the context of the present invention refers to an individual suffering from a disease or disturbance or pathology, including mammals and non-mammals. Examples of mammals include any member of the mammal (Mammalia): humans, quadrumana animals other than humans (eg, chimpanzees and other apes and monkeys), livestock such as cows, horses, sheep, goats, pigs But are not limited to, pets such as rabbits, dogs, cats, laboratory animals, Glires such as rats, mice, and guinea pigs. Non-human mammals include, but are not limited to, birds and fish. The mammal in the manner of practicing the methods and compositions provided herein is human.

The term " prevention ", " prophylaxis ", and " prevention (verb) " encompass reducing the likelihood of patient suffering or breast cancer.

The term " treatment ", as used herein, refers to treating a mammal, particularly a human related disorder or condition, and encompasses the following conditions.

(I) preventing the mammal from becoming ill or suffering from a disease, in particular a mammal which has been exposed to a disease or condition but has not yet been diagnosed as having the disease or disease, Preventing from showing signs of disease;

(Ii) controlling disease or pathology, i.e., controlling the development of disease or pathology;

(Iii) relieving disease and pathology, ie, weakening disease and pathology;

(Iv) relieving the symptoms of disease and pathology.

The terms " disease " and " pathology " used in the text may be interchangeable and may have different meanings. This is because some specific diseases or pathologies do not have known infectious agents (because the cause of the illness is not clear) and therefore can not be certified as a disease, As well.

The term " effective amount ", " therapeutically effective amount ", or " pharmaceutically effective amount ", as used herein, refers to the amount of at least one agent or compound capable of ameliorating one or more symptoms of the disease or condition being treated, . The result is a reduction in signs and symptoms or causes of the onset and / or alleviation, or any other change in demand of the biological system. For example, an " effective amount " for treatment is the amount of a composition of a compound disclosed in the present invention that is required to provide clinically significant neuropathic effects. For example, the dosage of the dosage-adjusted test is used to determine the appropriate effective amount for any individual case.

As used herein, " dosing, "" injecting, "" administering, " and the like, are methods of delivering a compound or composition to a required site that causes biological action. Such methods include oral administration routes, duodenal routes, parenteral injections (intravenous, subcutaneous, intraperitoneal, intramuscular, intramuscular or dermal injection), topical administration and rectal administration. Those skilled in the art are familiar with the input techniques that apply to the compounds and methods of the present invention, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed .; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred method of screening, the compounds and compositions of the present invention are administered orally.

As used herein, the term " agonist " refers to a molecule that increases the activity of other molecules or the activity of a receptor site, such as compounds, drugs, enzyme activators or hormone modulators.

The term " antagonist " as used herein refers to a molecule that eliminates or inhibits the activity of other molecules or receptor sites, for example, a compound, drug, enzyme inhibitor or hormone modulator.

As used herein, the term " modulating " means directly or indirectly interacting with a target to alter the activity of the target. For example, increasing target activity, inhibiting target activity, or increasing target activity or target activity.

The term " modulator " as used herein means a molecule that interacts directly or indirectly with a target. Such interactions include, but are not limited to, the interaction of agonists and antagonists.

Similar words such as " enhancement / enhancement ", as used in the present invention, mean increasing the effect of the required effect or prolonging the duration of the effect desired. Thus, the term " enhancing " when referring to an enhancement of the therapeutic effect, means an ability to increase the efficacy or prolong duration of other therapeutic agents acting on the system.

The term " amount of enhancing effect (amount capable of effectively enhancing the action) " as used in the present invention means an amount capable of enhancing the effect of causing other therapeutic agents in the necessary system.

The term " drug combination ", " other treatment administration ", " other therapeutic agent administration ", etc. used in the present invention refers to a drug treatment in which the active ingredients are mixed or combined, Static combination. The term " fixed combination " refers to the administration of the at least one compound according to the invention and at least one co-agent to a patient in the form of a unitary or single dosage form. The term " non-stationary combination " means to administer to a patient in the form of a monolith, a combination of at least one compound according to the invention and at least one co-agent, either sequentially or sequentially, To provide two or various levels of effective levels in a patient ' s body. Such administration is also applicable to cocktail therapy, for example, administering three or more active ingredients.

As used herein, the terms " co-administration ", " ... Quot; administration in combination with ", as well as their synonyms, refers to the administration of a selected therapeutic agent to the same patient, and is intended to encompass treatment strategies in which the agent is administered via the same or different routes of administration or the same or different dosing frequency have. In some embodiments, the compounds according to the present invention and other medicaments are co-administered. This term encompasses administering two or more drugs to an animal to allow simultaneous presence of the drug and / or other metabolites in the animal's body. The term includes administering the different compositions simultaneously and administering the different compositions at different times and / or administering one composition containing the active ingredients in a different order. Thus, in some embodiments, the compounds of the present invention and other agents are mixed and administered in one composition.

As used herein, the term " metabolite " refers to a derivative of a corresponding compound formed upon compound metabolism.

As used herein, the term " active metabolite " refers to a derivative of a corresponding compound that has activity to be formed upon compound metabolism.

As used herein, the term " metabolism " refers to any process in which a biological entity is converted to a specified substance, including, but not limited to, hydrolysis and enzymatic catalysis. Thus, the enzyme can cause the compound to undergo a specific structural change. For example, cytochrome P450 catalyzes a variety of redox reactions, and uridine diphosphate glucuronyltransferase catalyzes the conversion of activated glucuronic acid molecules into aromatic alcohols, aliphatic Catalyzes the transfer to aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. For more information on metabolism, see The Pharmacological Basis of Therapeutics , 9th Edition, McGraw-Hill (1996).

In one aspect, the invention provides a compound represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

here,

R ⁰ and R ¹ are each independently selected from hydrogen, a halogen, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, The carbon atoms of the cycloalkyl group, the heterocyclyl group and the heteroaryl group may be substituted with one or more substituents independently selected from halogen, -OH, -NH ₂ , -SH, alkyl groups, halogenated alkyl groups and alkoxy groups, Optionally oxidized;

The A ring and the B ring are each independently selected from an aryl group, a heteroaryl group and a heterocyclyl group; the carbon atoms of the heterocyclyl group and the heteroaryl group may be optionally oxidized;

R ² and R ³ are each independently halogen, -OH, -NH ₂ , -CN, -SH, -COOH, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an alkoxy group, alkoxy group, a heterocycloalkyl alkoxy group, a monoalkylamino group, a dialkylamino group, -S (O) - alkyl group and -S (O) ₂ - is selected from the group; the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic (O) -alkyl group and -S (O) ₂ -alkyl group are optionally and independently substituted with one or more substituents selected from the group consisting of halogen, - (C ₁ -C 6) alkyl, OH, a heterocyclyl group, or -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, or R ⁴ and R ⁵ and the nitrogen atom Together form a heterocyclyl group, said heterocycle Groups may optionally be substituted by an alkyl group and;

m and n each represent the number of R ² groups in ring A and the number of R ³ groups in ring B, and m and n are each independently selected from 0, 1, 2 or 3.

In one aspect, the present invention provides the compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof,

R ⁰ and R ¹ are each independently selected from an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, and the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally and independently substituted with halogen, -OH, an alkyl group, a halogenated alkyl group, and an alkoxy group, and the carbon atoms of the cycloalkyl group, the heterocyclyl group and the heteroaryl group may be optionally oxidized.

In another aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

R ⁰ and R ¹ are each independently selected from an alkyl group, a cycloalkyl group, an aryl group and a heteroaryl group, and the alkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally and independently substituted with halogen, -OH, an alkyl group and an alkoxy group , And the carbon atoms of the cycloalkyl group and the heteroaryl group may be optionally oxidized.

In another aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

Wherein one of R ⁰ and R ¹ is an alkyl group and the other is selected from a cycloalkyl group, an aryl group and a heteroaryl group, and R ⁰ and R ¹ are each independently and independently selected from the group consisting of halogen, -OH, -NH ₂ , -SH, an alkyl group, an alkoxy group and a halogenated alkyl group, and the carbon atom of the cycloalkyl group or the heteroaryl group may be optionally oxidized.

In one aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof,

^One of R < ⁰ > and R < ¹ > is an alkyl group or a halogenated alkyl group, and the other is selected from the following a) to d).

a) a 5-membered heteroaryl group containing at least one heteroatom selected from oxygen, sulfur and nitrogen, said heteroaryl group being optionally substituted by one or more substituents selected from halogen, -OH, an alkyl group, an alkoxy group and a halogenated alkyl group ; A thienyl group optionally substituted by one or more halogen is preferred;

b) a 6-membered heteroaryl group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, said heteroaryl group optionally being substituted with one or more substituents selected from halogen, -OH, alkyl, alkoxy and halogenated alkyl groups, And the carbon atom on the heteroaryl group may optionally be oxidized; a pyridyl group optionally substituted by one or more -OH is preferred;

c) a 5-membered or 6-membered cycloalkyl group, said cycloalkyl group may be optionally and independently substituted by one or more substituents selected from halogen, -OH, an alkyl group, an alkoxy group and a halogenated alkyl group, Is optionally oxidized; a cyclohexanone group or a cyclohexyl group optionally substituted by one or more -OH groups is preferred;

d) a phenyl group, said phenyl group may be optionally substituted with one or more substituents selected from halogen, -OH, an alkyl group and an alkoxy group.

In one aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof,

R ⁰ and R ¹ is one of hydrogen, is selected from a halogen and an alkyl group, that alkyl group may be substituted by a selective and a halogen, -OH, NH _2, substituents selected independently from an alkoxy group; or optionally, one or And the other of R < ⁰ > and R < ¹ > is a structure represented by the general formula (II)

In the structure represented by the general formula (II), the dotted line indicates that the 5-membered ring composed of X, Y and W and the carbon atoms connected thereto is saturated or unsaturated,

Wherein each of X, Y and W is independently selected from C, N, O and S; said 5 membered ring is optionally substituted with one or more groups selected from halogen, -OH, -SH, an alkyl group, a cycloalkyl group, an alkoxy group and an alkylthio group Wherein the alkyl, cycloalkyl, alkoxy and alkylthio groups are optionally and independently substituted with one or more groups selected from halogen, -OH, -NH ₂ , monoalkyl, dialkylamino and heterocyclyl groups, or And may be substituted by a plurality of substituents.

In another aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

At least one of X, Y and W is a heteroatom selected from N, O and S and the 5-membered ring may be optionally substituted by a substituent selected from one or more halogen and alkyl groups.

In another aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

The formula (II) is selected from the following formulas.

In another aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

Ring A and ring B are each independently selected from an aryl group and a heteroaryl group, wherein the carbon atom of the heteroaryl group may be optionally oxidized.

In another aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

Ring A and ring B are each independently selected from a 6-membered heteroaryl group containing an aryl group and one or two nitrogen atoms, wherein the carbon atom of the heteroaryl group may be optionally oxidized.

In another aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

Ring A and ring B are each independently selected from phenyl and pyridyl groups.

In another aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

R ² and R ³ are each independently selected from halogen, -OH, -NH ₂ , -CN, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, a heterocycloalkoxy group, a monoalkylamino group and a dialkylamino group Wherein said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heterocycloalkoxy, monoalkylamino and dialkylamino groups are optionally and independently substituted with halogen, -OH, heterocyclyl or -NR ⁴ R ⁵ , Wherein R < ⁴ > And R ⁵ are each independently selected from hydrogen, an alkyl group and a cycloalkyl group, or R ⁴ and R ⁵ and the nitrogen atom connected thereto together form a heterocyclyl group, said heterocyclyl group being optionally substituted with an alkyl group .

In another aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

R ² and R ³ are each independently selected from halogen, -OH, -NH ₂ , -CN, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, a heterocycloalkoxy group, a monoalkylamino group and a dialkylamino group The alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the alkylthio group, the heterocycloalkoxy group, the monoalkylamino group and the dialkylamino group may be optionally and independently substituted by a heterocyclyl group or -NR ⁴ R ⁵ , , Wherein R ⁴ and R ⁵ are each independently selected from halogen or an alkyl group, or R ⁴ and R ⁵ and the nitrogen atom connected thereto together constitute a heterocyclyl group, said heterocyclyl group being optionally substituted by an alkyl group .

In one aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof,

Ring A is selected from a phenyl group and a 6-membered heteroaryl group and also has at least one R ² group at the para position of the phenyl group or the para position of the 6-membered heteroaryl group;

Ring B is selected from a phenyl group and a 6-membered heteroaryl group, and there is also at least one R ³ group at the para position of the phenyl group or the para position of the 6-membered heteroaryl group.

In one aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof,

m and n are each independently selected from 1 or 2.

In one aspect, the present invention provides a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or precursor drug thereof, ≪ / RTI >

In another aspect, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof, used for the modulation of estrogen activity .

In another aspect, the present invention relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof in the manufacture of a medicament for the modulation of estrogenic activity Application.

In another aspect, the invention relates to a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, pharmaceutically acceptable salt or solvate thereof for use in the prevention and / or treatment of estrogen- Tautomer or prodrug thereof.

In another aspect, the invention relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof for the prevention and / or treatment of estrogen- / RTI > and / or for the manufacture of a medicament for treatment.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof, and a pharmaceutically acceptable carrier Or a pharmaceutically acceptable salt thereof.

Typically, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is administered by forming a suitable pharmaceutical composition with one or more pharmaceutically acceptable carriers. The pharmaceutical composition of the present invention may be in the form of a solid, semi-solid, liquid or gaseous form, for example tablets, capsules, powders, granules, ointments, solutions, suppositories, injectables, inhalants, gels, microspheres and aerosols .

Typical routes of administration for such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal absorption, inhalation, intestinal extrahepatic, sublingual, rectal, vaginal and nasal cavity. For example, capsules, tablets, granules and syrups are included as formulations suitable for oral use. The compound of the present invention contained in this formulation type may be a solid powder or granules; a solution or suspension in a water solvent or a non-aqueous solvent; an oil-in-water type oil-in-water emulsion; The form of the preparation can be prepared by conventional pharmaceutical methods from the active compound and one or more carriers or adjuvants. The carrier should be compatible with the active compound or other adjuvant. Examples of non-toxic carriers commonly used in solid preparations include mannitol, lactose, starch, magnesium stearate, cellulose, glucose and sucrose, but are not limited thereto. Examples of the liquid preparation carrier include, but are not limited to, water, physiological saline, glucose, glycol, and aqueous solution of polyglycol. The active compound may form a solution or suspension with the carrier.

The specific route of administration and dosage form should be established based on self-knowledge knowledge, which is familiar to those skilled in the art, depending on the physical / chemical characteristics of the compound itself and the severity of the disease to be treated.

In another aspect, the present invention provides a method of modulating the estrogenic activity of a mammal (particularly a human), said method comprising administering to a mammal (particularly a human) in need thereof a therapeutically effective amount of a compound of formula (I) Compounds, or pharmaceutically acceptable salts, stereoisomers, solvates, crystalline polymorphs, tautomers, or prodrugs thereof.

In one aspect of the invention, the estrogen receptor is administered by a compound represented by the general formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof, It is positively regulated in the system and central nervous system, and negative in the tissues of the breast and uterus.

In another aspect, the present invention provides a method of preventing and / or treating estrogen-dependent diseases and conditions in a mammal, particularly a human, comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) Or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof, for use as a medicament.

The estrogen-dependent diseases and conditions described in the text refer to diseases and conditions associated with estrogen receptor modulation. In one aspect of the invention, the estrogen-dependent diseases and conditions are selected from the group consisting of menopausal or postmenopausal disorders, vasomotor symptoms, genitourinary or exogenous atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, Endometrial cancer, breast cancer, etc.), depression, diabetes, demineralization of bone, and osteoporosis.

The compounds described in the present invention, or pharmaceutically acceptable salts, stereoisomers, solvates, crystalline polymorphs, tautomers, or prodrugs thereof are administered in a therapeutically effective amount, the therapeutically effective amount being varied by a series of factors, These elements include: That is, the activity of the specific compound employed, the metabolic stability and efficacy of the compound, the age of the patient, the weight, the overall health status, sex and food habits, the mode and time of administration, the frequency of excretion, The severity, and the subject receiving the treatment. Generally, a dose of about 0.01 mg / Kg body weight to about 100 mg / Kg body weight per day of a therapeutically effective dose of about 0.01 mg / Kg body weight to about 50 mg / Kg body weight, preferably about 1 mg / / Kg body weight to about 25 mg / Kg body weight. Particularly, the dose of the compound of the present invention is about 1 mg / Kg body weight to about 100 mg / Kg body weight; the oral dose is about 1 mg / Kg body weight to about 500 mg / Kg body weight to be.

The range of the effective drug dose described in the present invention is not limited, and only a range of preferable drug dose is presented. However, the most preferable drug dose should be adjusted depending on the mediator, and it will be apparent to those skilled in the art (see, for example, Berkow et al., Eds., The Merck Manual, 16 ^th edition, Merck and Co., Rahway, NJ, 1992).

Depending on demand, the total drug dose required for medicament therapy may be administered in multiple doses per day or in a single dose. Under normal circumstances, treatment begins with a small dose of drug relative to the optimal drug dose. Then, the dosage is gradually increased to reach the optimum effect. Medicinal compounds or compositions used in the diagnosis can be administered alone or in combination with other diagnostic procedures and / or drugs used for pathology or other symptoms. The subject of administration of the compounds and / or compositions of the present invention may be any mammal. Preferred subjects include primates (including humans, apes and monkeys), homozygotes (including horses, goats, cows, sheep, pigs), Rodenta (including mice, rats, rabbits and hamsters) ). A more preferable object is a person.

≪ Preparation of compound of the present invention &

The following reaction path diagram illustrates the preparation of the compounds of the invention.

It should be understood that the substituents and / or changes in the molecular formula can be combined in the case where a stable compound can be formed in the following description.

It will be clear to those skilled in the art that the functional groups of the intermediate compounds in the following processes may require protection of suitable protecting groups. These functional groups include a hydroxyl group, an amino group, a mercapto group, and a carboxyl group. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups such as tert-butyl methylsilyl, tert-butyl diphenylsilyl or trimethylsilyl groups, A tetrahydropyranyl group, a benzyl group, and the like. Suitable amino, amidino and guanidino protecting groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto groups include -C (O) -R "(where R" represents an alkyl group, an aryl group or an arylalkyl group), a paramethoxybenzyl group, a triphenylmethyl group and the like. Suitable protecting groups for the carboxy group include alkyl groups, aryl groups or arylalkyl esters.

Protecting groups may be added or deleted by standard techniques known in the art.

The use of protecting groups is described in detail in the fourth edition of Greene's Protective Groups in Organic Synthesis (2006). The protecting group may be a polymer resin.

The compounds represented by the general formula I of the present invention are prepared according to the route shown in the flow chart 1.

In Flow Chart 1, the McMurry coupling reaction proceeds between Compound II and Compound III, thereby obtaining an alkene derivative I. Compounds II and III can be purchased directly or can be prepared by synthetic methods known to those of ordinary skill in the art.

Example

The following examples, preparation methods and intermediates are provided as illustrations of the present invention and are not intended to limit the scope of the present invention.

Example 1

(Z) -4- [1- (6- chloro-3-pyridinyl) -2-phenyl-1- alkenyl) phenol ((Z) -4- (l- ( 6-chloropyridin-3-yl) -2-phenylbut-1-enyl) phenol)

Step A: (6-Chloro-3-pyridinyl) [4- (tetrahydro- 2H -pyran-2-oxyl) H- pyran-2-yloxy) phenyl) methanone)

Magnesium powder (1.67 g, 1.2 eq.) Is added to anhydrous THF (50 mL). The mixture is heated to 55 < 0 > C and iodine and bromoethane are added. Dissolved pyran (2- (4-Bromophenoxy) tetrahydro -2H -pyran) (16 g, 1.1 eq.) In THF - 2- (4- Bromo mope noksil) tetrahydro -2 H. Some of the above solution is added to the mixed solution of Mg-THF. After the reaction is initiated for 30 minutes, reflux is started. The remaining solution is added and the reaction solution is refluxed for 2 hours. The obtained MgBr-THF solution is used as the next step.

The MgBr-THF solution was dropwise added to an anhydrous THF solution of 6-chloronicotinoyl chloride (10.0 g, 1 eq.) Under nitrogen gas protection at 0 ° C, And the mixture was allowed to rise to room temperature, followed by stirring overnight at room temperature.

Water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated and then eluted with petroleum ether / ethyl acetate (5/1) by silica gel column chromatography to obtain the target product (13.6 g , 76%). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.78 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz , 1H), 7.15 (d, J = 8.0 Hz, 2H), 5.56 (t, J = 3.2 Hz, 1H), 3.83-3.90 (m, 1H), 3.63-3.67 (m, 1H), 2.02-2.05 ( 1H), 1.89-1.92 (m, 2H), 1.69-1.75 (m, 2H), 1.59-1.65

Step B :( Z) -4- [1- ( 6- chloro-3-pyridinyl) -2-phenyl-1- alkenyl) phenol ((Z) -4- (l- ( 6-chloropyridin-3 -yl) -2-phenylbut-1-enyl) phenol)

Under nitrogen gas protection at room temperature, slowly add TiCl ₄ (6.8 mL, 3 eq.) To a dry THF (150 mL) mixture of stirred zinc powder (8.06 g, 6 eq.). After completing the dropwise addition, the mixed solution is heated to 80 DEG C and refluxed for 1 hour. After cooling to room temperature, a solution of propiophenone (8.2 g, 3 equivalents) and (6-chloro-3-pyridinyl) [4- (tetrahydro- g, 1 eq.) in dry THF. The mixed solution is refluxed again for 2 hours. It is then quenched with saturated aqueous NaHCO ₃ solution and extracted with EtOAc. The extract was dried and concentrated, and then purified by column chromatography to obtain 6.3 g (92%, Z / E = 1/1) of Z / E mixture. The Z / E mixture was recrystallized in a mixture of petroleum ether and dichloromethane to obtain pure Z compound (2.8 g, 41%). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.85 (s, 1H), 7.06-7.25 (m, 8H), 6.97 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H) , 2.51 (q, J = 7.6 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H); m / z = 336 [M + 1] < ⁺ >.

Example 2

(E) -4- [1- (6- chloro-3-pyridinyl) -2-phenyl-1- alkenyl) phenol ((E) -4- (l- ( 6-chloropyridin-3-yl) -2-phenylbut-1-enyl) phenol)

The Z / E mixture prepared in Example 1 and Step B was recrystallized in methanol solution to give 3.0 g of the target product (E-type). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.34 (s, 1H), 7.07-7.48 (m, 7H), 6.70 (d, J = 8.4 Hz, 2H), 6.50 (d, J = 8.0 Hz, 2H) , 2.45 (q, J = 7.2 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H); m / z = 336 [M + 1] < ⁺ >.

Example 3

(Z) -4- (1- {6- [2- ( methylamino) ethoxy] -3-pyridinyl} -2-phenyl-1- alkenyl) phenol ((Z) -4- (l- (6- (2- (methylamino) ethoxy) pyridin-3-yl) -2-phenylbut-1-enyl)

NaH (373 mg, 8.0 eq.) Is added to a stirred solution of 2- (methylamino) ethanol (672 mg, 10 eq) in anhydrous THF (20 mL) under stirring. The mixture was stirred at room temperature for 1 hour and then 300 mg (1 equivalent) of (Z) -4- [1- (6-chloro-3-pyridinyl) -2- phenylbutyl- 1), and the reaction mixture is heated to reflux for 16 hours. After quenched, quenched with a saturated aqueous ammonium chloride solution and extracted with dichloromethane, the extract was dried and filtered to obtain the target product (200 mg, 60%) by column chromatography separation. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.59 (s, 1H), 7.18-7.20 (m, 2H), 7.08-7.16 (m, 3H), 7.01-7.06 (m, 3H), 6.77 (d, J = 8.4 Hz, 2H), 6.28 (d, J = 8.4 Hz, 1H), 4.28 (t, J = 5.2 Hz, 2H), 2.93 (t, J = 5.2 Hz, 2H), 2.46-2.55 (m, 5H ), 0.92 (t, J = 7.6 Hz, 3 H); m / z = 375 [M + 1] < ⁺ >.

Example 4

(E) -4- (1- {6- [2- ( methylamino) ethoxy] -3-pyridinyl} -2-phenyl-1- alkenyl) phenol ((E) -4- (l- (6- (2- (methylamino) ethoxy) pyridin-3-yl) -2-phenylbut-1-enyl)

(100 mg, prepared and obtained in Example 2) was obtained in the same manner as in Example 3, ( E ) -4- [1- (6-chloro-3-pyridinyl) ) As a raw material to obtain the target product (53 mg, 48%). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.09 (s, 1H), 7.31-7.7.34 (m, 1H), 7.09-7.10 (m, 5H), 6.68 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.4 Hz , 1H), 6.47 (d, J = 8.4 Hz, 2H), 4.44 (t, J = 5.2 Hz, 2H), 3.01 (t, J = 5.2 Hz, 2H), 2.46- 2.52 (m, 5 H), 0.9 (t, J = 7.2 Hz, 3 H); m / z = 375 [M + 1] < + >.

Example 5

(Z) -4- (1- {6- [2- ( dimethylamino) ethoxy] -3-pyridinyl} -2-phenyl-1- alkenyl) phenol ((Z) -4- (l- (6- (2- (dimethylamino) ethoxy) pyridin-3-yl) -2-phenylbut-1-enyl)

(798 mg, 10 eq.) And ( Z ) -4- [1- (6-chloro-3-pyridinyl) -2-phenylbutyl- (300 mg, 1 eq., Obtained in Example 1) is used as the starting material to obtain the target product (260 mg, 75%). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.54 (s, 1H), 7.14-7.20 (m, 2H), 7.01-7.09 (m, 5H), 6.93 (d, J = 8.0 Hz, 1H), 6.78 ( d, J = 8.0 Hz, 2H ), 5.84 (d, J = 8.8 Hz, 1H), 4.22 (t, J = 5.2 Hz, 2H), 2.70 (t, J = 5.2 Hz, 2H), 2.50 (q, J = 7.2 Hz, 2H), 2.35 (s, 6H), 0.91 (t, J = 7.6 Hz, 3H); m / z = 389 [M + 1] < ⁺ >.

Example 6

(S, Z) -4- {2- phenyl-1- [6- (pyrrolidin-3-oxyl) -3-pyridinyl] -1-butyl} phenol alkenyl ((S, Z) -4- (2-phenyl-1- (6- (pyrrolidin-3-yloxy) pyridin-3- yl) but-

(S) -1-t-butoxycarbonyl-3-hydroxypyrrolidine (558 mg, 10 eq.) And (Z) -4- [1- (6- The target product (87 mg, 76%) is obtained as a raw material from 3-pyridinyl) -2-phenylbutyl-1-alkenyl) phenol (100 mg, 1 eq. Obtained in Example 1). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.50 (s, 1H), δ 7.54 (s, 1H), 7.20-7.23 (m, 2H), 7.10-7.16 (m, 4H), 7.00 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.49 (d, J = 8.4 Hz, 1H), 5.28 (bs, 1H), 3.15-3.32 (m, 2H), 2.94- (M, 2H), 2.43 (q, J = 7.6 Hz, 1H) 1.90-2.10 (m, 1H), 1.79-1.89 (m, 1H), 0.86 (t, J = 7.6 Hz, 3H); m / z = 387 [M + 1] < ⁺ >.

Example 7

(Z) -4- (2-phenyl-1- {6- [2- (1-pyrrolidinyl) ethoxy] -3-pyridinyl} butyl-1-alkenyl) phenol ((Z) -4- (2-phenyl-1- (6- (2- (pyrrolidin-1-yl) ethoxy) pyridin-3- yl) but-

(343 mg, 10 eq.) And ( Z ) -4- [1- (6-chloro-3-pyridinyl) -2-phenylbutyl 1-alkenyl) phenol (100 mg, 1 eq., Obtained in Example 1) as a raw material. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.53 (s, 1H), 7.15-7.20 (m, 2H), 7.01-7.13 (m, 6H), 6.92 (d, J = 8.0 Hz, 1H), 6.76 ( d, J = 8.4 Hz, 2H ), 5.68 (brs, 1H), 4.26 (bs, 2H), 2.91 (brs, 2H), 2.72 (brs, 4H), 2.50 (q, J = 7.2 Hz, 2H), 1.89 (br s, 4H), 0.91 (t, J = 7.6 Hz, 3H); m / z = 415 [M + 1] < ⁺ >.

Example 8

(Z) -4- (1- {6- [2- (4- methyl-1-piperazinyl) ethoxy] -3-pyridinyl} -2-phenyl-1- alkenyl) phenol ((Z Pyridin-3-yl) -2-phenylbut-1-enyl) phenol)

(4-methyl-1-piperazinyl) ethanol (430 mg, 10 eq.) And ( Z ) -4- [1- The target product (160 mg, 95%) is obtained as a raw material from 2-phenylbutyl-1-alkenyl) phenol (100 mg, 1 equivalent obtained in Example 1). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.57 (s, 1H), 7.17-7.22 (m, 2H), 7.00-7.15 (m, 5H), 6.97 (d, J = 8.0 Hz, 1H), 6.76 ( J = 8.8 Hz, 2H), 6.03 (d, J = 8.8 Hz, 1H), 4.27 (t, J = 5.6 Hz, 2H), 2.75 (t, J = 5.6 Hz, 2H), 2.48-2.57 m, 12H), 2.32 (s, 3H), 0.92 (t, J = 7.6 Hz, 3H); m / z = 444 [M + 1] < ⁺ >.

Example 9

(Z) -4- (2-phenyl-1- {6- [2- (1-piperidyl) ethoxy] -3-pyridinyl} butyl-1-alkenyl) phenol ((Z) -4- (2-phenyl-1- (6- (2- (piperidin-1-yl) ethoxy) pyridin-3- yl) but-

(385 mg, 10 eq.) And ( Z ) -4- [l- (6-chloro-3-pyridinyl) -2-phenylbutyl -1-alkenyl) phenol (100 mg, 1 equiv., Obtained in Example 1) as a raw material. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.53 (s, 1H), 7.16-7.21 (m, 2H), 7.01-7.15 (m, 6H), 6.88 (d, J = 8.8 Hz, 1H), 6.77 ( d, J = 8.8 Hz, 2H ), 5.63 (d, J = 8.0 Hz, 1H), 4.25 (t, J = 5.6 Hz, 2H), 2.73 (t, J = 5.6 Hz, 2H), 2.40-2.62 ( m, 6H), 1.63-1.75 (m, 4H), 1.44-1.56 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); m / z = 429 [M + 1] < ⁺ >.

Example 10

(Z) -4- {1- [6- (2- morpholino-ethoxy) -3-pyridinyl] -2-phenyl-1- alkenyl) phenol ((Z) -4- (l- ( Pyridin-3-yl) -2-phenylbut-1-enyl) phenol)

4- (2-morpholinoethanol) (391 mg, 10 eq.) And ( Z ) -4- [1- The target product (110 mg, 86%) is obtained as a raw material from 1-alkenyl) phenol (100 mg, 1 equivalent obtained in Example 1). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.59 (s, 1H), 7.01-7.18 (m, 8H), 6.79 (d, J = 8.8 Hz, 2H), 6.27 (d, J = 8.4 Hz, 1H) , 4.29 (t, J = 5.6 Hz, 2H), 2.70 (t, J = 5.6 Hz, 2H), 2.46-2.52 (m, 6H), 1.29-1.40 (m, 4H), 0.92 (t, J = 7.6 Hz, 3H); m / z = 431 [M + 1] < ⁺ >.

Example 11

Phenyl) -4- (1- {4- [2- (methylamino) ethoxy] phenyl} -2- (3-thienyl) butyl- Methylamino) ethoxy) phenyl) -2- (thiophen-3-yl) but-1-enyl)

Step A: N - methoxy - N - methyl-thiophene-3-carboxamide (N-methoxy-N-methylthiophene -3-carboxamide)

Thionyl chloride (SOCl ₂ , 59 mL, 5.2 eq.) Is added to a dichloromethane solution of 3-thiophene-3-carboxylic acid (20 g, 1.0 eq) at 0 ° C. If the generation of gas is not vigorous, the mixed solution is refluxed at 50 캜 for 3 hours. Next, the mixture solution is concentrated, and the product after concentration can be directly used for the next step reaction without further purification.

Under 0 ℃, a dichloromethane solution of the agricultural and livestock water, N, O - dimethyl-hydroxylamine hydrochloride (N, O -dimethylhydroxylamine hydochloride) and the addition of (16.8 g, 1.1 eq.), And thus, triethylamine (44 mL, 2.0 eq.) Is slowly added and reacted by stirring at room temperature for 3 hours, followed by washing with water. After extracting with dichloromethane, the extract was dried and concentrated, and eluted with petroleum ether / ethyl acetate (5/1) by column chromatography to obtain 17.2 g (64%) of the target product. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.07 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 3.65 (s, 3H), 3.36 (s, 3 H).

Step B: 3-thiophen-3-yl) propane

After methyl-thiophene-3-carboxamide (8 g, 1.0 equivalent) of ethyl Grignard reagent (EtMgBr) and the addition of (3M, 1.2 eq., 18.6 mL), was added dropwise to dry THF completion of - N - methoxy - N , And the reaction mixture is stirred overnight at room temperature. The reaction mixture was washed with a saturated aqueous ammonium chloride solution, dried and concentrated, and eluted with petroleum ether / ethyl acetate (5/1) by column chromatography to obtain 3.4 g (52%) of a yellow oily target product . ^{1 H NMR (400 MHz, CDCl} 3) δ 8.05 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 2.92 (q, J = 7.6 Hz , 2H), 1.21 (t, J = 7.6 Hz, 3H).

Step C: 4- {1- [4- (2-Chloroethoxy) phenyl] -2- (3-thienyl) butyl- 1-alkenyl} phenyl) -2- (thiophen-3-yl) but-1-enyl) phenol)

(0.5 g, 1.0 eq.) And [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (prepared according to Example 1, Step B) by the conventional McMurry reaction step described in Step B, (95%, Z / E = 1/1) target product was obtained by reacting 4- (2-chloroethoxy) phenyl) (4-hydroxyphenyl) methanone (1.5 g, 1.5 eq.). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.10-7.14 (m, 1H), 7.02-7.09 (m, 2H), 6.76-6.92 (m, 5H), 6.68-6.71 (m, 1H), 6.60-6.66 (m, 1H), 6.55-6.59 ( m, 1 H), 4.62 (s, 1H), 4.49 (s, 1H), 4.24 (t, J = 6.0 Hz, 1H), 4.14 (t, J = 6.0 Hz J = 6.0 Hz, 1H), 3.82 (t, J = 6.0 Hz, 1H), 3.76 (t, J = 6.0 Hz, 1H), 2.43-2.49 (m, 2H), 0.98 (t, J = 7.6 Hz,

Step D: Synthesis of 4- (1- {4- [2- (methylamino) ethoxy] phenyl} -2- (3-thienyl) butyl- 2- (methylamino) ethoxy) phenyl) -2- (thiophen-3-yl) but-

A solution of 4- {1- [4- (2-chloroethoxy) phenyl] -2- (3-thienyl) butyl- 1-alkenyl} phenol (0.3 g, 1.0 eq. It is added to a _{10 mL CH 3 NH 2 (30} % aqueous solution). The mixture was refluxed overnight at 80 ° C and then eluted with a methanol / ammonia gas methanol solution (10/1) to give 185 mg (63%) of the target product (Z / E = 1/1) . ^{1 H NMR (400 MHz, CDCl} 3) δ 7.00-7.12 (m, 3H), 6.90-6.95 (m, 1H), 6.80-6.89 (m, 2H), 6.72-6.79 (m, 2H), 6.68-6.72 (m, 1H), 6.58 ( d, J = 8.8 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 4.09 (t, J = 5.2 Hz, 1H), 3.99 (t, J = 5.2 Hz 1H), 3.00 (t, J = 5.2 Hz, 1H), 2.94 (t, J = 5.2 Hz, 1H), 2.40-2.54 (m, 5H), 0.98 (t, J = 5.2 Hz, 3H); m / z = 380 [M + 1] < ⁺ >.

Example 12

(E) -4- (2- (5- chloro-3-thienyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl) phenol ((E) - Synthesis of 4- (2- (5-chlorothiophen-3-yl) -1- (4- (2- (methylamino) ethoxy) phenyl) but-

Step A: 5-Chloro- N -methoxy- N -methylthiophene-3-carboxamide

Stirring N - methoxy - N - methyl-thiophene-3-carboxamide (5.0 g, 1.0 equiv., Obtained in Example 12 was prepared in step A in) of CH ₃ COOH (50 mL) was added N - Chloro succinimide N-chlorosuccinimide (3.88 g, 1.0 eq.) Is added. The reaction mixture is refluxed at 120 < 0 > C for 4 hours. Quenched with water, extracted with ethyl acetate, and the extract is washed with saturated brine, dried and concentrated, and then 3.0 g (40%) of the target product is obtained by column chromatography separation.

Step B: Preparation of 5-chlorothiophen-3-yl) propan-1-one [

The target product can be obtained by the method described in Example 11 Step B.

Step C: (E) -4- {1- [4- ( 2-chloroethoxy) phenyl] -2- (5-chloro-3-thienyl) butyl-1-alkenyl} phenol ((E) - 4- (1- (4- (2-chloroethoxy) phenyl) -2- (5-chlorothiophen-3-yl) -but-

Chloro-3-thiophene acetone (1.5 g, 1.0 eq.) And [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) phenol were prepared by the conventional McMurry reaction described in Example 1, ) Methanone (2.0 g, 1.2 eq.) Are reacted to give 0.8 g (45%, type E) target product.

Step D: ( E ) -4- (2- (5-Chloro-3-thienyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl- 1 -alkenyl) phenol E ) -4- (2- (5-chlorothiophen-3-yl) -1- (4- (2- (methylamino) ethoxy) -phenyl) but-

( E ) -4- {1- [4- (2-chloroethoxy) phenyl] -2- (5-chloro-3- thienyl) butyl- (20 mL) of MeNH ₂ (30% aqueous solution, 10 mL) is then refluxed to obtain 120 mg (35%) of the target product. ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.30 (bs, 1H), 6.99-7.02 (m, 3H), 6.84-6.89 (m, 2H), 6.62-6.70 (m, 2H), 6.50-6.56 (m, 3H), 3.97 ( t, J = 5.6 Hz, 2H), 2.78 (t, J = 5.6 Hz, 2H), 2.26-2.38 (m, 5H), 0.89 (t, J = 7.2 Hz, 3H) ; m / z = 414 [M + 1] < ⁺ >.

Example 13

4- (2- (4-Hydroxycyclohexyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl) (4- (2- (methylamino) ethoxy) phenyl) but-1-enyl) phenol)

Step A: 4-Hydroxycyclohexane-1-acetone

Ethyl Grignard reagent (1 M, 3.0 eq., 20 mL) was added to a dry THF solution of 4-hydroxy- N -methoxy- N -methylcyclohexylcarbodiimide (1.0 g, 1.0 eq) . After completion of the dropwise addition, the mixture is stirred overnight. The reaction mixture is washed with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried, concentrated and purified by column chromatography eluting with petroleum ether / EtOAc (1: 1) to give 0.6 g (72%) of the target product. ^{1 H NMR (400 MHz, CDCl} 3) δ 3.50-3.64 (m, 1H), 2.47 (q, J = 7.2 Hz, 2H), 2.28-2.37 (m, 1H), 2.00-2.10 (m, 2H), J = 7.2 Hz, 3H), 1.85-1.94 (m, 2H), 1.70-1.80 (m,

Step B: Synthesis of 4- {1- [4- (2-chloroethoxy) phenyl] -2- (4- hydroxycyclohexyl) butyl- -chloroethoxy) phenyl) -2- (4-hydroxycyclohexyl) but-1-enyl) phenol)

4-hydroxycyclohexane-1-acetone (0.6 g, 1.0 eq.) And [4- (2-chloroethoxy) phenyl] Phenyl) methanone (1.6 g, 1.5 eq.) Were reacted to obtain 0.8 g (52%, Z / E = 1/1) cis-trans mixture. ¹ H NMR (400 MHz, CDCl ₃ )? 7.11-7.20 (m, 1H), 7.00-7.10 (m, 2H), 6.90-6.70 , J = 7.6 Hz, 1H) , 4.08-4.20 (m, 2H), 3.70-3.80 (m, 2H), 3.60 (brs, 1H), 2.47 (q, J = 7.6 Hz, 2H), 2.28-2.38 ( J = 7.6 Hz, 1H), 2.00-2.08 (m, 2H), 1.86-1.94 (m, 2H), 1.72-1.80 (m, 3H)

Step C: Synthesis of 4- (2- (4-hydroxycyclohexyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl- -hydroxycyclohexyl) -1- (4- (2- (methylamino) ethoxy) -phenyl) but-1-enyl) phenol)

(4-hydroxycyclohexyl) butyl-1-alkenyl} propanoate was obtained in the same manner as described in Example 11, Step D, from 4- {1- [4- A methanol (20 mL) solution of phenol (0.8 g, 1.0 eq) and MeNH ₂ (30% aqueous solution, 10 mL) was refluxed to obtain 20 mg (3%) target product (Z / E = 1/1) . ^{1 H NMR (400 MHz, CDCl} 3) δ 7.03 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.71 (d , J = 8.4 Hz, 2H) , 4.04 (t, J = 4.8 Hz, 2H), 2.96 (t, J = 4.8 Hz, 2H), 2.50 (s, 3H), 2.36-2.47 (m, 1H), 2.04 (q, J = 7.6 Hz, 2H), 1.90-2.01 (m, 2H), 1.40-1.80 (m, 6H), 0.87 (t, J = 7.6 Hz, 3H); m / z = 396 [M + 1] < ⁺ >.

Example 14

4- (1- (3-Bromo-4- (2-methylamino) ethoxy] phenyl} -2-phenylbutyl- (2- (methylamino) ethoxy) phenyl) -2-phenylbut-1-enyl) phenol)

Step A: 3-Bromo-4- (2-bromoethyl) -methylbenzoate

To a stirred solution of 3-bromo-4-hydroxymethylbenzoate (5.0 g, 1.0 eq.) In 20 mL DMF was added 1,2-dibromoethane (11 mL, 6.0 eq.) And potassium carbonate (6.0 g, 2.0 Equivalent). The mixture was heated to 60 占 폚 and allowed to react for 6 hours and then eluted with petroleum ether / ethyl acetate (3: 1) by column chromatography to obtain the target product (6.0 g, 80%). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.24 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.40 (t, J = 6.8 Hz 2H), 3.90 (s, 3H), 3.71 (t, J = 6.4 Hz, 2H)

Step B: 3-Bromo-4- (2-bromoethyl) -benzoic acid

Stirring 3-bromo-4- (2-bromoethyl) -methyl benzoate (4.0 g, 1.0 eq.) In _{MeOH / H 2 O (v /} v 2: 1, 60 mL) , sodium (0.715 hydroxide solution g, 1.5 eq.). Next, the mixture is refluxed for 25 minutes and then concentrated under reduced pressure. The concentrate is poured into water and washed with ethyl acetate. To the aqueous phase was added 3N hydrochloric acid to obtain the target compound (3.4 g, 87%, white solid). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.07 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.50 (t, J = 5.6 Hz, 2H), 3.85 (t, J = 5.6 Hz, 2H)

Step C: [3-Bromo-4- (2-bromoethyl) phenyl] (4-methoxyphenyl) methanone

To a stirred solution of 3-bromo-4- (2-bromoethyl) -benzoic acid (2.0 g, 1.0 eq) in dichloromethane (20 mL) was added thionyl chloride (2.2 mL, 5.0 eq.). The mixture is refluxed for 3 hours and then distilled to concentrate to obtain benzoyl chloride. No further purification is required.

Anisole (1.34 g, 2.0 eq.) Is added to a stirred solution of the above benzoyl chloride and aluminum trichloride (1.65 g, 2.0 eq) in dichloromethane (50 mL). The mixture was stirred overnight at room temperature and then eluted with petroleum ether / EtOAc (3: 1) by column chromatography separation to obtain the desired product (1.47 g, 57%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.03 (s, 1H), 7.71-7.84 (m, 3H), 6.91-7.04 (m, 3H), 4.43 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.74 (t, J = 6.4 Hz, 2H)

Step D: Preparation of [3-bromo-4- (2-bromoethyl) phenyl] (4-hydroxyphenyl) methanone

(BBr3) (0.4) was added to a dichloromethane (50 mL) solution of [3- bromo-4- (2-bromoethyl) phenyl] (4- methoxyphenyl) methanone mL, 3.0 eq.). After completion of the dropwise addition, the reaction mixture was stirred overnight at room temperature, concentrated, and then eluted with petroleum ether / EtOAc (2: 1) by column chromatography to obtain the target product (0.36 g, 62%). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.03 (s, 1H), 7.70-7.79 (m, 3H), 6.90-7.00 (m, 3H), 4.43 (t, J = 6.4 Hz, 2H), 3.72 ( t, J = 6.0 Hz, 2H)

Step E: 4- {1- [3-Bromo-4- (2-bromoethyl) phenyl] -2-phenylbutyl-

(0.2 g, 3.0 eq.) And [3-bromo-4- (2-bromoethyl) phenyl] (4-hydroxyphenyl) propanoic acid were prepared by the conventional McMurry reaction described in Example 1, Methanone (0.2 g, 1.0 eq.) Is reacted to yield 0.09 g (36%, Z / E = 1/1) of the target product. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.42 (s, 1H), 7.01-7.0 (m, 7H), 6.87 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H) , 6.71 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.36 (t, J = 6.8 Hz, 1H), 4.19 (t, J = 6.4 Hz, 1H), 3.70 (t, J = 6.4 Hz, 1H), 3.59 (t, J = 6.8 Hz, 1H), 2.46 (q, J = 6.4 Hz, 2H), 0.92 (t, J = 6.0 Hz, 3H)

Step F: Synthesis of 4- (1- {3-bromo-4- [2- (methylamino) ethoxy] phenyl} -2-phenylbutyl-

Phenyl] -2-phenylbutyl-1-alkenyl} phenol (0.09 g, 1.0 (dibenzylidene chloride)) was obtained in the same manner as in Example 11, (90%, Z / E = 1/1) is obtained by refluxing a methanol (20 mL) solution of MeNH ₂ (30% aqueous solution, 10 mL) ^{1 H NMR (400 MHz, CDCl} 3) δ 7.40 (s, 1H), 6.98-7.20 (m, 7H), 6.87 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H) , 6.68 (d, J = 8.8 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 4.17 (t, J = 5.2 Hz, 1H), 4.01 (t, J = 4.8 Hz, 1H), 3.06 (t, J = 4.8 Hz, 1H), 2.96 (t, J = 5.2 Hz, 1H), 2.40-2.60 (m, 5H), 0.88 (t, J = 5.2 Hz, 3H); m / z = 452 [M + 1] < ⁺ >.

Example 15

4- (1- {3-cyano-4- [2- (methylamino) ethoxy] phenyl} -2-phenylbutyl-

(150 mg, 1.0 eq) of 4- (1- {3-bromo-4- [2- (methylamino) ethoxy] phenyl} -2-phenylbutyl-1-alkenyl) phenol mL DMF is added cyanogen bromide (CuCN) (36 mg, 1.2 eq.). The mixture was heated to 120 ° C and stirred overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extracts were washed with water and saturated brine, dried and concentrated, and subjected to column chromatography (10 mg, 6%, Z / E = 1/1) was obtained by eluting with a methanol solution of dichloromethane / ammonia gas (1: 1). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.36 (s, 1H), 6.99-7.21 (m, 7H), 6.90 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H) , 6.68 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 4.32 (t, J = 5.6 Hz, 1H), 4.20 (t, J = 5.2 Hz, 1H), 3.46 (t, J = 5.6 Hz, 1H), 3.30 (t, J = 5.2 Hz, 1H), 3.29 (s, 3H), 2.40-2.50 (m, 2H), 0.90 (t, J = 5.6 Hz, 3H) ; m / z = 399 [M + 1] < ⁺ & gt ^; .

Example 16

(S) -4- {2-phenyl-1- [4- (2-pyrrolidinylmethoxy) phenyl] butyl-

Step A: Preparation of ( S ) -2-hydroxymethylpyrrolidine

Lithium aluminum hydride (LiAlH4) (6 g, 1.6 eq.) Was added very slowly to a 250 mL anhydrous tetrahydrofuran solution of ( S ) -pyrrolidine-2-carboxylic acid (11.5 g, 1.0 eq) . The reaction mixture is stirred at 0 < 0 > C for 1 hour and then slowly quenched at 6 [deg.] C with water. After addition of 6 mL of 10% aqueous sodium hydroxide solution, the suspension is filtered and washed with ethyl acetate. After the filtrate was dried and concentrated, the concentrate was purified by distillation under reduced pressure to obtain the product (5.75 g, 57%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 3.22 (d, J = 1.2 Hz, 2H), 2.95-3.01 (m, 1H), 2.73-2.79 (m, 1H), 2.64-2.70 (m, 1H ), 1.53-1.68 (m, 3H), 1.27-1. 34 (m, 1H).

Step B: ( S ) tert-Butyl-2- (hydroxymethyl) pyrrolidine-1-carboxylate (( S )

To a stirred solution of ( S ) -2-hydroxymethylpyrrolidine (3 g, 1.0 eq.) In 100 mL tetrahydrofuran was added (Boc) ₂₀ (7.1 g, 1.1 eq.) At 0 ° C. After addition of 100 mL aqueous solution of _{NaHCO 3 (5 g, 2.0 eq} ), and stir overnight at room temperature the reaction mixture. Water is then added to the mixture and extracted with ethyl acetate. The extract was dried and concentrated, and the desired product (5.7 g, 95%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 4.68 (brs, 1H), 3.96 (brs, 1H), 3.55-3.66 (m, 2H), 3.43-3.49 (m, 1H), 3.28-3.34 (m, 1H ), 1.97-2.05 (m, 1H), 1.76-1.85 (m, 2H), 1.47 (s, 9H).

Step C: Preparation of 4- [1- (4-hydroxyphenyl) -2-phenylbutyl-1-alkenyl]

(1.9 g, 3.0 eq.) And di (4-hydroxyphenyl group) methanone (1.0 g, 1.0 eq.) Were reacted by the conventional McMurry reaction as described in example 1 step B to give 1.3 g Obtain the product (88%).

Step D: (S) tert-Butyl-2 - ({4- [1- (4- hydroxyphenyl) -2- phenylbutyl- 1- alkenyl] phenoxy} methyl) pyrrolidine- ((S) -tert-butyl 2 - ((4- (1- (4-hydroxyphenyl) -2-phenylbut-1-enyl) -phenoxy) methyl) pyrrolidine-

(500 mg, 1.0 eq.), (S) 1-tert-butyl (4-hydroxyphenyl) Diisopropyl azodicarboxylate (DIAD) was added to anhydrous tetrahydrofuran solution of 2- (hydroxymethyl) pyrrolidine-carboxylate (480 mg, 1.5 eq.) And triphenylphosphine (625 mg, 1.5 eq. (480 mg, 1.5 eq.). The reaction mixture is stirred for 48 hours. The mixture is quenched with water and extracted with ethyl acetate. The extract was dried and concentrated, and the desired product (400 mg, 51%) was obtained by column chromatography.

Step E: Synthesis of ( S ) -4- {2-phenyl-1- [4- (2-pyrrolidinylmethoxy) phenyl]

Under 0 ℃, stirring (S) -tert- butyl 2 - ({4- [1- (4-hydroxyphenyl) -2-phenyl-1- alkenyl] phenoxy} methyl) pyrrolidine- 1-carboxylate (400 mg, 1.0 eq.) In 20 mL of dichloromethane was added 1 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 3 hours. The reaction was then quenched with a saturated aqueous solution of sodium hydrogencarbonate, And extracted with dichloromethane. The extract was dried and concentrated to obtain the target product (210 mg, 68%) by column chromatography separation. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.07-7.17 (m, 6H), 7.05 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.74 ( d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 8.4 Hz (M, 0.5H), 3.93-3.77 (m, 0.5H), 3.53-3.59 (m, 2H), 1.77-1.99 (m, 3H), 1.52-1.66 (m, 1H), 3.43-3.49 0.92 (t, J = 7.2 Hz, 3 H); m / z = 400 [M + 1] < ⁺ >.

Example 17

(R) -4- {2- phenyl-1- [4- (3-blood rolal alkoxyl) phenyl] butyl-1-alkenyl} phenol ((R) -4- (2- phenyl-l- (4- (pyrrolidin-3-yloxy) phenyl) but-1-enyl) phenol)

(150 mg, 0.474 mmol) and ( S ) tert- butylphenol in the same manner as in Example 16, Steps D and E, except that 4- [1- (4-hydroxyphenyl) (36 mg, 20%, Z / E = < RTI ID = 0.0 > 1/1). m / z = 386 [M + 1] < ⁺ >.

Example 18

4- (2-Phenyl-1- (4- (pyrrolidin-3-yloxy) phenyl) ) but-1-enyl) phenol)

Step A: Preparation of tert-butyl-3- (methylsulfonyloxy) pyrrolidine-1-carboxylate (teri-butyl 3-

To a solution of 1-tert-butyl-3-hydroxypyrrolidine-carboxylate (16 g, 85.4 mmol) and triethylamine (19 mL, 129 mmol) in dichloromethane (130 mL) under stirring at 0 ° C was added methyl A 20 mL dichloromethane solution of methanesulfonyl chloride (10 mL, 129 mmol) is added. After completion of the dropwise addition, the reaction solution is stirred at room temperature for 2.5 hours, quenched with a saturated aqueous solution of NaHCO ₃ , and extracted with dichloromethane. The extract was dried and concentrated to give the target product as a yellow solid (22.7 g, 100%).

Step B: Synthesis of tert-butyl-3- [4- (4-hydroxybenzoyl) phenoxy] pyrrolidine-1- carboxylate)

Pyrrolidine-carboxylate (0.6 g, 2.26 mmol), 4,4'-dihydroxydiphenylmethanone 1,2-dibromoethane (2.15 g, g, 10.0 mmol) and anhydrous K ₂ CO ₃ (313 mg, 2.26 mmol) were stirred in DMF (12 mL) at 100 ° C. for 3.5 hours, quenched by the addition of water and extracted with ethyl acetate . The extract was washed with water, dried and concentrated. Dichloromethane was added to the concentrate to precipitate a large amount of white solid. The solid was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography, Elution with petroleum ether / dichloromethane / acetone (4/2/1) gave the target product (400 mg, 46%).

Step C: Preparation of 4- {2-phenyl-1- [4- (3-pyrrolocoxyl) phenyl] butyl-

3- (4- (4-hydroxybenzoyl) phenoxy] pyrrolidine-1-carboxylate (395 mg, 1.03 mmol) and Propionate (276 mg, 2.06 mmol) was reacted to give 340 mg of the target product as a pale yellow solid (86%, Z / E = 1/1). m / z = 386 [M + 1] < ⁺ >.

Example 19

(4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} -2-butyl-1-alkenyl] -2- methoxyphenol 1-ene-2-yl) -2-methoxyphenol) in place of 1- (4- (2- (methylamino)

Step A: Acetic acid 2-methoxyphenyl propio

To the mixed solution of dichloromethane (20 mL) of 2-methoxyphenol (4.4 g, 35.4 mmol) and triethylamine (6.2 mL, 42.3 mmol) under stirring at 0 ° C was added propionyl chloride (3.3 g, 35.7 mmol). After completion of dropwise addition, the reaction solution is stirred at room temperature for 5 hours. It is then quenched by addition of saturated aqueous NaHCO ₃ solution and extracted with dichloromethane. The extract was dried and concentrated under reduced pressure to obtain the target product (6.0 g, 94%) as a yellow solid.

Step B: 4-Propionyl-2-methoxyphenol

Under an atmosphere at 100 占 폚, anhydrous trichloroaluminum (3.0 g, 22.5 mmol) was dissolved in anhydrous nitrobenzene (10 mL). After the reaction solution was stirred, acetic acid 2-methoxyphenol ester (2.0 g, 11.1 mmol) was added rapidly. The mixture is heated at 60 < 0 > C for 1.5 h, then is quenched, and 3 N NaOH aqueous solution is added and stirred for 15 min. The suspension is filtered and washed with water. The filtrate was washed twice with dichloromethane, and then was oxidized with a 3 N aqueous hydrochloric acid solution and extracted again with dichloromethane. The extract was dried and concentrated, and eluted with petroleum ether / ethyl acetate (10/1 to 5/1) by column chromatography to obtain the target product (874 mg, 44%) as a yellow oil.

Step C: 4- {1- [4- (2-Chloroethoxy) phenyl] -1- (4- hydroxyphenyl) -2-butyl- 1 -alkenyl} -2- methoxyphenol (4- 1- (4- (2-chloroethoxy) phenyl) -1- (4-hydroxyphenyl) but- 1 -en-2-yl) -2- methoxyphenol)

(4-hydroxyphenyl) methanone (318 mg, 1.15 mmol) and 4-propionyl-2 (4-methoxyphenyl) methanone were obtained by the conventional McMurry reaction described in Example 1, -Methoxyphenol (207 mg, 1.15 mmol) were reacted to obtain the target product (188 mg, 38.5%).

Step D: Synthesis of 4- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} -2-butyl- 1-alkenyl] -2-methoxyphenol

1-alkenyl} -2-methoxyphenol (88 mg, impure) was added to a stirred solution of 4- {1- [4- (2-chloroethoxy) phenyl] ) In MeOH (10 mL) is added 2 mL methylamine aqueous solution. The mixture is heated to 85 < 0 > C, stirred for 24 h, the solvent is removed by vacuum distillation and EtOAc is added. The mixture is washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate is concentrated under reduced pressure. The concentrate was eluted with a methanol / ammonia gas methanol solution (10/1) by column chromatography to obtain the target product as a white solid (42 mg, 48%, Z / E = 1/1) . m / z = 420 [M + 1] < ⁺ >.

Example 20

(4- (1- (4 - ((1-Methylpyrrolidin-2 (1-methylpyrrolidinemethoxy) phenyl) -2-phenylbutyl- -yl) methoxy) phenyl) -2-phenylbut-1-enyl) phenol)

(220 mg, 0.473 mmol) and 1-methyl-2-pyridin-2-ylamine were obtained in the same manner as in Example 16, Mitsunobu reaction was carried out with RLLD methanol (82 mg, 0.712 mmol) (prepared by DL-proline on the basis of the literature Arch Pharrn. Pharm. Med. C and m 1996, 329, 95-104) Obtain the product (33%). m / z = 414 [M + 1] < ⁺ >.

Example 21

Phenyl-1-alkenyl) phenol (4- (1- (3-Fluoro-4- (2- (methylamino) ethoxy) phenyl) -2-phenylbut-1-enyl) phenol)

Step A: 3-Fluoro-4-methoxybenzonitrile < RTI ID = 0.0 >

A mixed solution of 3-fluoro-4-methoxybromobenzene (30.0 g, 146 mmol) and DMF (45 mL) of CuCN (15.6 g, 174 mmol) was stirred overnight at 120 ° C. The reaction mixture is allowed to warm to room temperature, then diluted with water and extracted with ethyl acetate. The extract is washed with water and saturated brine, dried and concentrated to give 20.0 g (91%) of the target product as a yellow solid. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.44 (dd, J = 8.8 & 2.0 Hz, 1H), 7.36 (dd, J = 10.8 & 2.0 Hz, 1H), 7.02 (dd, J = 8.8 & 8.4 Hz, 1H), 3.96 (s, 3H).

Step B: 3-Fluoro-4-hydroxybenzonitrile

At 0 ° C, BBr ₃ (20 mL, 0.211 mol) is added to a solution of 3-fluoro-4-methoxybenzonitrile (15.6 g, 0.103 mol) in dichloromethane (100 mL). The reaction solution is refluxed for 3 days under the protection of nitrogen gas. Quench with ice water and extract the mixture with dichloromethane. The organic phase is washed with water and saturated brine, respectively, and dried with sodium sulfate. Concentration under reduced pressure gave 13.3 g (94%) of the target product as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ )? 7.38-7.42 (m, 2H), 7.09 (dd, J = 8.8 & 8.4 Hz, 1H), 5.68 (s, 1H).

Step C: Preparation of 4- (2-bromoethoxy) -3-fluorobenzonitrile

(1.2 g, 8.76 mmol), anhydrous K ₂ CO ₃ (2.43 g, 17.6 mmol) and 1,2-dibromoethane (4.5 mL, 52.0 mmol) in DMF (6 mL) is stirred overnight at 60 < 0 > C. The reaction solution is filtered, and the filtrate is extracted with ethyl acetate. The extract was washed with water and saturated brine, respectively, and dried over sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography to elute with petroleum ether / ethyl acetate (5/1) to obtain 1.52 g (71%) of subtitle compound as a colorless oil. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.43 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 12.0 Hz, 1H), 7.03 (dd, J = 8.0 & 8.4 Hz, 1H), 4.42 (t, J = 6.2 Hz, 2H), 3.68 (t, J = 6.2 Hz, 2H).

Step D: Preparation of 4- (2-bromoethoxy) -3-fluorobenzoic acid

The mixture of 4- (2-bromoethoxy) -3-fluorobenzonitrile (3.78 g, 15.5 mmol) in water (18 mL) and acetic acid (18 mL) is heated at 110 <0> C for 12 h. After the reaction solution is cooled to room temperature, it is neutralized with solid sodium hydrogencarbonate. Then, glacial acetic acid is added to oxidize, and the precipitated white solid is filtered, dissolved in dichloromethane, and dried over anhydrous sodium sulfate. Filtration and concentration afforded a pale yellow solid (2.65 g, 65%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 13.00 (brs, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 12.0 Hz, 1H), 7.29 (dd, J = 8.8 &amp; 8.4 Hz, 1H), 4.48 (t, J = 5.2 Hz, 2H), 3.85 (t, J = 5.2 Hz, 2H).

Step E: Preparation of 4- (2-bromoethoxy) -3-fluorobenzoyl chloride

The reaction solution of 4- (2-bromoethoxy) -3-fluorobenzoic acid (1.08 g, 4.1 mmol) and thionyl chloride (10 mL) was refluxed for 7 hours. Toluene was added to excess thionyl chloride and the mixture was dried under reduced pressure. The above procedure was repeated several times to obtain 1.07 g (93%) of the subtitle compound as a brown oil. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.93 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 11.2 Hz, 1H), 7.04 (dd, J = 8.4 & 8.4 Hz, 1H), 4.46 (t, J = 6.4 Hz, 2H), 3.70 (t, J = 6.4 Hz, 2H).

Step F: Preparation of [4- (2-bromoethoxy) -3-fluorophenyl] (4-methoxyphenyl) methanone

Under 0 ℃, 4- (2- bromoethoxy) -3-fluoro-benzoyl chloride (1.07 g, 3.80 mmol) and anhydrous _{AlCl 3 (1.01 g, 7.60 mmol} ) dry dichloromethane (18 mL) was added No Sol (822 mg, 7.60 mmol) in dichloromethane (2 mL). After stirring at room temperature for 6 hours, the reaction mixture was poured into 3 N hydrochloric acid and extracted twice with dichloromethane. The extract was combined, washed with saturated aqueous NaHCO ₃ and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (10/1 to 5/1) Eluting to obtain 1.05 g (77%) of subtitle compound as a white solid. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.79 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 11.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.03 (dd , J = 8.0 & 8.4 Hz, 1H), 6.98 (d, J = 9.2 Hz, 2H), 4.44 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.70 (t, J = 6.4 Hz , 2H).

Step G: Preparation of [4- (2-bromoethoxy) -3-fluorophenyl] (4-hydroxyphenyl) methanone

Under 0 ℃, dichloromethane of _{BBr 3 (0.5 mL, 5.29 mmol} ) of [4- (2-bromoethoxy) -3-fluorophenyl] (4-methoxyphenyl) -methanone (930 mg, 2.63 mmol) (6 mL). After stirring for 2 hours at room temperature under nitrogen gas protection, ice water is added and quenched. The mixture was extracted with dichloromethane, and the white suspension was removed by filtration. The organic phase is washed with water and saturated brine, respectively, and dried with sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography to elute with petroleum ether / ethyl acetate (5/1 to 2/1) to obtain 536 mg (60%) of subtitle compound as a pale yellow solid. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.74 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 12.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.03 (dd , J = 8.0 & 8.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 5.88 (s, 1H), 4.44 (t, J = 6.4 Hz, 2H), 3.70 (t, J = 6.4 Hz , 2H).

Step H: Synthesis of 4- {1- [4- (2-bromoethoxy) -3-fluorophenyl] -2-phenylbutyl-

3-fluorophenyl] (4-hydroxyphenyl) methanone (311 mg, 0.917 mmol) and propyl (4-hydroxyphenyl) methanone were obtained by the conventional McMurry reaction described in Example 1, Step B, (246 mg, 1.83 mmol) were reacted to give 403 mg of the target product as a pale yellow liquid (99.6%, Z / E = 1/1).

Step I: Preparation of 4- (1- {3-fluoro-4- [2- (methylamino) ethoxy] phenyl} -2-phenylbutyl-

To a stirred solution of 4- {1- [4- (2-bromoethoxy) -3-fluorophenyl] -2-phenylbutyl- 1-alkenyl} phenol (111 mg, 0.25 mmol) in MeOH Was added 1 mL of methylamine aqueous solution (30%), and the mixture was heated to 85 [deg.] C and stirred for 18 hours. The mixture is extracted with EtOAc. The extract was washed with water and saturated brine, dried over sodium sulfate, filtered, concentrated and eluted with a methanol / ammonia gas methanol solution (10/1) by column chromatography to give the title product as a pale yellow solid 56 mg, 57%, Z / E = 1/1). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.08-7.11 (m, 5H), 7.03 and 6.77 (d, J = 8.6 Hz , 2H), 6.91-6.96 (m, 1H), 6.76 and 6.44 (d, J J = 5.0 Hz, 2H), 2.55 and 2.48 (s, 2H), 4.17 and 4.01 (t, J = 5.0 Hz, 2H), 3.03 and 2.93 3H), 2.47 (q, J = 7.6 Hz, 2H), 0.91 (t, J = 7.6 Hz, 3H); m / z = 392 [M + 1] &lt; ⁺ &gt;.

Example 22

( Z ) -2-fluoro-4- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} -2-butyl-

Step A: 2-Methoxy-5-propionyl fluorobenzene

To a solution of 3-fluoro-4-methoxybenzonitrile (350 mg, 2.32 mmol) in anhydrous THF (15 mL) at 0 ° C was added ethylmagnesium bromide (1 M ether solution, 4.63 mL) do. After stirring overnight at room temperature, it is quenched with saturated aqueous NaHCO ₃ solution, extracted with ethyl acetate, washed with brine, dried and concentrated. The concentrate was purified by column chromatography eluting with petroleum ether / ethyl acetate (5/1) to give the target product as a yellow solid (239 mg, 57%).

Step B: 2-Fluoro-4-propionylphenol

2-Methoxy-5-propionyl fluorobenzene (421 mg, 2.31 mmol) was dissolved in 20 mL of 40% HBr solution and refluxed for 1 hour. After neutralizing with solid sodium carbonate at 0 ° C, it is extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated, followed by silica gel column chromatography elution with petroleum ether / ethyl acetate (5/1) to obtain the product as a yellow solid (257 mg, 66%).

Step C: Synthesis of 4- {1- [4- (2-chloroethoxy) phenyl] -1- (4-hydroxyphenyl) -2-butyl- 1 -alkenyl} -2-fluorophenol

(4-hydroxyphenyl) methanone (629 mg, 2.27 mmol) and 2-fluoro-4 (4-hydroxyphenyl) methanone were prepared by the conventional McMurry reaction described in Example 1, -Propionylphenol (255 mg, 1.52 mmol) were reacted to obtain 549 mg of the target product (88%).

Step D: ( Z ) -2-Fluoro-4- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} -2- Phenyl] phenol

1-alkenyl} -2-fluorophenol (310 mg, 0.75 mmol) was added to a solution of 4- {1- [4- (2- chloroethoxy) phenyl] In MeOH (10 mL) is added 2 mL methylamine aqueous solution (30%). The mixture was heated to 85 [deg.] C, stirred for 13 hours, and extracted with EtOAc. The extract was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated, and then eluted with a methanol / ammonia gas methanol solution (10/1) by column chromatography to obtain Z- mg, white solid) and E-form product (14 mg, dark brown crystals). m / z = 408 [M + 1] &lt; ⁺ &gt;.

Example 23

( E ) -2-fluoro-4- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} -2-butyl-

In the same manner as in Example 22, the title compound (14 mg, dark brown crystals) was obtained by column chromatography. m / z = 408 [M + 1] &lt; ⁺ &gt;.

Example 24

2-fluoro-4- (1- {4- [2- (methylamino) ethoxy] phenyl} -2-phenylbutyl- 1- alkenyl) phenol

Step A: 3-Fluoro-4-methoxybenzoic acid

A solution of 3-fluoro-4-methoxybenzonitrile (2.0 g, 13.2 mmol) in water (5 mL) and acetic acid (5 mL) is heated at 110 &lt; 0 &gt; C for 4 h. The reaction solution is cooled to room temperature, and neutralized with solid sodium carbonate. Next, glacial acetic acid was added to oxidize. The precipitated white solid was filtered, dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a pale yellow solid (2.03 g, 90%).

Step B: 3-Fluoro-4-methoxybenzoyl chloride

A mixture of 3-fluoro-4-methoxybenzoic acid (830 mg, 4.88 mmol) and thionyl chloride (10 mL) was refluxed for 2 hours. Toluene was added to an excess amount of thionyl chloride, followed by drying under reduced pressure. The above procedure was repeated several times to obtain the title compound in the form of a brown solid. The obtained compound is directly used for the next step reaction.

Step C: Preparation of [4- (2-chloroethoxy) phenyl] (3-fluoro-4-methoxyphenyl) methanone

To a dichloromethane (18 mL) solution of 3-fluoro-4-methoxybenzoyl chloride and anhydrous AlCl ₃ (1.30 g, 9.76 mmol) obtained in the above step at 0 ° C was added (2-chloroethoxy) 9.76 mmol) in dichloromethane (2 mL). After stirring at room temperature for 25 minutes, the reaction mixture is poured into 3 N hydrochloric acid solution. The reaction mixture was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of NaHCO ₃ and saturated brine, dried over sodium sulfate, filtered and concentrated to obtain the title compound. The obtained compound is directly used for the next step reaction.

Step D: Preparation of [4- (2-chloroethoxy) phenyl] (3-fluoro-4-hydroxyphenyl) methanone

(3-fluoro-4-methoxyphenyl) methanone obtained in the above step was dissolved in 20 mL of 40% HBr solution, refluxed for 1 hour, , Neutralized with solid sodium carbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated, and then subjected to silica gel column chromatography to elute with petroleum ether / ethyl acetate (5/1 to 2/1) to give the title compound as a pale yellow solid (731 mg, Yield 51%).

Step E: Synthesis of 4- {1- [4- (2-chloroethoxy) phenyl] -2-phenylbutyl- 1 -alkenyl} -2-fluorophenol

(3-fluoro-4-hydroxyphenyl) methanone (350 mg, 1.19 mmol) and propyl (4-hydroxyphenyl) methanone were obtained by the conventional McMurry reaction described in Example 1, Step B, (319 mg, 2.38 mmol) were reacted to obtain the target product (quantitative) as a yellow solid.

Step F: Preparation of 2-fluoro-4- (1- {4- [2- (methylamino) ethoxy] phenyl} -2-phenylbutyl-

To a stirred solution of 4- {1- [4- (2-chloroethoxy) phenyl] -2-phenylbutyl-1-alkenyl} -2-fluorophenol in 5 mL of MeOH, 30%), and the mixture is heated to 85 캜 and stirred overnight. The mixture was extracted with EtOAc, and the extract was washed with water and saturated brine, dried over sodium sulfate, filtered, concentrated and then subjected to column chromatography to elute with a methanol solution of dichloromethane / ammonia gas (10/1) (59%, Z / E = 1/1) which is a white solid. m / z = 392 [M + 1] &lt; ⁺ &gt;.

Example 25

(Z) -4- (1- {5- [2- ( dimethylamino) ethoxy] pyrimidin-2-yl} -2-phenyl-1- alkenyl) phenol hydrochloride ((Z) -4- ( (5- (2- (dimethylamino) ethoxy) pyrimidin-2-yl) -2-phenylbut-1-enyl)

Step A: (5- bromopyrimidin-2-yl) [4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] methanone ((5-bromopyrimidin-2- yl) (4- (tetrahydro -2 H -pyran-2-yloxy) - phenyl) methanone)

2- (4-bromophenoxyl) tetrahydro-2H-pyran (2.57 g, 10 mmol) and 2-cyano-5-bromopyrimidine (0.92 g, 5 mmol) were reacted to obtain 910 mg of the target product (50%).

Step B: [4- (Tetrahydro- 2H -pyran-2-oxyl) phenyl] (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- yl) pyrimidin-2-yl) -methanone ((4- (tetrahydro-2 H -pyran-2-yloxy) phenyl) (5- (4,4,5,5-tetramethyl- l, 3,2-dioxaborolan -2-yl) pyrimidin-2-yl) methanone)

(363 mg, 1 mmol), bispinolacortaidiboron (4,4,4,4-tetrahydronaphthalen-2-yl) (508 mg, 2 mmol), PdCl ₂ (DPPF) (73.1 mg, 2 mmol), and 4 ', 5,5,5,5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) 0.1 mmol) and dioxane (30 mL) of KOAc (200 mg, 2 mmol) was heated at 95 ° C for 5 hours, and then cooled to room temperature. After concentrating the reaction mixture, a target product (329 mg, 80%) in the form of a yellow oil is obtained by column chromatography separation.

Step C: (5-Hydroxypyrimidin-2-yl) [4- (tetrahydro-2H-pyran-

[4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] (5- (4,4,5,5-tetramethyl-1,3,2-dioxa-view it is 2-yl) pyrimidin 33% H ₂ O ₂ (0.5 mL) was added to a THF (20 mL) solution of the title compound (410 mg, 1 mmol) and the reaction solution was stirred at room temperature for 1 hour. The reaction product was quenched by adding a sodium sulfite solution, extracted with ethyl acetate, washed with water and saturated brine, dried, filtered and concentrated. The desired product (240 mg, 80% ).

Step D: {5- [2- (dimethylamino) ethoxy] pyrimidin-2-yl} [4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] methanone

(300 mg, 1 mmol) and 2- (dimethylamino) ethanol (180 mg, 0.25 mmol) in dichloromethane 2 mmol) and PPh ₃ (524 mg, 2 mmol) in THF (50 mL) was added dropwise DIAD (404 mg, 2 mmol) and the mixture was stirred overnight at room temperature. After concentrating the mixture, the product (297 mg, 80%) is obtained rapidly by column chromatography separation.

Step E: ( Z ) -4- (1- {5- [2- (Dimethylamino) ethoxy] pyrimidin-2- yl} -2-phenylbutyl- 1- alkenyl) phenol hydrochloride

Pyrimidin-2-yl} [4- (tetrahydro-2H-pyran-2-yloxy) -quinolinone was obtained by the conventional McMurry reaction described in Example 1, Phenyl] methanone (753 mg, 2 mmol) and propiophenone (800 mg, 6 mmol) were reacted to obtain a Z / E mixture. The mixture is separated and separated into Z-form and E-form by HPLC separation. The Z compound is concentrated in a 3 N HCl methanol solution to obtain the title compound (16 mg). ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.30 (s, 2H), 7.06-7.13 (m, 7H), 6.77 (d, J = 8.4 Hz, 2H), 4.40 (t, J = 4.8 Hz, 2H ), 3.57 (t, J = 4.8 Hz, 2H), 2.95 (s, 6H), 2.58 (q, J = 7.2 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H); m / z = 426 [M + 1] &lt; ⁺ &gt;.

Example 26

( E ) -4- (( E ) -4- (1- {5- [2- (dimethylamino) ethoxy] pyrimidin- (5- (2- (dimethylamino) ethoxy) pyrimidin-2-yl) -2-phenylbut-1-enyl)

The title compound (16 mg) was obtained in the same manner as in Example 25, Step E. ^{1 H NMR (400 MHz, CD} 3 OD) δ 8.62 (s, 2H), 7.14-7.20 (m, 5H), 6.70 (d, J = 8.4 Hz, 2H), 6.43 (d, J = 8.8 Hz, 2H ), 4.57 (t, J = 5.2 Hz, 2H), 3.67 (t, J = 5.2 Hz, 2H), 3.02 (s, 6H), 2.32 (q, J = 7.2 Hz, 2H), 0.90 (t, J = 7.2 Hz, 3 H); m / z = 426 [M + 1] &lt; ⁺ &gt;.

Example 27

(4- (1- (5- (2- (Dimethylamino) ethoxy) pyridin-2-yl} -2-phenylbutyl- ) ethoxy) pyridin-2-yl) -2-phenylbut-1-enyl) phenol)

Step A: 5- hydroxy - N - methoxy - N - methyl-2-pyridine carboxamide (5-hydroxy- N -methoxy- N -methylpicolinamide )

DIEA (2.5 eq.) Was added dropwise to a suspension of 5-hydroxy-2-picolinic acid (1.0 eq.), HATU (1.2 eq.) And N -methoxymethylamino hydrochloride do. The reaction solution is then stirred at room temperature overnight. Water is added, followed by extraction with dichloromethane. The extract was dried and concentrated, and the desired product (87%) was obtained by column chromatography separation.

Step B: 5- [2- (Dimethylamino) ethoxy] -N -methoxy- N -methyl-2-pyridinecarboxamide

0 ℃ under protection of nitrogen gas, 5-hydroxy - N - methoxy - N - methyl-2-pyridine carboxamide (1.0 equivalent), 2- (dimethylamino) ethanol (1.2 eq.) And PPh ₃ (1.2 eq. ) In anhydrous THF (5 mL) is added dropwise DIAD (1.2 eq.). The reaction is allowed to proceed overnight at room temperature, then quenched with water and extracted with ethyl acetate. The extract was dried and concentrated, and the desired product (40%) was obtained by column chromatography.

Step C: {5- [2- (Dimethylamino) ethoxy] pyridin-2-yl} [4- (tetrahydro-

To a solution of 2- (4-iodophenoxy) tetrahydro-2H-pyran (1.1 eq.) In THF under an atmosphere of nitrogen gas at -78 캜, an n-butyllithium hexane solution (1.1 eq.) Was added dropwise. The reaction solution was reacted at the above temperature for 20 minutes and then a solution of 5- [2- (dimethylamino) ethoxy] -N -methoxy- N -methyl-2-pyridinecarboxamide (1.0 equivalent) THF solution is added. After 2 hours, isopropanol and water are added, and the mixture is stirred at room temperature for 20 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with 0.5 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate, filtered, concentrated, and then subjected to silica gel column chromatography to obtain the title compound (47%).

Step D: Synthesis of 4- (1- {5- [2- (dimethylamino) ethoxy] pyridin-2-yl} -2-phenylbutyl-

Pyridin-2-yl} [4- (tetrahydro- 2H -pyran-2-oxyl) -pyridin-2-ylamine] was obtained in accordance with the conventional McMurry reaction described in Example 1, Phenyl] methanone (1 eq.) And propiophenone (2 eq.) To obtain the target product (Z / E = 1/1). m / z = 389 [M + 1] &lt; ⁺ &gt;.

Example 28

3-yl} -2-phenylbutyl-1-alkenyl) phenol hydrochloride &lt; / RTI &gt;

Step A: (6-Chloropyridin-3-yl) (4-methoxyphenyl) methanone

(4-methoxyphenyl) magnesium bromide (15 mmol) was added dropwise to a THF (100 mL) solution of 2-chloro-5-cyanopyridine (1.39 g, 10 mmol) under stirring at 0 占 폚. After the reaction solution was stirred for 1 hour at 0 ° C, 50 mL of a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine. After drying with Na ₂ SO ₄ , filtration and concentration, the product (1.24 g, 50%) is obtained rapidly by column chromatography separation.

Step B: Synthesis of {6- [3- (dimethylamino) propyl-1-alkynyl] pyridin-3-yl} (4- methoxyphenyl) methanone (6- (3- (dimethylamino) prop- ) pyridin-3-yl) (4-methoxyphenyl) methanone)

In 25mL shrink flask (Schlenk flask) (6- chloropyridin-3-yl) (phenyl) methanone (124 mg, 0.5 mmol), Pd (PPh 3) 2 Cl 2 (18 mg, 0.025 mmol ), CuI (10 mg, 0.05 mmol), Et ₃ N (10 mL) and N, N -dimethylpropargylamine (83 mg, 1.0 mmol) Gas and the mixture is reacted at 80 ° C for 24 hours. After concentration under reduced pressure, the concentrate was subjected to column chromatography separation to obtain the product (118 mg, 80%).

Step C: {6- [3- (Dimethylamino) propyl] pyridin-3-yl} (4- methoxyphenyl) methanone

To a flask was added {6- [3- (dimethylamino) propyl-1-alkynyl] pyridin-3- yl} (4- methoxyphenyl) methanone (294 mg, 1 equiv), Raney nickel Add methanol. The mixture is stirred at room temperature and under hydrogen gas (1 atmospheric pressure) for 2 hours. The catalyst is filtered off with diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the product (284 mg, 95%).

Step D: {6- [3- (Dimethylamino) propyl] pyridin-3-yl} (4-hydroxyphenyl) methanone

To a 10 mL methanol solution of {6- [3- (dimethylamino) propyl] pyridin-3-yl} (4-methoxyphenyl) methanone (298 mg, 1 mmol) at room temperature was added a solution of 10 mL of 48% HBr After refluxing for 3 hours, the mixture is allowed to stand. The crude product is obtained in the evaporator, and the compound obtained without further purification is used directly in the next step (284 mg, 100%).

Step E: 4- (1- {6- [3- (Dimethylamino) propyl] pyridin-3-yl} -2-phenylbutyl- 1- alkenyl) phenol hydrochloride

(568 mg, 2 mmol) was reacted with {6- [3- (dimethylamino) propyl] pyridine-3-yl} (4- hydroxyphenyl) methanone by the conventional McMurry reaction described in Example 1, The title product (55 mg, 7%, Z / E = 1/1) was obtained by reacting propiophenone (800 mg, 6 mmol). m / z = 423 [M + 1] &lt; ⁺ &gt;.

Example 29

6 - (1- {4- [2- (Methylamino) ethoxy] phenyl} -2-phenylbutyl-1-alkenyl) pyridin- phenyl) -2-phenylbut-1-enyl) pyridin-3-ol)

Step A: tert-Butyl-2- (4-bromophenoxy) ethyl (methyl) carbamate (terf-butyl 2- (4- bromophenoxy)

Tert-butyl 2-hydroxyethyl (methyl) carbamate (1.5 eq.), 4-bromophenol (1.0 eq.) In anhydrous tetrahydrofuran ) And PPh ₃ (1.5 eq.) In THF was added dropwise DIAD (1.5 eq.). The reaction is stirred at room temperature for 48 hours, quenched with water and extracted with EtOAc. After the extract is dried and concentrated, the target product is obtained by column chromatography separation.

Step B: tert-Butyl-2- [4- (5-hydroxypyridine-2-carbonyl) phenoxy] ethyl (methyl) carbamate ethyl- (methyl) carbamate)

After placing magnesium (3.5 eq.) In a 3-neck round bottom flask containing anhydrous THF (50 mL), the mixture is heated to 55 ° C, iodine (2 grains) is added and then 0.1 mL bromoethane is added . tert-butyl-2- (4-bromophenoxy) ethyl (methyl) carbamate (3.0 eq) was dissolved in 30 mL of anhydrous THF, Is added to a mixed solution of Mg-THF. After 30 minutes the reaction is initiated and refluxing begins. The remaining tert-butyl-2- (4-bromophenoxy) ethyl (methyl) carbamate solution is added dropwise to the mixed solution, and the dropping rate is preferably maintained in a reflux state. After completion of the addition, the reaction solution is refluxed for 2 hours and then cooled to room temperature. A solution of 5-hydroxy- N -methoxy- N -methyl-2-pyridinecarboxamide (1.0 eq) in THF (20 mL) was added dropwise at room temperature, stirred at room temperature for 30 minutes, , Quenched, and extracted with ethyl acetate. After the extract is dried and concentrated, the target product is obtained by column chromatography separation.

Step C: Preparation of 6- (1- {4- [2- (methylamino) ethoxy] phenyl} -2-phenylbutyl- 1 -alkenyl) pyridin-

Tert-butyl-2- [4- (5-hydroxypyridine-2-carbonyl) phenoxy] ethyl (methyl) carbamate was obtained by the conventional McMurry reaction described in Example 1, The desired product is obtained by reacting 2- (4- (5-hydroxypicolinoyl) phenoxy) ethyl (methyl) carbamate (1.0 eq.) With propiophenone (3.0 eq.). m / z = 375 [M + 1] &lt; ⁺ & gt ^; .

Example 30

Phenyl-1- {6- [3- (pyrrolidin-1-yl) propyl] pyridin- (6- (3- (pyrrolidin-1-yl) propyl) pyridin-3-yl) but-

Step A: 2- (4-Iodophenoxy) tetrahydro-2H-pyran

4-iodophenol (10.0 g, 45.5 mmol) was dissolved in 20 mL of 3,4-dihydro-2H-pyran. One drop of the acid was added to the mixture, the mixture was stirred for 30 minutes, Pour into filtration and wash with 300 mL (100 mL x 3) hexanes. The solid obtained by filtration is vacuum dried to obtain 9.1 g (65.9%) of the target product as a white solid.

Step B: 2-Chloro- N -methoxy- N -methyl-5-pyridinecarboxamide (6-chloro-N-

Oxalyl chloride (12.1 g, 95.2 mmol) was added dropwise to a solution of 6-chloronicotinic acid (10.0 g, 63.5 mmol) in THF (100 mL), and the reaction solution was stirred at room temperature for 1 hour and then concentrated, Is dissolved in 50 mL of dichloromethane. The solution was added to a solution of N, O -dimethylhydroxylamine hydrochloride (12.4 g, 126.9 mmol) and triethylamine (25.7 g, 253.9 mmol) in dichloromethane (100 mL), stirred at room temperature for 1 hour, After concentration, the desired product (9.4 g, 73.8%) in the form of a colorless oil is obtained by column chromatography separation.

Step C: N -Alkynylpropylpyrrolidine (l- (prop-2-ynyl) pyrrolidi)

(3-Bromoprop-1-yne) (60.5 g, 0.50 mol) is slowly added dropwise to 70.1 g (1.0 mol) of pyrrolidine at -10 ° C. After completion of the dropwise addition, the reaction mixture was stirred overnight at room temperature and distilled in a rectification column to obtain the target product (45.5 g, 83.5%) as a colorless oil.

Step D: (6-Chloropyridin-3-yl) [4- (tetrahydro-2H-pyran-

2- (4-iodophenoxy) tetrahydro- 2H -pyran (18.2 g, 59.9 mmol) was dissolved in THF (100 mL) under nitrogen gas protection, and the solution was cooled to -78 ° C., Solution (1.1 eq.) Is added dropwise. After completion of the dropwise addition, the reaction solution was stirred at -78 ° C for 0.5 hour to obtain a solution of 2-chloro- N -methoxy- N -methyl-5-pyridinecarboxamide (8.0 g, 39.9 mmol) in THF Lt; RTI ID = 0.0 &gt; -78 C &lt; / RTI &gt; for 2 hours. Add 100 mL saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate. The extract was dried and concentrated, and then the target product (8.4 g, 66.3%) as a yellow solid was obtained by column chromatography.

Step E: {6- [3- (pyrrolidin-1-yl) propyl-1-alkynyl] pyridin-3-yl} [4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] meth Rice field

To a 100 mL Schlenk flask was added (6-chloropyridin-3-yl) [4- (tetrahydro- 2H -pyran-2-oxyl) phenyl] methanone (4.0 g, 12.6 mmol) after the addition of Pro Parr Gylfi pyrrolidine (2.8 g, 25.2 mmol) - ( triphenylphosphine) palladium (1.5 g, 1.3 mmol), CuI (0.48 g, 2.5 mmol), Et 3 N (50 mL) and N , And the third stage is flushed with nitrogen gas. The mixture is stirred at 80 ° C for 2 hours. After concentration under reduced pressure, the concentrate was separated by column chromatography to obtain the target product (2.2 g, 44.9%) as a yellow solid.

Step F: {6- [3- (pyrrolidin-1-yl) propyl] pyridin-3-yl} [4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] methanone

(0.3 g, 0.6 mmol) was added to a solution of {6- [3- (pyrrolidin-1-yl) propyl-1-alkynyl] pyridin- Pyran-2-oxyl) phenyl] methanone (2.2 g, 5.6 mmol) and the mixture was stirred under hydrogen gas for 1 hour. Nickel is filtered off with diatomaceous earth and the filtrate is concentrated under reduced pressure to obtain a yellow solid target product (1.7 g, 77.3%).

Step G: Synthesis of 4- (2-phenyl-1- {6- [3- (pyrrolidin-1-yl) propyl] pyridin-

3-yl} [4- (tetrahydro-2H-pyran-2-yl) -propyl] -pyridin- (186 mg, 17.8%, Z / E = 3/1) was obtained by reacting propionamide (1.0 g, 7.6 mmol) m / z = 413 [M + 1] &lt; ⁺ &gt; _.

Example 31

4- (2-Phenyl-1- (4- (2-phenyl-1- {4- [3- (pyrrolidin- 1 -yl) propyl] phenyl} 3- (pyrrolidin-1-yl) propyl) phenyl) but-1-enyl) phenol)

Step A: {4- [3- (Pyrrolidin-1-yl) propyl-1-alkynyl] phenyl} [4- (tetrahydro-

In 25 mL shrink flask (Schlenk flask) (4-iodophenyl) [4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] methanone (408 mg, 1 mmol), Pd (PPh 3) _{2 Cl 2 (18 mg, 0.025} mmol), CuI (10 mg, 0.05 mmol), Et 3 N (10 mL) and N - Pro Parr Gylfi pyrrolidine (l- (prop-2-ynyl ) pyrrolidine) (165 mg , 1.5 mmol). The flask is flushed with a third of argon gas, and the mixture is stirred at 90 ° C for 3 hours. After concentration under reduced pressure, the objective product (312 mg, 80%) was obtained by subjecting the concentrate to column chromatography separation.

Step B: {4- [3- (pyrrolidin-1-yl) propyl] phenyl} [4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] methanone

{4- [3- (pyrrolidin-1-yl) propyl-1-alkynyl; phenyl} flask [4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] methanone (391 mg, 1 mmol), Raney nickel (0.1 g, 0.2 mmol) and 20 mL methanol. The mixture is stirred for 2 hours under hydrogen gas at room temperature and atmospheric pressure. After complete conversion (TLC detection), the catalyst is filtered off with diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the product (375 mg, 95%).

Step C: Preparation of 4- (2-phenyl-1- {4- [3- (pyrrolidin-1-yl) propyl] phenyl}

Yl) propyl] phenyl} [4- (tetrahydro- 2H -pyran-2-oxyl) propanoic acid methyl ester was obtained by the conventional McMurry reaction described in Example 1, (78 mg, 2 mmol) and propiophenone (800 mg, 6 mmol) were reacted to obtain the target product (208 mg, 25%, Z / E = 1/1). m / z = 412 [M + 1] &lt; ⁺ &gt;.

Example 32

3-yl} -2-phenylbutyl-1-alkenyl) phenol &lt; / RTI &

Step A: N -Methylpropargylamine

Under the ice of dry ice, propargyl bromide (64.0 g, 0.54 mol) is added to a 120 mL anhydrous methylamine solution. The reaction solution is reacted overnight in a sealant tube at room temperature. Next, open and heat at 45 ° C to remove excess methylamine. Dry ether (100 mL) is added, methylamine hydrochloride is removed by filtration, and the filtrate is distilled to obtain the desired product (5.0 g, 13.4%) in the form of a colorless oil and having a boiling point of 82-84 캜.

Step B: N -Methyl- N -tert-butyl methyl (prop-2-ynyl) carbamate

Di-tertbutyl dicarbonate (2.7 mL, 11.7 mmol) was added to a stirred solution of 0.8 g N -methylpropargylamine (1.0 mL, 11.8 mmol) in methanol (20 mL) Slowly add. The mixture is stirred for 1 hour. And concentrated under reduced pressure to obtain N -methyl- N -propargylcarbamic acid butyl group product (1.9 g, 97%) as a pale yellow oil.

Step C: Preparation of methyl (3- {5- [4- (tetrahydro-2H-pyran-2-oxyl) phenylacyl] pyridin- 3- (5- (4- (tetrahydro-2H-pyran-2-yloxy) benzoyl) -pyridin-2- yl) prop-

To a 25 mL Schlenk flask was added (6-chloropyridin-3-yl) [4- (tetrahydro- 2H -pyran-2-oxyl) phenyl] methanone (318 mg, 1.0 mmol), tetrakis triphenylphosphine) palladium (116 mg, 0.1 mmol), CuI (38 mg, 0.2 mmol), Et 3 N (5 mL) and N - methyl - N - propargyl-carboxylic acid butyl (169 mg, 1.0 mmol) Lt; / RTI &gt; The flask is flushed with nitrogen gas over a third order, and the mixture is stirred at 80 ° C for 2 hours. After concentration under reduced pressure, the concentrate was separated by column chromatography to obtain the target product (180 mg, 40%) as a yellow solid.

Step D: Methyl (3- {5- [4- (tetrahydro- 2H -pyran-2-oxyl) phenylacyl] pyridin- 2- yl} propylcarboxylate tert- (5- (4- (tetrahydro-2H-pyran-2-yloxy) benzoyl) -pyridin-2- yl) propyl) carbamate)

(2.4 mg, 0.04 mmol) was reacted with methyl (3- {5- [4- (tetrahydro- 2H -pyran-2-oxyl) phenylacyl] pyridin- Yl) carbamic acid butyl (180 mg, 0.4 mmol) and the mixture was stirred under hydrogen gas for 1 hour. Nickel is filtered off with diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain the target product (100 mg, 55.6%) which is a yellow solid.

Step E: Preparation of 4- (1- {6- [3- (methylamino) propyl] pyridin-3- yl} -2-phenylbutyl-

Example 1 step by a conventional McMurry reaction described in B, methyl (3- {5- [4- (tetrahydro -2 H - pyran-2-oxyl) phenacyl] pyridin-2-yl} propyl) carboxamide The target product (16 mg, 20%, Z / E = 1/1) was obtained by reacting butyl (100 mg, 0.22 mmol) with propiophenone (88 mg, 0.66 mmol). m / z = 373 [M + 1] &lt; ⁺ &gt;.

Example 33

4- (1- {4- [3- (methylamino) propyl] phenyl} -2-phenylbutyl-1-alkenyl) phenol

Step A: Preparation of methyl (3- {4- [4- (tetrahydro-2H-pyran-2-oxyl) phenacyl] phenyl} - (4- (tetrahydro-2H-pyran-2-yloxy) benzoyl) -phenyl) prop-2-yl) carbamate)

In 25 mL shrink flask (Schlenk flask) (4-iodophenyl) [4- (tetrahydro -2H- pyran-2-oxyl) phenyl] methanone (408 mg, 1 mmol), Pd (PPh 3) 2 Cl ₂ (18 mg, 0.025 mmol), CuI (10 mg, 0.05 mmol), Et ₃ N (10 mL) and N -methyl- N -propargylcarbamic acid butyl (255 mg, 1.5 mmol). The flask is flushed with a third of argon gas, and the mixture is stirred at 90 ° C for 3 hours. After concentration under reduced pressure, the objective product (270 mg, 60%) was obtained by column chromatography separation of the concentrate.

Step B: Preparation of methyl (3- {4- [4- (tetrahydro- 2H -pyran-2-oxyl) phenylacyl] phenyl} propylcarbamate tert- (tetrahydro-2H-pyran-2-yloxy) benzoyl) -phenyl) propyl) carbamate)

To a flask was added a solution of methyl (3- {4- [4- (tetrahydro- 2H -pyran-2-oxyl) (0.1 g, 0.2 mmol) and 20 mL methanol. The mixture is stirred for 2 hours under hydrogen gas at room temperature and atmospheric pressure. The catalyst is filtered off with diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the target product (364 mg, 80%).

Step C: Preparation of 4- (1- {4- [3- (methylamino) propyl] phenyl} -2-phenylbutyl-

By Example 1, step B a conventional McMurry reaction from the description, methyl (3- {4- [4- (tetrahydro -2 H - pyran-2-oxyl) phenacyl] phenyl} propyl) -carbamic acid tert-butyl (909 (224 mg, 30%, Z / E = 1/1) was obtained by reacting propiophenone (800 mg, 6 mmol) m / z = 372 [M + 1] &lt; ⁺ &gt; _.

Example 34

Alkynyl] phenyl} -2-phenylbutyl-1-alkenyl) phenol (hereinafter referred to as &quot;

Step A: (4-Bromo-3-fluorophenyl) [4- (tetrahydro- 2H -pyran-

0 ℃ under the nitrogen gas protection, 4-bromo-3-fluoro - N - methoxy - N - methyl a dry THF solution of the benzamide (1.00 g, 3.8 mmol) [ 4- ( tetrahydro -2 H - Pyran-2-oxyl) magnesium bromide (7.6 mmol) was added dropwise. After completion of the dropwise addition, the reaction solution is warmed to room temperature, stirred for 2 hours, quenched with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract is dried with anhydrous sodium sulfate, concentrated, and then chromatographed to obtain the desired product (1.1 g, 76%) as a colorless oil.

Step B: {3-fluoro-4- [3- (pyrrolidin-1-yl) propyl-1-alkynyl] phenyl} [4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] Methanone

To a 100 mL Schlenk flask was added (4-bromo-3-fluorophenyl) [4- (tetrahydro-2H-pyran-2-oxyl) phenyl] methanone (1.1 g, 2.9 mmol) tetrakis (triphenylphosphine) palladium (0.34 g, 0.29 mmol), CuI (0.11 g, 0.58 mmol), Et 3 N (20 mL) and N - addition of Pro Parr Gylfi pyrrolidine (0.63 g, 5.8 mmol) and , The flask is flushed with nitrogen over the third order. The mixture is stirred at 80 ° C for 2 hours. By subjecting the concentrate to concentration under reduced pressure, a target product (0.43 g, 36%) as a yellow solid is obtained.

Step C: Synthesis of 4- (1- {3-fluoro-4- [3- (pyrrolidin- 1 -yl) propyl-1-alkynyl] phenyl} -2- phenylbutyl-

The title compound was prepared from {3-fluoro-4- [3- (pyrrolidin-1-yl) propyl-1-alkynyl] phenyl} [4- (tetrahydro (155 mg, 0.38 mmol) and propiophenone (152 mg, 0.38 mmol) were reacted to obtain the target product (58 mg, 36%, Z / E = 1 / 1). m / z = 426 [M + 1] &lt; ⁺ & gt ^; _.

Example 35

( Z ) -4- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl-2-yl] cyclohexanone

Step A: 2,3,3-Triethoxycarbonylcyclohexanone

THF (80 mL) of diethyl malonate (40.0 g) was added to a dry THF (280 mL) solution of sodium hydride (23.0 g) under stirring at 40 ° C, and the addition was completed within 30 minutes. After completion of the dropwise addition, the mixture is stirred for 1 hour, the temperature is lowered to 15 DEG C, and then a solution of ethyl acrylate (52.5 g) in THF (80 mL) is added. The reaction solution is reacted at 45 DEG C for 30 minutes, quenched by adding water (100 mL), and the mixture is extracted with ethyl acetate. The extract was concentrated, and the desired product (40 g, 38%) was obtained by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1).

Step B: 4-Carboxycyclohexanone

A mixed solution of 2,3,3-triethoxycarbonylcyclohexanone (31.4 g, 0.1 mol), concentrated hydrochloric acid (30 mL) and water (145 mL) is refluxed overnight and extracted with ethyl acetate. The extract was concentrated and then 4-carboxycyclohexanone (4.2 g, 29%) was obtained by silica gel column chromatography separation (dichloromethane / methanol = 80/1).

Step C: Preparation of N -methyl- N -methoxy-4-carbonylcyclohexylcarboxamide

Oxalyl chloride (5.2 g, 0.44 mol) was slowly added dropwise to a solution of 4-carboxycyclohexanone (4.2 g, 0.0293 mol) in dichloromethane (20 mL), stirred at room temperature for 1 hour, concentrated, Methane (20 mL) was added followed by Et ₃ N (9 g, 0.116 mol) and N, O -dimethylhydroxylamine hydrochloride (3.5 g, 0.0359 mol). The reaction solution is stirred at room temperature for 2 hours, and water (100 mL) is added. The mixture was extracted with ethyl acetate. After concentrating the extract, the target product (2.1 g, 39%) is obtained by column chromatography separation.

Step D: N - methoxy - N - methyl-1,4-dioxa-spiro [4.5] decane-8-carboxamide (N -methoxy- N -methyl-l, 4-dioxaspiro [4.5] decane-8- carboxamide)

(30 mL) solution of N -methyl- N -methoxy-4-carbonylcyclohexylcarboxamide (2.1 g, 0.114 mol), glycol (0.9 g, 0.136 mol) and p- toluenesulfonate Is refluxed overnight and then concentrated. Water is added and the mixture is extracted with ethyl acetate. The extract was concentrated, and the desired product (1.0 g, 38.4%) was obtained by silica gel column chromatography (dichloromethane / methanol = 100/1).

Step E: Preparation of 4-propionylcyclohexanone glycol ketal (1- (1,4-dioxaspiro [4.5] decan-8-yl) propan-

Ethyl magnesium bromide solution (9 g, 0.043 mol) was added to anhydrous ether (20 g, 0.043 mol) of N -methoxy- N -methyl-1,4-dioxaspiro [4.5] decane- mL). The reaction is refluxed overnight and then water (200 mL) is added. The mixture was extracted with ethyl acetate. The extract was concentrated, and then the desired product (259 mg, 26%) was obtained by silica gel column chromatography (dichloromethane / methanol = 150/1).

Step F: ( Z ) -4- {1- [4- (2-Chloroethyl) phenyl] -2- (1,4- dioxaspiro [4.5] decan- phenol

(4-hydroxyphenyl) methanone (360 mg, 1.3 mmol) and 4-propionylcyclohexane (0.25 g, 0.10 mmol) were reacted according to the conventional McMurry reaction described in Example 1, Step B, (259 mg, 1.3 mmol) were reacted to obtain the target product (Z-form, 90 mg, 16%) and 110 mg E-form (19%).

Step G: Synthesis of ( Z ) -4- (1- {4- [2- (methylamino) ethoxy] phenyl} -2- (1,4- dioxaspiro [4.5] decan- -Alkenyl) phenol

( Z ) -4- {1- [4- (2-chloroethyl) phenyl] -2- (1,4-dioxaspiro [4.5] decan- (5 mL) of a 30% aqueous methylamine solution (5 mL) was reacted in a sealed tube overnight at 85 ° C, concentrated, and purified by column chromatography to obtain the target product 90 mg).

Step H: Synthesis of ( Z ) -4- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl-2-yl] cyclohexane On

( Z ) -4- (1- {4- [2- (methylamino) ethoxy] phenyl} -2- (1,4- dioxaspiro [4.5] decan- A solution of hydrochloric acid (3 M, 1.5 mL) was added to a methanol solution (10 mL) of the compound obtained in the previous step (2) and the reaction solution was stirred at room temperature for 2 hours, 20 mL of water was added, The pH value is adjusted to 7-8 by adding aqueous sodium hydrogen solution, and the mixture is extracted with ethyl acetate. The extract was dried, filtered and concentrated to obtain the target product (22 mg, 27.5%, Z type) by column chromatography (dichloromethane / methanol = 150/1). m / z = 394 [M + 1] &lt; ⁺ &gt;.

Example 36

( E ) -4- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl-2-yl] cyclohexanone

The objective product (32 mg, 39.5%) is obtained in the same manner as in Example 35, Steps G and H, using the (E) -product obtained in Step F of Example 35. [ m / z = 394 [M + 1] &lt; ⁺ &gt;.

Example 37

( Z ) -4- (1- (hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl-2-yl) -1-methylpyridin- - (1 H ) -one ((Z) -4- (1- (4-hydroxyphenyl) -1- (4- (2- (methylamino) ethoxy) phenylbut-1-en- methylpyridin-2 (1 H) -one)

Step A: Preparation of 2-carbonyl-1,2-dihydropyridine-4-carboxylic acid

Potassium hydroxide (40 g, 7.5 eq.) Is added to a stirred solution of 2-chloroisonicotinic acid (15 g, 1.0 eq) in water (200 mL) at 0 ° C. After heating to reflux for 36 hours, the solution is stirred and 3N hydrochloric acid solution is added so that the pH value is about 1-3. The suspension is filtered and washed with water to obtain a white solid product (13.1 g, 99%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 12.80 (brs, 2H), 7.47 (d, J = 6.4 Hz, 1H), 6.79 (s, 1H), 6.50 (dd, J = 6.8 & 1.6 Hz, 1H).

Step B: Methyl 1-methyl-2-carbonyl-1,2-dihydropyridine-4-

Sodium hydride 60% (4.3 g, 3.0 eq.) Was slowly added to a solution of 2-carbonyl-1,2-dihydropyridine-4-carboxylic acid (5 g, 1.0 eq) in 100 mL DMF at 0 & Stir at room temperature for 30 minutes. Methyl iodide (CH3I, 15.3 g, 3.0 eq.) Is then slowly added dropwise to the reaction at 0 &lt; 0 &gt; C. Stir at room temperature overnight, quenched the reaction with ice water, then extract with ethyl acetate. The extract was dried and concentrated, and the desired product (1.5 g, 25%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.34 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.65 (dd, J = 6.8 & 2.0 Hz, 1H), 3.91 (s, 3H), 3.57 (s, 3H).

Step C: Preparation of 1-methyl-2-carbonyl-1,2-dihydropyridine-4-

At room temperature, 1-methyl-2-carbonyl-1,2-dihydropyridin-4-carboxylic acid Lithium hydroxide monohydrate in 25mL of methanol solution (1 g, 1.0 _{eq.) (LiOHH 20) (755 mg} , 3.0 eq. ) &Lt; / RTI &gt; (5 mL) is added. Stir at room temperature for 2 hours. The solvent is removed and water and 3N hydrochloric acid solution are added so that the pH value is about 1 to 3, and the suspension is filtered and washed with water to obtain the target product (540 mg, 60%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 13.56 (brs, 1H), 7.80 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 1.6 Hz, 1H), 6.53 (d, J = 6.8 &amp; 1.6 Hz, 1H), 3.46 (s, 3H).

Step D: N - methoxy - N, 1- dimethyl-2-carbonyl-1,2-dihydropyridin-4-carboxamide

(540 mg, 1.0 eq.), EDCI (811 mg, 1.2 eq.) And HOBt (572 mg, 1.2 eq.) In 20 mL dichloromethane at room temperature was added to a solution of 1-methyl-2-carbonyl-l, 2-dihydropyridine- Is stirred at room temperature for 5 minutes. Next, N -methoxymethylamine hydrochloride (413 mg, 1.2 eq.) And triethylamine (1.1 g, 3.0 eq.) Were added and stirred overnight at room temperature. Water is added and extracted with dichloromethane. The extract was dried and concentrated, and the desired product (555 mg, 80%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.32 (d, J = 6.8 Hz, 1H), 6.78 (s, 1H), 6.32 (dd, J = 6.8 & 1.6 Hz, 1H), 3.61 (s, 3H) , 3.57 (s, 3H), 3.32 (s, 3H).

Step E: 1-Methyl-4-propylpyridin-2 ( 1H ) -one

To a solution of N -methoxy- N , 1 -dimethyl-2-carbonyl-1,2-dihydropyridine-4-carboxamide (200 mg, 1.0 eq.) In 10 mL anhydrous tetrahydrofuran was added 3M Magnesium ethyl bromide (0.7 mL, 2.0 eq.) Is added. Stir at room temperature for 1 hour, quenched the reaction by adding saturated aqueous ammonium chloride, and extract with dichloromethane. The extract was dried and concentrated, and the desired product (105 mg, 62%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.35 (d, J = 6.8 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.61 (dd, J = 6.8 & 1.6 Hz, 1H), 3.57 (s, 3H), 2.89 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H).

Step F: Synthesis of 4- {1- [4- (2-chloroethoxy) phenyl] -1- (4-hydroxyphenyl) butyl-1-alkenyl- H ) -one

Methyl-4-propylpyridin-2 ( 1H ) -one (105 mg, 1.0 eq.) And [4- (2- chloroethoxy) phenyl ] (4-hydroxyphenyl) methanone (352 mg, 2.0 eq.) Were reacted to obtain the target product (Z / E = 1/1).

Step G: Synthesis of ( Z ) -4- (1- (hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl- Pyridin-2- ( 1H ) -one

Stirring that is 4- {1- [4- (2-chloroethoxy) phenyl] -1- (4-hydroxyphenyl) butyl-1-alkenyl-2-yl) -1-methyl-pyridin -2 (1 H ) -One (30 mg, 1.0 eq.) In MeOH (10 mL) was added 5 mL methylamine aqueous solution (30%) and heated to 85 ° C and stirred for 36 hours. The solvent is removed under reduced pressure, water is added and extracted with EtOAc. The extract was dried and concentrated, and the desired product (3 mg, pure Z type), E-form product (2 mg) and Z / E mixture (230 mg, 49%) were obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 6.96-6.98 (m, 3H), 6.84 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 6.47 ( d, J = 2.0 Hz, 1H), 5.78 (dd, J = 6.8 & 2.0 Hz, 1H), 3.98 (t, J = 5.2 Hz, 2H), 3.47 (s, 3H) , 2.96 (t, J = 5.2 Hz, 2H), 2.52 (s, 3H), 2.36-2.38 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H); m / z = 405 [M + 1] &lt; ⁺ &gt;.

Example 38

( E ) -4- (1- (hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl-2-yl) -1-methylpyridin- - ( 1H ) -one

The title compound is obtained by example &lt; RTI ID = 0.0 &gt; 37. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.08 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 6.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.79 (d , J = 8.4 Hz, 2H) , 6.53 (d, J = 8.4 Hz, 2H), 6.51 (d, J = 1.6 Hz, 1H), 5.83 (dd, J = 7.2 & 2.0 Hz, 1H), 4.08 (t , J = 5.2 Hz, 2H) , 2.99 (t, J = 5.2 Hz, 2H), 2.52 (s, 3H), 2.41 (q, J = 7.2 Hz, 2H), 0.97 (t, J = 7.6 Hz, 3H ); m / z = 405 [M + 1] &lt; ⁺ &gt;.

Example 39

(Z) -4- (1- {6 [2- ( dimethylamino) ethylthio] pyridine-3-yl} 2-phenyl-1- alkenyl) phenol ((Z) -4- (l- ( 6 - (2- (methylamino) ethylthio) pyridin-3-yl) -2-phenylbut-1-enyl)

Step A: 2- (Methylamino) ethanol hydrochloride

A 50 mL concentrated hydrochloric acid solution of 2- (methylamino) ethanol (20 g, 1.0 eq) was stirred at room temperature for 2 hours and then concentrated to obtain the product (quantitative). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.95 (brs, 2H), 3.65 (t, J = 5.2 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.50-2.54 (m, 3H).

Step B: 2-Chloro- N -methylethylamine hydrochloride

To the 150 mL chloroform solution of 2- (methylamino) ethanol hydrochloride (29.7 g, 1.0 eq) in toluene was added thionyl chloride (41 g, 1.3 eq.) At 0 ° C and the mixture was refluxed for 3 hours , And the temperature is raised to room temperature. The solvent is removed by evaporation under reduced pressure, and the concentrate is stirred in 100 mL of 1:10 dichloromethane / petroleum ether to obtain a suspension. The suspension is filtered to obtain the product (18 g, 80%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.24 (brs, 2H), 3.93 (t, J = 6.0 Hz, 2H), 3.28 (t, J = 6.0 Hz, 2H), 2.56 (s, 3H) .

Step C: 2- (Methylamino) ethanethiol hydrochloride

Na ₂ S ₂ O ₃ (18.5 g, 1.0 eq.) Is added to a 150 mL aqueous solution of 2-chloro- N -methylethylamine hydrochloride (15 g, 1.0 eq.) In stirring under reflux for 48 hours. The mixture is stirred at room temperature and the solvent is removed under reduced pressure. The crude salt is dissolved in 60 mL of a 6M aqueous hydrochloric acid solution and heated at 90 ° C for 4 hours. The solvent is removed under reduced pressure and the target product is obtained by column chromatography. ¹ H NMR (400 MHz, DMSO- d ⁶ )? 4.95 (brs, 2H), 2.90 (s, 4H), 2.37 (s, 3H).

Step D: (Z) -4- (1- {6- [2- (Methylamino) ethanethiol] pyridin- 3- yl} -2-phenylbutyl-

Sodium hydride (120 mg, 12 equiv.) Having a content of 60% is slowly added to a 20 mL anhydrous tetrahydrofuran solution of 2- (methylamino) ethanethiol hydrochloride (217 mg, 10 eq.) In anhydrous tetrahydrofuran under stirring at 0 ° C. After stirring at room temperature for 1 hour, a solution of ( Z ) -4 - [(6-chloropyridin-3-yl) -2-phenylbutyl- 1 -alkenyl) phenol (80 mg, 1.0 eq. Is added to the reaction. The mixture is heated to reflux for 48 hours, then cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride solution, and extracted with dichloromethane. The extract was dried and concentrated, and the desired product (75 mg, 81%) was isolated by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.89 (dd, J = 2.4 & 0.8 Hz, 1H), 7.13-7.21 (m, 3H), 7.05-7.10 (m, 4H), 6.95 (dd, J = 8.4 & 2.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 2H), 3.23 (t, J = 6.4 Hz, 2H), 2.84 (t, J = 6.4 Hz, 2H), 2.50 (q, J = 7.2 Hz, 2H), 2.41 (s, 3H), 0.93 (t, J = 7.2 Hz, 3H); m / z = 391 [M + 1] &lt; ⁺ &gt;.

Example 40

( E ) -4- [1- (6- {methyl [2- (methylamino) ethyl] amino} pyridin-

( E ) -4 - [(6-chloropyridin-3-yl) -2-phenylbutyl-1-alkenyl) phenol (100 mg, 1.0 eq., Example 2 ) And N, N'- dimethylethylenediamine (262 mg, 10.0 eq.) Were reacted to obtain the target product. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.07 (d, J = 2.4 z, 1H), 7.06-7.14 (m, 6H), 6.69 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.8 Hz, 1H), 6.43 ( d, J = 8.8 Hz, 2H), 3.71 (t, J = 6.4 Hz, 2H), 3.08 (s, 3H), 2.88 (t, J = 6.4 Hz, 2H), 2.53 (q, J = 7.6 Hz, 2H), 2.48 (s, 3H), 0.95 (t, J = 7.6 Hz, 3H); m / z = 388 [M + 1] &lt; ⁺ &gt;.

Example 41

( Z ) -5- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl-2-yl] pyridin-

Step A: 6- hydroxy - N - methoxy - N - methyl-nicotinamide (6-hydroxy- N -methox - N -methylnicotinamide)

To a dichloromethane (150 mL) solution of 6-hydroxynicotinic acid (5.0 g, 1.0 eq.), EDCI (8.3 g, 1.2 eq.) And HOBt (5.8 g, 1.2 eq.) In dichloromethane (150 mL) under room temperature stirring was added N, O -dimethylhydroxylamine Hydrochloric acid salt (4.2 g, 1.2 eq.) And triethylamine (15 g, 4.0 eq.) Are added and the mixture is stirred at room temperature overnight. Water is added and the mixture is extracted with dichloromethane. The extract is dried and concentrated, and then 3.5 g (53%) of the target product is obtained by column chromatography separation. ^{1 H NMR (400 MHz, DMSO-} d 6) δ 11.82 (brs, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.72 (dd, J = 9.6 & 2.8 Hz, 1H), 6.32 (d, J = 9.6 Hz, 1H), 3.59 (s, 3H), 3.20 (s, 3H).

Step B: 1- (6-Hydroxypyridin-3-yl) propyl-1-one

To a solution of 6-hydroxy- N -methoxy- N -methylnicotinic acid carboxamide (800 mg, 1.0 eq.) In anhydrous THF (20 mL) under stirring at 0 ° C was added 3 M ethylmagnesium bromide (6.0 mL, ) Is added. The mixture is stirred at room temperature for 2 hours, quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The extract was dried and concentrated, and then the target product (320 mg, 48%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 12.13 (brs, 1H), 8.11 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 10.0 & 2.8 Hz, 1H), 6.60 (d, J = 9.6 Hz, 1H), 2.79 (q, J = 7.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H).

Step C: ( Z ) -5- {1- [4- (2-Chloroethoxy) phenyl] -1- (4-hydroxyphenyl) butyl-1-alkenyl-2-yl} pyridin-

(300 mg, 1.0 eq.) And [4- (2-chloroethoxy) -propyl] -pyrrolidine were prepared by the conventional McMurry reaction described in Example 1, Step B, ) Phenyl] (4-hydroxyphenyl) methanone (1.37 g, 2.5 eq.) Were reacted to obtain the target product (Z-type and E-type can be separated by column chromatography).

Step D: Synthesis of ( Z ) -5- (1- [4-hydroxyphenyl] -1- {4- [2- (methylamino) ethoxy] phenyl} butyl- 2-ol

( Z ) -5- {1- [4- (2-chloroethoxy) phenyl] -1- (4-hydroxyphenyl) butyl-1-alkenyl-2 -2-ol (0.02 g, 1.0 eq.) And methylamine (30% aqueous solution, 10 mL) in methanol (20 mL). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.37 (brs, 1H), 7.13 (dd, J = 9.2 & 2.8 Hz, 1H), 6.96 (s, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 4H), 6.12 (d, J = 9.2 Hz, 1H), 3.97 (t, J = 5.6 Hz, 2H) , 2.93 (t, J = 5.6 Hz, 2H), 2.40 (s, 3H), 2.29 (q, J = 7.2 Hz, 2H), 0.90 (t, J = 7.2 Hz, 3H); m / z = 391 [M + 1] &lt; ⁺ &gt;.

Example 42

1 - (4-hydroxyphenyl) -1 - {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl-2-yl] pyridin-

Step A: 5-Hydroxy- N -methoxy- N -methyl-2-pyridinecarboxamide

(6.2 g, 1.0 eq.) And N, O -dimethylhydroxylamine hydrochloride (5.2 g, 1.2 eq.) Were prepared by the conventional condensation method described in Example 41, To obtain the target product (4.25 g, 52%).

Step B: 1- (5-Hydroxypyridin-2-yl) propyl-1-one

Example 11, by a conventional method described in Step B, 5- hydroxy - N - methoxy - N - methyl-2-pyridine carboxamide (500 mg, 1.0 eq) and ethyl magnesium bromide (6.0 mL, 4.0 eq.) Was reacted to obtain the target product (200 mg, 48%).

Step C: Preparation of 6- {1- [4- (2-chloroethoxy) phenyl] -1- (4-hydroxyphenyl) butyl-1-alkenyl-2-yl} pyridin-

(150 mg, 1.0 eq.) And [4- (2-chloroethoxy) -propyl] -pyrrolidine were prepared by the conventional McMurry reaction described in Example 1, ) Phenyl] (4-hydroxyphenyl) methanone (549 mg, 2.0 eq.) Were reacted to obtain the target product (Z / E = 1/1).

Step D: Synthesis of 6- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl-2-yl] pyridin-

1- (4-hydroxyphenyl) butyl-1-alkenyl-2-yl (phenyl) } To a methanol (20 mL) solution of pyridin-3-ol (220 mg, 1.0 eq.) And methylamine (30% aqueous solution, 10 mL) was refluxed to obtain the target product (Z / E = 1/1). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.31 (brs, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.92-6.97 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.55-6.69 (m, 4H), 6.45 (d, J = 8.4 Hz, 1H), 4.06 ( t, J = 5.2 Hz, 1H ), 3.93 (t, J = 5.2 Hz, 1H), 2.93 (t, J = 5.6 Hz, 1H), 2.85 (t, J = 5.6 Hz, 1H), 2.46-2.50 ( m, 2H), 2.40 (s, 1.5H), 2.35 (s, 1.5H), 0.83 (t, J = 7.2 Hz, 3H); m / z = 391 [M + 1] &lt; ⁺ &gt;.

Example 43

2-phenylbutyl-1-alkenyl] pyridin-2 ( 1H ) -one was used in place of 1- [3- (dimethylamino)

Step A: 4-Chloro- N, N -dimethylpropylamine hydrochloride

Thionyl chloride (21 g, 1.2 equivalents) was added dropwise to a solution of 3- (dimethylamino) propyl-1-ol (15 g, 1.0 eq.) In 150 mL of chloroform under stirring at 0 ° C. Then, the mixture is heated under reflux for 5 hours. After raising to room temperature, the solvent was evaporated under reduced pressure to obtain the crude product and the crude product was washed with a 50 mL 1:10 dichloromethane / petroleum ether solution to obtain the desired product (22 g, 98%) .

Step B: N -Methoxy- N -methyl-2-carbonyl-1,2-dihydropyridine-4-carboxamide

To a solution of 2-carbonyl-1,2-dihydropyridine-4-carboxylic acid (8.0 g, 1.0 eq.), EDCI (13.2 g, 1.2 eq.) And HOBt (9.3 g, 1.2 eq.) In dichloromethane N, O -dimethylhydroxylamine hydrochloride (6.8 g, 1.2 eq.) And triethylamine (26.2 g, 4.5 eq.) Are added. The reaction mixture is stirred at room temperature overnight, concentrated and then the desired product (6.3 g, 60%) is obtained by column chromatography separation. ^{1 H NMR (400 MHz, CDCl} 3) δ 12.79 (s, 1H), 7.40 (d, J = 6.8 Hz, 1H), 6.77 (s, 1H), 6.43 (dd, J = 6.8 & 1.6 Hz, 1H) , 3.62 (s, 3H), 3.34 (s, 3H).

Step C: Synthesis of 1- [3- (dimethylamino) propyl] -N -methoxy- N -methyl-2-carbonyl-1,2-dihydropyridine-

To a stirred solution of N -methoxy- N -methyl-2-carbonyl-1,2-dihydropyridine-4-carboxamide (200 mg, 1.0 eq.) And 4-chloro- N, N -dimethylpropylamine hydrochloride (350 mg, 2.0 eq.) And anhydrous potassium carbonate (455 mg, 3.0 eq) in a 20 mL acetone solution is heated to reflux overnight. After the mixture is cooled to room temperature, water is added, and the mixture is extracted with dichloromethane. The extract was dried and concentrated, and the desired product (255 mg, 87%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.40 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 1.2 Hz, 1H), 6.30 (dd, J = 6.8 & 2.0 Hz, 1H), 4.02 (t, J = 7.2 Hz, 2H), 3.62 (s, 3H), 3.33 (s, 3H), 2.30 (t, J = 6.8 Hz, 2H), 2.23 (s, 6H), 1.93 (t, J = 7.2 Hz, 2H).

Step D: 1- [3- (dimethylamino) propyl] -4- [4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] pyridine -2 (1 H) - one

Magnesium (440 mg, 3.5 eq.) Is added to a 3-neck round bottom flask containing 50 mL anhydrous THF and the mixture is heated to 55 [deg.] C. Add iodine and 0.1 mL bromoethane. 2- (4-Bromophenol) tetrahydro- 2H -pyran (4.0 g, 3.0 eq.) Is dissolved in 30 mL of anhydrous THF and 3 mL of this solution is added to the Mg-THF suspension. After 30 minutes, the reaction is initiated and reflux is started. Then, the remaining 2- (4-bromophenol) tetrahydro- 2H -pyran solution is added at a dropping rate capable of maintaining the reflux within 5 minutes, followed by refluxing for 2 h, and then the mixture is cooled to room temperature. To a THF (20 mL) solution of 1 - [3- (dimethylamino) propyl] - N -methoxy- N -methyl-2-carbonyl-1,2-dihydropyridine- ) Is added dropwise. After completion of dropwise addition, the mixture is stirred at room temperature for 30 minutes, quenched with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was dried and concentrated, and the desired product (1.6 g, 80%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.85 (d, J = 9.2 Hz, 2H), 7.48 (d, J = 6.8 Hz, 1H), 7.11 (d, J = 9.2 Hz, 2H), 6.75 (d , J = 1.6 Hz, 1H) , 6.44 (dd, J = 6.8 & 2.0 Hz, 1H), 5.55 (t, J = 2.8 Hz, 1H), 4.05 (t, J = 7.2 Hz, 2H), 3.82-3.88 (m, 1H), 3.62-3.66 (m, 1H), 2.32 (t, J = 6.4 Hz, 2H), 2.24 ).

Step E: 1- [3- (dimethylamino) propyl] -4- [1- (4-hydroxyphenyl) -2-phenyl-1- alkenyl] pyridine -2 (1 H) - one

Example 1 step by a conventional McMurry reaction described in B, propiophenone (838 mg, 3.0 eq) and 1- [3- (dimethylamino) propyl] -4- [4- (tetrahydro -2 H - 2-oxyl) phenyl] pyridin-2 ( 1H ) -one (800 mg, 1.0 eq.) Were reacted to obtain the target product (Z form prepared by preparative HPLC). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.54 (brs, 1H), 7.34 (d, J = 6.8 Hz, 1H), 7.17-7.29 (m, 5H), 7.04 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.83 (d, J = 1.6 Hz, 1H), 5.75 (dd, J = 6.8 & 1.6 Hz, 1H), 3.75 (t, J = 6.8 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H), 2.73 (s, 6H), 2.37 (q, J = 7.2 Hz, 2H), 1.86-1.90 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H); m / z = 403 [M + 1] &lt; ⁺ &gt;.

Example 44

1- [4- (2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl] phenol

Step A: 1- (2,3-Dihydrobenzofuranyl-5-yl) propyl-1-one

Propionyl chloride (14 g, 1.8 eq.) And anhydrous aluminum chloride (11.1 g, 1.0 eq.) Were added to a 200 mL dichloromethane solution of 2,3-dihydrobenzofuran (10 g, 1.0 eq) Dissolve the dissolved 200 mL of dichloromethane solution. After completion of the dropwise addition, the mixture is stirred at room temperature for 1 hour, quenched by adding ice water, and extracted with dichloromethane. The extract is washed with saturated brine, dried and concentrated under reduced pressure. Hexane (100 mL) was added, and the mixture was allowed to warm to 0 &lt; 0 &gt; C and stirred for 30 minutes. The suspension is filtered, washed with cold hexane and dried to obtain a white solid product (11.8 g, 80%). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.86 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.66 (t, J = 8.8 Hz , 2H), 3.25 (t, J = 8.8 Hz, 2H), 2.94 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H).

Step B: Preparation of [4- (2-chloroethoxy) phenyl] (4-methoxyphenyl) methanone

Methoxybenzoyl chloride (62 g, 1.2 eq.) And anhydrous aluminum chloride (49 g, 1.0 eq.) Were added to a 400 mL dichloromethane solution of 1- (2-chloroethoxy) benzene (48 g, 1.0 eq. 1.2 equivalents) dissolved in 400 mL of dichloromethane is added dropwise. After completion of the dropwise addition, the mixture is stirred at room temperature for 1 hour, quenched by adding ice water, extracted with dichloromethane, washed with saturated brine, dried and concentrated under reduced pressure. Hexane (500 mL) is added to the concentrate, and the mixture is stirred at 0 DEG C for 30 minutes. The suspension is filtered, washed with cold hexane and dried to obtain a white solid (85 g, 96%). ^{1 H NMR (400 MHz, CDCl} 3) δ7.79 (dd, J = 6.8 & 2.0 Hz, 4H), 6.97 (dd, J = 8.8 & 2.0 Hz, 4H), 4.32 (t, J = 6.0 Hz, 2H ), 3.89 (s, 3H), 3.86 (t, J = 6.0 Hz, 2H).

Step C: Preparation of [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) methanone

Boron tribromide (BBr ₃ ) (52) was added to a 150 mL dichloromethane solution of [4- (2-chloroethoxy) phenyl] (4- methoxyphenyl) methanone (20 g, 1.0 eq. g, 3.0 eq.). Stir at room temperature for 4 hours and quenched with 500 mL ice water. The suspension is filtered and washed with water to obtain the product (16 g, 85%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 10.36 (s, 1H), 7.69 (dd, J = 6.8 & 2.0 Hz, 2H), 7.64 (dd, J = 6.8 & 2.0 Hz, 2H), 7.11 ( (d, J = 7.2 and 2.0 Hz, 2H), 6.90 (dd, J = 6.8 & 2.0 Hz, 2H), 4.38 (t, J = 5.2 Hz, 2H), 4.01 (t, J = 5.2 Hz, 2H).

Step D: Synthesis of 4- {1- [4- (2-chloroethoxy) phenyl] -2- (2,3-dihydro-5-benzofuranyl) butyl-

To a suspension of zinc powder (595 mg, 6 eq.) In anhydrous THF (20 mL) was added TiCl ₄ (0.5 mL, 3 eq.) Under nitrogen gas protection at 0 ° C. The mixed solution is heated to reflux for 1 hour and then cooled to room temperature. (4-hydroxyphenyl) methanone (420 mg, 2.5 eq.) And 2,3-dihydro-5-propionylbenzofuran , 1.0 eq.) In anhydrous THF (10 mL) is added dropwise. After completion of the dropwise addition, the reaction mixture is heated to reflux for 1 hour, then quenched with saturated aqueous NaHCO ₃ solution, filtered and the filtrate is extracted with EtOAc. The extract is dried and concentrated under reduced pressure. The concentrate was subjected to column chromatography separation to obtain 500 mg (78%, Z / E = 1/1) target product.

Step E: Synthesis of 4- [2- (2,3-dihydro-5-benzofuranyl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-

Phenyl) -2- (2,3-dihydro-5-benzofuranyl) butyl-1-alkenyl} phenol (500 mg, 1.0 &lt; Equivalent) in 20 mL of MeOH was added 10 mL of an aqueous solution of CH ₃ NH _2, and the mixture was heated to 85 ° C and reacted for 24 hours. The solvent is removed by concentration under reduced pressure, water is added to the concentrate, and the mixture is extracted with ethyl acetate. The extract is dried and concentrated, and then the target product (Z / E = 1/1) is obtained by column chromatography separation. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.10 and 7.01 (d, J = 8.8 Hz , 2H), 6.92 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.82 and 6.74 (d, J = 8.8 Hz, 2H), 6.79 and 6.75 (d, J = 8.8 Hz , 2H), 6.57 (d, J = 8.4 Hz, 1H), 6.51 and 6.45 (d, J = 8.8 Hz , 2H), 4.51 ( t, J = 8.4 Hz, 2H ), 4.10 and 3.96 (t, J = 4.8 Hz , 2H), 3.09 (t, J = 8.8 Hz, 2H), 3.01 and 2.93 (t, J = 4.8 Hz , 2H), 2.54 and 2.50 (s, 3H), 2.39-2.46 (m, 2H), 0.90-0.94 (m, 3H); m / z = 416 [M + 1] &lt; ⁺ &gt;.

Example 45

( Z ) -4- (2- (1 H -indazolyl-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl) phenol

Step A: Methyl 4-amino-3-methylbenzoate

To a 1 L methanol solution of methyl-4-nitro-3-methylbenzoate (50 g, 1.0 eq) in an atmosphere of stirring was added an aqueous solution of ammonium chloride (137 g, 10 equivalents) dissolved in 60 mL water and an iron powder g, 7 eq.) is added and the reaction mixture is heated to reflux for 4 hours. The reaction mixture is then cooled to room temperature and filtered. Water is added and extracted with ethyl acetate. The extract is washed with water, dried and concentrated to give directly white solid target product (26 g, 62%).

Step B: Preparation of 4-diazonium tetrafluoroborate-3-methyl-benzoate (4- (methoxycarbonyl) -2-methylbenzenediazonium tetrafluoroborate)

(HBF ₄ ) (40% solution) of cold 4-amino-3-methylmethylmethylbenzoate (15 g, 1.0 eq.) In 75 mL water of sodium nitrite (12.54 g, 2.0 eq. Aqueous solution) is added dropwise. After completion of the dropwise addition, the mixture is stirred at room temperature for 15 minutes. The precipitate is filtered off, washed with ice water and dried to obtain the target product (16 g, 90%) which is a white solid.

Step C: Preparation of methyl 1 H-indazol-carboxylate -5- (methyl 1H-indazole-5- carboxylate)

A mixture of 4-diazonium tetrafluoroborate-3-methyl-methyl benzoate (12 g, 1.0 eq.), Potassium acetate (16.6 g, 2.5 eq.) And 18- 200 mL) was stirred at room temperature for 24 h, and the residue was partitioned between water and ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain the desired product (6.5 g, 55%).

Step D: 5-Indazole carboxylic acid

Under stirring, an aqueous solution of sodium hydroxide (4.4 g, 3.0 eq.) In 150 mL water is added to a solution of 5-indazolmethyl benzoate (6.5 g, 1.0 eq.) In MeOH (200 mL). The reaction mixture is refluxed for 1 hour. The organic solvent is removed by distillation under reduced pressure, and the remaining aqueous solution is washed with ethyl acetate and oxidized with a 3N hydrochloric acid solution so that the pH value is 5-6. The precipitate is collected by filtration and washed with water to obtain a yellow solid target product (6.2 g, 98%).

Step E: Preparation of N -methoxy- N -methyl-5-indazole carboxamide

(6.0 g, 1.0 eq), N, O -dimethylhydroxylamine hydrochloride (5.4 g, 1.5 eq), HOBt (6.0 g, 1.2 eq.) And EDCI (8.5 g, 1.2 eq.) To a mixture of this in 100 mL dichloromethane is added dropwise triethylamine (15 g, 4.0 eq.). After completion of the dropwise addition, the mixture was stirred overnight at room temperature, concentrated, and then the desired product (4.4 g, 58%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 10.40 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1 H), 3.56 (s, 3 H), 3.42 (s, 3 H).

Step F: 5-Propionyl indazole

Under 0 ℃, ethyl Grignard reagent (3M, 2.0 eq., 6.5 mL) of N - is added to the dry THF solution of methyl-5-indazol-carboxamide (2.0 g, 1.0 eq.) -Methoxy-N. After completion of the dropwise addition, the mixture is stirred for 2 hours and extracted with ethyl acetate. The extract was dried and concentrated, and then eluted with petroleum ether / ethyl acetate (1/1) by column chromatography to obtain 1.8 g (95%) of the target product. ^{1 H NMR (400 MHz, CDCl} 3) δ 11.20 (s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 3.08 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H).

Step G: Synthesis of 4- {1- [4- (2-chloroethoxy) phenyl] -2- (1 H -indazolyl-5-yl) butyl-

Titanium tetrachloride (4.0 eq, 1.1 mL) was added slowly to a dry THF mixture of zinc powder (1.65 g, 10.0 eq.) With stirring under nitrogen gas protection at room temperature. The obtained mixture is refluxed for 1 hour and the temperature is lowered to room temperature. (1.3 g, 3.0 eq.) And [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (0.7 g, 1.0 eq.) In dry THF , Heated to 80 &lt; 0 &gt; C, refluxed for 1 hour, quenched with aqueous sodium carbonate solution and extracted with ethyl acetate. The extract was dried and concentrated, and then the title product (0.3 g, 70%, Z / E = 1/1) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.96 (s, 1H), 7.53 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.71-6.88 (m, 1H), 6.72 (d, J = 8.8 Hz, 2H), 6.43 (d, J = 8.8 Hz, 1H), 4.35 (t, J = 7.2 Hz, 1H), 4.24 ( t, J = 7.2 Hz, 1H), 3.83 (t, J = 6.0 Hz, 1H), 3.70 (t, J = 6.0 Hz, 1H), 2.47-2.54 (m, 2H) , 0.93 (t, J = 7.2 Hz, 3 H).

Step H: Preparation of (Z ) -4- (2- (1 H -indazolyl-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-

To a stirred solution of 4- {1- [4- (2-chloroethoxy) phenyl] -2- (1 H -indazolyl-5-yl) butyl- 1-alkenyl} phenol (0.3 g, 1.0 eq) To methanol (20 mL) is added 10 mL methylamine (30% aqueous solution). The mixture is refluxed overnight. The organic solvent is removed by concentration under reduced pressure, and the remaining mixture is extracted with ethyl acetate. The extract was dried and concentrated and then subjected to column chromatography to elute with a methanol solution of dichloromethane / ammonia gas (10/1) to obtain a Z type target product (5 mg) and an E type product (11 mg) . ^{1 H NMR (400 MHz, DMSO-} d 6) δ 12.92 (s, 1H), 9.11 (s, 1H), 7.93 (s, 1H), 7.50 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.01-7.19 (m, 2H ), 6.88 (d, J = 9.2 Hz, 2H), 6.60 (d, J = 9.2 Hz, 2H), 6.36 (d, J = 8.8 Hz, 2H), 4.03 ( t, J = 6.0 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.20-2.40 (m, 5H), 0.81 (t, J = 6.0 Hz, 3H); m / z = 414 [M + 1] &lt; ⁺ &gt;.

Example 46

( E ) -4- (2- (1 H -indazolyl-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-

The title compound (E-form, 11 mg) was obtained by separating out the product of Example 2. ^{1 H NMR (400 MHz, DMSO-} d 6) δ 12.92 (s, 1H), 9.41 (s, 1H), 7.92 (s, 1H), 7.51 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.98-7.16 (m, 2H ), 6.60-6.80 (m, 4H), 6.36 (d, J = 8.8 Hz, 2H), 3.82 (t, J = 6.0 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H), 2.40-2.50 (m, 5H), 0.79 (t, J = 6.8 Hz, 3H); m / z = 414 [M + 1] &lt; ⁺ &gt;.

Example 47

1- [4- (2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl] phenol

Step A: 4-Hydroxy-3-nitrobenzoic acid

A mixture of 4-chloro-3-nitrobenzoic acid (20 g, 1.0 eq) and sodium hydroxide (20.5 g, 2.0 eq) in 100 mL water is refluxed overnight at 100 &lt; 0 &gt; C. After the temperature is lowered to room temperature, the pH value is adjusted to 7 with concentrated hydrochloric acid. The precipitate formed is filtered off, washed with cold water and dried to obtain a white solid target product (18.4 g, 98%).

Step B: 4-Hydroxy-3-aminobenzoic acid

The mixture of 4-hydroxy-3-nitrobenzoic acid (10 g, 1.0 eq) and 2 g Pd / C catalyst in 100 mL methanol is stirred overnight at room temperature and under hydrogen gas (1 atm: 1 atm) and filtered. The filtrate was concentrated under reduced pressure to obtain the target product (8.0 g, 95%). ¹ H NMR (400 MHz, DMSO- d ⁶ )? 10.00 (br s, 1H), 7.19 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H).

Step C: 5-Carboxybenzoxazole

The mixture of 4-hydroxy-3-amino-benzoic acid (8.0 g, 1.0 eq.) In 60 mL triethylorthoformate (CH (OEt) ₃ ) was heated to reflux for 3 hours and then allowed to warm to room temperature. The remaining triethylorthoformate was removed by distillation under reduced pressure to obtain the target product (7.8 g, 92%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 13.00 (brs, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H).

Step D: N -Methoxy- N -methylbenzo [d] oxazole-5-carboxamide

(7.8 g, 1.0 eq.), N, O -dimethylhydroxylamine hydrochloride (7.0 g, 1.5 eq.), HOBt (7.76 g, 1.2 eq.) And EDCI Triethylamine (19 g, 4.0 eq.) Is added dropwise to a solution of the compound of formula (I) in 100 mL of dichloromethane. The mixture is then stirred at room temperature overnight, concentrated and then eluted with petroleum ether / ethyl acetate (1/1) by column chromatography separation to obtain 6.0 g (51%) of the target product. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.18 (s, 1H), 8.16 (1H), 7.80 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 3.56 (s , &Lt; / RTI &gt; 3H), 3.41 (s, 3H).

Step E: 5-Propionylbenzooxazole

Ethyl Grignard reagent (1 M, 2.0 eq., 58 mL) was added to a solution of N -methoxy- N -methylbenzo [d] oxazole-5-carboxamide (6.0 g, 1.0 eq) in dry tetrahydrofuran Solution. After completion of the dropwise addition, the mixture is stirred for 2 hours. The reaction mixture is quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried and concentrated and then subjected to column chromatography to elute with petroleum ether / ethyl acetate = 1: 1 to obtain the target product (0.6 g, 12%).

Step F: Synthesis of 4- {2- (benzo [d] oxazol-5-yl) -1- [4- (2- chloroethoxy) phenyl] butyl-

(0.6 g, 1.0 eq.) And [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) propanoate were prepared by the conventional McMurry reaction described in Example 1, Methanone (1.42 g, 1.5 eq.) Is reacted to yield 0.23 g (15%, Z / E = 1/1) target product.

Step G: Synthesis of 4- [2- (benzo [d] oxazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-

Yl) -1- [4- (2-chloroethoxy) phenyl] butyl-1-allylcarbamate was prepared from 4- {2- (benzo [d] oxazol- (25%, Z / E = 1/1) is obtained by refluxing a methanol (20 mL) solution of the title compound (0.1 g, 1.0 eq.) And methylamine (30% aqueous solution) ^{1 H NMR (400 MHz, CDCl} 3) δ 7.08 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.68-6.80 (m, 6H), 6.58-6.64 (m, 4H), 6.49-6.55 (m, 4H). 6.46 (d, J = 8.8 Hz , 2H), 5.89 (s, 2H), 4.09 (t, J = 5.6 Hz, 2H), 3.97 (t, J = 5.2 Hz, 2H), 3.00 (t, J = 5.2 2H), 2.92 (t, J = 5.6 Hz, 2H), 2.54 (s, 3H), 2.50 (s, 3H), 2.39-2.49 (m, 4H), 0.80-1.00 (m, 6H).

Example 48

1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl] phenol

Step A: 2,3-Dihydro-5- (3-chloropropionyl) benzofuran

To a solution of aluminum trichloride (2.22 g, 1.0 eq.) In 50 mL dichloromethane is added 3-chloropropanoyl chloride (2.54 g, 1.2 eq.). The mixture is stirred at room temperature for 10 minutes, then dihydrobenzofuran (2.0 g, 1.0 eq.) Is added. After stirring overnight at room temperature, the reaction mixture is quenched with cold water and extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the desired product (1.5 g, 62%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.86 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.68 (t, J = 8.8 Hz 2H), 3.92 (t, J = 6.8 Hz, 2H), 3.40 (t, J = 8.8 Hz, 2H), 3.26 (t, J = 6.8 Hz, 2H).

Step B: Preparation of (4-hydroxyphenyl) {4- [2- (methylamino) ethoxy] phenyl} methanone

(2.0 g, 1.0 eq.) And methylamine (30% aqueous solution) in a similar manner to that described in Example 1, Step E, to a suspension of [4- (2- chloroethoxy) phenyl] A solution of methanol (30 mL) was subjected to refluxing to obtain the target product (1.4 g, 65%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 7.67 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 4.18 (t, J = 5.6 Hz, 2H), 2.89 (t, J = 6.0 Hz, 2H), 2.37 (s, 3H).

Step C: Preparation of 4- [4-chloro-2- (2,3-dihydro-5-benzofuranyl) -1- {4- [2- (methylamino) ethoxy] phenyl} ]phenol

(0.85 g, 1.0 eq.) And (4-hydroxyphenyl) {l, 3-dihydro-5- (3- chloropropionyl) benzofuran Reaction of 4- [2- (methylamino) ethoxy] phenyl} methanone (1.0 g, 1.0 eq.) Affords 1.2 g of the target product (85%, Z / E = 1/1). ^{1 HNMR (400 MHz, DMSO- d} 6) δ 9.87 (s, 1H), 7.02-7.54 (m, 6H), 6.70-6.84 (m, 5H), 4.22 (t, J = 8.4 Hz, 2H), 4.03 (t, J = 6.0 Hz, 2H), 3.48 (t, J = 5.6 Hz, 2H), 2.89-3.05 (m, 4H), 2.42 (s, 3H), 2.13 (t, J = 8.4 Hz, 2H) ; m / z = 450 [M + 1] &lt; ⁺ &gt;.

Example 49

1- {3-fluoro-4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl} phenol

Step A: 3-Fluoro-4-methoxybenzonitrile

A mixed solution of 3-fluoro-4-methoxybromobenzene (30.0 g, 146 mmol) and DMF (45 mL) of CuCN (15.6 g, 174 mmol) was stirred overnight at 120 ° C. The reaction mixture is allowed to warm to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, respectively, and dried over sodium sulfate. Concentration under reduced pressure removes the solvent to afford 20.0 g (91%) of the title compound as a yellow solid. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.44 (dd, J = 8.8 & 2.0 Hz, 1H), 7.36 (dd, J = 10.8 & 2.0 Hz, 1H), 7.02 (dd, J = 8.8 & 8.4 Hz, 1H), 3.96 (s, 3H).

Step B: 3-Fluoro-4-hydroxybenzonitrile

At 0 ° C, BBr ₃ (20 mL, 0.211 mol) is added to a solution of 3-fluoro-4-methoxybenzonitrile (15.6 g, 0.103 mol) in dichloromethane (100 mL). Refluxed for 3 days under nitrogen gas protection and stirred. Quench with ice water and extract with dichloromethane. The organic layer is washed with water and saturated brine, respectively, and dried with sodium sulfate. Concentration under reduced pressure removed the solvent to give 13.3 g (94%) of the title compound as a gray solid. ^{1 H NMR (400 MHz, CDC} l3) δ 7.38-7.42 (m, 2H), 7.09 (dd, J = 8.8 & 8.4 Hz, 1H), 5.68 (s, 1H).

Step C: Preparation of 4- (2-bromoethoxy) -3-fluorobenzonitrile

(1.2 g, 8.76 mmol), anhydrous K ₂ CO ₃ (2.43 g, 17.6 mmol) and 1,2-dibromoethane (4.5 mL, 52.0 mmol) in DMF (6 mL) is stirred overnight at 60 &lt; 0 &gt; C. The reaction solution is filtered and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5/1) to give the title compound as colorless oil subtitle compound (1.52 g, 71%). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.43 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 12.0 Hz, 1H), 7.03 (dd, J = 8.0 & 8.4 Hz, 1H), 4.42 (t, J = 6.2 Hz, 2H), 3.68 (t, J = 6.2 Hz, 2H).

Step D: Preparation of 4- (2-bromoethoxy) -3-fluorobenzoic acid

The mixture of 4- (2-bromoethoxy) -3-fluorobenzonitrile (3.78 g, 15.5 mmol) in water (18 mL) and acetic acid (18 mL) do. The reaction solution is cooled to room temperature and neutralized with solid sodium hydrogencarbonate. The white solid obtained by oxidation with addition of glacial acetic acid precipitates, is collected by filtration and is dissolved in dichloromethane. The obtained solution is dried with anhydrous sodium sulfate, filtered and then dried to obtain 2.65 g (65%) of a pale yellow solid. ^{1 H NMR (400 MHz, DMSO-} d 6) δ 13.00 (brs, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 12.0 Hz, 1H), 7.29 (dd, J = 8.8 &amp; 8.4 Hz, 1H), 4.48 (t, J = 5.2 Hz, 2H), 3.85 (t, J = 5.2 Hz, 2H).

Step E: Preparation of 4- (2-bromoethoxy) -3-fluorobenzoyl chloride

4- (2-bromoethoxy) -3-fluorobenzoic acid (1.08 g, 4.1 mmol) and thionyl chloride (10 mL) were refluxed for 7 hours. Excess thionyl chloride was dried under reduced pressure with addition of toluene and repeated several times to obtain the desired product (1.07 g, 93%) as a brown oil. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.93 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 11.2 Hz, 1H), 7.04 (dd, J = 8.4 & 8.4 Hz, 1H), 4.46 (t, J = 6.4 Hz, 2H), 3.70 (t, J = 6.4 Hz, 2H).

Step F: Preparation of [4- (2-bromoethoxy) -3-fluorophenyl] (4-methoxyphenyl) methanone

Under 0 ℃, 4- (2- bromoethoxy) -3-fluoro-benzoyl chloride (1.07 g, 3.80 mmol) and anhydrous _{AlCl 3 (1.01 g, 7.60 mmol} ) dry dichloromethane (18 mL) was added No Sol (822 mg, 7.60 mmol) in dichloromethane (2 mL). After stirring at room temperature for 6 hours, the reaction mixture was poured into 3 N hydrochloric acid solution and extracted with dichloromethane. The extract was washed with a saturated aqueous solution of NaHCO ₃ and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (10/1 to 5/1) To give the title product as a white solid (1.05 g, 77%). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.79 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 11.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.03 (dd , J = 8.0 & 8.4 Hz, 1H), 6.98 (d, J = 9.2 Hz, 2H), 4.44 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.70 (t, J = 6.4 Hz , 2H).

Step G: Preparation of [4- (2-bromoethoxy) -3-fluorophenyl] (4-hydroxyphenyl) methanone

Under 0 ℃, dichloromethane of _{BBr 3 (0.5 mL, 5.29 mmol} ) of [4- (2-bromoethoxy) -3-fluorophenyl] (4-methoxyphenyl) -methanone (930 mg, 2.63 mmol) (6 mL). The reaction solution is stirred at room temperature for 2 hours, quenched by addition of ice water, and the mixture is extracted with dichloromethane. The extract was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5/1 to 2/1) to give a pale yellow solid (536 mg, 60%). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.74 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 12.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.03 (dd , J = 8.0 & 8.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 5.88 (s, 1H), 4.44 (t, J = 6.4 Hz, 2H), 3.70 (t, J = 6.4 Hz , 2H).

Step H: Synthesis of 4- {1- [4- (2-bromoethoxy) -3-fluorophenyl] -2- (2,3- dihydro-5-benzofuranyl) butyl-

(4-hydroxyphenyl) methanone (150 mg, 0.442 mmol) by the conventional McMurry reaction step described in example 1, step D, And 3,4-dihydro-5-propionylbenzofuran (94 mg, 0.533 mmol, obtained by step A of Example 1) were reacted to give 145 mg (68%) of the target product as an off-white solid .

Step I: Preparation of 4- {2- (2,3-dihydro-5-benzofuranyl) -1- {3-fluoro-4- [2- (methylamino) ethoxy] phenyl} Phenyl} phenol

Under stirring, a solution of 4- {1- [4- (2-bromoethoxy) -3-fluorophenyl] -2- (2,3-dihydro-5-benzofuranyl) butyl- (142 mg, 0.294 mmol) in methanol (5 mL) was added 1 mL of methylamine (30% aqueous solution) and heated to 85 ° C. for 18 hours. The organic solvent is removed by concentration under reduced pressure, and the remaining mixture is extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated, and then eluted with a methanol / ammonia gas methanol solution (10/1) by column chromatography to obtain a target product (56 mg, 57%, Z / E = 5/4). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.04 and 6.71 (d, J = 8.6 Hz , 2H), 6.91-7.00 (m, 2H), 6.82 (m, 1H), 6.79 and 6.49 (d, J = 8.8 Hz, 2H), 6.53-6.63 (m , 3H), 4.52 (t, J = 8.8 Hz, 2H), 4.27 and 4.14 (t, J = 4.8 Hz , 2H), 3.16 and 3.12 (t, J = 4.8 Hz , 2H), 3.09 (t, J = 8.4 Hz, 2H), 2.65 and 2.60 (s, 3H), 2.41 (q, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H); m / z = 434 [M + 1] &lt; ⁺ &gt;.

Example 50

4- [2- (benzo [c] [1,2,5] thiadiazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl; Phenol) but-1-enyl) phenol) [0158]

Step A: N - (2-nitro-4-propionyl-phenyl) -acetamide (N - (2-nitro- 4-propionylphenyl) acetamide)

2 mL of 98% nitric acid is added to a solution of N - (4-propionylphenyl) acetamide (1.91 g, 10 mmol) in 20 mL of concentrated acid in 10 min, and the temperature of the reaction solution is kept at -10 ° C . After stirring for 0.5 hours, pour the reaction solution into 100 mL of cold water. The precipitate was collected by filtration and washed with water to obtain a crude product (1.18 g, 50%), which was used directly in the next step of the reaction.

Step B: Preparation of 2- (4-amino-3-nitrophenyl) propan-1-one

A solution of N - (2-nitro-4-propionylphenyl) acetamide (3.36 g, 10 mmol) in 30 mL of 35% hydrochloric acid is heated to reflux for 1 hour. Ammonia water is added to adjust the pH to 7 under stirring, and the precipitate is collected by filtration to obtain 1.75 g (90%) of the target product as a yellow solid.

Step C: Preparation of 4-propionyl-o-phenylenediamine

To a solution of 2-nitro-4-propionyl aniline (1.94 g, 10 mmol) in methanol (50 mL) was added 0.5 g 10% Pd / C and the mixture was stirred at room temperature and under a hydrogen gas (1 atm: 1 atm) Hydrogenate for 1 hour. The reaction solution is filtered, and the filtrate is concentrated to obtain the target product (1.48 g, 90%).

Step D: Synthesis of 1- (benzo [ c ] [1,2,5] thiadiazol-5-yl) propyl-

SOCl ₂ (2.6 g, 22 mmol) was added dropwise to a toluene (50 mL) solution of aniline (1.86 g, 20 mmol) at 0 ° C and the reaction was refluxed for 2 hours. After the mixture was cooled to room temperature, 4-propionyl-o-phenylenediamine (1.65 g, 10 mmol) was added. The reaction solution was refluxed for 2 hours, then allowed to stand and concentrated to rapidly obtain the target product (960 mg, 50%) as a yellow solid by column chromatography separation. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.62 (s, 1H), 8.21 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 3.15 (q, J = 7.2 Hz , 2H), 1.30 (t, J = 7.2 Hz, 3H).

Step E: Synthesis of 4- {2- (benzo [ c ] [1,2,5] thiadiazol-5-yl) -1- [4- (2-chloroethoxy) phenyl] butyl- phenol

(Benzo [c] [1,2] thiadiazol-5-yl) propyll-one (713 mg, 4 mmol) was obtained by the conventional McMurry reaction step described in example 1, (83 mg, 10%, Z / E = 1: 1) was obtained by reacting [4- (2-chloroethoxy) phenyl] ).

Step F: Synthesis of 4- [2- (benzo [ c ] [1,2,5] thiadiazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} Alkenyl] phenol

Under stirring, 4- {2- (benzo [c] [1,2,5] thiadiazol-5-yl) -1- [4- (2-chloro ethoxy) phenyl] butyl-1-alkenyl} 3 mL of methylamine (30% aqueous solution) is added to a methanol (10 mL) solution of phenol (83 mg), and the mixture is heated to 85 ° C and reacted for 15 hours. The organic solvent is removed by concentration under reduced pressure, and the remaining mixture is extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated, and then eluted with a dichloromethane / ammonia gas methanol solution (10/1) by column chromatography to obtain the target product as a yellow solid (11 mg, Z / E = 1/1). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.81 (s, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.15 and 7.06 (d, J = 8.4 Hz , 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.79 ( d, J = 8.4 Hz, 2H), 6.78 and 6.72 (d, J = 8.6 Hz , 2H), 6.48 and 6.42 (d, J = 8.6 Hz , 2H), 4.12 and 3.92 ( t, J = 4.8 Hz, 2H ), 3.03 and 2.91 (t, J = 4.8 Hz , 2H), 2.60 (q, J = 7.2 Hz, 2H), 2.55 and 2.47 (s, 3H), 0.97 (t, J = 7.2 Hz, 3 H); m / z = 432 [M + 1] &lt; ⁺ &gt;.

Example 51

( Z ) -4- (2- (1 -methyl-1 H -benzo [d] imidazol-5-yl) Alkenyl) phenol

Step A: 4- (Methylamino) -3-nitrobenzoic acid

A solution of 4-chloro-3-nitrobenzoic acid (30 g, 1.0 eq.) In 200 mL of methylamine aqueous solution was stirred at 100 &lt; 0 &gt; C for 14 h, then concentrated by rotary evaporation. At 0 ° C, the concentrate is poured into 200 mL of 2N aqueous hydrochloric acid solution. The suspension is filtered and washed with water to obtain the target product (quantitative) which is a yellow solid. ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.58 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.95 (dd, J = 9.2 & 2.0 Hz, 1H) , 7.02 (d, J = 9.2 Hz, 1 H), 2.98 (s, 3H).

Step B: 3-Amino-4- (methylamino) benzoic acid

(29 g, 1.0 eq.) And Pd / C (5 g, 10% eq.) In 300 mL methanol was stirred under hydrogen gas and room temperature for 48 hours . The filtrate was concentrated under reduced pressure to obtain the product (9 g, 36.5%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 7.21 (dd, J = 8.4 & 2.0 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H) , 5.28 (brs, 1 H), 4.60 (brs, 2 H), 2.76 (s, 3 H).

Step C: 1- methyl -1 H - benzo [d] imidazole-5-carboxylic acid

Under stirring, 50 mL of formic acid is added to a solution of 3-amino-4- (methylamino) benzoic acid (9 g, 1.0 eq.) In 50 mL of water and the mixture is reacted overnight by heating to 85 ° C. The mixture is stirred at room temperature, concentrated under reduced pressure, and dissolved in water. Add 200 mL of 2 N aqueous hydrochloric acid solution to adjust the pH to 1-3. The suspension is filtered and washed with water to obtain the product (9.7 g, 84%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.48 (s, 1H), 8.37 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H) , &Lt; / RTI &gt; 4.06 (s, 3H).

Step D: N - methoxy - N, 1- dimethyl -1 H - benzo [d] imidazol-5-carboxamide

1-methyl -1 H - benzo [d] imidazole-5-carboxylic acid (9.7g, 1.0 eq), EDCI (10.5 g, 1.2 eq.) And HOBt (7.4 g, 1.2 eq.) Suspension in a 150 mL of dichloromethane Was stirred at room temperature for 5 minutes and then N, O -dimethylhydroxylamine hydrochloride (6.7 g, 1.5 eq) and triethylamine (18.5 g, 4.0 eq.) Were added. The reaction mixture is stirred at room temperature overnight. Water is added and extracted with dichloromethane. The extract was dried and concentrated, and the desired product (9.5 g, 80%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.20 (d, J = 1.2 Hz, 1H), 7.93 (s, 1H), 7.72 (dd, J = 8.8 & 1.6 Hz, 1H), 7.40 (dd, J = 8.4 &amp; 0.8 Hz, 1H), 3.87 (s, 3H), 3.57 (s, 3H), 3.40 (s, 3H).

Step E: 1- (1- methyl -1 H - benzo [d] imidazol-5-yl) propyl-1-one

To a solution of N -methoxy- N , 1 -dimethyl- 1H -benzo [d] imidazole-5-carboxamide (900 mg, 1.0 eq.) In anhydrous tetrahydrofuran (30 mL) Magnesium ethyl bromide (9 mL, 6.0 eq) is slowly added. The reaction mixture is stirred at room temperature overnight, quenched with a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The extract was dried and concentrated, and the desired product (730 mg, 94%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.44 (s, 1H), 8.04 (J = 8.4 & 1.6 Hz, 1H), 7.95 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 3.10 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H).

Step F: (Z) -4- {1- [4- (2- chloroethoxy) phenyl] -2- (1-methyl -1 H - benzo [d] imidazol-5-yl) butyl-1 Alkenyl} phenol

Example 1, by a McMurry reaction step described in Step D, 1- (1- methyl -1 H - benzo [d] imidazol-5-yl) propyl-1-one (730 mg, 2.2 eq.) And [ (500 mg, 1.0 eq.) Were reacted to obtain the target product (the Z type and E type were separated by column chromatography) in the same manner as in Example 1, except for using 4- (2-chloroethoxy) phenyl] do. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.81 (s, 1H), 7.62 (s, 1H), 7.11-7.15 (m, 3H), 7.01 (dd, J = 8.4 & 1.2 Hz, 1H), 6.83 ( dd, J = 6.8 & 2.0 Hz , 2H), 6.79 (dd, J = 6.8 & 2.0 Hz, 2H), 6.49 (dd, J = 6.8 & 2.0 Hz, 2H), 4.05 (t, J = 5.6 Hz, 2H ), 3.79 (s, 3H), 3.69 (t, J = 6.0 Hz, 2H), 2.53 (q, J = 7.2 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H).

Step G: ( Z ) -4- (2- (1-Methyl-1 H -benzo [ d ] imidazol- -1-alkenyl) phenol

Under stirring, (Z) -4- {1- [ 4- (2- chloroethoxy) phenyl] -2- (1-methyl -1 H - benzo [d] imidazol-5-yl) butyl-1 Alkenyl} phenol (20 mg, 1.0 eq.) In methanol (10 mL) was added 5 mL of methylamine aqueous solution, and the mixture was heated to 85 ° C and reacted for 72 hours. The organic solvent is removed by concentration under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. The extract is dried and concentrated, and then the target product (Z type) is obtained by column chromatography separation. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.80 (s, 1H), 7.60 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 9.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 6.45 (d, J = 8.4 Hz, 2H), 3.89 (t , J = 5.2 Hz, 2H) , 3.80 (s, 3H), 2.88 (t, J = 5.2 Hz, 2H), 2.52 (q, J = 7.2 Hz, 2H), 2.46 (s, 3H), 0.88 (t , &Lt; / RTI &gt; J = 7.2 Hz, 3H); m / z = 428 [M + 1] &lt; ⁺ &gt;.

Example 52

( E ) -4- (2- (1 -methyl-1 H -benzo [ d ] imidazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} Alkenyl) phenol

( E ) -4- {1- [4- (2-chloroethoxy) phenyl] -2- (1- Methyl- 1H -benzo [ d ] imidazol-5-yl) butyl-1-alkenyl} phenol and methylamine (30% aqueous solution) is subjected to reflux reaction to obtain the target product (E type). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.78 (s, 1H), 7.63 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.4 Hz, 1H), 7.01 (dd, J = 8.4 & 1.2 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 6.40 (d, J = 8.4 Hz, 2H), 4.10 (t, J = 5.2 Hz, 2H), 3.77 (s, 3H), 2.99 (t, J = 5.2 Hz, 2H), 2.50-2.55 (m, 5H), 0.91 (t, J = 7.2 Hz, 3H) ; m / z = 428 [M + 1] &lt; ⁺ &gt;.

Example 53

1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl) phenol

Step A: 1- (Benzofuranyl-5-yl) propyl-1-one

(62 g, 1.2 eq.) Was added to 400 mL of anhydrous 1,4-dioxane in the presence of 1- (2,3-dihydrobenzofuran-5-yl) propyl- The solution in dioxane is refluxed overnight, allowed to warm to room temperature, quenched by addition of saturated sodium bicarbonate solution, and extracted with ethyl acetate. The extract is washed with saturated brine, dried and concentrated, and then the desired product (10.3 g, 26%) is obtained by column chromatography separation. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.27 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 8.8 & 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 3.07 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

Step B: Preparation of 4- {2- [benzofuranyl-5-yl] -1- [4- (2- chloroethoxy) phenyl] butyl-

Propyl-1-one (250 mg, 1.0 eq.) And [4- (2-chloroethoxy) -piperazin-1-one were obtained by the conventional McMurry reaction step described in example 1, ) Phenyl] (4-hydroxyphenyl) methanone (794 mg, 2.0 eq.) Were reacted to obtain 480 mg of the target product (80%, Z / E = 1/1).

Step C: Preparation of 4- (2- {benzofuranyl-5-yl} -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-

(30 mg, 1.0 eq.) Of 4- {2- [benzofuranyl-5-yl] -1- [4- (2- chloroethoxy) phenyl] butyl-1-alkenyl} phenol 15 mL) was added 5 mL of methylamine aqueous solution, and the mixture was heated to 85 DEG C and reacted for 48 hours. The organic solvent is removed by concentration under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. The extract was dried and concentrated, and the desired product (230 mg, 49%, Z / E = 1/1) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.55 (d, J = 2.0 Hz, 1H), 7.36 (s, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.8 Hz , 1H), 7.08 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H ), 6.74 (d, J = 8.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 8.4 Hz , 1H), 4.11 (t, J = 4.8 Hz, 1H), 3.92 (t, J = 4.8 Hz, 1H), 3.01 (t, J = 5.2 Hz, 1H), 2.89 ( t, J = 5.2 Hz, 1H), 2.45-2.54 (m, 5H), 0.89-0.94 (m, 3H); m / z = 414 [M + 1] &lt; ⁺ &gt;.

Example 54

1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl] phenol

Step A: 5- (2-Ethyl-1,3-dioxan-2-yl) benzofuran

Toluene sulfonic acid (65 mg, 0.1 eq.) In 20 mL toluene was added to a solution of 1- (benzofuranyl-5-yl) propyl-1-one (650 mg, 1.0 eq.), Is refluxed for 72 h, then allowed to warm to room temperature, quenched by addition of saturated sodium bicarbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated, and then the target product (710 mg, 87%) was obtained by column chromatography separation. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.69 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.39 (dd , J = 8.4 & 1.6 Hz, 1H), 6.76 (dd, J = 2.4 & 0.4 Hz, 1H), 4.02-4.05 (m, 2H), 3.78-3.81 (m, 2H), 1.96 (q, J = 7.2 Hz, 2H), 0.89 (t, J = 7.2 Hz, 3H).

Step B: 2-Chloro-5- (2-ethyl-1,3-dioxan-2-yl)

To a solution of 5- (2-ethyl-1,3-dioxan-2-yl) benzofuran (350 mg, 1.0 eq.) In anhydrous tetrahydrofuran (20 mL) was added 2.5M n-BuLi n-hexane solution (1.6 mL, 2.4 equivalents) was added dropwise and stirred for 50 minutes under nitrogen gas protection at 0 deg. A solution of anhydrous tetrahydrofuran (10 mL), in which hexachloroethane (915 mg, 2.4 eq.) Was added dropwise, was stirred at room temperature for 1 hour, quenched by addition of saturated ammonium chloride solution, Extract with ethyl acetate. The extract was dried and concentrated, and the desired product (260 mg, 65%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.58 (d, J = 0.4 Hz, 1H), 7.37-7.38 (m, 2H), 6.57 (s, 1H), 4.01-4.05 (m, 2H), 3.77- 3.80 (m, 2H), 1.94 (q, J = 7.6 Hz, 2H), 0.88 (t, J = 7.2 Hz, 3H).

Step C: Preparation of 1- (2-chlorobenzofuranyl-5-yl) propyl-1-one

To the methanol (15 mL) solution of 2chloro-5- (2-ethyl-1,3-dioxan-2-yl) benzofuran (250 mg, 1.0 eq) in 3 mL of 3N hydrochloric acid was added under stirring at room temperature . Stir at room temperature for 30 minutes, quenched the reaction by adding saturated aqueous sodium hydrogen carbonate solution, and extract with ethyl acetate. The extract is washed with saturated brine, dried and concentrated, and the desired product (140 mg, 68%) is obtained by column chromatography separation. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.15 (d, J = 1.6 Hz, 1H), 7.95 (dd, J = 8.4 & 1.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.68 (s, 1H), 3.06 (q, J = 6.8 Hz, 2H), 1.25 (t, J = 6.8 Hz, 3H).

Step D: Preparation of 4- {2- [2-chlorobenzofuranyl-5-yl] -1- [4- (2- chloroethoxy) phenyl] butyl-

(140 mg, 1.0 eq.) And [4- (2- (2-chlorobenzofuran-5-yl) propyl) -pyrrolidine were prepared by the conventional McMurry reaction step described in example 1, The target product (220 mg, 72%, Z / E = 1/1) was obtained by the reaction of 4-chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (371 mg, 2.0 eq. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.23 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.16 and 7.10 (d, J = 8.6 Hz , 2H), 7.00 and 6.99 (d, J = 8.4 Hz, 1H), 6.90 and 6.81 (d, J = 8.6 Hz , 2H), 6.76 and 6.70 (d, J = 8.8 Hz , 2H), 6.52 and 6.44 (d, J = 9.0 Hz , 2H), J = 6.0 Hz, 2H), 3.83 and 3.72 (t, J = 6.0 Hz, 2H), 2.50 (q, J = 7.2 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3 H).

Step E: Synthesis of 4- [2- (2-chlorobenzofuran-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-

Phenyl] butyl-1-alkenyl} phenol (220 mg, 1.0 eq.) Was added dropwise to a stirred solution of 4- {2- [2- chlorobenzofuran- In methanol (15 mL) was added 5 mL of methylamine aqueous solution, and the mixture was heated to 85 DEG C and reacted for 48 hours. The organic solvent is removed by concentration under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. The extract was dried and concentrated, and the desired product (105 mg, 48%, Z / E = 1/1) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.23 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.14 and 7.08 (d, J = 8.4 Hz , 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.87 and 6.78 (d, J = 8.8 Hz , 2H), 6.73 and 6.69 (d, J = 8.8 Hz , 2H), 6.49 and 6.42 (d, J = 8.6 Hz , 2H), 6.45 ( s, 1H), 4.10 and 3.92 (t, J = 5.0 Hz , 2H), 3.00 and 2.89 (t, J = 5.0 Hz , 2H), 2.53 and 2.46 (s, 3H), 2.50 (q, J = 7.6 Hz , &Lt; / RTI &gt; 2H), 0.91 (t, J = 7.6 Hz, 3H); m / z = 448 [M + 1] &lt; ⁺ &gt;.

Example 55

(Z) -4- [2- (2-chlorobenzofuran-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl] phenol

The target product (Form Z) is obtained by HPLC separation of the Z / E mixture of Example 11. ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.43 (brs, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H) , 6.99 (d, J = 8.4 Hz, 2H), 6.90 (s, 1H), 6.75 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.4 Hz, 2H), 3.84 ( t, J = 5.4 Hz, 2H), 2.73 (t, J = 5.4 Hz, 2H), 2.43 (q, J = 7.4 Hz, 2H), 2.26 (s, 3H), 0.84 (t, J = 7.4 Hz, 3 H); m / z = 448 [M + 1] &lt; ⁺ &gt;.

Example 56

(E) -4- [2- (2-chlorobenzofuran-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} butyl-1-alkenyl] phenol

The target product (Form E) is obtained by HPLC separation of the Z / E mixture of Example 11. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.24 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 6.8 Hz, 2H), 7.00 (d, J = 8.6 Hz , 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 6.8 Hz, 2H), 6.45 (s, 1H), 6.41 (d, J = 6.4 Hz, 2H), 4.08 (t , J = 5.0 Hz, 2H) , 2.99 (t, J = 5.2 Hz, 2H), 2.51 (s, 3H), 2.49 (q, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H ); m / z = 448 [M + 1] &lt; ⁺ &gt;.

Example 57

(Z) -2- {4- [2- (2- chloro-benzo furanyl-5-yl) -1- (4-methoxyphenyl) butyl-1-alkenyl] phenoxy} - N - methyl amine

Step A: Preparation of 2-chloro-5- {1- [4- (2-chloroethoxy) phenyl] -1- [4-methoxyphenyl] butyl-

(200 mg, 1.0 eq.) And [4- (2- (2-chlorobenzofuran-5-yl) propyl) -pyrrolidine were prepared by the conventional McMurry reaction step described in example 1, The target product (440 mg, 98%, Z / E = 1) was obtained by the reaction of 4-methoxyphenyl) methanone (418 mg, 1.5 eq., Prepared by the step B of Example 1) 1/1).

Step B: (Z) -2- {4- [2- (2- chloro-benzo furanyl-5-yl) -1- (4-methoxyphenyl) butyl-1-alkenyl] phenoxy} - N - Methylethylamine

Phenyl] -1- [4-methoxyphenyl] butyl-1-alkenyl (2-chloro-5- 2-yl} benzofuranyl (440 mg, 1.0 eq.) And methylamine (30% aqueous solution, 10 mL) was subjected to refluxing reaction to obtain (Z) Which can be separated by a &lt; / RTI &gt; _{1 H NMR (400 MHz, CDCl} 3) δ 7.24 (d, J = 2.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 7.01 (dd , J = 8.4 & 2.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 8.8 Hz, 2H), 6.45 (s , 1H), 3.92 (t, J = 5.2 Hz, 2H), 3.83 (s, 3H), 2.88 (t, J = 5.2 Hz, 2H), 2.50 (q, J = 7.6 Hz, 2H), 2.45 (s , 3H), 0.92 (t, J = 7.6 Hz, 3H); m / z = 462 [M + 1] &lt; ⁺ &gt;.

Example 58

Phenyl] -2- (2-chlorobenzofuran-5-yl) butyl-1-alkenyl] phenol

Yl] -1- [4- (2-chloroethoxy) phenyl] butyl-1-allyl ester was obtained in the same manner as in Example 1, (105 mg, 48%, Z / E = 1/1) was obtained by subjecting a methanolic solution of the title compound (220 mg, 1.0 eq., Prepared by step D of Example 11) do. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.22 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.07 (d , J = 8.8 Hz, 1H) , 6.97-7.01 (m, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.8 Hz , 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 6.43-6.44 (m, 1H), 4.46 (M, 2H), 1.73-2.00 (m, 8H), 0.91 (t, J = 7.6 Hz, 3H); m / z = 516 [M + 1] &lt; ⁺ &gt;.

Example 59

1- {6- [2- (methylamino) ethoxy] pyridin-3-yl} butyl-1-alkenyl] phenol

Step A: (6-Chloropyridin-3-yl) [4- (tetrahydro- 2H -pyran-

Magnesium (1.67 g, 1.2 eq.) Is added to anhydrous THF (50 mL), heated to 55 ° C, iodine (2 grains) is added followed by 0.1 mL bromoethane. 2- (4-Bromophenoxy) tetrahydro- 2H -pyran (16 g, 1.1 eq.) Is dissolved in THF and a portion of the solution is added to the mixture of Mg-THF. After initiation of the reaction, the remainder of the solution is added to the mixed solution, and the reaction solution is refluxed for 2 hours, and the obtained Grignard reagent is prepared. 6-chloronicotinoyl chloride (10.0 g, 1 equivalent) is dissolved in anhydrous THF, and the solution is allowed to stand at 0 ° C under nitrogen gas protection, and the Grignard reagent is added thereto within 20 minutes. The mixture is warmed to room temperature and stirred overnight. Water is added and extracted with ethyl acetate. After concentrating the extract, by separation by column chromatography, eluting with petroleum ether / ethyl acetate (5/1), (6-chloro-3-yl) [4- (tetrahydro -2 H - pyran -2 -Oxyl) phenyl] methanone The expected product (13.6 g, 76%) is obtained. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.78 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.0Hz, 2H), 7.46 (d, J = 8.4 Hz , 1H), 7.15 (d, J = 8.0Hz, 2H), 5.56 (t, J = 3.2 Hz, 1H), 3.83-3.90 (m, 1H), 3.63-3.67 (m, 1H), 2.02-2.05 ( 1H), 1.89-1.92 (m, 2H), 1.69-1.75 (m, 2H), 1.59-1.65

Step B: Synthesis of 4- [1- (6-chloropyridin-3-yl) -2- (2,3-dihydrobenzofuran-5-yl) butyl-

(610 mg, 1.1 eq., Prepared according to Example 1) by the conventional McMurry reaction step described in Example 1, Step D, using 1- (2,3-dihydrobenzofuran- prepared by the following steps a) and (6-chloro-3-yl) [4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] by reacting methanone (1.0 g, 1.0 eq.), the target product (440 mg, 37%, Z / E = 1/1).

Step C: 4- (2- {2,3-Dihydrobenzofuran-5-yl} -1- {6- [2- (methylamino) ethoxy] pyridin- Phenyl) phenol

To a solution of 2- (methylamino) -ethanol (875 mg, 10 eq.) In anhydrous THF (20 mL) was added NaH (373 mg, 8.0 eq.) Under stirring at 0 ° C and the mixture was stirred at room temperature for 1 hour Yl) butyl-1-alkenyl] phenol (440 mg, 1.0 eq.) Was added to a solution of 4- [1- (6-chloropyridin- Lt; / RTI &gt; The mixture is refluxed for 16 hours, allowed to stand, quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The extract was dried and concentrated, and the desired product (197 mg, 41%) was obtained by column chromatography. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.06 (d, J = 2.4 Hz, 0.5H), 7.60 (d, J = 2.0 Hz, 0.5H), 7.32 (dd, J = 8.4 & 2.4 Hz, 0.5H ), 7.07 (dd, J = 8.4 & 2.4 Hz, 0.5H), 7.03 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 0.5H), 6.78 (d, J = 8.4 Hz, 1.5H), 6.69 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 0.5H), 6.59 (d, J = 8.0 Hz , 1H), 6.49 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 8.4 Hz, 0.5H), 4.53 (t, J = 8.4 Hz, 2H), 4.46 (t, J = 5.2 Hz, 1H), 4.31 (t, J = 5.2 Hz, 1H), 3.10 (t, J = 8.4 Hz, 2H), 3.05 (t, J = 5.2 Hz, 1H), 2.96 (t, J = 5.2 Hz, 1H) , 2.55 (s, 1.5H), 2.50 (s, 1.5H), 2.45 (q, J = 7.6 Hz, 2H), 0.94 (t, J = 7.2 Hz, 3H); m / z = 417 [M + 1] &lt; ⁺ &gt;.

Example 60

1- {4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} butyl-1-alkenyl] phenol

Yl] -1- [4- (2-chloroethoxy) phenyl] butyl-1-allyl ester was obtained in the same manner as in Example 1, (51 mg, 68%, Z / E = 1 / 2.6) as a yellow solid was subjected to refluxing reaction with a methanol (3 mL) solution of the title compound (70 mg, 1.0 eq.) And tetrahydropyrrole . ^{1 H NMR (400 MHz, CDCl} 3) δ 7.24 (s, 1H), 7.20 (d, J = 9.2 Hz, 1H), 7.09 and 7.06 (d, J = 8.4 Hz , 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.78 and 6.72 (d, J = 8.2 Hz , 2H), 6.68 (d, J = 8.6 Hz, 2H), 6.46 and 6.45 (s, 1H), 6.41 and 6.27 (d, J = 8.4 Hz, 2H), 4.10 and 3.89 (t, J = 5.8 Hz , 2H), 2.94 and 2.83 (t, J = 6.2 Hz , 2H), 2.68 and 2.61 (m, 4H), 2.49 (q, J = 7.4 Hz , 2H), 1.84 and 1.81 (m, 4H), 0.91 (t, J = 7.4 Hz, 3H); m / z = 488 [M + 1] &lt; ⁺ &gt;.

Example 61

1- [4- (2- (piperidin-1-yl) ethoxy] phenyl} butyl-1-alkenyl] phenol

Yl] -1- [4- (2-chloroethoxy) phenyl] butyl-1-allyl ester was obtained in the same manner as in Example 1, (63 mg, 82%, Z / E = 1/1) as a pale yellow solid was subjected to refluxing reaction with a methanol (3 mL) solution of 2- . ^{1 H NMR (400 MHz, CDCl} 3) δ 7.24 and 7.22 (s, 1H), 7.21 (d, J = 9.2 Hz, 1H), 7.09 and 7.06 (d, J = 8.6 Hz , 2H), 7.01 and 6.99 ( d, J = 8.8 Hz, 1H ), 6.78 and 6.69 (d, J = 8.2 Hz , 2H), 6.68 and 6.66 (d, J = 8.6 Hz , 2H), 6.47 and 6.45 (s, 1H), 6.42 and 6.25 (d, J = 8.6 Hz, 2H), 4.10 and 3.90 (t, J = 6.0 Hz, 2H), 2.81 and 2.70 (t, J = 6.0 Hz, 2H), 2.48-2.57 1.68 (m, 6H), 0.89 - 0.93 (m, 3H); m / z = 502 [M + 1] &lt; ⁺ &gt;.

Example 62

1 - [4- (2-morpholinoethoxy) phenyl] butyl-1-alkenyl} phenol

Yl] -1- [4- (2-chloroethoxy) phenyl] butyl-1-allyl ester was obtained in the same manner as in Example 1, (63 mg, 1.0 eq.) And morpholino (1 mL) were refluxed to give the target product as a pale yellow solid (61 mg, 79%, Z / E = 1/2) . ^{1 H NMR (400 MHz, CDCl} 3) δ 7.23 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.13 and 7.09 (d, J = 8.6 Hz , 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.83 and 6.80 (d, J = 8.6 Hz , 2H), 6.72 and 6.69 (d, J = 8.6 Hz , 2H), 6.45 (s, 1H), 6.43 (d, J = 8.8 Hz, 2H), 4.12 and 3.94 (t, J = 5.6 Hz , 2H), 3.76 and 3.71 (t, J = 4.8 Hz , 4H), 2.83 and 2.71 (t, J = 5.6 Hz , 2H), 2.61 and 2.52 (t J = 4.4 Hz, 4H), 2.49 (q, J = 7.2 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H); m / z = 504 [M + 1] &lt; ⁺ &gt;.

Example 63

1- [4- (2- (4-methylpiperazin-1-yl) ethoxy] phenyl} butyl-1-alkenyl] phenol

Yl] -1- [4- (2-chloroethoxy) phenyl] butyl-1-allyl ester was obtained in the same manner as in Example 1, (70 mg, 1.0 eq.) And N-methylpiperazine (1 mL) in methanol (8 mL) was subjected to a refluxing reaction to obtain the target product as a yellow solid (60 mg, 76%, Z / E = ). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.23 (s, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.12 and 7.08 (d, J = 8.8 Hz , 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.83 and 6.78 (d, J = 8.8 Hz , 2H), 6.72 and 6.69 (d, J = 8.8 Hz , 2H), 6.45 and 6.44 (s, 1H), 6.42 (d, J = 8.8 Hz, 2H), 4.12 and 3.93 (t, J = 5.6 Hz , 2H), 2.84 and 2.73 (t, J = 5.6 Hz , 2H), 2.40-2.62 (m, 10H), 2.31 and 2.82 (s, 3H) , 0.91 (t, J = 7.2 Hz, 3 H); m / z = 517 [M + 1] &lt; ⁺ &gt;.

Example 64

1- [4- (2- (diethylamine) ethoxy] phenyl} butyl-1-alkenyl] phenol

Yl] -1- [4- (2-chloroethoxy) phenyl] butyl-1-allyl ester was obtained in the same manner as in Example 1, (61 mg, 81%, Z / E = 1 / 1.25) as a brown solid by refluxing a methanol (8 mL) solution of 2- . ^{1 H NMR (400 MHz, CDCl} 3) δ 7.23 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.12 and 7.09 (d, J = 8.8 Hz , 2H), 7.00 and 6.99 (d, J = 8.4 Hz, 1H), 6.83 and 6.80 (d, J = 8.8 Hz , 2H), 6.71 and 6.69 (d, J = 8.4 Hz , 2H), 6.45 (s, 1H), 6.43 (d, J = 8.8 Hz, 2H), 4.08 and 3.90 (t, J = 5.8 Hz , 2H), 2.92 and 2.80 (t, J = 5.8 Hz , 2H), 2.69 and 2.62 (q, J = 7.0 Hz , 4H), 2.50 (q , J = 7.6 Hz, 2H), 1.10 and 1.04 (q, J = 7.2 Hz, 6H), 0.91 (t, J = 7.6 Hz, 3H); m / z = 490 [M + 1] &lt; ⁺ &gt;.

Example 65

1- [4- (2- (ethylamino) ethoxy] phenyl} butyl-1-alkenyl] phenol

Yl] -1- [4- (2-chloroethoxy) phenyl] butyl-1-allyl ester was obtained in the same manner as in Example 1, (38 mg, 54%, Z / E = 1 / 1.2) was obtained by refluxing a methanol (8 mL) solution of the title compound (70 mg, 1.0 eq.) And ethylamine do. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.23 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.12 and 7.03 (d, J = 8.6 Hz , 2H), 6.99 (d, J = 8.8 Hz, 1H), 6.83 and 6.75 (d, J = 8.8 Hz , 2H), 6.71 and 6.65 (d, J = 8.6 Hz , 2H), 6.44 (s, 1H), 6.45 and 6.40 (d, J = 8.4 Hz, 2H), 4.10 and 3.92 (t, J = 4.8 Hz , 2H), 3.04 and 2.93 (t, J = 4.8 Hz , 2H), 2.78 and 2.71 (q, J = 7.2 Hz , 2H), 2.50 (q J = 7.2 Hz, 2H), 1.18 and 1.13 (q, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H); m / z = 462 [M + 1] &lt; ⁺ &gt;.

Example 66

1- [4- (2- (dimethylamino) ethoxy] phenyl} butyl-1-alkenyl] phenol

Yl] -1- [4- (2-chloroethoxy) phenyl] butyl-1-allyl ester was obtained in the same manner as in Example 1, (27 mg, 38%, Z / E = 1 / 1.2) as a white solid by refluxing a methanol (8 mL) solution of 2- do. ^{1 H NMR (400 MHz, CDCl} 3) δ 7.23 and 7.21 (s, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.08 and 7.06 (d, J = 9.2 Hz , 2H), 7.00 and 6.97 ( d, J = 8.4 Hz, 1H ), 6.79 and 6.67 (d, J = 8.6 Hz , 2H), 6.66 (d, J = 8.4 Hz, 2H), 6.45 and 6.24 (d, J = 8.8 Hz , 2H), 6.43 and 6.41 (s, 1H), 4.10 and 3.89 (t, J = 5.2 Hz , 2H), 2.86 and 2.75 (t, J = 5.2 Hz , 2H), 2.49 (q, J = 7.2 Hz, 2H), 2.44 And 2.37 (s, 6H), 0.91 (t, J = 7.2 Hz, 3H); m / z = 462 [M + 1] &lt; ⁺ &gt;.

Example 67

1- {4- [2- (piperazin-1-yl) ethoxy] phenyl} butyl-1-alkenyl] phenol

Yl] -1- [4- (2-chloroethoxy) phenyl] butyl-1-allyl ester was obtained in the same manner as in Example 1, (75 mg, 1.0 eq., Prepared according to example 11, reaction step D) and N- Boc piperazine (500 mg) in methanol (3 mL) was isolated by column chromatography , Then treated with a solution of trifluoroacetic acid (1 mL) in dichloromethane (3 mL). Next, the target product (Z / E = 1/1) is obtained by column chromatography separation. m / z = 503 [M + 1] &lt; ⁺ &gt;.

Example 68

1- {6- [2- (methylamino) ethoxy] pyridin-3-yl} butyl-1-alkenyl] phenol

1- (6-chloropyridin-3-yl) butyl-1-alkenyl] -lH-indolecarboxamide was prepared in the same manner as in Example 16, The target product (Z / E = 1/1) is obtained by reacting phenol (70 mg, 1.0 eq.) With 2- (methylamino) -ethanol (128 mg, 10 eq.). m / z = 449 [M + 1] &lt; ⁺ &gt;.

Example 69

Butyl-1-alkenyl] phenol (prepared by reacting 4- [2- (2-chlorobenzofuran-5-yl) (2- (2-Chlorobenzofuran-5-yl) -1- (6- (2- (methylamino) ethylthio) pyridin- 3- yl) but-

Step A: 2- (Methylamino) ethanol hydrochloride

2- (Methylamino) ethanol (20 g, 1.0 eq.) Is stirred in 50 mL concentrated hydrochloric acid for 2 hours at room temperature and then concentrated to obtain the desired product (quantitative). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.95 (brs, 2H), 3.65 (t, J = 5.2 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.50-2.54 (m, 3H).

Step B: 2-Chloro- N -methylethylamine hydrochloride

Thionyl chloride (41 g, 1.3 equivalents) is added dropwise to a solution of 2- (methylamino) ethanol hydrochloride (29.7 g, 1.0 eq.) In 150 mL chloroform under stirring at 0 캜. After refluxing for 3 hours, the temperature is raised to room temperature. Concentrate under reduced pressure to remove the solvent, add the concentrate to a 100 mL 1:10 dichloromethane / petroleum ether solution, and filter to obtain the desired product (28 g, 80%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 9.24 (brs, 2H), 3.93 (t, J = 6.0 Hz, 2H), 3.28 (t, J = 6.0 Hz, 2H), 2.56 (s, 3H) .

Step C: 2- (Methylamino) ethylthiol hydrochloride (2- (methylamino) ethanethiol hydrochloride)

Na ₂ S ₂ O ₃ (18.5 g, 1.0 eq.) Was added to a solution of 2-chloro- N -methylethylamine hydrochloride (15 g, 1.0 eq.) In 150 mL water under stirring and the mixture was stirred for 48 h Heat to reflux. After the mixture is cooled to room temperature, the filtrate is concentrated under reduced pressure to remove the solvent, and the desired product is obtained by subjecting the concentrate to column chromatography. ¹ H NMR (400 MHz, DMSO- d ⁶ )? 4.95 (brs, 2H), 2.90 (s, 4H), 2.37 (s, 3H).

Step D: Synthesis of 4- [2- (2-chlorobenzofuran-5-yl) -1- {6- [2- (methylamino) ethylthio] pyridin-

1- (6-chloropyridin-3-yl) butyl-1-alkenyl] -lH-indolecarboxamide was prepared in the same manner as in Example 16, The target product (Z / E = 1/1) was obtained by reacting phenol (70 mg, 1.0 eq.) With 2- (methylamino) ethanethiol hydrochloride (217 mg, 10 eq. do. m / z = 465 [M + 1] &lt; ⁺ &gt;.

Example 70

Amino] pyridin-3-yl) butyl-1-alkenyl] phenol (hereinafter referred to as &quot;

1- (6-chloropyridin-3-yl) butyl-1-alkenyl] -lH-indolecarboxamide was prepared in the same manner as in Example 16, The target product (Z / E = 1/1) is obtained by reacting phenol (70 mg, 1.0 eq.) With N, N'- dimethylethylenediamine (150 mg, 10 eq.). m / z = 462 [M + 1] &lt; ⁺ &gt;.

Example 71

Yl} butyl-1-alkenyl] -1- {6- [3- (pyrrolidin- 1 -yl) phenol

Step A: 2- (4-Iodophenoxy) tetrahydro- 2H -pyran

4-iodophenol (10.0 g, 45.5 mmol) was dissolved in 20 mL of 3,4-dihydro- 2H -pyran and a drop of agric acid was added. The mixture was stirred for 30 minutes, Pour into hexane. Filter, wash with 300 mL (100 mL x 3) hexanes and vacuum dry to obtain 9.1 g (65.9%) of the target product as a white solid.

Step B: 2-Chloro- N -methoxy- N -methyl-5-pyridinecarboxamide

Oxalyl chloride (12.1 g, 95.2 mmol) was added dropwise to a THF solution (100 mL) of 6-chloronicotinic acid (10.0 g, 63.5 mmol), and the reaction solution was stirred at room temperature for 1 hour and concentrated under reduced pressure. Was dissolved in 50 mL of dichloromethane and the solution was added to a dichloromethane (100 mL) solution of N, O -dimethylhydroxylamine hydrochloride (12.4 g, 126.9 mmol) and triethylamine (25.7 g, 253.9 mmol) , Stirred at room temperature for 1 hour, concentrated and then subjected to column chromatography separation to obtain the desired product (9.4 g, 73.8%) in the form of a colorless oil.

Step C: N -Propylgapyrolidine

At -10 ° C, propargyl bromide (60.5 g, 0.50 mol) is slowly added dropwise to the pyrrolidine (70.1 g, 1.0 mol). After completion of the dropwise addition, the reaction mixture was stirred overnight at room temperature and distilled by a rectification column to obtain the target product (45.5 g, 83.5%) as a colorless oil.

Step D: (6-Chloropyridin-3-yl) [4- (tetrahydro- 2H -pyran-

2- (4-iodophenoxy) tetrahydro- 2H -pyran (18.2 g, 59.9 mmol) was dissolved in 100 mL of dry THF under nitrogen gas protection, and the solution was cooled to -78 ° C., Lithium is added dropwise. After completion of the dropwise addition, the mixture was stirred at -78 ° C for 0.5 hours, and a THF (50 mL) solution of 2-chloro- N -methoxy- N -methyl-5-pyridinecarboxamide (8.0 g, 39.9 mmol) And the mixture is reacted for 2 hours while keeping it at -78 ° C. Then quenched by the addition of 100 mL saturated ammonium chloride, and the mixture is extracted with ethyl acetate. The extract was dried over sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography to obtain the target product (8.4 g, 66.3%) as a yellow solid.

Step E: Synthesis of {6- [3- (pyrrolidin-1-yl) propyl-1-alkynyl] pyridin- 3- yl} [4- (tetrahydro-

2-oxyl) phenyl] methanone (4.0 g, 12.6 mmol), tetrakis (triphenylphosphine) palladium (II) chloride in a 100 mL shrink flask (Schlenk flask) phenyl phosphine) palladium (1.5 g, 1.3 mmol, 10 mol%), CuI (0.48 g, 2.5 mmol, 20 mol%), Et 3 N (50 mL) and N - Pro Parr Gylfi pyrrolidine (2.8 g, 25.2 mmol). The flask is flushed over with a third of nitrogen gas, and the mixture is reacted at 80 ° C for 2 hours. Concentration under reduced pressure removes the solvent and the concentrate is separated by column chromatography to give the target product as a yellow solid (2.2 g, 44.9%).

Step F: {6- [3- (pyrrolidin-1-yl) propyl] pyridin-3-yl} [4- (tetrahydro -2 H - pyran-2-oxyl) phenyl] methanone

At room temperature, Raney nickel (0.3 g, 0.6 mmol, 10 mol%) was added to a solution of 6- [3- (pyrrolidin- 1 -yl) propyl- 1 -alkynyl] pyridin- -2 H - pyran-2-oxyl) phenyl] methanone (2.2 g, and added to methanol (20 mL) solution of 5.6 mmol), and the mixture is stirred for 1 hour at a hydrogen gas. Nickel is removed by filtration, and the filtrate is concentrated under reduced pressure to obtain the target product (1.7 g, 77.3%).

Step G: Synthesis of 4- [2- (2-chlorobenzofuran-5-yl) -1- {6- [3- (pyrrolidin- 1 -yl) propyl] pyridin- Alkenyl] phenol

Propyl] pyridin-3-yl} [4- (tetrahydro-2H-pyran-2-ylmethyl) -pyrrolidine was prepared by the general McMurry reaction step described in example 1, -2-oxyl) phenyl] methanone and 1- (2-chlorobenzofuranyl-5-yl) propyl-1-on are reacted to obtain the target product (Z / E = 1/1). m / z = 487 [M + 1] &lt; ⁺ &gt;.

<Biological activity>

Measurement of IC ₅₀ values

In vitro growth inhibitory activity of anti-estrogenic activity on MCF-7 cells

Human mammary carcinoma cell MCF-7 (# HTB-22, purchased from ATCC) with high estrogen receptor α expression was maintained in DMEM medium supplemented with 10% fetal bovine serum (Gibco®) and 10 μg / ml bovine insulin (Sigma®) do. Cells were cultured in 15 ml medium of 75 cm2 plastic culture bottle (Corning®) under 37 ° C., 95% air and 5% CO 2 environment, grown in a single layer cell culture, Subculture.

For the related experiments of 17? -Estradiol (E2), the cells in the logarithm growing stage undergo E2 removal treatment two days before. Replace the DMEM medium containing phenol red with DMEM / F12 medium without phenol red, replace the FBS in the medium with FBS treated with activated charcoal, remove the steroids contained in the medium, and descend as the hormone level increases. Cells are cultured in DMEM / F12 medium without E2 (37 ° C, 95% air, 5% CO ₂ ) in a 96 well cell culture plate (Corning®) at a density of 4 x 10 ³ / well. The compounds used in the experiment are stored in DMSO (0.01 M) and diluted with DMSO and diluted with the medium. Next, add E2 at an appropriate concentration while adding to the cells. The final compound concentration is 3 x ^{10 -10 to 1} x ^{10 -5} and the final concentration of DMSO is 0.1%. The cells are incubated at 37 ° C for 7 days, and the medium containing the compound and E2 is replaced every 2 days to ensure the activity of the compound.

After 7 days, the viable cell mass was calculated by the amount of ATP converted by the luminescence enzyme (Cell Titre Glo® luciferase kit, Promega®). This method can examine the estrogenic action that stimulates estrogen-dependent cell growth under conditions that do not contain estrogen. Percentage of stimulus can be calculated with the maximum of E2 stimulation as 100%. In this experiment, when calculating the percentage of antagonist effects, the complete inhibition (100%) of the inhibition at a concentration of 1 x 10 ^-5 M compound was determined. The inhibition curve and inhibitory IC ₅₀ values were determined using Prism 5 software . &Lt; / RTI &gt;

Biological data of selected compounds

The compounds prepared above are analyzed by the biological methods described in the text. The results are shown in the following table.

[Table 1]

The compounds disclosed in the present invention exhibit strong anti-estrogenic action against MCF-7 cells.

toxicity

Through further research, it has been shown that the compounds of the present invention have relatively weak toxicity.

As shown in the Figure and table below, after 21 days of administration of tamoxifen (20 mg / kg) to nude mice, the body weight was reduced by 20% and the representative compounds of the present invention (CT-946-01 ) Was administered at a high dose of 30 mg / kg, resulting in a 7% body weight gain.

Anti-tumor (MCF-7) effect and weight change:

[Table 2]

PO: per os;

QD: once a day (quapua die);

TGI: Target Group Index;

BW: Body Weight

Although the embodiments of the present invention have been described above, the embodiments are merely illustrative. Various modifications and improvements can be made to the embodiments illustrated in the present invention. It will be understood by those skilled in the art that various changes, substitutions, and alterations may be made without departing from the scope of the present invention. The scope of the present invention is defined by the appended claims, and the methods and structures included in the scope are also within the scope of the present invention.

Claims (13)

A compound represented by the general formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,

here
R ⁰ and R ¹ are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; the alkyl, cycloalkyl, The carbon atom of the cycloalkyl group, the heterocyclyl group and the heteroaryl group may be substituted with one or more substituents independently selected from halogen, -OH, -NH ₂ , -SH, an alkyl group, a halogenated alkyl group and an alkoxy group Optionally oxidized;
A ring and B ring are each independently selected from an aryl group, a heteroaryl group and a heterocyclyl group, wherein the carbon atoms of the heterocyclyl group and the heteroaryl group may be optionally oxidized;
R ² and R ³ are each independently selected from the group consisting of halogen, -OH, -NH ₂ , -CN, -SH, -COOH, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an alkoxy group, alkoxy group, a heterocycloalkyl alkoxy group, a monoalkylamino group, a dialkylamino group, -S (O) - alkyl group and -S (O) ₂ - is selected from the group; the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic (O) -alkyl group and -S (O) ₂ -alkyl group are optionally and independently substituted with one or more substituents selected from the group consisting of halogen, - (C ₁ -C 6) alkyl, OH, a heterocyclyl group or -NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are each independently selected from hydrogen, an alkyl group, a cycloalkyl group, or R ⁴ and R ⁵ And the nitrogen atoms linked to them together form a heterocyclyl group, said heterocyclyl group optionally being substituted by an alkyl group;
m and n each represent the number of R ² groups in ring A and the number of R ³ groups in ring B, and m and n are each independently selected from 0, 1, 2 or 3. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,
Wherein R ⁰ and R ¹ are each independently selected from an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally and independently halogen , -OH, an alkyl group, a halogenated alkyl group and an alkoxy group, and the carbon atoms of the cycloalkyl group, the heterocyclyl group and the heteroaryl group may be optionally oxidized;
or,
R ⁰ and R ¹ are each independently selected from an alkyl group, a cycloalkyl group, an aryl group and a heteroaryl group, and the alkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally and independently substituted with halogen, -OH, And the carbon atoms of the cycloalkyl group and the heteroaryl group may be optionally oxidized;
or,
^One of R ⁰ and R ¹ is an alkyl group or a halogenated alkyl group, and the other is selected from the following (a) to (d).
(a) a 5-membered heteroaryl group containing at least one heteroatom selected from oxygen, sulfur and nitrogen. Wherein said heteroaryl group may be optionally substituted with one or more substituents selected from halogen, -OH, an alkyl group, an alkoxy group and a halogenated alkyl group, and is preferably a thienyl group substituted by one or more halogen.
(b) a 6-membered heteroaryl group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen. Wherein the heteroaryl group may be optionally substituted with one or more substituents selected from halogen, -OH, an alkyl group, an alkoxy group, and a halogenated alkyl group, and the carbon atoms on the heteroaryl group may be selectively oxidized, A pyridyl group substituted by one or more -OH is preferred.
(c) a 5 or 6 membered cycloalkyl group. The cycloalkyl group may be optionally and independently substituted with one or more substituents selected from halogen, -OH, alkyl group, alkoxy group and halogenated alkyl group, and the carbon atom on the cycloalkyl group may be optionally oxidized, A cyclohexanone group or a cyclohexyl group substituted by one or more -OH groups is preferable.
(d) a phenyl group. The phenyl group may be optionally substituted with one or more substituents selected from halogen, -OH, an alkyl group and an alkoxy group. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,
Wherein one of R ⁰ and R ¹ is selected from hydrogen, halogen and an alkyl group, wherein the alkyl group may be optionally and independently substituted by a substituent selected from halogen, -OH, NH ₂ , alkoxy groups, Lt; RTI ID = 0.0 &gt; halogen,
And the other of R &lt; ⁰ &gt; and R &lt; ¹ &gt; is a structure represented by the following formula (II)

In the structure represented by the general formula (II), the dotted line indicates that the five-membered ring composed of X, Y and W and the carbon atoms connected thereto is saturated or unsaturated,
Wherein X, Y and W are each independently selected from C, N, O and S and wherein the 5 membered ring is optionally substituted with one or more substituents selected from halogen, -OH, -SH, an alkyl group, a cycloalkyl group, an alkoxy group and an alkylthio group Wherein the alkyl, cycloalkyl, alkoxy and alkylthio groups are optionally and independently substituted with one or more groups selected from halogen, -OH, -NH ₂ , monoalkyl, dialkylamino and heterocyclyl groups, or And may be substituted by a plurality of substituents.
or,
At least one of X, Y and W is a heteroatom selected from N, O and S, said 5 membered ring being optionally substituted by a substituent selected from one or more halogen and alkyl groups;
or
The general formula (II) is selected from the following structures.

The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,
Ring A and ring B are each independently selected from an aryl group and a heteroaryl group wherein the carbon atom of the heteroaryl group may be optionally oxidized;
or,
Ring A and ring B are each independently selected from an aryl group and a 6-membered heteroaryl group containing one or two nitrogen atoms, wherein the carbon atom of the heteroaryl group may be optionally oxidized;
or,
Ring A and ring B are each independently selected from a phenyl group and a pyridyl group. A compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,
R ² and R ³ are each independently selected from halogen, -OH, -NH ₂ , -CN, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, a heterocycloalkoxy group, a monoalkylamino group and a dialkylamino group and, on the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, heterocycloalkyl alkoxy group, a monoalkylamino group and a dialkylamino group are optionally and independently by halogen, -OH, -NR ⁴ R ⁵ or a heterocyclyl group Wherein R ⁴ and R ⁵ are each independently selected from hydrogen, an alkyl group and a cycloalkyl group, or R ⁴ and R ⁵ and the nitrogen atom connected thereto form together a heterocyclyl group, and the heterocyclyl The group may be optionally substituted by an alkyl group;
or,
R ² and R ³ are each independently selected from halogen, -OH, -NH ₂ , -CN, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, a heterocycloalkoxy group, a monoalkylamino group and a dialkylamino group And the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heterocycloalkoxy, monoalkylamino and dialkylamino groups may be optionally and independently substituted by a heterocyclyl group or -NR ⁴ R ⁵ , , Wherein R ⁴ and R ⁵ are each independently selected from halogen or an alkyl group, or R ⁴ and R ⁵ and the nitrogen atom connected thereto together constitute a heterocyclyl group, said heterocyclyl group being optionally substituted by an alkyl group . 6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,
Ring A is selected from a phenyl group and a 6-membered heteroaryl group, and at least one R ² group is located at the para position of the phenyl group or the para position of the 6-membered heteroaryl group; or
Ring B is selected from a phenyl group and a 6-membered heteroaryl group, and also at least one R ³ at the para position of the phenyl group or the para position of the 6-membered heteroaryl group. 7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof,
m and n are each independently selected from 1 or 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof, wherein said compound is selected from the following compounds:

The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof for use in the modulation of estrogenic activity. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or light-emitting substance thereof, for use in the prevention and / or treatment of estrogen dependent diseases and conditions drug. 9. A pharmaceutical composition comprising a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof, and a pharmaceutically acceptable carrier . A mammal in need thereof, in particular a human, is provided a therapeutically effective amount of a compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof, In a mammal, particularly a human, comprising administering to a mammal an effective amount of a compound of formula (I). 13. The method of claim 12,
Estrogen-dependent diseases and conditions are selected from menopausal or postmenopausal disorders, vasomotor symptoms, genitourinary or external atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, cancer, depression, diabetes, degeneration of bone and osteoporosis do.

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