JP2015504049A - Novel aryl alkene derivatives and their use in selective estrogen receptor modulators - Google Patents

Abstract

The present invention provides a novel ethylene derivative represented by the general formula (I), which is used as a selective estrogen receptor modulator (SERMs) for preventing and / or treating estrogen-dependent diseases or diseases. Used for.

Description

  The present invention provides a series of substituted ethylene derivatives as selective estrogen receptor modulators (SERMs), pharmaceutical compositions thereof, pharmaceutical applications, and prevention and / or prevention of estrogen-dependent diseases in mammals (especially humans). It relates to a method of treatment.

  The estrogen receptor (ER) is an important nuclear transcription factor and plays an important physiological role in the reproductive system, bone tissue, cardiovascular system and central nervous system. Within a woman's body, estrogen receptors are contained in more than 400 tissues or organs including, for example, the uterus, vagina, breast, pelvis (ligament and connective tissue), skin, bladder, urethra, skeleton and cerebrum. As women enter menopause, as estrogen decreases significantly, corresponding changes occur in tissues, organs, and systems that contain receptors associated with estrogen. This usually results in a series of climacteric syndromes in elderly women, including facial flushing, sweating, insomnia, 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, USA, 1991. pp 3-22 And Rekers H: Mastering the menopause. In: A report of the menopause.Expert reports on the medical and the es the St. of the Strategic Strategies for the 1990, Ed. Burger H & Bullet M, Part. Ed. Burger H & Bullet M, Parthenon Publishing, Park Ridge, NJ, USA, 1991. pp 23-43). In addition, long-term deficiency of estrogen can lead to osteoporosis, senile dementia (Alzheimer's disease) and cardiovascular disease.

  Estrogen replacement therapy is increasingly used in the treatment of climacteric syndrome in women. In addition, estrogen replacement therapy has been shown to be beneficial in reducing osteoporotic fractures and preventing Alzheimer's disease (Henderson VW: Estrogens, cognition, and as women's risk of Alzheimer's disease. Am J Med 103 (3A): 11S-18S, 1997), and LDL-cholesterol levels can be reduced, thereby preventing cardiovascular disease (Grodstein F, Stampfer, MJ: Estrogens for women at varying risk). of coronary disease.Maturitas 30: 19-26, 1998). However, the use of estrogen replacement therapy has increased the risk of breast and endometrial cancer (Lobo RA: Benefits and risks of estrogen replacement therapy. Am J Obstet Gynecol 173: 982-990, 1995).

  Selective estrogen receptor modulators (SERMs) have different activities on estrogen receptors in different tissues. They mimic estrogens in some tissues and develop antiestrogenic effects in some other tissues. Utilizing these properties of SERMs, it exerts an agonistic (excitatory) action on estrogen receptors in bone tissue, cardiovascular system and central nervous system, but antagonizes estrogen receptors in tissues such as mammary gland and uterus. It is possible to design an ideal medicine that has an effect, and to avoid side effects caused by estrogen replacement therapy.

  As the first approved SERMs to treat osteoporosis, raloxifene is ER antagonistic in breast and uterine cells and ER excitability in bone tissue and cardiovascular system ing. However, as a clinical effect in breast cancer treatment, raloxifene is not superior to tamoxifen and may cause side effects such as flushing of the face, leg cramps, headache, weight gain (Davies GC et al. , Obstet Gyneco 193: 558-565 (1999)).

  Clearly, there is a need to develop safer and more effective medicines to prevent and treat estrogen-dependent diseases and conditions.

According to one embodiment of the present invention, a compound represented by the general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, Or provide a prodrug.

Where
R ⁰ and R ¹ are each independently selected from hydrogen, halogen, alkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group, in which an alkyl group, cycloalkyl group, heterocyclic ring Group, aryl group and heteroaryl group are optionally independently one or more substituents selected from halogen, —OH, —NH ₂ , —SH, alkyl groups, halogenated alkyl groups, and alkoxy groups. Substituted and optionally carbon atoms of said cycloalkyl, heterocyclic and heteroaryl groups may be oxidized,
A ring and B ring are each independently selected from an aryl group, a heteroaryl group and a heterocyclic group, and the carbon atom of said heterocyclic group and heteroaryl group may optionally be 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 heterocyclic group, an alkoxy group, An alkylthio group, a cycloalkoxy group, a heterocycloalkoxy group, a monoalkylamino group, a dialkylamino group, a —S (O) -alkyl group, and a —S (O) ₂ -alkyl group, , Alkynyl group, cycloalkyl group, heterocyclic group, alkoxy group, alkylthio group, cycloalkoxy group, heterocycloalkoxy group, monoalkylamino group, dialkylamino group, -S (O) -alkyl group, and -S (O ) 2 _- is selected from an alkyl group; the alkyl group, alkenyl group, alkynyl group, Shikuroa Kill group, a heterocyclic group, an alkoxy group, an alkylthio group, cycloalkoxy group, heterocycloalkoxy group, monoalkylamino group, dialkylamino group, -S (O) - alkyl, and -S (O) 2 _- group Are optionally substituted with a halogen, —OH, heterocyclic group, or —NR ⁴ R ⁵ , where R ⁴ and R ⁵ are each independently hydrogen, alkyl groups, cycloalkyl groups Or R ⁴ and R ⁵ together with the nitrogen atom to which they are attached form a heterocyclic group, said heterocyclic group optionally substituted with an alkyl group,
m and n are the number of R ² groups in ring A and the number of R ³ groups in ring B, respectively, and m and n are each independently selected from 0, 1, 2, or 3 Is done.

  According to another aspect of the present invention, a compound represented by the general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph thereof for adjusting estrogen activity , Tautomers, or prodrugs are provided.

  According to another aspect of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for preventing and / or treating estrogen-dependent diseases and symptoms , Solvates, crystalline polymorphs, tautomers, or prodrugs are provided.

  According to another aspect of the present invention, a compound represented by the general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof And a pharmaceutically acceptable carrier.

  According to another aspect of the present invention, a compound represented by the general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate thereof in the manufacture of a medicament for regulating estrogen activity , Use of crystalline polymorphs, tautomers, or prodrugs.

  According to another aspect of the present invention, a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing and / or treating an estrogen-dependent disease or disease , Stereoisomers, solvates, crystalline polymorphs, tautomers, or prodrugs are provided for use.

  According to another aspect of the present invention, there is provided a method for preventing and / or treating estrogen-dependent diseases and conditions in mammals, particularly humans, said method being represented by a therapeutically effective amount of general formula (I). Or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof is administered to a mammal in need thereof, particularly a human. Including.

It is a figure which shows the body weight change of the nude mouse in the test of anti-tumor (MCF-7).

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise specified, all patents, patent applications, and published materials cited in this application are hereby incorporated by reference in their entirety.

  It should be understood that the foregoing general description and the following detailed description are exemplary and are only for the purpose of interpreting the invention and are not intended to be limiting of the invention. What is written in the singular includes the plural unless specifically stated otherwise in the specification. It should be understood that the singular forms used in the specification and claims include plural forms of what they refer to, unless the context clearly indicates otherwise. Further, unless otherwise specified, “or” or “or” as used in the present invention should be understood to mean “and / or”. Further, the term “including” and other forms used, for example, “having”, “comprising”, “included” and “containing” are not limiting.

In the reference (Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4 ^TH ED.” Vols. A (2000) and B (2001), Plenum Press, New York), definitions of standard chemical terms can be found. Unless otherwise stated, routine methods in the art such as, for example, mass spectra, NMR, IR and UV / Vis spectroscopy spectra and pharmacological methods are used. Unless otherwise defined, terms relating to analytical chemistry, organic synthetic chemistry, pharmaceuticals and medicinal chemistry, and experimental steps and techniques herein are those known in the art. Standard techniques can be used in the course of chemical synthesis, chemical analysis, pharmaceutical manufacture, formulation and transport, and patient treatment. For example, the reaction can be carried out and purified by the manufacturer's instructions for use of the kit, the method known in the art or the description of the present invention. In general, the techniques and methods may be practiced by the description of a number of summary documents and specific documents cited and discussed herein and by well-known ordinary methods in the art. . Herein, one skilled in the art can select functional groups and their substituents to provide stable structural moieties and compounds.

When a substituent is described by a general chemical formula written from left to right, the substituent includes the chemically same substituent obtained by writing from right to left. For example, —CH ₂ O— is the same as —OCH ₂ —.

  It should be understood that the section headings used herein are used only for the purpose of adjusting the structure of the description and do not limit the subject matter described. All documents or parts of documents cited in this application include, but are not limited to, for example, patents, patent applications, texts, books, manuals and papers, here for all purposes. The entirety of which is expressly incorporated herein by reference.

  In the chemical functional group named here, the total number of carbon atoms may be indicated by a simple symbol. For example, the alkyl group represented by the C1-C6 alkyl group has 1 to 6 carbon atoms in total. The total number of carbon atoms indicated by the mnemonic does not include carbon atoms in possible substituents.

  In addition to the above, the following terms used in the specification and claims of the present invention have the stated meaning unless otherwise specified.

  The terms “halogen”, “halogenated”, “halo” or “halide” mean bromine, chlorine, fluorine, and iodine.

  As used herein, the terms “aromatic”, “aromatic ring”, “aromatic”, “aromatic group” refer to a ring moiety in one or more planar rings, 4n + 2n It has a delocalized electron conjugated system containing one electron (where n is an integer). Aromatic rings can be formed with 5, 6, 7, 8, 9, or 10 or more atoms. Aromatic compounds are optionally substituted and can be monocyclic or condensed polycyclic. The term “aromatic compound” includes all carbocycles (eg, benzene rings), and rings containing one or more heteroatoms (eg, pyridine).

  The term “heteroatom” or “hetero” as used herein alone or as part of another component means an atom other than carbon and hydrogen. Heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, tin, but are not limited to these atoms. In embodiments having two or more heteroatoms, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be one another. It may be a difference.

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

  The term “alkyl (group)” used herein alone or as part of another component, eg, an alkyl halide (group), is an optionally substituted linear or optionally substituted It means a branched monovalent saturated hydrocarbon. It has 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and is bonded to the rest of the molecule by a single bond, for example a methyl group , Ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, 2-methylhexyl group , 3-methylhexyl group, n-octyl group, n-nonyl group, n-decyl group and the like.

The term “alkoxy (group)” as used herein refers to the group —OR _a , where R _a is an “alkyl (group)” as defined above. Examples of the alkoxy (group) include, but are not limited to, a methoxy group, an ethoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group.

The term “alkylthio group” as used herein means _a —SR _a group, where R _a is an “alkyl (group)” as defined above. Examples of the alkylthio (group) include, but are not limited to, a methylthio group, an ethylthio group, and an isopropylthio group.

As used herein, the term “monoalkylamino (group)” means a —NHR _a group, where R _a is an “alkyl (group)” as defined above. Examples of the monoalkylamino (group) include, but are not limited to, a methylamino group, an ethylamino group, and an isopropylamino group.

As used herein, the terms “bisalkylamino (group)”, “dialkylamino (group)” mean _a —NR _a R _b group, where R _a and R _b are as defined above. Independent “alkyl (group)”. Examples of “bisalkylamino (group)” and “dialkylamino (group)” include, but are not limited to, a dimethylamino group, a diethylamino group, a dipropylamino group, and a methylethylamino group.

  The term “alkenyl (group)” used herein, alone or as part of another component, refers to a straight or branched monovalent hydrocarbon group that contains only carbon and hydrogen atoms. And having at least one double bond and having 2 to 14 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. In addition, it is bonded to other parts of the molecule by a single bond, such as vinyl group, 1-propenyl group, allyl group, 1-butenyl group, 2-butenyl group, 1-pentenyl group, 1,4-pentadiene group, etc. Is mentioned.

  The term “alkynyl (group)” as used herein alone or as part of another component refers to a straight or branched monovalent hydrocarbon group, which contains only carbon and hydrogen atoms. Contains at least one triple bond. It can also optionally contain more triple bonds or more double bonds and has 2 to 14 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. It has a carbon atom and is bonded to the other part of the molecule by a single bond, and examples thereof include an ethynyl group, a 1-propynyl group, a 1-butynyl group, and a 1-ene-4-pentynyl group.

  The term “cycloalkyl (group)” as used herein alone or as part of another component is a stable monovalent non-aromatic mono- or polycyclic hydrocarbon group comprising carbon atoms And saturated or unsaturated containing only 3-15, preferably 3-10, more preferably 3-8 carbon atoms, which contain only hydrogen atoms and can contain fused or bridged ring systems belongs to. It is also linked to the rest of the molecule by a single bond. As “cycloalkyl (group)”, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, 1H-indenyl group, 2,3-dihydroindenyl group, 1,2,3, 4-tetrahydronaphthyl group, 5,6,7,8-tetrahydronaphthyl group, 8,9-dihydro-7H-benzocyclohepta-6-enyl group, 6,7,8,9-tetrahydro-5H-benzocyclohept Tenenyl group, 5,6,7,8,9,10-hexahydrobenzocyclooctenyl group, fluorenyl group, dicyclo [2.2.1] heptenyl group, dicyclo [2.2.2] octyl group, dicyclo [ 3.1.1] heptyl group, dicyclo [3.2.1] octyl group, dicyclo [2.2.2] octenyl group, and the like. The present invention is not limited.

As used herein, the term “cycloalkoxy (group)” means an —OR _b group, wherein R _b is the aforementioned “cycloalkyl (group)”.

  The term “heterocyclic group”, “heterocyclic group / heterocycle” used herein alone or as part of another component means a stable 3-18 membered monovalent non-aromatic ring. 2 to 12 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise, the heterocyclic groups may be monocyclic, bicyclic, tricyclic, or tetracyclic and can include fused or bridged ring systems. Also, nitrogen, carbon or sulfur in the heterocyclic group may be optionally oxidized, the nitrogen atom may optionally be quaternized, and the heterocyclic group may be partially saturated or fully saturated. The carbon atom in the heterocyclic group may be bonded to the other part of the molecule by one single bond. A heteroatom in the heterocyclic group may be bonded to the other part of the molecule by one single bond. A fused ring-containing heterocyclic group may contain one or more aromatic rings or heteroaromatic rings provided that it is an atom in the non-aromatic ring that is bonded to the rest of the molecule. In the present application, the heterocyclic group is preferably a stable 4- to 11-membered monovalent non-aromatic monocyclic or bicyclic ring, and includes 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Preferably, it contains one stable 4- to 8-membered monovalent non-aromatic monocycle, and more preferably contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. . Examples of the heterocyclic group include, but are not limited to, a nitrogen heterocyclobutyl group, a morpholinyl group, a piperazinyl group, a piperidinyl group, a pyrrolidinyl group, and a thienyl group.

  As used herein, the terms “heterocyclooxy (group)”, “heterocyclic oxy (group)”, and “heterocycloalkoxy (group)” mean an —ORc group, where Rc is the above “ A "heterocyclic group".

  The term "aromatic ring", "aromatic ring group", "aromatic group / aryl (group)" used alone or as part of another component herein, or prefixed with "aromatic" (Eg, the aryl group portion of the “aralkyl group”) is a hydrocarbon cyclic system, which is hydrogen, 6-18 cyclic carbon atoms, preferably 6-10 cyclic Is meant to contain carbon atoms and at least one aromatic ring. In the present invention, the aromatic ring group may be monocyclic, bicyclic, tricyclic, or tetracyclic and may include fused or bridged ring systems. The carbon atom of the aryl group may be bonded to the rest of the molecule by a single bond. Examples of the aryl group include, but are not limited to, a phenyl group, a naphthalenyl group, and an anthryl group. In the present invention, the aryl group is preferably a C6-C10 aryl group, more preferably a phenyl group.

  The term “heteroaryl (group)” as used herein alone or as part of another component is a 5 to 16 membered cyclic system, which has 1 to 15 carbon atoms, preferably Preferably it contains 1 to 10 carbon atoms. Further, it contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. Unless stated otherwise, heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic, and the point of attachment to another part of the molecule is an aromatic ring atom. If so, it may contain fused or bridged ring systems. Nitrogen, carbon and sulfur atoms in the heteroaromatic ring may be optionally oxidized and the nitrogen atom may optionally be quaternized. In the present invention, the heteroaryl group is a stable 4- to 11-membered mono (mono) aromatic ring, and it preferably contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. More preferably, it is a stable 5- to 8-membered single aromatic ring, and it contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Heteroaryl groups include benzimidazolyl, benzothiazolyl, benzoxazolyl, carbazolyl, indolyl, isoindolyl, isoquinolyl, quinolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyridazinyl, 1H-pyridine -2-yl group, 1H-pyridin-4-yl group, 1H-pyridin-2-ketone-4-yl group, pyridinyl group, pyrimidinepyrrolyl group, quinolyl group, quinolinyl group, thiazolyl group, tetrazolyl group However, it is not limited to these. In the present application, the heteroaryl group is a 5- to 8-membered heteroaryl group and preferably contains 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Further, a pyridinyl group, a pyrimidyl group, a thiazolyl group, an oxopyridinyl group, a 1H-pyridin-2-keto-4-yl group, or a thienyl group is more preferable.

  As used herein, the term “arbitrary”, “selective” or “in some cases” means that the circumstances and circumstances described below may or may not occur, The description includes the occurrence of the circumstances and situations as well as the absence of the circumstances and situations. For example, in the “optionally substituted aryl group”, the aryl group may be substituted or unsubstituted. The description also includes substituted aryl groups as well as aryl groups that are not yet substituted.

  As used herein, the terms “group” and “chemical group” mean a specific part or functional group of a molecule. A chemical group is always recognized as a chemical entity inserted or added to a molecule.

  “Stereoisomers” refer to compounds that are joined together by similar bonds through the same atoms, but having different three-dimensional structures. In the present invention, various stereoisomers and mixtures thereof are considered.

  Unless stated otherwise, the compounds described in this invention contain olefinic double bonds and have E and Z isomers.

  “Tautomer” means an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. In the present invention, all compounds include any tautomers thereof.

  As used herein, the term “crystalline polymorph” or “polymorphism (phenomenon)” means that the compounds of the present invention have many crystal lattice forms. Some compounds of the present invention can have more than one crystal form, including in the present invention all crystalline polymorphic forms, or mixtures thereof.

  Intermediate compounds of formula (I), all crystal polymorphs of the above categories and the properties of the crystals are also included within the scope of the present invention. Likewise, all tautomeric forms are also included.

  The compounds of the present invention, or pharmaceutically acceptable salts thereof, can contain one or more asymmetric centers and can be enantiomers, diastereomers, and other stereoisomers. The absolute configuration is indicated by (R)-or (S)-. The present invention includes all possible isomers, and their racemic and optically pure forms. Optically active (+) and (-), or (R)-and (S)-isomers may be prepared using chiral synthons and chiral reagents, or general techniques such as chromatography or You may isolate | separate using a fractional crystal.

  Conventional techniques for preparing / separating single enantiomers include chiral synthesis on appropriate optically pure precursors, or racemates (e.g., using chiral high performance liquid chromatography (HPLC)). Or salt or derivative racemate). For example, “Gerald Gubitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; 3: 341-63, 2010; Fumiss et al. (Eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. sup., TH ED, Longman Scientific and Techn. 809-816; Heller, Acc. Chem. Res. 1990, 23, 128. ".

  The term “pharmaceutically acceptable salt” as used herein means that it may be a pharmaceutically acceptable acid addition salt or a base addition salt.

  “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid that maintains the biological potency and properties of the free base of the compound, has no biological or other side effects, and To do. Examples of the inorganic acid include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of the organic acid include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfone. Acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethylsulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, Galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glutamic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glyceroline ethanolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, Malonic acid, mandelic acid, methanesulfonic acid, mucous acid, naphthalene , 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, succinic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, Examples include 4-aminosalicylic acid, sebacic acid, octadecanoic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid, but are not limited thereto.

  “Pharmaceutically acceptable base addition salt” means a salt that retains the biological potency and properties of the free acid of the compound, and is free of biological or other side effects. These salts are obtained by reacting the free acid with an inorganic or organic base. Salts produced by reacting with inorganic bases include sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. It is not limited to. The inorganic salt is preferably an ammonium salt, a sodium salt, a potassium salt, a calcium salt, or a manganese salt.

  Organic bases that form salts include primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins such as ammonia, Isopropylamine, trimethylamino, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylaminoethanol (deanol), 2-dimethylaminoethanol (2-dimethylaminoethanol), 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine , Caffeine, procaine, hydrabamine, choline, betaine, venetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanol Min, tromethamine, purines, piperazine, piperidine, N- ethylpiperidine, but, polyamine resins, and the like.

  Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamino, dicyclohexylamine, choline and caffeine.

  Crystals often form solvates of the compounds of the present invention. The term “solvate” as used herein means an aggregate formed by combining one or more compound molecules of the present invention and one or more solvent molecules.

  The solvent may be water, in which case the solvate is a hydrate. Moreover, an organic solvent may be sufficient. Accordingly, the compounds of the present invention exist as hydrate forms including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. Also good. The compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention simply hold water accidentally or some other with water. It may be a mixture with a solvent. The compounds of the present invention may react in one solvent or may precipitate or crystallize in one solvent. Solvates of the compounds of the invention are also included within the scope of the invention.

  The present invention also includes prodrugs of the compounds of the present invention. “Prodrug” means that a compound can be converted under physiological conditions or by solvation to a compound of the invention which has a biologically active effect. Accordingly, the term “prodrug” means a pharmaceutically acceptable metabolic precursor of a compound according to the present invention. Prodrugs may not be active at the time of administration to a subject in need, but can be converted to compounds of the invention that are active in vivo. Prodrugs are usually rapidly converted in vivo to the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds always have advantages in terms of solubility, histocompatibility, or delayed release in the organism of mammalian organisms. Prodrugs contain amino and carboxy protecting groups that are well known to those skilled in the art. Specific methods for preparing prodrugs are described, for example, in "Saulnier, MG, et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; et al., J. Med. Chem. 2000, 43, 475 ".

  As used herein, “pharmaceutical composition” refers to a vehicle for delivering a compound of the present invention and a compound having biological activity, generally accepted in the art, to a mammal (eg, humans). Is a mixed preparation. Such a medium includes all pharmaceutically acceptable carriers.

  As used herein, the term “acceptable” associated with a formulation, composition, or ingredient means that there is no lasting adverse effect on the overall health status of the subject being treated.

  As used herein, the term “pharmaceutically acceptable” means a substance (eg, carrier or diluent) that does not affect the biological activity or properties of the compounds herein, and is relatively Means non-toxic, i.e. the substance does not cause a bad biological reaction when administered to an individual or does not interact with any components contained in the composition in a bad form. Means.

  “Pharmaceutically acceptable carrier” means an adjuvant, carrier, excipient, additive, deodorant, diluent, preservative, dye, which is approved by the relevant government departments and can be administered to humans and livestock. / Coloring agents, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, tonicity agents, solvents, or emulsifiers are included, but are not limited thereto.

  As used herein, the term “SERM” means a selective estrogen receptor modulator and they exhibit an estrogen receptor agonistic action in one or more target tissues, but one or more other. It shows estrogen receptor antagonistic action in the target tissues.

  As used herein, the term “subject”, “patient” or “individual” means an individual suffering from a disease, disorder (abnormality) or disease, including mammals and non-mammals. Examples of mammals include any member of the mammalian class, such as humans; non-human primates (eg, chimpanzees, and other monkeys, and monkeys); cows, horses, sheep, Domestic animals such as goats and pigs; domestic animals such as rabbits, dogs and cats; laboratory animals including but not limited to rodents such as rats, mice and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

  The terms “prevention”, “prevention (noun)” and “prevent (verb)” include the possibility of reducing the incidence or development of a patient with breast cancer.

As used herein, the term “treatment” means treating a related disease or condition in a mammal, particularly a human,
(I) Mammals, in particular, mammals that have been exposed to a previously existing disease or disease environment but have not yet been diagnosed as having the disease or disease should not cause the disease or disease involved. Prevention,
(Ii) inhibit the disease or condition, ie prevent its progression,
(Iii) alleviating the disease or condition, ie debilitating the disease or condition,
(Iv) alleviating symptoms resulting from the disease or condition.
As used herein, the terms “disease” and “condition” may be substituted for each other or may have different meanings. This is because certain diseases or illnesses have no known virulence factors (as a result, the etiology is not yet clear), cannot be recognized as diseases, and are only recognized as undesirable conditions or syndromes. This is because the specific symptoms of the syndrome are more or less verified by clinical researchers.

  The terms “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” as used herein can alleviate to some extent one or more symptoms of a disease or condition to be treated after taking. Means a dose of at least one medicament or compound; The result is a change that reduces and / or reduces the cause of a sign, symptom, or disease, or any other demand for a biological system. For example, an “effective amount” for treatment is a dose of a composition comprising a compound disclosed herein that is in demand to provide a clinically significant ameliorative effect. For example, an effective dose suitable for the disease of any individual can be determined using techniques for sequential dose addition testing.

  As used herein, “take”, “administration”, “dosing” and the like are methods by which a compound or composition can be transported to a site where biological action is required. These methods include oral administration, transduodenal administration, parenteral injection (administration) (including intravenous, subcutaneous, intramuscular, intravascular injection or infusion), topical administration, and rectal administration methods. . Those skilled in the art are familiar with administration techniques applicable to the compounds and methods herein. See, for example, Goodman and Gilman, The Pharmaceuticals Basis of Therapeutics, current ed. And Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co .; , See Easton, Pa. In preferred embodiments, the compounds and compositions herein are administered orally.

  The term “agonist” as used herein refers to a molecule that enhances the activity of another molecule or the activity of a receptor site. For example, a compound, a medicine, an enzyme activator or a hormone regulator.

  As used herein, the term “antagonist” refers to a molecule that eliminates or suppresses the activity of another molecule or the activity of a receptor site. For example, a compound, a medicine, an enzyme inhibitor or a hormone regulator.

  The term “modulation” as used herein means to interact directly or indirectly with the target to alter the activity of the target. For example, increasing the activity of the target, suppressing the activity of the target, limiting the activity of the target, or extending the activity of the target.

  As used herein, the term “modulator” means a molecule that interacts directly or indirectly with a target. Such interactions include, but are not limited to, agonist and antagonist interactions.

  Terms such as the term “enhancement / enhancement” as used herein means increasing the efficacy of a required effect or extending the duration of a required effect. Thus, the term “enhancement” when referring to enhancing the therapeutic agent effect means the ability to increase or prolong the effect or duration acting on the other therapeutic agent strain.

  As used herein, the term “a dose of potentiating effect (amount that can effectively enhance the effect)” means an amount that can enhance the effect on the line that other therapeutic agents demand.

  As used herein, the terms “combination of pharmaceuticals”, “perform other treatments”, “administer other therapeutic agents” and the like are drugs obtained by mixing or combining more than one active ingredient. It is treatment. This includes fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means the simultaneous administration of at least one compound described herein and at least one combination agent to a patient in the form of a single entity or single dosage form. The term “non-fixed combination” refers to the simultaneous administration of at least one compound described herein and at least one combination agent to a patient in the form of a single entity, combined administration, or sequentially at variable time intervals. Is meant to be administered, wherein such administration provides an effective level of two or more compounds in the patient. These can also be employed in cocktail therapy, for example, administering three or more active ingredients.

  As used herein, the terms “administered in combination” and “administered in combination with” and their synonyms, etc., refer to administration of the selected therapeutic agent to the same patient and the same or different routes of administration or It refers to a therapeutic strategy that involves administering a medicament through different administration times. In some embodiments, the compounds described herein are administered in combination with other pharmaceutical agents. These terms include administering two or more drugs to an animal so that the drug and / or its metabolites are present in the animal at the same time. These terms include administering different compositions simultaneously, administering different compositions at different times, and / or administering one composition containing different active ingredients. Thus, in some embodiments, a compound of the present invention and other medicament are administered in a single composition.

  The term “metabolite” as used herein refers to a derivative of the compound that is formed when the compound is metabolized.

  The term “active metabolite” as used herein means a derivative having the activity of the compound formed when the compound is metabolized.

  As used herein, the term “metabolizes” means all steps (including but not limited to hydrolysis and enzyme catalyzed reactions) in which the organism converts a particular substance. Thus, the enzyme can generate specific structural changes in the compound. For example, cytochrome P450 catalyzes a variety of redox reactions, uridine diphosphate glucuronyl transferase, glucuronic acid molecules are aromatic alcohols, aliphatic alcohols. (Aliphatic alcohols), carboxylic acids (carboxylic acids), amines (amines) and transfer to free sulfhydryl groups (free sulfhydryl groups). For more information on metabolic, refer to The Pharmaceutical Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).

According to one embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or pro Provide drag.

Where
R ⁰ and R ¹ are each independently selected from hydrogen, halogen, alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein alkyl group, cycloalkyl group, heterocyclic group , Aryl groups and heteroaryl groups are optionally substituted with one or more groups selected from halogen, —OH, —NH ₂ , —SH, alkyl groups, halogenated alkyl groups, and alkoxy groups. And carbon atoms of the cycloalkyl group, heterocyclic group and heteroaryl group may optionally be oxidized,
A ring and B ring are each independently selected from an aryl group, a heteroaryl group and a heterocyclic group, and the carbon atom of the heterocyclic 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 heterocyclic group, an alkoxy group, An alkylthio group, a cycloalkoxy group, a heterocycloalkoxy group, a monoalkylamino group, a dialkylamino group, a —S (O) -alkyl group, and a —S (O) ₂ -alkyl group, , Alkynyl group, cycloalkyl group, heterocyclic group, alkoxy group, alkylthio group, cycloalkoxy group, heterocycloalkoxy group, monoalkylamino group, dialkylamino group, -S (O) -alkyl group, and -S (O ) ₂ - alkyl group is optionally independently halogen, -OH, a heterocyclic group or -NR, It may be substituted with R ^5, wherein, R ⁴ and R ⁵ are each independently hydrogen, an alkyl group, selected from cycloalkyl, or R ⁴ and R ⁵ with the nitrogen to which they are bound to them Together with the atoms form one heterocyclic group, which may optionally be substituted with an alkyl group;
m and n are respectively 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

According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Providing a prodrug, where
R ⁰ and R ¹ are each independently selected from an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, and the alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl The group may optionally be independently substituted with one or more groups selected from halogen, —OH, alkyl groups, halogenated alkyl groups, and alkoxy groups, and may be a cycloalkyl group, a heterocyclic group, And the carbon atom of the heteroaryl group may be optionally oxidized.

According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Providing a prodrug, where
R ⁰ and R ¹ are each independently selected from an alkyl group, a cycloalkyl group, an aryl group and a heteroaryl group, wherein the alkyl group, heterocyclic group, aryl group and heteroaryl group are optionally independently And may be substituted with one or more groups selected from halogen, —OH, alkyl groups, and alkoxy groups, and carbon atoms of cycloalkyl groups and heteroaryl groups may be optionally oxidized. .

According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Providing a prodrug, where
One of R ⁰ and R ¹ is an alkyl group and the other is a group selected from a cycloalkyl group, an aryl group and a heteroaryl group, each optionally independently of halogen, —OH, —NH ₂ , —SH, an alkyl group, an alkoxy group, and a halogenated alkyl group may be substituted with one or more groups, and the carbon atom of the cycloalkyl group or heteroaryl group is optionally oxidized. May be.

According to one embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or pro Provide a drag, where
One of R ⁰ and R ¹ is an alkyl group or halogen-substituted alkyl, and the other is a group 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 is optionally selected from halogen, —OH, alkyl groups, alkoxy groups and halogen-substituted alkyls It is preferably a thienyl group optionally substituted with one or more groups and optionally substituted with one or more halogens.
b) a 6-membered heteroaryl group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, wherein said heteroaryl group is optionally halogen, —OH, alkyl group, alkoxy group and halogenated alkyl And a carbon atom in the heteroaryl group may be optionally oxidized and is a pyridinyl group optionally substituted with one or more —OH. It is preferable.
c) a 5- or 6-membered cycloalkyl group, wherein the cycloalkyl group is optionally substituted with one or more groups selected independently from halogen, —OH, alkyl groups, alkoxy groups and alkyl halides. The carbon atom in the cycloalkyl group may be optionally oxidized, and is preferably a cyclohexanone group or a cyclohexyl group optionally substituted with one or more —OH.
d) Phenyl group, wherein the phenyl group may optionally be substituted with one or more groups selected from halogen, —OH, alkyl groups and alkoxy groups.

According to one embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or pro Provide a drag, where
One of R ⁰ and R ¹ is selected from hydrogen, halogen and an alkyl group, in which said alkyl group may independently be optionally substituted with a halogen, —OH, NH ₂ , an alkoxy group, or , Selected from alkyl groups optionally substituted with one or more halogens, and
Another one of R ⁰ and R ¹ is a structure represented by the following general formula (II).

In the structure represented by the general formula (II), a dotted line indicates that a 5-membered ring composed of X, Y and W and a carbon atom bonded thereto is saturated or unsaturated,
Wherein X, Y and W are each independently selected from C, N, O and S, and the five-membered ring is optionally halogen, —OH, —SH, an alkyl group, a cycloalkyl group, an alkoxy group. May be substituted with one or more groups selected from a group and an alkylthio group, wherein the alkyl group, cycloalkyl group, alkoxy group and alkylthio group are independently optionally halogen, —OH, —NH ₂ , It may be substituted with one or more groups selected from a monoalkylalkyl group, a dialkylamino group and a heterocyclic group.

According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Providing a prodrug, where
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 with one or more groups selected from a halogen and an alkyl group. .

According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Providing a prodrug, where
Formula (II) is

Chosen from.

According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Providing a prodrug, where
A ring and B ring are each independently selected from an aryl group and a heteroaryl group, wherein the carbon atoms of the heteroaryl group may be optionally oxidized.

According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Providing a prodrug, where
A ring and B ring are each independently selected from an aryl group and a 6-membered heteroaryl group containing one or two nitrogen atoms, in which the carbon atoms of the heteroaryl group are optionally oxidized. May be.

According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Providing a prodrug, where
A ring and B ring are each independently selected from a phenyl group and a pyridinyl group.

According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Providing a prodrug, where
R ² and R ³ are each independently halogen, —OH, —NH ₂ , —CN, alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, heterocycloalkoxy group, monoalkylamino group, and Selected from dialkylamino groups, wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, heterocycloalkoxy group, monoalkylamino group, and dialkylamino group are optionally independently halogen, -OH, ^May be substituted with a heterocyclic group, or —NR ⁴ R ⁵ , in which R ⁴ and R ⁵ are each independently selected from hydrogen, an alkyl group, and a cycloalkyl group, or R ⁴ and R ⁵ form one heterocyclic group together with the nitrogen atom to which they are attached to, those Heterocyclic group may be optionally substituted by an alkyl group.

According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Providing a prodrug, where
R ² and R ³ are each independently halogen, —OH, —NH ₂ , —CN, alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, heterocycloalkoxy group, monoalkylamino group, And 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 are each independently an optionally substituted heterocyclic group, Or may be substituted with —NR ⁴ R ⁵ , in which R ⁴ and R ⁵ are each independently selected from a halogen or an alkyl group, or R ⁴ and R ⁵ are attached thereto. Together with the nitrogen atom, a heterocyclic group is optionally formed It may be substituted with Le group.

According to one embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or pro Provide a drag, where
Ring A is selected from phenyl and a 6-membered heteroaryl group, and has at least one R ² group in the para-coordination of the phenyl group or the para-coordination of the 6-membered heteroaryl group;
Ring B is selected from a phenyl group and a 6-membered heteroaryl group, and has at least one R ³ group in the para-coordination of the phenyl group or the para-coordination of the 6-membered heteroaryl group.

According to one embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or pro Provide a drag, where
m and n are each independently selected from 1 or 2.

According to one embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or pro Providing a drug, wherein said compound is selected from:

  According to another embodiment of the present invention, a compound represented by the general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, for adjusting estrogen activity. Forms, tautomers, or prodrugs are provided.

  According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Provided is the use of a prodrug in the manufacture of a medicament for modulating estrogenic activity.

  According to another embodiment of the present invention, a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, stereoisomerism for preventing and / or treating estrogen-dependent diseases and diseases Isomers, solvates, crystalline polymorphs, tautomers, or prodrugs are provided.

  According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or Provided is the use of a prodrug in the manufacture of a medicament for preventing and / or treating estrogen-dependent diseases and conditions.

  According to another embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer or pro Pharmaceutical compositions comprising a drug and a pharmaceutically acceptable carrier are provided.

  In general, the compounds of the invention, or pharmaceutically acceptable salts thereof, are administered in the form of a suitable pharmaceutical composition formed with one or more pharmaceutically acceptable carriers. The pharmaceutical composition of the present invention is manufactured in the form of a solid, semi-solid, liquid or gas, for example, tablet, capsule, powder, granule, ointment, liquid, suppository, injection, inhalant, gel, microcloth Fair and aerosol agents are included.

  Representative routes for administering these pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and intranasal. For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compounds of the present invention contained in these dosage forms may be solid powders or granules, may be solutions or suspensions in aqueous or non-aqueous solvents, oil-in-water, water-in-oil emulsions, etc. It may be. The above dosage forms can be prepared from the active compound and one or more carriers or adjuvants using conventional pharmacological methods. The carrier must be compatible with the active compound or other adjuvants. For solid formulations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Liquid carriers include, but are not limited to, water, saline, dextrose, ethylene glycol, polyethylene glycol and the like. The active compound can form a solution or suspension with the carrier. The specific route of administration and dosage form will depend on the physical / chemical properties of the compound itself and the severity of the disease to be treated and can be determined by one skilled in the art by routine methods.

  According to another embodiment of the present invention, there is provided a method of modulating estrogen activity in a mammal (particularly human), comprising a therapeutically effective amount of a compound represented by general formula (I) or a compound thereof It includes administering a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug to a mammal (particularly human) in need thereof.

  According to one embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or pro By drug, estrogen receptors are upregulated in bone tissue, cardiovascular system and central nervous system, and downregulated in tissues at sites such as breast and uterus.

  According to another embodiment of the present invention, there is provided a method for preventing and / or treating estrogen-dependent diseases and conditions in mammals, particularly humans, which comprises a therapeutically effective amount of the general formula (I) Or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof is administered to a mammal in need, particularly a human. Including.

  As used herein, estrogen-dependent diseases and conditions refer to diseases and conditions in which modulation of the estrogen receptor participates. According to one embodiment of the invention, the estrogen-dependent diseases and conditions are climacteric or postmenopausal disorders, vasomotor symptoms, genitourinary or vulvar atrophy, atrophic vaginitis, endometriosis, feminine function Selected from the group consisting of disorders, cancer (eg, endometrial cancer, breast cancer, etc.), depressive symptoms, diabetes, bone demineralization, and osteoporosis.

  A compound described in the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer or prodrug thereof is administered in a therapeutically effective amount and is therapeutically effective. The amount will vary depending on a series of factors, such as the activity of the specific compound used, the stability of the compound's metabolism and the length of the drug's duration, patient age, weight, overall health status, Includes gender and eating and drinking, mode and time of administration, frequency of excretion, combination of drugs, severity of a particular disorder or disease, and the subject being treated. Generally, a therapeutically effective daily dosage is about 0.001 mg / Kg body weight to about 100 mg / Kg body weight, preferably 0.01 mg / Kg body weight to about 50 mg / Kg body weight, More preferred is Kg body weight to about 25 mg / Kg body weight. In particular, the parenteral dosage of the compounds of the present invention may be from about 1 mg / Kg body weight to about 100 mg / Kg body weight, and the oral dosage may be from about 1 mg / Kg body weight to about 500 mg / Kg body weight. .

The effective dosage ranges provided herein are not intended to be limiting, but merely represent preferred dosage ranges. The most preferred dosage will need to be tailored to the individual subject and can be understood and determined by one of ordinary skill in the art (eg, Berkow et al., Eds., The Merck Manual, 16 ^th edition, Merck and Co., Rahway, NJ, 1992).

  If desired, the total dose required for each treatment can be administered multiple times over the day, or can be administered in a single dose. Usually, treatment is initiated with a dosage that is less than the optimum dosage. Thereafter, the dosage is increased by small increments until the optimum effect is achieved. The diagnostic pharmaceutical compound or composition may be administered alone or in combination with other diagnostic routines and / or pharmaceuticals for pathology or other symptoms. The subject of administration of the compound and / or composition of the present invention may be any mammal, but examples of the subject of administration include primates (including humans, apes and monkeys), cloven hoofs (horses, goats, cattle, Preferred are sheep, pigs, rodents (mouse, rat, rabbit, hamster) and meats (including cats and dogs). The most preferred subject is mankind (human).

  Preparation of the compounds of the invention

  The following reaction pathway diagram illustrates a method for preparing the compounds of the present invention.

  In the following description, it should be understood that combinations of substituents and / or variables of the above molecular formula are allowed only when resulting in a stable compound.

  It should be understood by those skilled in the art that in the process described below, the functional group of the intermediate compound may need to be protected by a suitable protecting group. Such functional groups include hydroxy groups, amino groups, mercapto groups, and carboxy groups. Suitable hydroxy protecting groups include trialkylsilyl groups or diarylalkylsilyl groups (eg, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, or trimethylsilyl group), tetrahydropyranyl groups, benzyl groups, and the like. It is done. Suitable amino, amidino and guanidino protecting groups include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto protecting groups include —C (O) —R ″ (where R ″ is an alkyl group, an aryl group, or an arylalkyl group), a paramethoxybenzyl group, a trityl group, and the like. Suitable carboxy protecting groups include alkyl groups, aryl groups, or arylalkyl esters.

  Protecting groups can be added or removed based on standard techniques known to those skilled in the art.

  The use of protecting groups is described in detail in Greene's Protective Groups in Organic Synthesis (2006, 4th edition). The protecting group may be a polymer resin.

The compounds of general formula (I) according to the invention can be prepared according to the procedure shown in the pathway diagram 1.

In FIG. 1, the McMurry coupling reaction was completed in Compound II and Compound III to give ethylene derivative I. Compound II and compound III are commercially available or may be prepared by synthetic methods known to those skilled in the art.
In the following experiments, the preparation methods and related intermediates are provided as illustrations of the invention and are not intended to limit the scope of the invention.

Example 1
(Z) -4- [1- (6-Chloropyridin-3-yl) -2-phenylbut-1-enyl) phenol ((Z) -4- (l- (6-chloropyridin-3-yl) -2 -Phenylbut-l-enyl) phenol)

Step A: (6-Chloropyridin-3-yl) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone ((6-chloropyridin-3-yl) (4- (tetrahydro-2H-pyran- 2-yloxy) phenyl) methaneone)

Magnesium scrap (1.67 g, 1.2 eq) is added to anhydrous THF (50 ml). The mixture is heated to 55 ° C. and granular iodo and bromoethane are added. 2- (4-Bromophenoxy) tetrahydro-2H-pyran (16 g, 1.1 eq) is dissolved in THF. A portion of this solution is taken and added to the Mg-THF mixture. Thirty minutes after the reaction was started, refluxing was started, and after adding an excess of the above solution, the reaction solution was refluxed for 2 hours to prepare a MgBr-THF solution for use in the next step.
Under nitrogen gas protection at 0 ° C., the above MgBr-THF solution was added dropwise to an anhydrous THF solution of 6-chloronicotinoyl chloride (10.0 g, 1 equivalent) over 0 minutes, and mixed. The solution was warmed to room temperature and stirred at room temperature overnight.
Water was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated, subjected to silica gel column chromatography separation, and eluted with petroleum ether / ethyl acetate (5/1) 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 (m, 1H), 1.89-1.92 (m, 2H) ), 1.69-1.75 (m, 2H), 1.59-1.65 (m, 1H)

Step B: (Z) -4- [1- (6-Chloropyridin-3-yl) -2-phenylbut-1-enyl) phenol ((Z) -4- (1- (6-chloropyridin-3-yl) ) -2-phenylbut-1-enyl) phenol)

While stirring a dry THF (150 ml) mixture of zinc powder (8.06 g, 6 eq) under nitrogen gas protection at room temperature, TiCl ₄ (6.8 ml, 3 eq) is slowly added to it. After completion of dropping, the mixture is heated to 80 ° C. and refluxed for 1 hour. After cooling to room temperature, propiophenone (8.2 g, 3 equivalents) and (6-chloropyridin-3-yl) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone ( 6.5 g, 1 eq) of dry THF solution is added. Further, the mixture is refluxed for 2 hours. It is then quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The extract was dried and concentrated, and purified using column chromatography to obtain 6.3 g (92%, Z / E = 1/1) of Z / E mixture. The Z / E mixture was recrystallized in a mixed solution of petroleum ether and dichloromethane to give the pure Z-isomer 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-Chloropyridin-3-yl) -2-phenylbut-1-enyl) phenol ((E) -4- (1- (6-chloropyridin-3-yl) -2 -Phenylbut-1-enyl) phenol)

The Z / E mixture obtained in Step B in Example 1 was recrystallized with a methanol solution to obtain 3.0 g of the desired product (E-isomer). 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] pyridin-3-yl} -2-phenylbut-1-enyl) phenol ((Z) -4- (1- (6- (2- (methylamino) ethoxy) pyridin-3-yl) -2-phenylbut-1-enyl) phenol)

To a stirred solution of 2- (methylamino) -ethanol (672 mg, 10 eq) in anhydrous THF (20 ml) at 0 ° C. is added NaH (373 mg, 8.0 eq). The mixture was stirred at room temperature for 1 hour before (Z) -4- [1- (6-chloropyridin-3-yl) -2-phenylbut-1-enyl) phenol (300 mg, 1 equivalent, prepared in Example 1). The reaction mixture is heated to reflux for 16 hours. The mixture was cooled, quenched with a saturated aqueous ammonium chloride solution, and extracted with dichloromethane. The extract was dried and filtered, and subjected to column chromatography separation to obtain the desired product (200 mg, 60%). 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, 3H) M / z = 375 [M + 1] ⁺ .

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

Using the same method as Example 3, (E) -4- [1- (6-chloropyridin-3-yl) -2-phenylbut-1-enyl) phenol (100 mg, prepared in Example 2) The target product (53 mg, 48%) was obtained as a raw material. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.31-7.734 (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, 5H), 0.9 (t, J = 7 .2 Hz, 3H); m / z = 375 [M + 1] ⁺ .

Example 5
(Z) -4- (1- {6- [2- (dimethylamino) ethoxy] pyridin-3-yl} -2-phenylbut-1-enyl) phenol

Using the same method as in Example 3, 2- (dimethylamino) -ethanol (798 mg, 10 equivalents) and (Z) -4- [1- (6-chloropyridin-3-yl) -2-phenylbut-1 -The target product (260 mg, 75%) was obtained starting from -enyl) phenol (300 mg, 1 equivalent, prepared in Example 1). 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-oxy) pyridin-3-yl] but-1-enyl} phenol

Using the same method as in Example 3, (S) -pyrrolidin-3-ol ((S) -pyrrolidin-3-ol) (558 mg, 10 eq), and (Z) -4- [1- (6-chloro The target product (87 mg, 76%) was obtained using pyridin-3-yl) -2-phenylbut-1-enyl) phenol (100 mg, 1 equivalent, prepared in Example 1) as a raw material. 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), 2.94-3.05 (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-pyrrolidine) ethoxy] pyridin-3-yl} but-1-enyl) phenol ((Z) -4- (2-phenyl) -1- (6- (2- (pyrrolidin-1-yl) ethoxy) pyridin-3-yl) but-1-enyl) phenol)

Using the same method as in Example 3, 2- (1-pyrrolidine) ethanol (343 mg, 10 eq) and (Z) -4- [1- (6-chloropyridin-3-yl) -2-phenylbut-1 -The target product (140 mg, 95%) was obtained from the starting material (enyl) phenol (100 mg, 1 equivalent, prepared in Example 1). 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 (brs, 4H), 0.91 (t, J = 7.6) Hz, 3H); m / z = 415 [M + 1] ⁺ .

Example 8
(Z) -4- (1- {6- [2- (4-Methyl-1-piperazine) ethoxy] pyridin-3-yl} -2-phenylbut-1-enyl) phenol ((Z) -4- ( 1- (6- (2- (4-methylpiperazin-1-yl) ethyl) pyridin-3-yl) -2-phenylbut-1-enyl) phenol)

Using the same method as in Example 3, 2- (4-methyl-1-piperazine) ethanol (430 mg, 10 eq), and (Z) -4- [1- (6-chloropyridin-3-yl) -2 Using 2-phenylbut-1-enyl) phenol (100 mg, 1 equivalent, prepared in Example 1) as a starting material, the desired product (160 mg, 95%) was obtained. 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 (d, 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] pyridin-3-yl} but-1-enyl) phenol ((Z) -4- (2-phenyl) -1- (6- (2- (piperidin-1-yl) ethoxy) pyridin-3-yl) but-1-enyl) phenol)

Using the same method as Example 3, 2- (1-piperidyl) ethanol (385 mg, 10 eq) and (Z) -4- [1- (6-chloropyridin-3-yl) -2-phenylbut-1 -The target product (106 mg, 83%) was obtained from the starting material (enyl) phenol (100 mg, 1 equivalent, prepared in Example 1). 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-morpholinoethoxy) pyridin-3-yl] -2-phenylbut-1-enyl) phenol ((Z) -4- (1- (6- (2- morpholinoethoxy) pyridin-3-yl) -2-phenylbut-1-enyl) phenol)

Using the same method as Example 3, 2-morpholine ethanol (391 mg, 10 equivalents) and (Z) -4- [1- (6-chloropyridin-3-yl) -2-phenylbut-1-enyl) phenol (100 mg, 1 equivalent, prepared in Example 1) was used as a raw material to obtain the desired product (110 mg, 86%). 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
4- (1- {4- [2- (methylamino) ethoxy] phenyl} -2- (3-thiophene) but-1-enyl) phenol (4- (1- (4- (2- (Methylamino) ethoxy) ) Phenyl) -2- (thiophen-3-yl) but-1-enyl) phenol)

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

At 0 ° C., thionyl chloride (59 ml, 5.2 eq) is added to a solution of 3-thiophenecarboxylic acid (20 g, 1.0 eq) in dichloromethane. When gas evolution ceases, the mixture is refluxed at 50 ° C. for 3 hours. Thereafter, the mixture is concentrated, and the product after the concentration does not need to be further purified, and is used directly in the next step reaction.
At 0 ° C., N, O-dimethylhydroxylamine hydrochloride (16.8 g, 1.1 eq) was added to a dichloromethane solution of the concentrate (concentrated product) followed by triethylamine (44 ml, 2.0 eq). ), And the mixture is allowed to react at room temperature with stirring for 3 hours, washed with water, extracted with dichloromethane, the extract is dried, concentrated, separated by column chromatography, petroleum ether / ethyl acetate ( Elution at 5/1) gave 17.2 g (64%) of the desired 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, 3H).

Step B: 3-thiophenepropanone (1- (thiophen-3-yl) propan-1-one)

After dry addition of Grignard reagent EtMgBr (3M, 1.2 eq, 18.6 ml) to dry THF of N-methoxy-N-methylthiophene-3-carboxamide (8 g, 1.0 eq) The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with a saturated aqueous solution of ammonium chloride, dried, concentrated, separated by column chromatography, eluted with petroleum ether / ethyl acetate (5/1), 3.4 g (52%) yellow oil. The desired product was obtained. 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-thiophene) but-1-enyl} phenol

Using the common step of the McMurry reaction described in Step B of Example 1, thiophenepropanone (1- (thiophen-3-yl) propan-1-one) (0.5 g, 1.0 eq) and [4- (2-Chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (1.5 g, 1.5 eq) is reacted with 1.3 g (95%, Z / E = 1/1) of the desired product. Obtained. 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, 1H), 4.62 (s, 1H), 4 .49 (s, 1H), 4.24 (t, J = 6.0 Hz, 1H), 4.14 (t, 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, 3H) .

Step D: 4- (1- {4- [2- (Methylamino) ethoxy] phenyl} -2- (3-thiophene) but-1-enyl) phenol (4- (1- (4- (2- ( methylamino) ethyl) phenyl) -2- (thiophen-3-yl) but-1-enyl) phenol)

Stir a solution of 4- {1- [4- (2-chloroethoxy) phenyl] -2- (3-thiophene) but-1-enyl} phenol (0.3 g, 1.0 equiv) in MeOH (10 ml). While adding 10 ml of CH ₃ NH ₂ (30% aqueous solution) to it. Reflux the mixture at 80 ° C. overnight, perform column chromatography separation and elute with dichloromethane / ammonia in methanol (MeOH (NH ₃ )) (10/1) to give 185 mg (63%) of the desired product. (Z / E = 1/1) was obtained. 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-thiophene) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl) phenol ((E) -4- ( 2- (5-chlorothiophen-3-yl) -1- (4- (2- (methylamino) ethoxy) phenyl) but-1-enyl) phenol)

Step A: 5-chloro-N-methoxy-N-methylthiophene-3-carboxamide (5-chloro-N-methoxy-N-methylthiophene-3-carboxamide)

While stirring a solution of N-methoxy-N-methylthiophene-3-carboxamide (5.0 g, 1.0 eq, prepared in Example 12, Step A) in CH ₃ COOH (50 ml), N-chloro Succinimide (3.88 g, 1.0 eq) is added. The reaction mixture is refluxed at 120 ° C. for 4 hours. After quenching with water, extraction was performed with ethyl acetate, and the extract was washed with saturated brine, dried and concentrated, and subjected to column chromatography separation to obtain 3.0 g (40%) of the desired product.

Step B: 5-Chloro-3-thiophenepropanone (1- (5-chlorothiophen-3-yl) propan-1-one)

The target product was obtained using the method described in Step B of Example 11.

Step C: (E) -4- {1- [4- (2-Chloroethoxy) phenyl] -2- (5-chloro-3-thiophene) but-1-enyl} phenol

Using the common steps of the McMurry reaction described in Step B in Example 1, 5-chloro-3-thiophenepropanone (1.5 g, 1.0 eq) and [4- (2-chloroethoxy) phenyl] (4 -Hydroxyphenyl) methanone (2.0 g, 1.2 eq) was reacted to give 0.8 g (45%, E-isomer) of the desired product.

Step D: (E) -4- (2- (5-Chloro-3-thiophene) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl) phenol

Using the same method as Step D in Example 11, (E) -4- {1- [4- (2-chloroethoxy) phenyl] -2- (5-chloro-3-thiophene) but-1-enyl} Phenol (0.8 g, 1.0 eq) and MeNH ₂ (30% aqueous solution, 10 ml) in methanol (20 ml) were refluxed to give 120 mg (35%) of the desired 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} but-1-enyl) phenol (4- (2- (4-Hydroxycyclohexyl) -1- ( 4- (2- (methylamino) ethyl) phenyl) but-1-enyl) phenol)

Step A: 4-Hydroxycyclohexyl-1-propanone

To a dry THF solution of 4-hydroxy-N-methyl-N-methoxycyclohexanecarboxamide (1.0 g, 1.0 eq) at 0 ° C., Grignard reagent EtMgBr (1 M, 3.0 eq, 20 ml) was added. To do. After the addition was complete, the mixture was stirred overnight. The reaction mixture is washed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The extract was dried, concentrated, separated by column chromatography and washed with petroleum ether / EtOAc (1: 1) to give 0.6 g (72%) of the desired 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), 1.88-1.94 (m, 2H), 1.70-1.80 (m, 1H), 1.21-1.49 ( m, 4H), 1.05 (t, J = 7.2 Hz, 3H)

Step B: 4- {1- [4- (2-Chloroethoxy) phenyl] -2- (4-hydroxycyclohexyl) but-1-enyl} phenol

Using the common steps of the McMurry reaction described in Step B in Example 1, 4-hydroxycyclohexyl-1-propanone (0.6 g, 1.0 eq) and [4- (2-chloroethoxy) phenyl] (4 -Hydroxyphenyl) methanone (1.6 g, 1.5 eq) was reacted to give 0.8 g (52%, Z / E = 1/1) of cis-trans mixture. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.11-7.20 (m, 1H), 7.00-7.10 (m, 2H), 6.90-6.70 (m, 1H), 6.60-6.89 (m, 3H), 6.58 (d, 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 (m, 1H), 2.00-2.08 (M, 2H), 1.86-1.94 (m, 2H), 1.72-1.80 (m, 1H), 1.20-1.49 (m, 4H), 1.04 (t , J = 7.6 Hz, 3H)

Step C: 4- (2- (4-Hydroxycyclohexyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl) phenol

Using the same method as described in Step D in Example 11, 4- {1- [4- (2-chloroethoxy) phenyl] -2- (4-hydroxycyclohexyl) -but-1-enyl} phenol (0. 8 g, 1.0 eq) and MeNH ₂ (30% aqueous solution, 10 ml) in methanol (20 ml) were refluxed to give 20 mg (3%) of the desired 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-phenylbut-1-enyl) phenol (4- (1- (3-Bromo-4- (2- ( methylamino) ethyl) phenyl) -2-phenylbut-1-ethyl) phenol)

Step A: 3-Bromo-4- (2-bromoethyl) -methyl benzoate

While stirring 20 ml of a solution of methyl 3-bromo-4-hydroxybenzoate (5.0 g, 1.0 eq) in DMF, 1,2-dibromoethane (11 ml, 6.0 eq) and potassium carbonate (6 0.0 g, 2.0 eq.). The mixture was heated to 60 ° C., reacted for 6 hours, separated by column chromatography and eluted with petroleum ether / ethyl acetate (3: 1) to give the desired 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

While stirring a solution of 3-bromo-4- (2-bromoethyl) -benzoic acid (4.0 g, 1.0 equiv) in MeOH / H ₂ O (v / v 2: 1, 60 ml), sodium hydroxide was added thereto. (0.715 g, 1.5 eq) is added. The mixture is then refluxed for 25 minutes and concentrated in vacuo. The concentrate is poured into water and washed with ethyl acetate. 3N hydrochloric acid was added to the aqueous phase 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

While stirring a solution of 3-bromo-4- (2-bromoethyl) -benzoic acid (2.0 g, 1.0 equiv) in dichloromethane (20 ml), thionyl chloride SOCl ₂ (2.2 ml, 5.0 equiv) Add. The mixture is refluxed for 3 hours, after which benzoyl chloride is obtained by concentration by distillation and does not require further purification.
To a stirred solution of the benzoyl chloride and aluminum trichloride (1.65 g, 2.0 eq) in dichloromethane (50 ml) is added anisole (1.34 g, 2.0 eq). The mixture was stirred at room temperature overnight, subjected to column chromatography separation, eluting with petroleum ether / EtOAc (3: 1) to give 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: [3-Bromo-4- (2-bromoethyl) phenyl] (4-hydroxyphenyl) methanone

To a solution of [3-bromo-4- (2-bromoethyl) phenyl] (4-methoxyphenyl) methanone (0.6 g, 1.0 eq) in dichloromethane (50 ml) was added tribromoborane (0.4 ml, 3.0 ml). Equivalent). When the addition is complete, the reaction mixture is stirred at room temperature overnight, concentrated, subjected to column chromatography separation and eluted with petroleum ether / EtOAc (2: 1) to give the desired product (0.36 g, 62%). Got. 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-phenylbut-1-enyl} phenol

Using the common steps of the McMurry reaction described in Step B in Example 1, acetophenone (0.2 g, 3.0 eq) and [3-bromo-4- (2-bromoethyl) phenyl] (4-hydroxyphenyl) Reaction with methanone (0.2 g, 1.0 equivalent) gave 0.09 g (36%, Z / E = 1/1) of the desired 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: 4- (1- {3-Bromo-4- [2- (methylamino) ethoxy] phenyl} -2-phenylbut-1-enyl) phenol

Using the same method as in Step D in Example 11, 4- {1- [3-bromo-4- (2-bromoethyl) phenyl] -2-phenylbut-1-enyl group} phenol (0.09 g, 1.0 Eq.) And MeNH ₂ (30% aqueous solution, 10 ml) in methanol (20 ml) were refluxed to give 73 mg of the desired product (90%, Z / E = 1/1). 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-phenylbut-1-enyl) phenol

Stir 5 ml of a DMF solution of 4- (1- {3-bromo-4- [2- (methylamino) ethoxy] phenyl} -2-phenylbut-1-enyl) phenol (150 mg, 1.0 eq) at room temperature. While adding cuprous cyanide (36 mg, 1.2 eq) to it. The mixture is heated to 120 ° C. and stirred overnight, the reaction mixture is poured into water and the mixture formed is extracted with ethyl acetate, and the extracts are washed with water and saturated brine respectively, dried and concentrated. Column chromatography separation and elution with dichloromethane / ammonia in methanol (1: 1) to give the desired product (10 mg, 6%, Z / E = 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] ⁺ .

Example 16
(S) -4- {2-phenyl-1- [4- (2-pyrrolidinylmethoxy) phenyl] but-1-enyl} phenol

Step A: (S) -2-pyrrolidinylmethanol ((S) -pyrrolidin-2-ylethanol)

At 0 ° C., lithium aluminum hydride (6 g, 1.6 eq) is added very slowly to 250 ml of anhydrous tetrahydrofuran solution of (S) -pyrrolidine-2-carboxylic acid (11.5 g, 1.0 eq). . The reaction mixture is stirred for 1 hour at 0 ° C. and slowly quenched with 6 ml of water at 0 ° C. After adding 6 ml of 10% aqueous sodium hydroxide solution, the suspension is filtered and washed with ethyl acetate. The filtrate was dried and concentrated, and the concentrate was distilled under reduced pressure and purified to give 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-carboxylate ((S) -tert-butyl 2- (hydroxymethyl) pyrrolidine-1-carboxylate)

While stirring 100 ml of tetrahydrofuran (S) -2-pyrrolidinylmethanol (3 g, 1.0 eq) at 0 ° C., (Boc) ₂ O (7.1 g, 1.1 eq) was added to it. Added. After adding 100 ml of an aqueous solution of NaHCO ₃ (5 g, 2.0 eq), the reaction mixture was stirred at room temperature overnight. Thereafter, water is added to the mixture and extracted with ethyl acetate. The extract was dried and concentrated and subjected to column chromatography separation to obtain the desired product (5.7 g, 95%). 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: 4- [1- (4-Hydroxyphenyl) -2-phenylbut-1-enyl] phenol

Using the common steps of the McMurry reaction described in Step B in Example 1, propiophenone (1.9 g, 3.0 eq) and bis (4-hydroxyphenyl) methanone (1.0 g, 1.0 eq) And 1.3 g of the desired product (88%) was obtained.

Step D: (S) tert-butyl-2-({4- [1- (4-hydroxyphenyl) -2-phenylbut-1-enyl] phenoxyl} methyl) pyrrolidine-1-carboxylate

Under nitrogen gas protection at 0 ° C., 4- [1- (4-hydroxyphenyl) -2-phenylbut-1-enyl] phenol (500 mg, 1.0 equivalent), (S) tert-butyl-2- ( Hydroxymethyl) pyrrolidine 1-carboxylate (480 mg, 1.5 eq) and triphenylphosphine (625 mg, 1.5 eq) in anhydrous tetrahydrofuran were stirred and added to diisopropyl azodicarboxylate (480 mg, 1.5 eq). Equivalent). The reaction mixture is stirred for 48 hours. The mixture is quenched with water and extracted with ethyl acetate. The extract was dried, concentrated, and subjected to column chromatography separation to obtain the desired product (400 mg, 51%).

Step E: (S) -4- {2-Phenyl-1- [4- (2-pyrrolidinylmethoxy) phenyl] but-1-enyl} phenol

At 0 ° C., (S) tert-butyl-2-({4- [1- (4-hydroxyphenyl) -2-phenylbut-1-enyl] phenoxyl} methyl) pyrrolidine-1-carboxylate (400 mg, 1 0.02) in dichloromethane, with stirring, add 1 ml of trifluoroacetic acid, stir at room temperature for 3 hours, quench the reaction with saturated aqueous sodium bicarbonate and extract with dichloromethane. The extract was dried and concentrated, and subjected to column chromatography separation to obtain the desired product (210 mg, 68%). 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, 1H), 3.96-4.00 (m, 0.5H) , 3.89-3.93 (m, 0.5H), 3.82-3.85 (m, 0.5H), 3.73-3.77 (m, 0.5H), 3.53- 3.59 (m, 0.5 H), 3.43-3.49 (m, 0.5 H), 2.90-3.11 (m, 2H), 2.44-2.51 (m, 2H), .77-1.99 (m, 3H), 1.52-1.66 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H); m / z = 400 [M + 1] + .

Example 17
(R) -4- {2-Phenyl-1- [4- (pyrrolidin-3-yloxy) phenyl] but-1-enyl} phenol

Using the same method as steps D and E in Example 16, using 4- [1- (4-hydroxyphenyl) -2-phenylbut-1-enyl] phenol (150 mg, 0.474 mmol) and (S) tert-butyl. Reaction with -3-hydroxypyrrolidine-1-carboxylate (107 mg, 0.571 mmol) followed by Boc deprotection with TFA / dichloromethane yields the desired product (36 mg, 20%, Z / E = 1/1) Got. m / z = 386 [M + 1] ⁺ .

Example 18
4- {2-Phenyl-1- [4- (pyrrolidin-3-yloxy) phenyl] but-1-enyl} phenol

Step A: tert-Butyl 3- (mesyloxy) pyrrolidine-1-carboxylate

While stirring a solution of tert-butyl-3-hydroxypyrrolidine-1-carboxylate (16 g, 85.4 mmol) and triethylamine (19 ml, 129 mmol) in dichloromethane (130 ml) at 0 ° C., it was added to methanesulfonyl chloride (10 ml, 129 mmol). 20 ml of dichloromethane solution) is added. When the addition is complete, the reaction is stirred at room temperature for 2.5 hours, then quenched with saturated aqueous NaHCO ₃ and extracted with dichloromethane. The extract was dried and concentrated to obtain the desired product (22.7 g, 100%) as a yellow solid.

Step B: tert-Butyl-3- [4- (4-hydroxybenzoyl) phenoxyl] pyrrolidine-1-carboxylate

tert-Butyl-3- (mesyloxy) pyrrolidine-1-carboxylate (0.6 g, 2.26 mmol), 4,4′-dihydroxybenzophenone 1,2-dibromoethane (2.15 g, 10.0 mmol) and anhydrous A mixture of K ₂ CO ₃ (313 mg, 2.26 mmol) in DMF (12 ml) is stirred at 100 ° C. for 3.5 hours, quenched with additional water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated. The concentrate is added to dichloromethane to precipitate a large amount of white solid, the solid is filtered, the filtrate is concentrated under reduced pressure, and the concentrate is separated by column chromatography. And eluted with petroleum ether / dichloromethane / propanone (4/2/1) to obtain the desired product (400 mg, 46%).

Step C: 4- {2-Phenyl-1- [4- (pyrrolidin-3-yloxy) phenyl] but-1-enyl} phenol

Using the general procedure for the McMurry reaction described in Step B in Example 1, tert-butyl 3- [4- (4-hydroxybenzoyl) phenoxyl] pyrrolidine-1-carboxylate (395 mg, 1.03 mmol), Reaction with propiophenone (276 mg, 2.06 mmol) gave 340 mg of the desired product (86%, Z / E = 1/1) as a pale yellow solid. m / z = 386 [M + 1] ⁺ .

Example 19
4- [1- (4-Hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} -2-but-1-enyl] -2-anisolephenol

Step A: 2-methoxyphenyl propionate

While stirring a mixed solution of 2-methoxyphenol (4.4 g, 35.4 mmol) and triethylamine (6.2 ml, 42.3 mmol) in dichloromethane (20 ml) at 0 ° C., propionic acid chloride (3.3 g, 35 .7 mmol) is added. When the addition is complete, the reaction is stirred for 5 hours at room temperature, then quenched with saturated aqueous NaHCO ₃ and extracted with dichloromethane. The extract was dried and concentrated in vacuo to give the desired product (6.0 g, 94%) as a yellow solid.

Step B: 4-propionyl-2-methoxyphenol

At 100 ° C., anhydrous aluminum trichloride (3.0 g, 22.5 mmol) is dissolved in anhydrous nitrobenzene (10 ml). After cooling the reaction, 2-methoxyphenylpropionate (2.0 g, 11.1 mmol) is added rapidly. The mixture is heated at 60 ° C. for 1.5 hours and after cooling, 3N aqueous NaOH is added and stirred for 15 minutes. The suspension is filtered and washed with water. The filtrate is washed twice with dichloromethane, then acidified with 3N aqueous hydrochloric acid and extracted again with dichloromethane. The extract was dried, concentrated, separated by column chromatography, and eluted with petroleum ether / ethyl acetate (10/1 to 5/1) to give the desired product (874 mg, 44%) as a yellow oil. .

Step C: 4- {1- [4- (2-Chloroethoxy) phenyl] -1- (4-hydroxyphenyl) -2-but-1-enyl} -2-methoxyphenol

Using a common step of the McMurry reaction described in Step B in Example 1, [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (318 mg, 1.15 mmol) and 4-propionyl-2- Reaction with methoxyphenol (207 mg, 1.15 mmol) gave the desired product (188 mg, 38.5%).

Step D: 4- [1- (4-Hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} -2-but-1-enyl] -2-methoxyphenol

4- {1- [4- (2-chloroethoxy) phenyl] -1- (4-hydroxyphenyl) -2-but-1-enyl} -2-methoxyphenol (88 mg, impurity) in MeOH (10 ml) While stirring, 2 ml of methylamino aqueous solution is added thereto. The mixture was heated to 85 ° C. and then stirred for 24 hours, distilled under reduced pressure to remove the solvent, EtOAc was added, the mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered, The filtrate is concentrated under reduced pressure. The concentrate is subjected to column chromatography separation and eluted with dichloromethane / ammonia methanol solution (10/1) to obtain the desired product (42 mg, 48%, Z / E = 1/1) as a white solid. It was. m / z = 420 [M + 1] ⁺ .

Example 20
4- {1- [4-((1-Methyl-pyrrolidin-2-yl) methoxy) phenyl] -2-phenylbut-1-enyl} phenol

Using the same method as in Step D in Example 16, 4,4 ′-(2-phenylbut-1-ene-1,1-diyl) diphenol ((4,4 ′-(2-phenylbut-1-ene- 1,1-diyl) diphenol) (220 mg, 0.473 mmol), and 1-methyl-2-pyrrolidinylmethanol (82 mg, 0.712 mmol) (literature Arch. Pharn. Pharm. Med. Chem. 1996, 329). , 95-104, prepared from DL-proline) to give 65 mg of the desired product (33%), m / z = 414 [M + 1] ⁺ .

Example 21
4- (1- {3-Fluoro-4- [2- (methylamino) ethoxy] phenyl} -2-phenylbut-1-enyl) phenol

Step A: 3-Fluoro-4-methoxybenzonitrile (4-Methoxybenzonitrile)

4-Bromo-2-fluoro-1-methoxybenzene (30.0 g, 146 mmol) and CuCN (15.6 g, 174 mmol) in a DMF (45 ml) mixed solution of 120 were added. Stir overnight at ° C. The reaction mixture is cooled to room temperature, then diluted with water and extracted with ethyl acetate. The extracts were each washed with water and saturated brine, dried and concentrated to obtain 20.0 g (91%) of the desired 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 is refluxed for 3 days under nitrogen gas protection. Ice water is added to quench and the mixture is extracted with dichloromethane. The organic phase is washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Concentration in vacuo gave 13.3 g of the desired product (94%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.42 (m, 2H), 7.09 (dd, J = 8.8 & 8.4 Hz, 1H), 5.68 (s, 1H).

Step C: 4- (2-Bromoethoxy) -3-fluorobenzonitrile

Under nitrogen gas protection, 3-fluoro-4-hydroxybenzonitrile (1.2 g, 8.76 mmol), anhydrous K ₂ CO ₃ (2.43 g, 17.6 mmol), and 1,2-dibromoethane (4 0.5 ml, 52.0 mmol) in DMF (6 ml) was stirred at 60 ° C. overnight. The reaction solution was filtered, and the filtrate was extracted with ethyl acetate. The extracts are each washed with water and saturated saline and dried over anhydrous sodium sulfate. Concentration under reduced pressure, silica gel column chromatography separation, and elution with petroleum ether / ethyl acetate (5/1) gave 1.52 g (71%) of the 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: 4- (2-Bromoethoxy) -3-fluorobenzoic acid

A mixture of 4- (2-bromoethoxy) -3-fluorobenzonitrile (3.78 g, 15.5 mmol) in water (18 ml) and concentrated sulfuric acid (18 ml) is heated at 110 ° C. for 12 hours. The reaction is cooled to room temperature and then neutralized with solid sodium bicarbonate. Thereafter, glacial acetic acid is added to acidify, the precipitated white solid is filtered and dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to give a product (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 & 8.4 Hz, 1H), 4.48 (t, J = 5.2 Hz, 2H), 3.85 (t, J = 5. 2 Hz, 2H).

Step E: 4- (2-Bromoethoxy) -3-fluorobenzoic acid chloride

A reaction solution of 4- (2-bromoethoxy) -3-fluorobenzoic acid (1.08 g, 4.1 mmol) and thionyl chloride (10 ml) is refluxed for 7 hours. To the excess thionyl chloride, toluene was added and dried together under reduced pressure, and 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: [4- (2-Bromoethoxy) -3-fluorobenzene] (4-methoxyphenyl) methanone

To a dry dichloromethane (18 ml) solution of 4- (2-bromoethoxy) -3-fluorobenzoic acid chloride (1.07 g, 3.80 mmol) and anhydrous AlCl ₃ (1.01 g, 7.60 mmol) at 0 ° C. Add a solution of anisole (822 mg, 7.60 mmol) in dichloromethane (2 ml). After stirring for 6 hours at room temperature, the reaction mixture is poured into 3N hydrochloric acid and extracted twice with dichloromethane. The extracts were combined, washed with a saturated aqueous NaHCO ₃ solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, subjected to silica gel column chromatography separation, and petroleum ether / ethyl acetate (10/1 To give 1.05 g (77%) of the 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: [4- (2-Bromoethoxy) -3-fluorobenzene] (4-hydroxyphenyl) methanone

At 0 ° C., BBr ₃ (0.5 ml, 5.29 mmol) was added to [4- (2-bromoethoxy) -3-fluorobenzene] (4-methoxyphenyl) methanone (930 mg, 2.63 mmol) in dichloromethane (6 ml). ) Add to solution. After stirring for 2 hours at room temperature under nitrogen gas protection, ice water is added to quench, and the mixture is extracted with dichloromethane and filtered to remove the white suspension. The organic phase is washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, separated by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (2/1 by 5/1) to give 536 mg (60%) of the 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: 4- {1- [4- (2-Bromoethoxy) -3-fluorobenzene] -2-phenylbut-1-enyl} phenol

Using the general procedure for the McMurry reaction described in Step B in Example 1, [4- (2-bromoethoxy) -3-fluorobenzene] (4-hydroxyphenyl) methanone (311 mg, 0.917 mmol) and propio Reaction with phenone (246 mg, 1.83 mmol) gave 403 mg (99.6%, Z / E = 1/1) of the desired product as a pale yellow liquid.

Step I: 4- (1- {3-Fluoro-4- [2- (methylamino) ethoxy] phenyl} -2-phenylbut-1-enyl) phenol

While stirring a solution of 4- {1- [4- (2-bromoethoxy) -3-fluorobenzene] -2-phenylbut-1-enyl} phenol (111 mg, 0.25 mmol) in MeOH (5 ml), 1 ml of an aqueous amino acid solution (30%) was added, heated to 85 ° 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, subjected to column chromatography separation, and eluted with dichloromethane / ammonia methanol solution (10/1). The desired product (56 mg, 57%, Z / E = 1/1) was obtained as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.08-7.11 (m, 5H), 7.03 sum 6.77 (d, J = 8.6 Hz, 2H), 6.91-6. 96 (m, 1H), 6.76 sum 6.44 (d, J = 8.4 Hz, 2H), 6.51-6.58 (m, 2H), 4.17 sum 4.01 (t, J = 5.0 Hz, 2H), 3.03 sum 2.93 (t, J = 5.0 Hz, 2H), 2.55 sum 2.48 (s, 3H), 2.47 (q, J = 7.6 Hz, 2H), 0.91 (t, J = 7.6 Hz, 3H); m / z = 392 [M + 1] ⁺ .

Example 22
(Z) -2-Fluoro-4- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} -2-but-1-enyl] phenol

Step A: 1- (3-Fluoro-4-methoxyphenyl) propan-1-one (1- (3-fluoro-4-methoxyphenyl) propan-1-one)

At 0 ° C., ethylmagnesium bromide (1 M ethyl ether solution, 4.63 ml) is added to a solution of 3-fluoro-4-methoxybenzonitrile (350 mg, 2.32 mmol) in anhydrous THF (15 ml). Stir at room temperature overnight, then quench with saturated aqueous NaHCO ₃ , extract with ethyl acetate, wash with brine, dry concentrate. The concentrate was subjected to column chromatography separation and eluted with petroleum ether / ethyl acetate (5/1) to give the desired product (239 mg, 57%) as a yellow solid.

Step B: 1- (3-Fluoro-4-hydroxyphenyl) propan-1-one (1- (3-fluoro-4-hydroxyphenyl) propan-1-one)

1- (3-Fluoro-4-methoxyphenyl) propan-1-one (421 mg, 2.31 mmol) is dissolved in 20 ml of 40% HBr solution and refluxed for 1 hour. Neutralize with solid sodium carbonate at 0 ° C. and then extract with ethyl acetate. The extract was washed with saturated brine, dried, concentrated, subjected to silica gel column chromatography separation and eluted with petroleum ether / ethyl acetate (5/1) to give the product (257 mg, 66%) as a yellow solid. )

Step C: 4- {1- [4- (2-Chloroethoxy) phenyl] -1- (4-hydroxyphenyl) -2-but-1-enyl} -2-fluorophenol

Using the common steps of the McMurry reaction described in Step B in Example 1, [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (629 mg, 2.27 mmol) and 1- (3-fluoro -4-hydroxyphenyl) propan-1-one (1- (3-fluoro-4-hydroxyphenyl) propan-1-one) (255 mg, 1.52 mmol) was reacted with 549 mg of the desired product (88%). Obtained.

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

4- {1- [4- (2-chloroethoxy) phenyl] -1- (4-hydroxyphenyl) -2-but-1-enyl} -2-fluorophenol (310 mg, 0.75 mmol) in MeOH (10 ml ) Add 2 ml of aqueous methylamino solution (30%) to the solution. The mixture is heated to 85 ° C., stirred for 13 hours and extracted with EtOAc. The extract was washed with water and saturated brine, dried over sodium sulfate, filtered, concentrated, subjected to column chromatography separation, and eluted with a dichloromethane / ammonia methanol solution (10/1). -The isomer product (39 mg, white solid) and the E-isomer product (14 mg, sepia crystals) were obtained. m / z = 408 [M + 1] ⁺ .

Example 23
(E) -2-Fluoro-4- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} -2-but-1-enyl] phenol

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

Example 24
2-Fluoro-4- (1- {4- [2- (methylamino) ethoxy] phenyl} -2-phenylbut-1-enyl) 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 concentrated sulfuric acid (5 ml) is heated at 110 ° C. for 4 hours. The reaction is cooled to room temperature and then neutralized with solid sodium carbonate. Thereafter, the mixture is acidified by adding glacial acetic acid, and the precipitated white solid is filtered and dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a product (2 0.03 g, 90%).

Step B: 3-Fluoro-4-methoxybenzoic acid chloride

A mixture of 3-fluoro-4-methoxybenzoic acid (830 mg, 4.88 mmol) and thionyl chloride (10 ml) is refluxed for 2 hours. Toluene is added to the excess thionyl chloride and dried under reduced pressure. Such an operation is repeated several times to obtain the title compound as a brown solid, which is directly used for the next step reaction.

Step C: [4- (2-Chloroethoxy) phenyl] (3-fluoro-4-methoxyphenyl) methanone

To a solution of 3-fluoro-4-methoxybenzoic acid chloride prepared in the above step and anhydrous AlCl ₃ (1.30 g, 9.76 mmol) at 0 ° C. in dichloromethane (18 ml), (2-chloroethoxy) benzene was added. A solution of (1.53 g, 9.76 mmol) in dichloromethane (2 ml) is added. After stirring at room temperature for 25 minutes, the reaction solution is poured into a 3N hydrochloric acid solution. Extract with dichloromethane, wash the extract with saturated aqueous NaHCO ₃ and saturated brine, dry over sodium sulfate, filter and concentrate to give the title compound, which is used directly in the next step reaction.

Step D: [4- (2-Chloroethoxy) phenyl] (3-fluoro-4-hydroxyphenyl) methanone

[4- (2-Chloroethoxy) phenyl] (3-fluoro-4-methoxyphenyl) methanone prepared in the above step was dissolved in 20 ml of 40% HBr solution, refluxed for 1 hour, and solid at 0 ° C. Neutralize with sodium carbonate and extract with ethyl acetate. The extract is washed with saturated brine, dried and concentrated, subjected to silica gel column chromatography separation, and eluted with petroleum ether / ethyl acetate (5/1 to 2/1) to give the title as a pale yellow solid The compound (731 mg, yield of 3 steps 51%) was obtained.

Step E: 4- {1- [4- (2-Chloroethoxy) phenyl] -2-phenylbut-1-enyl} -2-fluorophenol

Using the general procedure for the McMurry reaction described in Step B in Example 1, [4- (2-chloroethoxy) phenyl] (3-fluoro-4-hydroxyphenyl) methanone (350 mg, 1.19 mmol) and pro Reaction with piophenone (319 mg, 2.38 mmol) gave the desired product (quantitative) as a yellow solid.

Step F: 2-Fluoro-4- (1- {4- [2- (methylamino) ethoxy] phenyl} -2-phenylbut-1-enyl) phenol

While stirring a solution of 4- {1- [4- (2-chloroethoxy) phenyl] -2-phenylbut-1-enyl} -2-fluorophenol in MeOH (5 ml), 2 ml of an aqueous methylamino solution (30%) was added thereto. Was added and heated to 85 ° C. 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, subjected to column chromatography separation, and dichloromethane / ammonia methanol solution (10/1). Elution gave the desired product (59%, Z / E = 1/1) as a white solid. m / z = 392 [M + 1] ⁺ .

Example 25
(Z) -4- (1- {5- [2- (dimethylamino) ethoxy] pyrimidin-2-yl} -2-phenylbut-1-enyl) phenol hydrochloride

Step A: (5-Bromopyrimidin-2-yl) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone

Using the general-purpose Grignard reaction method described in Step A in Example 1, 2- (4-bromophenoxy) tetrahydro-2H-pyran (2.57 g, 10 mmol) and 2-cyano-5-bromopyrimidine (0.92 g) 5 mmol) to give 910 mg of the desired product (50%).

Step B: [4- (Tetrahydro-2H-pyran-2-oxy) phenyl] (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2- Il) Methanone

(5-Bromopyrimidin-2-yl) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone (363 mg, 1 mmol) and 4,4,4 ′, 4 ′, 5,5,5 ′ , 5′-octamethyl-2,2′-bi [1,3,2-dioxaborolane] (4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxabololane)) (508 mg, 2 mmol), PdCl ₂ (DPPF) (73.1 mg, 0.1 mmol) and KOAc (200 mg, 2 mmol) in dioxane (30 ml) at 95 ° C. After heating for hours, it was cooled to room temperature. The reaction mixture was concentrated and subjected to column chromatography separation to give the desired product (329 mg, 80%) as a yellow oil.

Step C: (5-Hydroxypyrimidin-2-yl) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone

[4- (Tetrahydro-2H-pyran-2-oxy) phenyl] (5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-yl) methanone 33% H ₂ O ₂ (0.5 ml) was added to a solution of (410 mg, 1 mmol) in THF (20 ml) and the reaction was stirred at room temperature for 1 hour. The reaction was quenched by adding sodium sulfite solution, extracted with ethyl acetate, washed with water and saturated brine, dried, filtered, concentrated and subjected to column chromatography separation to obtain the desired product (240 mg, 80%).

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

(5-Hydroxypyrimidin-2-yl) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone (300 mg, 1 mmol), 2- (dimethylamino) enol (180 mg, 2 mmol) and PPh ₃ (524 mg 2 mmol) in THF (50 ml) was added dropwise DIAD (404 mg, 2 mmol) and then stirred at room temperature overnight. The mixture was concentrated and flash chromatographic separation was performed to give the product (297 mg, 80%).

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

{5- [2- (Dimethylamino) ethoxy] pyrimidin-2-yl} [4- (tetrahydro-2H-pyran-2-oxy) phenyl using the generic step of the McMurry reaction described in Step B in Example 1 Methanone (753 mg, 2 mmol) was reacted with propiophenone (800 mg, 6 mmol) to give a Z / E mixture. This mixture was subjected to HPLC separation to obtain Z-isomer and E-isomer products, respectively. The Z-isomer compound was concentrated in 3N HCl in methanol to give 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] ⁺ .

Example 26
(E) -4- (1- {5- [2- (dimethylamino) ethoxy] pyrimidin-2-yl} -2-phenylbut-1-enyl) phenol hydrochloride

The title compound (16 mg) was obtained using the same method as Step E in Example 25. 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), 02 (s, 6H), 2.32 (q, J = 7.2 Hz, 2H), 0.90 (t, J = 7.2 Hz, 3H); m / z = 426 [M + 1] ⁺ .

Example 27
4- (1- {5- [2- (Dimethylamino) ethoxy] pyridin-2-yl} -2-phenylbut-1-enyl) phenol

Step A: 5-Hydroxy-N-methoxy-N-methylpicolinamide (5-hydroxy-N-methoxy-N-methylpicolinamide)

While stirring at room temperature, a suspension of 5-hydroxypicolinic acid (1.0 eq), HATU (1.2 eq) and N-methoxymethanamine hydrochloride (1.2 eq) in dry DMF was added to DIEA ( 2.5 equivalents) is added dropwise. The reaction is then stirred overnight at room temperature. After adding water, it was extracted with dichloromethane. The extract was dried and concentrated, and subjected to column chromatography separation to obtain the desired product (87%).

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

5-hydroxy-N-methoxy-N-methylpicolinamide (1.0 eq), 2- (dimethylamino) ethanol (1.2 eq), and PPh ₃ (1. at 0 ° C. under nitrogen gas protection). 2 equivalents) in anhydrous THF (5 ml) is reacted dropwise with DIAD (1.2 equivalents). Stir at room temperature overnight, then add water to quench and extract with ethyl acetate. The extract was dried and concentrated and subjected to column chromatography separation to obtain the desired product (40%).

Step C: {5- [2- (Dimethylamino) ethoxy] pyridin-2-yl} [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone

A butyllithium / n-hexane solution (1.1 eq) was added dropwise to a THF solution of 2- (4-iodophenoxy) tetrahydro-2H-pyran (1.1 eq) under nitrogen gas protection at −78 ° C. To do. The reaction solution was reacted at this temperature for 20 minutes, and then 5- [2- (dimethylamino) ethoxy] -N-methoxy-N-methylpicolinamide (1.0 equivalent) in THF at a temperature of −78 ° C. Add the solution. After 2 hours, add isopropanol and water and stir at room temperature for 20 minutes. Extract the reaction with ethyl acetate. The extract was washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography separation to give the title compound (47%) Got.

Step D: 4- (1- {5- [2- (Dimethylamino) ethoxy] pyridin-2-yl} -2-phenylbut-1-enyl) phenol

{5- [2- (Dimethylamino) ethoxy] pyridin-2-yl} [4- (tetrahydro-2H-pyran-2-oxy) phenyl using the general procedure for the McMurry reaction described in Step B in Example 1 Methanone (1 equivalent) and propiophenone (2 equivalents) were reacted to obtain the desired product (Z / E = 1/1). m / z = 389 [M + 1] ⁺ .

Example 28
4- (1- {6- [3- (Dimethylamino) propyl] pyridin-3-yl} -2-phenylbut-1-enyl) phenol hydrochloride

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

While stirring at 0 ° C., (4-methoxyphenyl) magnesium bromide (15 mmol) is added dropwise to a solution of 2-chloro-5-cyanopyridine (1.39 g, 10 mmol) in THF (100 ml). The reaction solution was continuously stirred at 0 ° C. for 1 hour, after which 50 ml of saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over Na ₂ SO ₄ , Filtration, concentration and flash chromatography separation gave the product (1.24 g, 50%).

Step B: {6- [3- (Dimethylamino) prop-1-ynyl] pyridin-3-yl} (4-methoxyphenyl) methanone

A 25 ml Schlenk flask was charged with (6-chloropyridin-3-yl) (4-methoxyphenyl) 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) are added, flushed with argon gas three times, and the mixture is stirred at 80 ° C. for 24 hours. Let react for hours. Concentrated under reduced pressure and the concentrate was subjected to column chromatography separation to give the product (118 mg, 80%).

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

In a flask, {6- [3- (dimethylamino) prop-1-ynyl] pyridin-3-yl} (4-methoxyphenyl) methanone (294 mg, 1 eq), Raney nickel (0.2 eq), and Add 20 ml of methanol. The mixture is stirred for 2 hours in 1 atmosphere of hydrogen gas at room temperature. The catalyst is removed by filtration through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the product (284 mg, 95%).

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

At room temperature, 10 ml of a solution of 48% HBr is added to 10 ml of methanol solution of {6- [3- (dimethylamino) propyl] pyridin-3-yl} (4-methoxyphenyl) methanone (298 mg, 1 mmol), Reflux for 3 hours and cool. Spin dry to obtain the crude product that does not need further purification and is used directly in the next step reaction (284 mg, 100%).

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

Using the general procedure for the McMurry reaction described in Step B in Example 1, {6- [3- (dimethylamino) propyl] pyridin-3-yl} (4-hydroxyphenyl) methanone (568 mg, 2 mmol) and pro Reaction with piophenone (800 mg, 6 mmol) gave the desired product (55 mg, 7%, Z / E = 1/1). m / z = 423 [M + 1] ⁺ .

Example 29
6- (1- {4- [2- (Methylamino) ethoxy] phenyl} -2-phenylbut-1-enyl) pyridin-3-ol

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

Stir a THF mixture of tert-butyl 2-ethoxymethylcarbamate (1.5 eq), 4-bromophenol (1.0 eq) and PPh ₃ (1.5 eq) with protection under nitrogen gas at 0 ° C. While adding DIAD (1.5 equivalents) dropwise. The reaction is stirred at room temperature for 48 hours, quenched with water and extracted with EtOAc. The extract was dried and concentrated, and subjected to column chromatography separation to obtain the desired product.

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

Magnesium waste (3.5 equivalents) is placed in a three-necked flask charged with anhydrous THF (50 ml), the mixture is heated to 55 ° C., 2 tablets of iodine are added, followed by 0.1 ml of bromoethane. tert-Butyl 2- (4-bromophenoxy) ethyl (methyl) carbamate (3.0 eq) is dissolved in 30 ml of anhydrous THF, and 3 ml of this solution is added to the mixed solution of Mg-THF. Initiate reaction after 30 minutes and begin to reflux. Excess tert-butyl 2- (4-bromophenoxy) ethyl (methyl) carbamate solution is dropped into the mixed solution, and the dropping rate is preferably a rate at which the reaction solution can be maintained in a reflux state. After completion of the dropping, the reaction solution was refluxed for 2 hours and then cooled to room temperature. At room temperature, a solution of 5-hydroxy-N-methoxy-N-methylpicolinamide (1.0 equivalent) in THF (20 ml) was added dropwise, and then stirred at room temperature for 30 minutes, followed by addition of saturated aqueous ammonium chloride and quenching. And extract with ethyl acetate. The extract was dried and concentrated, and subjected to column chromatography separation to obtain the desired product.

Step C: 6- (1- {4- [2- (Methylamino) ethoxy] phenyl} -2-phenylbut-1-enyl) pyridin-3-ol

Using the general procedure for the McMurry reaction described in Step B in Example 1, tert-butyl 2- [4- (5-hydroxypyridine-2-carbonyl) phenoxyl] ethyl (methyl) carbamate (1.0 eq) and , Propiophenone (3.0 equivalents) was reacted to obtain the desired product. m / z = 375 [M + 1] ⁺ .

Example 30
4- (2-Phenyl-1- {6- [3- (pyrrolidin-1-yl) propyl] pyridin-3-yl} but-1-enyl) phenol

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

4-Iodophenol (10.0 g, 45.5 mmol) is dissolved in 20 ml of 3,4-dihydro-2H-pyran, 1 drop of concentrated sulfuric acid is added, the mixture is stirred for 30 minutes, and then 1000 ml of n-hexane. , Filtered, washed with 300 ml (100 ml × 3) of hexane, and the solid obtained by filtration was vacuum-dried to obtain 9.1 g (65.9%) of the desired 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 solution of 6-chloronicotinic acid (10.0 g, 63.5 mmol) in THF (100 ml), and the reaction was stirred at room temperature for 1 hour and concentrated. Dissolve the concentrate in 50 ml dichloromethane. This 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) and stirred at room temperature for 1 hour. Concentration and column chromatography separation gave the desired product (9.4 g, 73.8%) as a colorless oil.

Step C: N-propargylpyrrolidine (1- (prop-2-ynyl) pyrrolidine)

At −10 ° C., propargyl bromide (60.5 g, 0.50 mol) is gradually added dropwise to 70.1 g (1.0 mol) of pyrrolidine. When the addition was completed, the reaction solution was stirred overnight at room temperature and distilled in a rectifying column to obtain the desired product (45.5 g, 83.5%) as a colorless oil.

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

Under nitrogen gas protection, 2- (4-iodophenoxy) tetrahydro-2H-pyran (18.2 g, 59.9 mmol) was dissolved in THF (100 ml) and further cooled to −78 ° C. A butyllithium hexane solution (1.1 equivalent) is added dropwise. When the addition was completed, the reaction solution was stirred at −78 ° C. for 0.5 hour, and 2-chloro-N-methoxy-N-methyl-5-pyridinecarboxamide (8.0 g, 39.9 mmol) in THF (50 ml). The solution is added dropwise and at the same time the temperature is maintained at −78 ° C. for 2 hours. Add 100 ml of saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate. The extract was dried, concentrated and subjected to column chromatography separation to obtain the target product (8.4 g, 66.3%) as a yellow solid.

Step E: {6- [3- (Pyrrolidin-1-yl) prop-1-ynyl] pyridin-3-yl} [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone

To a 100 ml Schlenk flask, (6-chloropyridin-3-yl) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone (4.0 g, 12.6 mmol), tetrakis (tri triphenylphosphine) palladium (1.5g, 1.3mmol), CuI ( 0.48g, 2.5mmol), Et 3 N (50ml), and N- propynyl pyrrolidine (2.8 g, 25.2 mmol) were charged, then And flushed with nitrogen gas three times. The mixture is stirred at 80 ° C. for 2 hours. After concentration under reduced pressure, the concentrate was subjected to column chromatography separation to obtain the desired product (2.2 g, 44.9%) as a yellow solid.

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

At room temperature, Raney nickel (0.3 g, 0.6 mmol) was added to {6- [3- (pyrrolidin-1-yl) prop-1-ynyl] pyridin-3-yl} [4- (tetrahydro-2H-pyran- 2-Oxy) phenyl] methanone (2.2 g, 5.6 mmol) is added to a 20 ml methanol solution and the mixture is stirred for 1 hour in an atmosphere of hydrogen gas. Nickel was removed by filtration through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the desired product (1.7 g, 77.3%) as a yellow solid.

Step G: 4- (2-Phenyl-1- {6- [3- (pyrrolidin-1-yl) propyl] pyridin-3-yl} but-1-enyl) phenol

Using the general procedure for the McMurry reaction described in Step B in Example 1, {6- [3- (pyrrolidin-1-yl) propyl] pyridin-3-yl} [4- (tetrahydro-2H-pyran-2- Oxy) phenyl] methanone (1.0 g, 2.5 mmol) and propiophenone (1.0 g, 7.6 mmol) are reacted to give the desired product (186 mg, 17.8%, Z / E = 3/1). ) m / z = 413 [M + 1] ⁺ .

Example 31
4- (2-Phenyl-1- {4- [3- (pyrrolidin-1-yl) propyl] phenyl} but-1-enyl) phenol

Step A: {4- [3- (Pyrrolidin-1-yl) prop-1-ynyl] phenyl} [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone

In a 25 ml Schlenk flask, (4-iodophenyl) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone (408 mg, 1 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (18 mg, 0.025mmol), CuI (10mg, 0.05mmol ), Et 3 N (10ml), and N- propynyl pyrrolidine (165 mg, 1.5 mmol) to join the. After flushing the flask three times with argon gas, the mixture is stirred at 90 ° C. for 3 hours. After concentration under reduced pressure, the concentrate was subjected to column chromatography separation to obtain the desired product (312 mg, 80%).

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

Into the flask, {4- [3- (pyrrolidin-1-yl) prop-1-ynyl] phenyl} [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone (391 mg, 1 mmol), Raney nickel (0 0.1 g, 0.2 mmol) and 20 ml of methanol. The mixture is stirred for 2 hours at room temperature and 1 atmosphere of hydrogen gas. After all conversion (TLC detection), the catalyst is removed by filtration through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the product (375 mg, 95%).

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

{4- [3- (Pyrrolidin-1-yl) propyl] phenyl} [4- (tetrahydro-2H-pyran-2-oxy) phenyl] using the generic step of the McMurry reaction described in Step B in Example 1 Methanone (798 mg, 2 mmol) was reacted with propiophenone (800 mg, 6 mmol) to obtain the desired product (208 mg, 25%, Z / E = 1/1). m / z = 412 [M + 1] ⁺ .

Example 32
4- (1- {6- [3- (methylamino) propyl] pyridin-3-yl} -2-phenylbut-1-enyl) phenol

Step A: N-methylpropargylamine (N-methylprop-2-yn-1-amine)

While cooling with dry ice, propargyl bromide (64.0 g, 0.54 mol) is added to 120 ml of anhydrous methylamine solution. The reaction is allowed to react overnight in a shield tube at room temperature. Subsequently open and heat at 45 ° C. to remove excess methylamine. Add dry ether (100 ml), filter to remove methylamine hydrochloride, distill the filtrate to a colorless oil and have the desired product (5.0 g, 13.4%), boiling point 82-84 ° C. Got.

Step B: tert-butylmethyl (prop-2-ynyl) carbamate

Under a temperature of 25 ° C., while stirring a solution of 0.8 g of N-methylpropargylamine (1.0 ml, 11.8 mmol) in methanol (20 ml), di-tert-butyl dicarbonate (2.7 ml, 11. 7 mmol) is added slowly. The mixture is stirred for 1 hour. Concentration under reduced pressure gave a crude product of tert-butylmethyl (prop-2-ynyl) carbamate (1.9 g, 97%) as a pale yellow oil.

Step C: tert-Butyl methyl (3- {5- [4- (tetrahydro-2H-pyran-2-oxy) benzoyl] pyridin-2-yl} prop-2-ynyl) carbamate

A 25 ml Schlenk flask was charged with (6-chloropyridin-3-yl) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone (318 mg, 1.0 mmol), tetrakis (triphenylphosphine). ) palladium (116mg, 0.1mmol), CuI ( 38mg, 0.2mmol), Et 3 N (5ml), and tert- butyl methyl (prop-2-ynyl) carbamate (169 mg, 1.0 mmol) is added. The flask is flushed with nitrogen gas three times and the mixture is stirred at 80 ° C. for 2 hours. After concentration under reduced pressure, the concentrate was subjected to column chromatography separation to obtain the target product (180 mg, 40%) as a yellow solid.

Step D: tert-Butyl methyl (3- {5- [4- (tetrahydro-2H-pyran-2-oxy) benzoyl] pyridin-2-yl} propyl) carbamate

3 ml of methanol solution of tert-butyl methyl (3- {5- [4- (tetrahydro-2H-pyran-2-oxy) benzoyl] pyridin-2-yl} propynyl) carbamate (180 mg, 0.4 mmol) at room temperature To the mixture is added Raney nickel (2.4 mg, 0.04 mmol) and the mixture is stirred in hydrogen gas for 1 hour. Nickel was removed by filtration through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the desired product (100 mg, 55.6%) as a yellow solid.

Step E: 4- (1- {6- [3- (Methylamino) propyl] pyridin-3-yl} -2-phenylbut-1-enyl) phenol

Methyl (3- {5- [4- (tetrahydro-2H-pyran-2-oxy) benzoyl] pyridin-2-yl} propyl) carbamic acid using the general procedure for the McMurry reaction described in Step B in Example 1 Tert-butyl (100 mg, 0.22 mmol) was reacted with propiophenone (88 mg, 0.66 mmol) to obtain the desired product (16 mg, 20%, Z / E = 1/1). m / z = 373 [M + 1] ⁺ .

Example 33
4- (1- {4- [3- (methylamino) propyl] phenyl} -2-phenylbut-1-enyl) phenol

Step A: tert-Butyl methyl (3- {4- [4- (tetrahydro-2H-pyran-2-oxy) benzoyl] phenyl} prop-2-ynyl) carbamate

In a 25 ml Schlenk flask, (4-iodophenyl) [4- (tetrahydro-2H-pyran-2-oxy) 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 tert-butylmethyl (prop-2-ynyl) carbamate (255 mg, 1.5 mmol). The flask is flushed with argon gas three times and the mixture is stirred at 90 ° C. for 3 hours. After concentration under reduced pressure, the concentrate was subjected to column chromatography separation to obtain the desired product (270 mg, 60%).

Step B: tert-butyl methyl (3- {4- [4- (tetrahydro-2H-pyran-2-oxy) benzoyl] phenyl} propyl) carbamate

To the flask was added tert-butyl methyl (3- {4- [4- (tetrahydro-2H-pyran-2-oxy) benzoyl] phenyl} prop-2-ynyl) carbamate (450 mg, 1 mmol), Raney nickel (0.1 g 0.2 mmol) and 20 ml of methanol. The mixture is stirred for 2 hours in a hydrogen gas atmosphere at room temperature and 1 atm. The catalyst is removed by filtration through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the desired product (364 mg, 80%).

Step C: 4- (1- {4- [3- (Methylamino) propyl] phenyl} -2-phenylbut-1-enyl) phenol

Using the general procedure for the McMurry reaction described in Step B in Example 1, tert-butyl methyl (3- {4- [4- (tetrahydro-2H-pyran-2-oxy) benzoyl] phenyl} propyl) carbamate ( 909 mg, 2 mmol) and propiophenone (800 mg, 6 mmol) were reacted to obtain the desired product (224 mg, 30%, Z / E = 1/1). m / z = 372 [M + 1] ⁺ .

Example 34
4- (1- {3-Fluoro-4- [3- (pyrrolidin-1-yl) prop-1-ynyl] phenyl} -2-phenylbut-1-enyl) phenol (4- (1- (3-Fluoro -4- (3- (pyrrolidin-1-yl) prop-1-ynyl) phenyl) -2-phenylbut-1-enyl) phenol)

Step A: (4-Bromo-3-fluorobenzene) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone

Under nitrogen gas protection at 0 ° C., a solution of 4-bromo-3-fluoro-N-methoxy-N-methylbenzamide (1.00 g, 3.8 mmol) in dry THF was added to [4- (tetrahydro-2H-pyran. 2-Oxy) magnesium bromide (7.6 mmol) is added dropwise. After completion of the dropwise addition, the reaction solution is warmed to room temperature and stirred for 2 hours, a saturated aqueous ammonium chloride solution is added to quench, and the mixture is extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography separation to obtain the desired product (1.1 g, 76%) as a colorless oil.

Step B: {3-Fluoro-4- [3- (pyrrolidin-1-yl) prop-1-ynyl] phenyl} [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone

In a 100 ml Schlenk flask, (4-bromo-3-fluorobenzene) [4- (tetrahydro-2H-pyran-2-oxy) 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-propynylpyrrolidine (0.63 g, 5.8 mmol) are charged and the flask is flushed with nitrogen gas And washed out 3 times. Stir the mixture at 80 ° C. for 2 hours. After concentration under reduced pressure, the concentrate was subjected to column chromatography separation to obtain the target product (0.43 g, 36%) as a yellow solid.

Step C: 4- (1- {3-Fluoro-4- [3- (pyrrolidin-1-yl) prop-1-ynyl] phenyl} -2-phenylbut-1-enyl) phenol

Using the general procedure for the McMurry reaction described in Step B in Example 1, {3-fluoro-4- [3- (pyrrolidin-1-yl) prop-1-ynyl] phenyl} [4- (tetrahydro-2H- Pyran-2-oxy) phenyl] methanone (155 mg, 0.38 mmol) is reacted with propiophenone (152 mg, 0.38 mmol) to give the desired product (58 mg, 36%, Z / E = 1/1). Got. m / z = 426 [M + 1] ⁺ .

Example 35
(Z) -4- [1- (4-hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-en-2-yl] cyclohexanone ((Z) -4- (1- (4-hydroxyphenyl) -1- (4- (2- (methylamino) ethoxy) phenyl) but-1-en-2-yl) cyclohexone)

Step A: 2,3,3-Triethoxycarbonylcyclohexanone

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

Step B: 4-oxocyclohexane carboxylic acid

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 subjected to silica gel column chromatography separation (dichloromethane / methanol = 80/1) to give 4-oxocyclohexanecarboxylic acid (4.2 g, 29%).

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

To a solution of 4-oxocyclohexanecarboxylic acid (4.2 g, 0.0293 mol) in dichloromethane (20 ml), oxalyl chloride (5.2 g, 0.44 mol) was gradually added dropwise, stirred at room temperature for 1 hour and concentrated. dichloromethane was added (20 ml), _{further, Et 3 N (9g, 0.116mol} ) and N, O- dimethylhydroxylamine hydrochloride (3.5g, 0.0359mol) is added. Stir the reaction at room temperature for 2 hours and add water (100 ml). Extract the mixture with ethyl acetate. The extract was concentrated and subjected to column chromatography separation to obtain the desired product (2.1 g, 39%).

Step D: N-methoxy-N-methyl-1,4-dioxaspiro [4.5] decane-8-carboxamide

N-methyl-N-methoxy-4-carbonylcyclohexylcarboxamide (2.1 g, 0.114 mol), ethanediol (0.9 g, 0.136 mol), and p-toluenesulfonic acid (0.1 g) in toluene ( The solution is refluxed overnight and then concentrated. Water is added and the mixture is extracted with ethyl acetate. The extract was concentrated and subjected to silica gel column chromatography separation (dichloromethane / methanol = 100/1) to obtain the desired product (1.0 g, 38.4%).

Step E: 1- (1,4-Dioxaspiro [4.5] decan-8-yl) propan-1-one (1- (1,4-dioxaspiro [4.5] decan-8-yl) propan-1 -One)

Ethylmagnesium bromide solution (9 g, 0.043 mol) was added to N-methoxy-N-methyl-1,4-dioxaspiro [4.5] decane-8-carboxamide (1.0 g, 4.3 mmol) in anhydrous ether ( 20 ml) is added dropwise to the solution. The reaction is refluxed overnight, after which water (200 ml) is added. Extract the mixture with ethyl acetate. The extract was concentrated and subjected to silica gel column chromatography separation (dichloromethane / methanol = 150/1) to obtain the desired product (259 mg, 26%).

Step F: (Z) -4- {1- [4- (2-Chloroethyl) phenyl] -2- (1,4-dioxaspiro [4.5] decan-8-yl) but-1-enyl} phenol

  Using the generic step for the McMurry reaction described in Step B in Example 1, [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (360 mg, 1.3 mmol) and 1- (1,4 -Dioxaspiro [4.5] decan-8-yl) propan-1-one (1- (1,4-dioxaspiro [4.5] decan-8-yl) propan-1-one) (259 mg, 1.3 mmol ) To give the desired product (Z-isomer, 90 mg, 16%), and 110 mg E-isomer product (19%).

Step G: (Z) -4- (1- {4- [2- (methylamino) ethoxy] phenyl} -2- (1,4-dioxaspiro [4.5] decan-8-yl) but-1- Enyl) phenol

(Z) -4- {1- [4- (2-Chloroethyl) phenyl] -2- (1,4-dioxaspiro [4.5] decan-8-yl) but-1-enyl} phenol (90 mg, 0 .20 mmol) and 30% aqueous methylamine solution (5 ml) in a shielded tube in methanol (5 ml) solution at 85 ° C. overnight, concentrated, subjected to column chromatography separation, and the desired product ( 90 mg) was obtained.

Step H: (Z) -4- [1- (4-Hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-en-2-yl] cyclohexanone

(Z) -4- (1- {4- [2- (methylamino) ethoxy] phenyl} -2- (1,4-dioxaspiro [4.5] decan-8-yl) but-1-enyl) phenol While stirring a methanol solution (10 ml) of (90 mg), an aqueous hydrochloric acid solution (3M, 1.5 ml) was added thereto, the reaction solution was stirred at room temperature for 2 hours, and then 20 ml of water was added, followed by saturated bicarbonate. Aqueous sodium solution is added to adjust the pH to 7-8, and the mixture is extracted with ethyl acetate. The extract was dried, filtered, concentrated and subjected to column chromatography separation (dichloromethane / methanol = 150/1) to obtain the desired product (22 mg, 27.5%, Z-isomer). m / z = 394 [M + 1] ⁺ .

Example 36
(E) -4- [1- (4-Hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-en-2-yl] cyclohexanone

Using the (E) -product separated in Step F in Example 35, the target product (32 mg, 39.5%) was obtained in the same manner as Steps G and H in Example 35. m / z = 394 [M + 1] ⁺ .

Example 37
(Z) -4- (1- (hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl-2-yl) -1-methylpyridine-2- (1H ) -On

Step A: 2-oxo-1,2-dihydropyridine-4-carboxylic acid (2-oxo-1,2-dihydropyridine) -4-carboxylic acid

At 0 ° C., 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). Heat to reflux for 36 hours, cool, and adjust to pH 1-3 by adding 3N hydrochloric acid solution. The suspension was filtered and washed with water to give the product (13.1 g, 99%) as a white solid. 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-oxo-1,2-dihydropyridine-4-carboxylic acid

At 0 ° C., a solution of 2-oxo-1,2-dihydropyridine-4-carboxylic acid (5 g, 1.0 eq) in 100 ml DMF was added to a solid of 60% sodium hydride (4.3 g, 3.0 eq). ) Is added slowly and then stirred at room temperature for 30 minutes. Thereafter, methyl iodide (15.3 g, 3.0 eq) is slowly added dropwise to the reaction system at 0 ° C. Stir overnight at room temperature, quench the reaction by adding ice water and extract with ethyl acetate. The extract was dried, concentrated and subjected to column chromatography separation to obtain the desired product (1.5 g, 25%). 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: 1-Methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid

To a 25 ml methanol solution of methyl 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (1 g, 1.0 eq) at room temperature was added lithium hydroxide monohydrate (755 mg, 3.0 eq). ) In water (5 ml). Stir at room temperature for 2 hours. The solvent was removed, water and 3N hydrochloric acid solution were added to a pH value of about 1-3, the suspension was filtered and washed with water to give the desired 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 & 1.6 Hz, 1H), 3.46 (s, 3H).

Step D: N-methoxy-N, 1-dimethyl-2-oxo-1,2-dihydropyridine-4-carboxamide (N-methoxy-N, 1-dimethyl-2-oxo-1,2-dihydropyridine-4 carbamide)

1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (540 mg, 1.0 equiv) with EDCI (811 mg, 1.2 equiv), and HOBt (572 mg, 1.2 equiv) The suspension in 20 ml dichloromethane is stirred for 5 minutes at room temperature. N-methoxymethanamine hydrochloride (413 mg, 1.2 eq) and triethylamine (1.1 g, 3.0 eq) were then added and stirred overnight at room temperature. Add water and extract with dichloromethane. The extract was dried, concentrated and subjected to column chromatography separation to obtain the desired product (555 mg, 80%). 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 10 ml anhydrous tetrahydrofuran solution of N-methoxy-N, 1-dimethyl-2-carbonyl-1,2-dihydropyridine-4-carboxamide (200 mg, 1.0 equivalent) at 0 ° C. was added 3M ethylmagnesium bromide (0.7 ml, 2.0 equivalents) is added. Stir at room temperature for 1 hour, quench with saturated aqueous ammonium chloride and extract with dichloromethane. The extract was dried, concentrated, and subjected to column chromatography separation to obtain the desired product (105 mg, 62%). 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: 4- {1- [4- (2-Chloroethoxy) phenyl] -1- (4-hydroxyphenyl) but-1-enyl-2-yl) -1-methylpyridin-2 (1H) -one

Using the common steps of the McMurry reaction described in Step B in Example 1, 1-methyl-4-propylpyridin-2 (1H) -one (105 mg, 1.0 eq) and [4- (2-chloroethoxy ) Phenyl] (4-hydroxyphenyl) methanone (352 mg, 2.0 equivalents) to give the desired product (Z / E = 1/1).

Step G: (Z) -4- (1- (hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl-2-yl) -1-methylpyridine-2 -(1H) -ON

4- {1- [4- (2-chloroethoxy) phenyl] -1- (4-hydroxyphenyl) but-1-enyl-2-yl) -1-methylpyridin-2 (1H) -one (30 mg, 1.0 ml) of MeOH (10 ml) is stirred, 5 ml of aqueous methylamino solution (30%) is added, heated to 85 ° C. and stirred for 36 hours. Remove the solvent under reduced pressure, add water and extract with EtOAc. The extract is dried, concentrated and subjected to column chromatography separation to give the desired product (3 mg, pure Z-isomer), E-isomer (2 mg) and Z / E mixture (230 mg, 49%). It was. 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] ⁺ .

Example 38
(E) -4- (1- (hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl-2-yl) -1-methylpyridine-2- (1H ) -On

Example 37 gave the title compound. 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] ⁺ .

Example 39
(Z) -4- (1- {6 [2- (methylamino) ethylthio] pyridin-3-yl} 2-phenylbut-1-enyl) phenol

Step A: 2- (Methylamino) ethanol hydrochloride

50 ml of a concentrated hydrochloric acid solution of 2- (methylamino) ethanol (20 g, 1.0 equivalent) 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-methylethanamine hydrochloride

At 0 ° C., thionyl chloride (41 g, 1.3 eq) was added to 150 ml of a chloroform solution of 2- (methylamino) ethanol hydrochloride (29.7 g, 1.0 eq) and heated to reflux for 3 hours at room temperature. Allow to cool. The solvent was removed by evaporation under reduced pressure and the concentrate was stirred in 100 ml of 1:10 dichloromethane / petroleum ether to give a suspension and filtered to give 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) ethylthio hydrochloride

While stirring 150 ml of an aqueous solution of 2-chloro-N-methylethylamine hydrochloride (15 g, 1.0 eq), Na ₂ S ₂ O ₃ (18.5 g, 1.0 eq) was added to it and heated for 48 hours. Reflux. Cool to room temperature and remove the solvent under reduced pressure. The crude salt is dissolved in 60 ml of 6M aqueous hydrochloric acid and heated at 90 ° C. for 4 hours. The solvent was removed under reduced pressure, and column chromatography separation was performed to obtain the desired product. ¹ H NMR (400 MHz, DMSO-d ⁶ ) δ 4.95 (brs, 2H), 2.90 (s, 4H), 2.37 (s, 3H).

Step D: (Z) -4- (1- {6- [2- (methylamino) ethylthio] pyridin-3-yl} -2-phenylbut-1-enyl) phenol

While stirring at 0 ° C., 60% sodium hydride (120 mg, 12 equivalents) is gradually added to 20 ml of anhydrous tetrahydrofuran solution of 2- (methylamino) ethylthiohydrochloride (217 mg, 10 equivalents). Stir at room temperature for 1 hour, then add (Z) -4-[(6-chloropyridin-3-yl) -2-phenylbut-1-enyl) phenol (80 mg, 1.0 eq.) To the reaction system. 2) is added. The mixture is heated to reflux for 48 hours, cooled to room temperature, quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The extract was dried, concentrated and subjected to column chromatography separation to obtain the desired product (75 mg, 81%). 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] ⁺ .

Example 40
(E) -4- [1- (6- {Methyl [2- (methylamino) ethyl] amino} pyridin-3-yl) -2-phenylbut-1-enyl] phenol

Using the same method as described in step D in example 39, (E) -4-[(6-chloropyridin-3-yl) -2-phenylbut-1-enyl) phenol (100 mg, 1.0 eq. Example 2) was reacted with N, N-dimethylethylenediamine (262 mg, 10.0 equivalents) to give the desired 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] ⁺ .

Example 41
(Z) -5- [1- (4-Hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-en-2-yl] pyridin-2-ol

Step A: 6-Hydroxy-N-methoxy-N-methylnicotinamide

With stirring at room temperature, 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) ) To the solution was added N, O-dimethylhydroxylamine hydrochloride (4.2 g, 1.2 eq), and triethylamine (15 g, 4.0 eq), stirred at room temperature overnight and water added. The mixture is extracted with dichloromethane. The extract was dried and concentrated, and subjected to column chromatography separation to obtain 3.5 g (53%) of the desired product. 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) propan-1-one

While stirring at 0 ° C., 6M-hydroxy-N-methoxy-N-methylnicotinamide (800 mg, 1.0 equivalent) in anhydrous THF (20 ml) was added to 3M ethylmagnesium bromide (6.0 ml, 4.0 ml). Eq.) Is added. The mixture is stirred at room temperature for 2 hours, quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The extract was dried, concentrated, and subjected to column chromatography separation to obtain the desired product (320 mg, 48%). 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) but-1-en-2-yl} pyridine-2-alcohol

Using the general procedure for the McMurry reaction described in Step B in Example 1, 1- (6-hydroxypyridin-3-yl) propan-1-one (300 mg, 1.0 eq) and [4- (2- Chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (1.37 g, 2.5 equivalents) to give the desired product (Z- and E-isomers can be separated by column chromatography). .

Step D: (Z) -5- (1- [4-hydroxyphenyl] -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-en-2-yl) pyridin-2-ol

Using the same method as described in Step D in Example 11, (Z) -5- {1- [4- (2-chloroethoxy) phenyl] -1- (4-hydroxyphenyl) but-1-ene-2 -Il} pyridin-2-ol (0.02 g, 1.0 equivalent) and a solution of methylamine (30% aqueous solution, 10 ml) in methanol (20 ml) were refluxed to obtain the desired product. 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] ⁺ .

Example 42
6- [1- (4-Hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-en-2-yl] pyridin-3-ol

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

Using the general condensation method described in Step A in Example 41, 5-hydroxy-2-pyridinecarboxylic acid (6.2 g, 1.0 eq) and N, O-dimethylhydroxylamine hydrochloride (5. 2 g, 1.2 eq) to give the desired product (4.25 g, 52%).

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

Using the general method described in Step B in Example 11, 5-hydroxy-N-methoxy-N-methyl-2-pyridinecarboxamide (500 mg, 1.0 eq) and ethylmagnesium bromide (6.0 ml) 4.0 equivalents) to give the desired product (200 mg, 48%).

Step C: 6- {1- [4- (2-Chloroethoxy) phenyl] -1- (4-hydroxyphenyl) but-1-en-2-yl} pyridin-3-ol

Using the general procedure for the McMurry reaction described in Step B in Example 1, 1- (5-hydroxypyridin-2-yl) propan-1-one (150 mg, 1.0 eq) and [4- (2- Chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (549 mg, 2.0 equivalents) was reacted to give the desired product (Z / E = 1/1).

Step D: 6- [1- (4-Hydroxyphenyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-en-2-yl] pyridin-3-ol

Using the same method as described for D in Example 11, 6- {1- [4- (2-chloroethoxy) phenyl] -1- (4-hydroxyphenyl) but-1-en-2-yl} pyridine- 3-ol (220 mg, 1.0 equivalent) and methylamine (30% aqueous solution, 10 ml) in methanol (20 ml) were refluxed to obtain the desired 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, 1.5 H), 2.35 (s, 1.5H), 0.83 (t, J = 7.2 Hz, 3H); m / z = 391 [ ^+1] +.

Example 43
1- [3- (Dimethylamino) propyl] -4- [1- (4-hydroxyphenyl) -2-phenylbut-1-enyl] pyridin-2 (1H) -one

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

While stirring at 0 ° C., thionyl chloride (21 g, 1.2 eq) is added dropwise to 150 ml of a chloroform solution of 3- (dimethylamino) propan-1-ol (15 g, 1.0 eq). Thereafter, the mixture is heated to reflux for 5 hours. After cooling to room temperature, the solvent was evaporated to dryness under reduced pressure to give a crude product, which was washed with 50 ml of 1:10 dichloromethane / petroleum ether solution to give the desired product (22 g, 98%). It was.

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

Of 2-oxo-1,2-dihydropyridine-4-carboxylic acid (8.0 g, 1.0 equiv), EDCI (13.2 g, 1.2 equiv), and HOBt (9.3 g, 1.2 equiv) To a dichloromethane (150 ml) solution is added N, O-dimethylhydroxylamine hydrochloride (6.8 g, 1.2 eq) and triethylamine (26.2 g, 4.5 eq). The reaction mixture was stirred at room temperature overnight, concentrated, and subjected to column chromatography separation to obtain the desired product (6.3 g, 60%). 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: 1- [3- (Dimethylamino) propyl] -N-methoxy-N-methyl-2-carbonyl-1,2-dihydropyridine-4-carboxamide

With stirring, N-methoxy-N-methyl-2-carbonyl-1,2-dihydropyridine-4-carboxamide (200 mg, 1.0 eq), 4-chloro-N, N-dimethylpropylamine hydrochloride (350 mg , 2.0 eq.), And 20 ml of a propanone solution of anhydrous potassium carbonate (455 mg, 3.0 eq.) Overnight at reflux. After cooling to room temperature, water is added and extracted with dichloromethane. The extract was dried, concentrated and subjected to column chromatography separation to obtain the desired product (255 mg, 87%). 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-2H-pyran-2-oxy) phenyl] pyridin-2 (1H) -one

Into a three-necked flask charged with 50 ml of anhydrous THF, magnesium (440 mg, 3.5 eq) is added and the mixture is heated to 55 ° C. Add iodine tablets 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. Initiate reaction after 30 minutes and begin to reflux. Then, within 5 minutes, an excess 2- (4-bromophenol) tetrahydro-2H-pyran solution was added at a dropping rate capable of maintaining reflux, followed by refluxing for 2 hours, cooling to room temperature, and 1- [3 -(Dimethylamino) propyl] -N-methoxy-N-methyl-2-carbonyl-1,2-dihydropyridine-4-carboxamide (1.4 g, 1.0 eq) in THF (20 ml) was added dropwise, When the addition is complete, the mixture is stirred at room temperature for 30 minutes, quenched with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was dried and concentrated and subjected to column chromatography separation to obtain the desired product (1.6 g, 80%). 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 (s, 6H), 1.88-2.08 (m, 5H), 1.62-1.74 (m , 4H).

Step E: 1- [3- (Dimethylamino) propyl] -4- [1- (4-hydroxyphenyl) -2-phenylbut-1-enyl] pyridin-2 (1H) -one

Using the general procedure for the McMurry reaction described in Step B in Example 1, propiophenone (838 mg, 3.0 eq) and 1- [3- (dimethylamino) propyl] -4- [4- (tetrahydro- 2H-pyran-2-oxy) phenyl] pyridin-2 (1H) -one (800 mg, 1.0 eq) to give the desired product (Z-isomer is prepared by preparative chromatography). . 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] ⁺ .

Example 44
4- [2- (2,3-Dihydro-5-benzofuranyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] phenol

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

While stirring at 0 ° C., 200 ml of 2,3-dihydrobenzofuran (10 g, 1.0 equivalent) in dichloromethane was added to propionic acid chloride (14 g, 1.8 equivalent) and anhydrous aluminum chloride (11.1 g, 1.0 equivalent). 200 ml of a dissolved dichloromethane solution is added dropwise. After completion of the dropwise addition, the mixture is stirred at room temperature for 1 hour, and brine is added to quench the reaction, followed by extraction with dichloromethane. The extract is washed with saturated brine, dried and concentrated under reduced pressure. Hexane (100 ml) is added, cooled to 0 ° C., stirred for 30 minutes, the suspension is filtered and washed with cold hexane and dried to give the product as a white solid (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: [4- (2-Chloroethoxy) phenyl] (4-methoxyphenyl) methanone

While stirring at 0 ° C., 400 ml of a solution of 1- (2-chloroethoxy) benzene (48 g, 1.0 eq) in dichloromethane was added to 4-methoxybenzoic acid chloride (62 g, 1.2 eq) and anhydrous aluminum chloride (49 g). , 1.2 equivalents) is added dropwise in 400 ml dichloromethane solution. After completion of the dropwise addition, the mixture is stirred at room temperature for 1 hour, and brine is added to quench the reaction, followed by extraction with dichloromethane. The extract is washed with saturated brine, dried, and concentrated under reduced pressure. Add hexane (500 ml) to the concentrate, cool to 0 ° C., stir for 30 min, filter the suspension, wash with cold hexane and dry to give the product as a white solid (85 g, 96%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (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: [4- (2-Chloroethoxy) phenyl] (4-hydroxyphenyl) methanone

While stirring at 0 ° C., 150 ml of [4- (2-chloroethoxy) phenyl] (4-methoxyphenyl) methanone (20 g, 1.0 eq) in dichloromethane was added to tribromoborane (52 g, 3.0 eq). Is dripped. Stir at room temperature for 4 hours and quench with 500 ml of ice water. The suspension was filtered and washed with water to give 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 (dd, J = 7.2 & 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: 4- {1- [4- (2-Chloroethoxy) phenyl] -2- (2,3-dihydro-5-benzofuranyl) but-1-enyl} phenol

TiCl ₄ (0.5 ml, 3 equivalents) is added dropwise to a suspension of zinc powder (595 mg, 6 equivalents) in anhydrous THF (20 ml) under nitrogen gas protection at 0 ° C. The mixture is heated to reflux for 1 hour and cooled to room temperature. Then, at 0 ° C., 2,3-dihydro-5-propionylbenzofuran (670 mg, 2.5 eq) and [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (420 mg, 1.0 eq) ) In anhydrous THF (10 ml) is added dropwise. When the addition is complete, the reaction mixture is heated to reflux for 1 hour, cooled, quenched with saturated aqueous NaHCO ₃ , filtered, and the filtrate is extracted with EtOAc. The extract is dried and concentrated in vacuo. The concentrate was subjected to column chromatography separation to obtain 500 mg of the desired product (78%, Z / E = 1/1).

Step E: 4- [2- (2,3-Dihydro-5-benzofuranyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] phenol

Of 4- {1- [4- (2-chloroethoxy) phenyl] -2- (2,3-dihydro-5-benzofuranyl) but-1-enyl} phenol (500 mg, 1.0 eq) with stirring. 10 ml of CH ₃ NH ₂ aqueous solution is added to 20 ml of MeOH solution, heated to 85 ° C. and reacted for 24 hours. Concentrate under reduced pressure to remove the solvent, add water to the concentrate and extract with ethyl acetate. The extract was dried, concentrated and subjected to column chromatography separation to obtain the desired product (Z / E = 1/1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.10 sum 7.01 (d, J = 8.8 Hz, 2H), 6.92 (s, 1H), 6.83 (d, J = 8. 4 Hz, 1H), 6.82 sum 6.74 (d, J = 8.8 Hz, 2H), 6.79 sum 6.75 (d, J = 8.8 Hz, 2H), 6.57 ( d, J = 8.4 Hz, 1H), 6.51 sum 6.45 (d, J = 8.8 Hz, 2H), 4.51 (t, J = 8.4 Hz, 2H), 4. 10 sum 3.96 (t, J = 4.8 Hz, 2H), 3.09 (t, J = 8.8 Hz, 2H), 3.01 sum 2.93 (t, J = 4.8 Hz) , 2H), 2.54 sum 2.50 (s, 3H), 2.39-2.46 (m, 2H), 0.90-0.94 (m, 3H); m / z = 416 [M + 1 ] ⁺ .

Example 45
(Z) -4- (2- (1H-indazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl) phenol

Step A: Methyl 4-amino-3-methylbenzoate

While stirring at room temperature, an aqueous solution prepared by dissolving ammonium chloride (137 g, 10 equivalents) in 60 ml of water in 1 L of a methanol solution of methyl 4-nitro-3-methylbenzoate (50 g, 1.0 equivalent), iron powder ( 96 g, 7 eq) and the reaction mixture is heated to reflux for 4 hours. Cool to room temperature, filter, add water and extract with ethyl acetate. The extract was washed with water, dried and concentrated to give the desired product (26 g, 62%) directly as a white solid.

Step B: Methyl 4-diazotetrafluoroborate-3-methylbenzoate

At 0 ° C., an aqueous solution of sodium nitrite (12.54 g, 2.0 eq) in 75 ml of water was added cold methyl 4-amino-3-methylbenzoate (15 g, 1.0 eq) tetrafluoroboric acid (40 % Aqueous solution) is added dropwise. After the addition is complete, the mixture is stirred at room temperature for 15 minutes. The precipitate was filtered, washed with ice water and dried to give the desired product (16 g, 90%) as a white solid.

Step C: Methyl 5-indazolecarboxylate (methyl 1H-indazole-5-carboxylate)

Methyl 4-diazotetrafluoroborate-3-methylbenzoate (BF ₄ salt (BF ₄ salt)) (12 g, 1.0 eq), potassium acetate (16.6 g, 2.5 eq), and 18- A suspension of crown-6 (1.8 g, 0.1 eq) in chloroform (200 ml) is stirred at room temperature for 24 hours and the residue is partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the desired product (6.5 g, 55%).

Step D: 5-indazolecarboxylic acid

While stirring, an aqueous solution of sodium hydroxide (4.4 g, 3.0 eq) in 150 ml of water is added to a solution of methyl 5-indazolebenzoate (6.5 g, 1.0 eq) in MeOH (200 ml). The reaction mixture is refluxed for 1 hour. The organic solvent was removed by distillation under reduced pressure, the excess aqueous solution was washed with ethyl acetate, and acidified to pH 5-6 with 3N hydrochloric acid solution, filtered to collect the precipitate, washed with water and washed with yellow The desired product (6.2 g, 98%) was obtained as a solid.

Step E: N-methoxy-N-methyl-5-indazolecarboxamide

At 0 ° C., 5-indazolecarboxylic acid (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) in 100 ml dichloromethane are added dropwise triethylamine (15 g, 4.0 eq). When the addition was completed, the mixture was stirred at room temperature overnight, concentrated, and subjected to column chromatography separation to obtain the desired product (4.4 g, 58%). 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, 1H), 3.56 (s, 3H), 3.42 (s, 3H).

Step F: 5-propionylindazole

At 0 ° C., Grignard reagent EtMgBr (3M, 2.0 eq, 6.5 ml) was added to a solution of N-methoxy-N-methyl-5-indazolecarboxamide (2.0 g, 1.0 eq) in anhydrous THF. Added. When the addition is complete, the mixture is stirred for 2 hours and extracted with ethyl acetate. The extract was dried, concentrated, separated by column chromatography and eluted with petroleum ether / ethyl acetate (1/1) to obtain 1.8 g (95%) of the desired 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: 4- {1- [4- (2-Chloroethoxy) phenyl] -2- (1H-indazol-5-yl) but-1-enyl} phenol

Stir at room temperature and slowly add titanium tetrachloride (4.0 eq, 1.1 ml) to a dry THF mixture of zinc powder (1.65 g, 10.0 eq) under nitrogen gas protection. The resulting mixture is heated to reflux for 1 hour and allowed to cool to room temperature. A mixture of 5-propionylindazole (1.3 g, 3.0 eq) and [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (0.7 g, 1.0 eq) in dry THF. Add, heat to 80 ° C., reflux for 1 hour, quench with aqueous sodium carbonate and extract with ethyl acetate. The extract was dried, concentrated and subjected to column chromatography separation to give the title product (0.3 g, 70%, Z / E = 1/1). 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, 3H).

Step H: (Z) -4- (2- (1H-indazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl) phenol

Of 4- {1- [4- (2-chloroethoxy) phenyl] -2- (1H-indazol-5-yl) but-1-enyl} phenol (0.3 g, 1.0 eq) with stirring. To a methanol (20 ml) solution, 10 ml of methylamine (30% aqueous solution) is added. Reflux the mixture overnight. Concentrate under reduced pressure to remove the organic solvent and extract the excess mixture with ethyl acetate. The extract was dried, concentrated, separated by column chromatography and eluted with dichloromethane / ammonia in methanol (10/1) to give the desired product of Z-isomer (5 mg) and the product of E-isomer (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] ⁺ .

Example 46
(E) -4- (2- (1H-indazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl) phenol

The one prepared in Example 2 was separated to give the title compound (E-isomer, 11 mg). 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] ⁺ .

Example 47
4- [2- (Benzo [d] oxazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] 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 of water is refluxed at 100 ° C. overnight. After dropping to room temperature, adjust to pH 7 with concentrated hydrochloric acid. The formed precipitate was filtered off, washed with cold water and dried to give the desired product (18.4 g, 98%) as a white solid.

Step B: 4-Hydroxy-3-aminobenzoic acid

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

Step C: 5-Benzoxazole carboxylic acid (benzo [d] oxazole-5-carboxylic acid)

A mixture of 4-hydroxy-3-amino-benzoic acid (8.0 g, 1.0 eq) in 60 ml of triethyl orthoformate is heated to reflux for 3 hours and cooled to room temperature. Distillation under reduced pressure removed residual triethyl orthoformate to obtain the desired 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

At 0 ° C., 5-benzoxazolecarboxylic acid (7.8 g, 1.0 eq), N, O-dimethylhydroxylamine hydrochloride (7.0 g, 1.5 eq), HOBt (7.76 g, 1.eq). To a solution of EDCI (11 g, 1.2 eq) in 100 ml of dichloromethane is added dropwise triethylamine (19 g, 4.0 eq). The mixture was then stirred at room temperature overnight, concentrated, separated by column chromatography and eluted with petroleum ether / ethyl acetate (1/1) to give 6.0 g (51%) of the desired 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, 3H), 3.41 (s, 3H).

Step E: 1- (Benzo [d] oxazol-5-yl) propan-1-one (1- (benzo [d] oxazol-5-yl) propan-1-one)

At 0 ° C., Grignard reagent EtMgBr (1 M, 2.0 eq, 58 ml) was added to dry tetrahydro N-methoxy-N-methylbenzo [d] oxazole-5-carboxamide (6.0 g, 1.0 eq). Join the furan solution. When the addition is complete, the mixture is stirred for 2 hours. The mixture is quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The extract was dried, concentrated, separated by column chromatography, and eluted with petroleum ether / ethyl acetate = 1: 1 to obtain the desired product (0.6 g, 12%).

Step F: 4- {2- (Benzo [d] oxazol-5-yl) -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol

Using the general procedure for the McMurry reaction described in Step D in Example 1, 1- (benzo [d] oxazol-5-yl) propan-1-one (0.6 g, 1.0 eq), [4- (2-Chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (1.42 g, 1.5 equivalents) was reacted to give 0.23 g (15%, Z / E = 1/1) desired product. .

Step G: 4- [2- (Benzo [d] oxazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] phenol

Using the same method as described in Step E in Example 1, 4- {2- (benzo [d] oxazol-5-yl) -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} Phenol (0.1 g, 1.0 equivalent) and methylamino (30% aqueous solution in methanol (20 ml)) were reacted under reflux to obtain 20 mg of the desired product (25%, Z / E = 1/1). . 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 Hz, 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
4- [4-Chloro-2- (2,3-dihydro-5-benzofuranyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] phenol

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

To a solution of aluminum chloride (2.22 g, 1.0 eq) in 50 ml dichloromethane is added 3-chloropropionic acid chloride (2.54 g, 1.2 eq) dropwise. The mixture is stirred at room temperature for 10 minutes, after which benzodihydrofuran (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 over anhydrous sodium sulfate and filtered. The filtrate was concentrated and subjected to column chromatography separation to obtain the desired product (1.5 g, 62%). 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: (4-Hydroxyphenyl) {4- [2- (methylamino) ethoxy] phenyl} methanone

Using the same method as described in Step E in Example 1, [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (2.0 g, 1.0 eq) and methylamino (30% aqueous solution) ) In methanol (30 ml) was refluxed to obtain the desired 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: 4- [4-Chloro-2- (2,3-dihydro-5-benzofuranyl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] phenol

2,3-Dihydro-5- (3-chloropropionyl) benzofuran (0.85 g, 1.0 eq) and (4-hydroxyphenyl) using the general procedure for the McMurry reaction described in Step D in Example 1. Reaction with {4- [2- (methylamino) ethoxy] phenyl} methanone (1.0 g, 1.0 equivalent) gave 1.2 g of the desired product (85%, Z / E = 1/1). . ¹ H NMR (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] ⁺ .

Example 49
4- {2- (2,3-dihydro-5-benzofuranyl) -1- {3-fluoro-4- [2- (methylamino) ethoxy] phenyl} but-1-enyl} phenol

Step A: 3-Fluoro-4-methoxybenzonitrile (4-Methoxybenzonitrile)

A mixed solution of 4-bromo-3-fluoro-1-methoxybenzene (30.0 g, 146 mmol) and CuCN (15.6 g, 174 mmol) in DMF (45 ml) was stirred at 120 ° C. overnight. The reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layers are washed with water and saturated saline, respectively, and dried with sodium sulfate. The solvent was removed by concentration under reduced pressure to obtain 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). Reflux and stir for 3 days under nitrogen gas protection. Add ice water to quench and extract with dichloromethane. The organic layers are washed with water and saturated saline, respectively, and dried with sodium sulfate. The solvent was removed by concentration under reduced pressure to give 13.3 g (94%) of the title compound as a gray solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.42 (m, 2H), 7.09 (dd, J = 8.8 & 8.4 Hz, 1H), 5.68 (s, 1H).

Step C: 4- (2-Bromoethoxy) -3-fluorobenzonitrile

Under nitrogen gas protection, 3-fluoro-4-hydroxybenzonitrile (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) was stirred at 60 ° C. overnight. The reaction mixture is filtered and extracted with ethyl acetate. The extracts are washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated, followed by silica gel column chromatography separation, eluting with petroleum ether / ethyl acetate (5/1), and colorless. The subtitle compound (1.52 g, 71%) was obtained as an 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: 4- (2-Bromoethoxy) -3-fluorobenzoic acid

A mixture of 4- (2-bromoethoxy) -3-fluorobenzonitrile (3.78 g, 15.5 mmol) in water (18 ml) and sulfuric acid (18 ml) is heated to 110 ° C. and allowed to react for 12 hours. The reaction is cooled to room temperature and then neutralized with solid sodium bicarbonate. Acetic acid is added to acidify to give a precipitate that is a white solid, collected by filtration and dissolved in dichloromethane. The obtained solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotation. Then, 2.65 g (65%) of a product as a pale yellow solid was obtained. ¹ H NMR (400 MHz, DMSO-d6) 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 & 8.4 Hz, 1H), 4.48 (t, J = 5.2 Hz, 2H), 3.85 (t, J = 5.2) Hz, 2H).

Step E: 4- (2-Bromoethoxy) -3-fluorobenzoic acid chloride

4- (2-Bromoethoxy) -3-fluorobenzoic acid (1.08 g, 4.1 mmol) and thionyl chloride (10 ml) are refluxed for 7 hours. Toluene was added to the excess thionyl chloride and dried together under reduced pressure. Such operation was 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: [4- (2-Bromoethoxy) -3-fluorobenzene] (4-methoxyphenyl) methanone

To a dry dichloromethane (18 ml) solution of 4- (2-bromoethoxy) -3-fluorobenzoic acid chloride (1.07 g, 3.80 mmol) and anhydrous AlCl ₃ (1.01 g, 7.60 mmol) at 0 ° C. Add a solution of anisole (822 mg, 7.60 mmol) in dichloromethane (2 ml). After stirring at room temperature for 6 hours, the reaction mixture is poured into 3N hydrochloric acid solution and extracted with dichloromethane. The extract was washed with saturated aqueous NaHCO ₃ solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and subjected to silica gel column chromatography separation, petroleum ether / ethyl acetate (10/1 to 5/1). To give the desired product (1.05 g, 77%) 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: [4- (2-Bromoethoxy) -3-fluorobenzene] (4-hydroxyphenyl) methanone

At 0 ° C., BBR ³ (0.5 ml, 5.29 mmol) was added to [4- (2-bromoethoxy) -3-fluorobenzene] (4-methoxyphenyl) methanone (930 mg, 2.63 mmol) in dichloromethane (6 ml). ) Add to solution. The reaction mixture is stirred at room temperature for 2 hours, ice water is added to quench the reaction mixture, and the mixture is extracted with dichloromethane. The extract was washed with water and saturated brine, dried over sodium sulfate, filtered, concentrated, separated by silica gel column chromatography, and eluted with petroleum ether / ethyl acetate (5/1 to 2/1). The target product (536 mg, 60%) was obtained 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: 4- {1- [4- (2-Bromoethoxy) -3-fluorobenzene] -2- (2,3-dihydro-5-benzofuranyl) but-1-enyl} phenol

Using the general procedure for the McMurry reaction described in Step D in Example 1, [4- (2-bromoethoxy) -3-fluorobenzene] (4-hydroxyphenyl) methanone (150 mg, 0.442 mmol), 2, Reaction with 3-dihydro-5-propionylbenzofuran (94 mg, 0.533 mmol, prepared in Step A of Example 1) gave 145 mg (68%) of the desired product as an off-white solid.

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

With stirring, 4- {1- [4- (2-bromoethoxy) -3-fluorobenzene] -2- (2,3-dihydro-5-benzofuranyl) but-1-enyl} phenol (142 mg, .0. 294 mmol) in methanol (5 ml) is added 1 ml of methylamine (30% aqueous solution), heated to 85 ° C. and allowed to react for 18 hours. Concentrate under reduced pressure to remove the organic solvent and extract the excess mixture with ethyl acetate. The extract was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated, subjected to column chromatography separation, and eluted with dichloromethane / ammonia methanol solution (10/1) to give the desired product ( 56 mg, 57%, Z / E = 5/4). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.04 sum 6.71 (d, J = 8.6 Hz, 2H), 6.91-7.00 (m, 2H), 6.82 (m, 1H), 6.79 sum 6.49 (d, J = 8.8 Hz, 2H), 6.53-6.63 (m, 3H), 4.52 (t, J = 8.8 Hz, 2H) ), 4.27 sum 4.14 (t, J = 4.8 Hz, 2H), 3.16 sum 3.12 (t, J = 4.8 Hz, 2H), 3.09 (t, J = 8.4 Hz, 2H), 2.65 sum 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] ⁺ .

Example 50
4- [2- (Benzo [c] [1,2,5] thiadiazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] phenol

Step A: N- (2-Nitro-4-propionylphenyl) acetamide

Within 10 minutes, 2 ml of 98% nitric acid is added to a solution of N- (4-propionylphenyl) acetamide (1.91 g, 10 mmol) in 20 ml concentrated sulfuric acid to maintain the reaction temperature at -10 ° C. After stirring for 0.5 hour, the reaction solution is poured into 100 ml of cold water. The precipitate is collected by filtration and washed with water to give the crude product (1.18 g, 50%) which is used directly in the next step reaction.

Step B: 1- (4-Amino-3-nitrophenyl) propan-1-one (1- (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 and cooled. While stirring, aqueous ammonia was added to adjust to pH 7, and the precipitate was collected by filtration to obtain 1.75 g (90%) of the desired product as a yellow solid.

Step C: 1- (3,4-Diaminophenyl) propan-1-one (1- (3,4-diaminophenyl) propan-1-one)

To a solution of 1- (4-amino-3-nitrophenyl) propan-1-one (1.94 g, 10 mmol) in methanol (50 ml) was added 0.5 g of 10% Pd / C and the mixture was charged with 1 atm of hydrogen. Hydrogenate under gas at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to obtain the desired product (1.48 g, 90%).

Step D: 1- (Benzo [c] [1,2,5] thiadiazol-5-yl) propan-1-one

At 0 ° C., SOCl ₂ (2.6 g, 22 mmol) is added dropwise to a solution of anilinium (1.86 g, 20 mmol) in toluene (50 ml), and then the reaction is refluxed for 2 hours. After cooling to room temperature, 4-propionylorthophenylenediamine (1.65 g, 10 mmol) is added. The reaction was refluxed for 2 hours, then cooled, concentrated and flash chromatographed to yield the desired product (960 mg, 50%) as a yellow solid. 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: 4- {2- (Benzo [c] [1,2,5] thiadiazol-5-yl) -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol

Using the general procedure for the McMurry reaction described in Step D in Example 1, 1- (benzo [c] [1,2,5] thiadiazol-5-yl) propan-1-one (713 mg, 4 mmol), [ 4- (2-Chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (554 mg, 2 mmol) was reacted to obtain the desired product (83 mg, 10%, Z / E = 1: 1).

Step F: 4- [2- (Benzo [c] [1,2,5] thiadiazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] phenol

With stirring, 4- {2- (benzo [c] [1,2,5] thiadiazol-5-yl) -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (83 mg ) In methanol (10 ml) is added 3 ml of methylamine (30% aqueous solution), heated to 85 ° C. and allowed to react for 15 hours. Concentrate under reduced pressure to remove the organic solvent and extract the excess mixture with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate, filtered and concentrated, subjected to column chromatography separation, eluting with dichloromethane / ammonia methanol solution (10/1) to give a yellow solid The desired product (11 mg, Z / E = 1/1) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (s, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.15 sum 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 sum 6.72 (d, J = 8.6 Hz, 2H), 6.48 sum 6.42 (d, J = 8.6 Hz, 2H), 4.12 sum 3.92 (t, J = 4.8 Hz, 2H), 03 sum 2.91 (t, J = 4.8 Hz, 2H), 2.60 (q, J = 7.2 Hz, 2H), 2.55 sum 2.47 (s, 3H), 0.97 (T, J = 7.2 Hz, 3H); m / z = 432 [M + 1] ⁺ .

Example 51
(Z) -4- (2- (1-Methyl-1H-benzo [d] imidazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl) 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 aqueous methylamino is stirred at 100 ° C. for 14 hours, cooled and concentrated under reduced pressure. At 0 ° C., the concentrate is added to 200 ml of 2N aqueous hydrochloric acid. The suspension was filtered and washed with water to obtain the desired product (quantitative) as 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, 1H), 2.98 (s, 3H).

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

4- (Methylamino) -3-nitrobenzoic acid) (29 g, 1.0 eq.) And a mixture of Pd / C (5 g, 10% eq.) In 300 ml of methanol were stirred under hydrogen gas at room temperature for 48 hours. And filter. The filtrate was concentrated under reduced pressure to give 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, 1H), 4.60 (brs, 2H), 2.76 (s, 3H).

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

While stirring, 50 ml of formic acid is added to a solution of 3-amino-4- (methylamino) benzoic acid (9 g, 1.0 equivalent) in 50 ml of water, heated to 85 ° C. and allowed to react overnight. Cool the mixture, concentrate under reduced pressure and dissolve in water. 200 ml of 2N hydrochloric acid aqueous solution is added to adjust the pH value to 1-3. The suspension was filtered and washed with water to give 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), 4.06 (s, 3H).

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

1-methyl-1H-benzo [d] imidazole-5-carboxylic acid (9.7 g, 1.0 eq), EDCI (10.5 g, 1.2 eq), and HOBt (7.4 g, 1.2 eq) ) In dichloromethane (150 ml) was stirred at room temperature for 5 minutes, after which N, O-dimethylhydroxylamine hydrochloride (6.7 g, 1.5 eq) and triethylamine (18.5 g, 4.0 eq) Add. The reaction mixture is stirred at room temperature overnight. Add water and extract with dichloromethane. The extract was dried, concentrated and subjected to column chromatography separation to obtain the desired product (9.5 g, 80%). 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 & 0.8 Hz, 1H), 3.87 (s, 3H), 3.57 (s, 3H), 3.40 (s, 3H ).

Step E: 1- (1-Methyl-1H-benzo [d] imidazol-5-yl) propan-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) at 0 ° C. was added 3M ethylmagnesium bromide (9 ml). , 6.0 eq.) Is added slowly. The reaction mixture is stirred at room temperature overnight, quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The extract was dried, concentrated and subjected to column chromatography separation to obtain the desired product (730 mg, 94%). 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-1H-benzo [d] imidazol-5-yl) but-1-enyl} phenol

Using the general procedure for the McMurry reaction described in Step D in Example 1, with 1- (1-methyl-1H-benzo [d] imidazol-5-yl) propan-1-one (730 mg, 2.2 eq) , [4- (2-chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (500 mg, 1.0 equivalent), and the desired product (Z-isomer and E-isomer are separated by column chromatography). Is possible). 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-1H-benzo [d] imidazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1- Enyl) phenol

With stirring, (Z) -4- {1- [4- (2-chloroethoxy) phenyl] -2- (1-methyl-1H-benzo [d] imidazol-5-yl) but-1-enyl} To a solution of phenol (20 mg, 1.0 equivalent) in methanol (10 ml) is added 5 ml of an aqueous methylamino solution, heated to 85 ° C., and allowed to react for 72 hours. Concentrate under reduced pressure to remove the organic solvent, add water and extract with ethyl acetate. The extract was dried and concentrated, and subjected to column chromatography separation to obtain the desired product (Z-isomer). 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, J = 7 .2 Hz, 3H); m / z = 428 [M + 1] ⁺ .

Example 52
(E) -4- (2- (1-Methyl-1H-benzo [d] imidazol-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl) phenol

(E) -4- {1- [4- (2-chloroethoxy) phenyl] -2- () obtained by column chromatography separation in Example 8 using the same method as described in Step E in Example 1. 1-Methyl-1H-benzo [d] imidazol-5-yl) but-1-enyl} phenol and a methanol solution of methylamino (30% aqueous solution) are refluxed to give the desired product (E-isomer). Got. 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] ⁺ .

Example 53
4- (2- {benzofuran-5-yl} -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl) phenol

Step A: 1- (Benzofuran-5-yl) propan-1-one

1- (2,3-Dihydrobenzofuran-5-yl) propan-1-one (40 g, 1.0 eq) and 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1 , 2-dicarbonitrile (4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitol) (62 g, 1.2 eq) in 400 ml of anhydrous 1,4-dioxane. Reflux overnight, cool to room temperature, quench with saturated sodium bicarbonate solution and extract with ethyl acetate. The extract was washed with saturated brine, dried, concentrated, and subjected to column chromatography separation to obtain the desired product (10.3 g, 26%). 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: 4- {2- [Benzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol

Using the general procedure for the McMurry reaction described in Step D in Example 1, 1- (benzofuran-5-yl) propan-1-one (250 mg, 1.0 eq) and [4- (2-chloroethoxy) Phenyl] (4-hydroxyphenyl) methanone (794 mg, 2.0 equivalents) was reacted to give 480 mg of the desired product (80%, Z / E = 1/1).

Step C: 4- (2- {benzofuran-5-yl} -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl) phenol

With stirring, 4- {2- [benzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (30 mg, 1.0 eq) in methanol (15 ml) To the solution is added 5 ml of aqueous methylamino solution and the mixture is heated to 85 ° C. and allowed to react for 48 hours. Concentrate under reduced pressure to remove the organic solvent, add water and extract with ethyl acetate. The extract was dried, concentrated and subjected to column chromatography separation to obtain the desired product (230 mg, 49%, Z / E = 1/1). 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 = 8.8 Hz, 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] ⁺ .

Example 54
4- [2- (2-Chlorobenzofuran-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] phenol

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

Of 1- (benzofuran-5-yl) propan-1-one (650 mg, 1.0 eq), ethanediol (3.5 g, 15.0 eq), and p-toluenesulfonic acid (65 mg, 0.1 eq) The solution in 20 ml of toluene is refluxed for 72 hours, cooled to room temperature, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, the extract washed with saturated brine, dried and concentrated. Column chromatography separation to obtain the desired product (710 mg, 87%) 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 ( d, 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-dioxolan-2-yl) benzofuran (2-chloro-5- (2-ethyl-1,3-dioxolan-2-yl) benzofuran)

While stirring at 0 ° C., 2.5M n-BuLi was added to a solution of 5- (2-ethyl-1,3-dioxolan-2-yl) benzofuran (350 mg, 1.0 eq) in anhydrous tetrahydrofuran (20 ml). n-Hexane solution (1.6 ml, 2.4 eq) is added dropwise and stirred at 0 ° C. under nitrogen gas protection for 50 minutes. A solution of hexachloroethane (915 mg, 2.4 eq) in anhydrous tetrahydrofuran (10 ml) is added dropwise, stirred at room temperature for 1 hour, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The extract was dried, concentrated and subjected to column chromatography separation to obtain the desired product (260 mg, 65%). 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: 1- (2-Chlorobenzofuran-5-yl) propan-1-one

While stirring at room temperature, a solution of 2-chloro-5- (2-ethyl-1,3-dioxolan-2-yl) benzofuran (250 mg, 1.0 equivalent) in methanol (15 ml) was added to 3 ml of a 3N aqueous hydrochloric acid solution. Add. Stir at room temperature for 30 minutes, quench with saturated aqueous sodium bicarbonate and extract with ethyl acetate. The extract was washed with saturated brine, dried, concentrated, and subjected to column chromatography separation to obtain the desired product (140 mg, 68%). 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: 4- {2- [2-Chlorobenzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol

Using the general procedure for the McMurry reaction described in Step D in Example 1, 1- (2-chlorobenzofuran-5-yl) propan-1-one (140 mg, 1.0 eq) and [4- (2- Chloroethoxy) phenyl] (4-hydroxyphenyl) methanone (371 mg, 2.0 equivalents) was reacted to give the desired product (220 mg, 72%, Z / E = 1/1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.16 sum 7.10 (d, J = 8. 6 Hz, 2H), 7.00 sum 6.99 (d, J = 8.4 Hz, 1H), 6.90 sum 6.81 (d, J = 8.6 Hz, 2H), 6.76 sum 6.70 (d, J = 8.8 Hz, 2H), 6.52 sum 6.44 (d, J = 9.0 Hz, 2H), 6.45 (s, 1H), 4.73 sum 4 .48 (s, 1H), 4.26 sum 4.08 (t, J = 6.0 Hz, 2H), 3.83 sum 3.72 (t, J = 6.0 Hz, 2H), 50 (q, J = 7.2 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H).

Step E: 4- [2- (2-Chlorobenzofuran-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] phenol

Methanol of 4- {2- [2-chlorobenzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (220 mg, 1.0 eq) with stirring (15 ml) To the solution is added 5 ml of an aqueous methylamine solution, heated to 85 ° C., and allowed to react for 48 hours. Concentrate under reduced pressure to remove the organic solvent, add water and extract with ethyl acetate. The extract was dried, concentrated, and subjected to column chromatography separation to obtain the desired product (105 mg, 48%, Z / E = 1/1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.14 sum 7.08 (d, J = 8. 4 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.87 sum 6.78 (d, J = 8.8 Hz, 2H), 6.73 sum 6.69 ( d, J = 8.8 Hz, 2H), 6.49 sum 6.42 (d, J = 8.6 Hz, 2H), 6.45 (s, 1H), 4.10 sum 3.92 (t , J = 5.0 Hz, 2H), 3.00 sum 2.89 (t, J = 5.0 Hz, 2H), 2.53 sum 2.46 (s, 3H), 2.50 (q, J = 7.6 Hz, 2H), 0.91 (t, J = 7.6 Hz, 3H); m / z = 448 [M + 1] ⁺ .

Example 55
(Z) -4- [2- (2-Chlorobenzofuran-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] phenol

The Z / E mixture separated in Example 11 was prepared by HPLC to obtain the desired product (Z-isomer). 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, 3H); m / z = 448 [M + 1] ⁺ .

Example 56
(E) -4- [2- (2-Chlorobenzofuran-5-yl) -1- {4- [2- (methylamino) ethoxy] phenyl} but-1-enyl] phenol

The Z / E mixture separated in Example 11 was prepared by HPLC to obtain the desired product (E-isomer). 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] ⁺ .

Example 57
(Z) -2- {4- [2- (2-Chlorobenzofuran-5-yl) -1- (4-methoxyphenyl) but-1-enyl] phenoxyl} -N-methylethylamine

Step A: 2-Chloro-5- {1- [4- (2-chloroethoxy) phenyl] -1- [4-methoxyphenyl] but-1-enyl-2-yl} benzofuran

Using the general procedure for the McMurry reaction described in Step D in Example 1, 1- (2-chlorobenzofuran-5-yl) propan-1-one (200 mg, 1.0 eq) and [4- (2- Chloroethoxy) phenyl] (4-methoxyphenyl) methanone (418 mg, 1.5 eq, prepared in Step B in Example 1) to give the desired product (440 mg, 98%, Z / E = 1 / 1) was obtained.

Step B: (Z) -2- {4- [2- (2-Chlorobenzofuran-5-yl) -1- (4-methoxyphenyl) but-1-enyl] phenoxyl} -N-methylethylamine

Using the same method as described in Step E in Example 1, 2-chloro-5- {1- [4- (2-chloroethoxy) phenyl] -1- [4-methoxyphenyl] but-1-enyl-2 -Il} benzofuran (440 mg, 1.0 eq) and methylamine (30% aqueous solution, 10 ml) in methanol (20 ml) were refluxed to give the (Z-isomer) product (Z-isomer and E The isomers can be separated by column chromatography). 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] ⁺ .

Example 58
4- [1- {4- [2- (Azepan-1-yl) ethoxy] phenyl} -2- (2-chlorobenzofuran-5-yl) but-1-enyl] phenol

Using the same method as described in Step E in Example 1, 4- {2- [2-chlorobenzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (220 mg, 1.0 equivalent, prepared in Step D in Example 11) and a methanol solution of azepane (500 mg) were refluxed to give the desired product (105 mg, 48%, Z / E = 1/1) was obtained. 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 -4.48 (m, 1H), 4.25-4.27 (m, 1H), 3.00-3.71 (m, 6H), 2.44-2.51 (m, 2H), 1 . 73-2.00 (m, 8H), 0.91 (t, J = 7.6 Hz, 3H); m / z = 516 [M + 1] ⁺ .

Example 59
4- [2- (2,3-Dihydrobenzofuran-5-yl) -1- {6- [2- (methylamino) ethoxy] pyridin-3-yl} but-1-enyl] phenol

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

Magnesium waste (1.67 g, 1.2 eq) is placed in anhydrous THF (50 ml) and heated to 55 ° C., 2 tablets of iodine are added, followed by 0.1 ml of bromoethane. 2- (4-Bromophenoxy) tetrahydro-2H-pyran (16 g, 1.1 eq) is dissolved in THF and a portion of this solution is taken and added to the Mg-THF mixture. After causing the reaction, excess of the above solution is dropped into the mixed solution, and the reaction solution is refluxed for 2 hours to prepare and place a Grignard reagent. 6-chloronicotinoyl chloride (10.0 g, 1 eq) is dissolved in anhydrous THF, cooled to 0 ° C. under nitrogen gas protection and the Grignard reagent is added within 20 minutes. The mixture is warmed to room temperature and stirred overnight. Add water and extract with ethyl acetate. Concentrate the extract and perform column chromatography separation, eluting with petroleum ether / ethyl acetate (5/1) to give (6-chloropyridin-3-yl) [4- (tetrahydro-2H-pyran-2- The desired product (13.6 g, 76%) of oxy) phenyl] methanone was 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 = 8.0 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), 83-3.90 (m, 1H), 3.63-3.67 (m, 1H), 2.02-2.05 (m, 1H), 1.89-1.92 (m, 2H), 1.69-1.75 (m, 2H), 1.59-1.65 (m, 1H)

Step B: 4- [1- (6-Chloropyridin-3-yl) -2- (2,3-dihydrobenzofuran-5-yl) but-1-enyl] phenol

Using the general procedure for the McMurry reaction described in Step D in Example 1, 1- (2,3-dihydrobenzofuran-5-yl) propan-1-one (610 mg, 1.1 eq., Step A in Example 1) And (6-chloropyridin-3-yl) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone (1.0 g, 1.0 equivalent). The product (440 mg, 37%, Z / E = 1/1) was obtained.

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

While stirring at 0 ° C., NaH (373 mg, 8.0 eq) was added to a solution of 2- (methylamino) -ethanol (875 mg, 10 eq) in anhydrous THF (20 ml) and the mixture was stirred at room temperature for 1 h. 4- [1- (6-chloropyridin-3-yl) -2- (2,3-dihydrobenzofuran-5-yl) but-1-enyl] phenol (440 mg, 1.0 eq) was added. To do. The mixture is refluxed for 16 hours, cooled, quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The extract was dried, concentrated, and subjected to column chromatography separation to obtain the desired product (197 mg, 41%). 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 H , 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] ⁺ .

Example 60
4- [2- (2-Chlorobenzofuran-5-yl) -1- {4- [2- (pyrrolidin-1-yl) ethoxy] phenyl} but-1-enyl] phenol

Using the same method as described in Step E in Example 1, 4- {2- [2-chlorobenzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (70 mg, 1.0 equivalent) and a solution of pyrrolidine (1 ml) in methanol (3 ml) were refluxed to give the desired product (51 mg, 68%, Z / E = 1 / 2.6) as a yellow solid. Obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24 (s, 1H), 7.20 (d, J = 9.2 Hz, 1H), 7.09 sum 7.06 (d, J = 8. 4 Hz, 2H), 7.00 (d, J = 8.8 Hz, 1H), 6.78 sum 6.72 (d, J = 8.2 Hz, 2H), 6.68 (d, J = 8.6 Hz, 2H), 6.46 sum 6.45 (s, 1H), 6.41 sum 6.27 (d, J = 8.4 Hz, 2H), 4.10 sum 3.89 (t , J = 5.8 Hz, 2H), 2.94 sum 2.83 (t, J = 6.2 Hz, 2H), 2.68 sum 2.61 (m, 4H), 2.49 (q, J = 7.4 Hz, 2H), 1.84 sum 1.81 (m, 4H), 0.91 (t, J = 7.4 Hz, 3H); m / z = 488 [M + 1] ⁺ .

Example 61
4- [2- (2-Chlorobenzofuran-5-yl) -1- {4- [2- (piperidin-1-yl) ethoxy] phenyl} but-1-enyl] phenol

Using the same method as described in Step E in Example 1, 4- {2- [2-chlorobenzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (70 mg, 1.0 equivalent) and a solution of piperidine (1 ml) in methanol (3 ml) were refluxed to obtain the desired product (63 mg, 82%, Z / E = 1/1) as a pale yellow solid. It was. 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. (M, 6H), 1.47-1.68 (m, 6H), 0.89-0.93 (m, 3H); m / z = 502 M + ^1] +.

Example 62
4- {2- (2-Chlorobenzofuran-5-yl) -1- [4- (2-morpholinoethoxy) phenyl] but-1-enyl} phenol

Using the same method as described in Step E in Example 1, 4- {2- [2-chlorobenzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (70 mg, 1.0 equivalent) and a solution of morpholine (1 ml) in methanol (3 ml) were refluxed to obtain the desired product (61 mg, 79%, Z / E = 1/2) as a pale yellow solid. It was. 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 = .2 Hz, 3H); m / z = 504 [M + 1] +.

Example 63
4- [2- (2-Chlorobenzofuran-5-yl) -1- {4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} but-1-enyl] phenol

Using the same method as described in Step E in Example 1, 4- {2- [2-chlorobenzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (70 mg, 1.0 equivalent) and a solution of N-methylpiperazine (1 ml) in methanol (8 ml) were refluxed to give the desired product (60 mg, 76%, Z / E = 1/1) as a yellow solid. .7) was obtained. 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 2.31. 82 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H); m / z = 517 [M + 1] ⁺ .

Example 64
4- [2- (2-Chlorobenzofuran-5-yl) -1- {4- [2- (diethylamine) ethoxy] phenyl} but-1-enyl] phenol

Using the same method as described in Step E in Example 1, 4- {2- [2-chlorobenzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (70 mg, 1.0 equivalent) and a solution of diethylamine (3 ml) in methanol (8 ml) were refluxed to give the desired product as a brown solid (61 mg, 81%, Z / E = 1 / 1.25) Got. 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), 0.9 (T, J = 7.6 Hz, 3H); m / z = 490 [M + 1] +.

Example 65
4- [2- (2-Chlorobenzofuran-5-yl) -1- {4- [2- (ethylamino) ethoxy] phenyl} but-1-enyl] phenol

Using the same method as described in Step E in Example 1, 4- {2- [2-chlorobenzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (70 mg, 1.0 equivalent) and a solution of ethylamine (3 ml) in methanol (8 ml) were refluxed to give the desired product (38 mg, 54%, Z / E = 1 / 1.2) as a white solid. Got. 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), 0.9 (T, J = 7.2 Hz, 3H); m / z = 462 [M + 1] +.

Example 66
4- [2- (2-Chlorobenzofuran-5-yl) -1- {4- [2- (dimethylamino) ethoxy] phenyl} but-1-enyl] phenol

Using the same method as described in Step E in Example 1, 4- {2- (2-chlorobenzofuran-5-yl) -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (70 mg, 1.0 equivalent) and a solution of dimethylamine (1 ml) in methanol (8 ml) were refluxed to give 20 mg of the desired product (27 mg, 38%, Z / E = 1 / 1.2) as a white solid. Got. 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 = 4 2 [M + ^1] +.

Example 67
4- [2- (2-Chlorobenzofuran-5-yl) -1- {4- [2- (piperazin-1-yl) ethoxy] phenyl} but-1-enyl] phenol

Using the same method as described in Step E in Example 1, 4- {2- [2-chlorobenzofuran-5-yl] -1- [4- (2-chloroethoxy) phenyl] but-1-enyl} phenol (70 mg, 1.0 equivalent, prepared in Reaction Step D in Example 11) and a methanol (3 ml) solution of N-Boc piperazine (500 mg) were refluxed and subjected to column chromatography separation. Then, after treating with a solution of trifluoroacetic acid (1 ml) in dichloromethane (3 ml), column chromatography separation was performed to obtain the desired product (Z / E = 1/1). m / z = 503 [M + 1] ⁺ .

Example 68
4- [2- (2-Chlorobenzofuran-5-yl) -1- {6- [2- (methylamino) ethoxy] pyridin-3-yl} but-1-enyl] phenol

Using the same method as described in Step C in Example 16, 4- [2- (2-chlorobenzofuran-5-yl) -1- (6-chloropyridin-3-yl) but-1-enyl] phenol ( 70 mg, 1.0 equivalent) and 2- (methylamino) -ethanol (128 mg, 10 equivalents) were reacted to obtain the desired product (Z / E = 1/1). m / z = 449 [M + 1] ⁺ .

Example 69
4- [2- (2-Chlorobenzofuran-5-yl) -1- {6- [2- (methylamino) ethylthio] pyridin-3-yl} but-1-enyl] phenol

Step A: 2- (Methylamino) ethanol hydrochloride

A solution of 2- (methylamino) ethanol (20 g, 1.0 equivalent) in 50 ml of concentrated hydrochloric acid was stirred at room temperature for 2 hours and then concentrated to obtain the desired product (quantitative). ¹ H NMR (400 MHz, DMSO-d6) 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-methylethanamine hydrochloride

Thionyl chloride (41 g, 1.3 eq) is added dropwise to a solution of 2- (methylamino) ethanol hydrochloride (29.7 g, 1.0 eq) in 150 ml chloroform with stirring at 0 ° C. After refluxing for 3 hours, it was cooled to room temperature. The solvent was removed by concentration under reduced pressure, and the concentrate was added to 100 ml of 1:10 dichloromethane / petroleum ether solution and filtered to obtain the desired product (28 g, 80%). ¹ H NMR (400 MHz, DMSO-d6) 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) ethylthio hydrochloride

To a solution of 2-chloro-N-methylethylamine hydrochloride (15 g, 1.0 eq) in 150 ml water with stirring, Na ₂ S ₂ O ₃ (18.5 g, 1.0 eq) was added and the mixture Is heated to reflux for 48 hours. After cooling to room temperature, the solvent was removed by concentration under reduced pressure, and the concentrate was subjected to column chromatography separation to obtain the desired product. ¹ H NMR (400 MHz, DMSO-d6) δ 4.95 (brs, 2H), 2.90 (s, 4H), 2.37 (s, 3H).

Step D: 4- [2- (2-Chlorobenzofuran-5-yl) -1- {6- [2- (methylamino) ethylthio] pyridin-3-yl} but-1-enyl] phenol

Using the same method as described in Step C in Example 16, 4- [2- (2-chlorobenzofuran-5-yl) -1- (6-chloropyridin-3-yl) but-1-enyl] phenol ( 70 mg, 1.0 equivalent) and 2- (methylamino) ethylthio hydrochloride (217 mg, 10 equivalents) were reacted to obtain the desired product (Z / E = 1/1). m / z = 465 [M + 1] ⁺ .

Example 70
4- [2- (2-Chlorobenzofuran-5-yl) -1- (6- {methyl [2- (methylamino) ethyl] amino} pyridin-3-yl) but-1-enyl] phenol

Using the same method as described in Step C in Example 16, 4- [2- (2-chlorobenzofuran-5-yl) -1- (6-chloropyridin-3-yl) but-1-enyl] phenol ( 70 mg, 1.0 equivalent) and N, N′-dimethylethylenediamine (150 mg, 10 equivalents) were reacted to obtain the desired product (Z / E = 1/1). m / z = 462 [M + 1] ⁺ .

Example 71
4- [2- (2-Chlorobenzofuran-5-yl) -1- {6- [3- (pyrrolidin-1-yl) propyl] pyridin-3-yl} but-1-enyl] phenol

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

4-Iodophenol (10.0 g, 45.5 mmol) is dissolved in 20 ml of 3,4-dihydro-2H-pyran, 1 drop of concentrated sulfuric acid is added, the mixture is stirred for 30 minutes, and then 1000 ml of n-hexane is added. The product was added, filtered, washed with 300 ml of hexane (100 ml × 3), and vacuum-dried to obtain 9.1 g (65.9%) of the desired 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 was stirred at room temperature for 1 hour and concentrated under reduced pressure. The resulting concentrate was dissolved in 50 ml of dichloromethane and this solution was dissolved in N, O-dimethylhydroxylamine hydrochloride (12.4 g, 126.9 mmol) and triethylamine (25.7 g, 253.9 mmol) in dichloromethane. (100 ml) was added to the solution, stirred at room temperature for 1 hour, concentrated, and subjected to column chromatography separation to obtain the desired product (9.4 g, 73.8%) as a colorless oil.

Step C: 1- (prop-2-ynyl) pyrrolidine (1- (prop-2-ynyl) pyrrolidine)

At −10 ° C., propargyl bromide (Bromoprop-1-yne, 60.5 g, 0.50 mol) is gradually added dropwise to pyrrolidine (70.1 g, 1.0 mol). When the addition was completed, the reaction solution was stirred overnight at room temperature and distilled in a rectifying column to obtain the desired product (45.5 g, 83.5%) as a colorless oil.

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

Under nitrogen gas protection, 2- (4-iodophenoxy) tetrahydro-2H-pyran (18.2 g, 59.9 mmol) was dissolved in 100 ml of dry THF, cooled to −78 ° C., and then n- Butyl lithium is added dropwise. When the addition was complete, the mixture was stirred at −78 ° C. for 0.5 h, then 2-chloro-N-methoxy-N-methyl-5-pyridinecarboxamide (8.0 g, 39.9 mmol) in THF (50 ml). ) Add the solution dropwise and react for 2 hours while maintaining at -78 ° C. Thereafter, 100 ml of saturated ammonium chloride is added and quenched, and the mixture is extracted with ethyl acetate. The extract was dried over sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography separation to obtain the desired product (8.4 g, 66.3%) as a yellow solid.

Step E: {6- [3- (Pyrrolidin-1-yl) prop-1-ynyl] pyridin-3-yl} [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone

In a 100 ml Schlenk flask, (6-chloropyridin-3-yl) [4- (tetrahydro-2H-pyran-2-oxy) phenyl] methanone (4.0 g, 12.6 mmol), tetrakis (triphenylphosphine) palladium. (1.5g, 1.3mmol, 10mol%) , CuI (0.48g, 2.5mmol, 20mol%), Et 3 N (50ml), and N- propynyl pyrrolidine (2.8 g, 25.2 mmol) added To do. The flask is flushed with nitrogen gas three times and the mixture is allowed to react at 80 ° C. for 2 hours. The solvent was removed by concentration under reduced pressure, and the concentrate was subjected to column chromatography separation to obtain the desired product (2.2 g, 44.9%) as a yellow solid.

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

At room temperature, Raney nickel (0.3 g, 0.6 mmol, 10 mol%) was added to 6- [3- (pyrrolidin-1-yl) prop-1-ynyl] pyridin-3-yl} [4- (tetrahydro-2H— Pyran-2-oxy) phenyl] methanone (2.2 g, 5.6 mmol) is added to a methanol (20 ml) solution and the mixture is stirred under hydrogen gas for 1 hour. The nickel was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the desired product (1.7 g, 77.3%).

Step G: 4- [2- (2-Chlorobenzofuran-5-yl) -1- {6- [3- (pyrrolidin-1-yl) propyl] pyridin-3-yl} but-1-enyl] phenol

Using the generic step for the McMurry reaction described in Step D in Example 1, {6- [3- (pyrrolidin-1-yl) propyl] pyridin-3-yl} [4- (tetrahydro-2H-pyran-2- Oxy) phenyl] methanone and 1- (2-chlorobenzofuran-5-yl) propan-1-one were reacted to obtain the desired product (Z / E = 1/1). m / z = 487 [M + 1] ⁺ .

Biological activity Measurement of IC ₅₀ value In vitro inhibition (inhibition) of antiestrogenic activity in MCF-7 cells
Human breast cancer cells MCF-7 (# HTB-22, manufactured by ATCC) with high expression of estrogen receptor α were added to DMEM (10% fetal bovine serum (Gibco®) and 10 μg / ml bovine insulin supplemented). Keep in Sigma® medium. Cells were cultured in 15 ml medium in a 75 cm ² plastic tissue (cell) culture flask (Corning®) in an environment of 95% air and 5% CO ₂ at 37 ° C. to obtain a monolayer cell culture And subculture twice a week.

Regarding the test for 17β-estradiol (E2), cells in logarithmic growth phase are subjected to E2 removal treatment two days in advance. That is, in order to replace the DMEM medium containing phenol red with DMEM / F12 medium not containing phenol red, remove steroids contained in the medium, and reduce the level of hormone as much as possible, Replace with FBS treated with activated carbon. Cells 96-well cell culture plate - Doo (Corning (R)), were seeded at a density of 4 × 10 ³ / well, 24 hours at DMEM / F12 medium without _{E 2} (37 ℃, CO ₂ 5%) was cultured. The compound used for the test is dissolved and stored in DMSO (0.01 M), and after DMSO is diluted with a gradient, it is diluted with a medium and then added to the prepared cells, and at the same time, an appropriate concentration of E2 is added. . The final concentration of the compound is 3 × 10 ⁻¹⁰ to 1 × 10 ⁻⁵ M, and the final concentration of DMSO is 0.1%. The cells are cultured for 7 days at 37 ° C., and the medium containing the compound and E2 is changed once every two days to maintain chemical activity.

After 7 days, the number of surviving cells is calculated by the number of ATP converted from luciferase (Cell Tire Glo® luciferase kit, Promega®). According to such a method, estrogenicity stimulated by estrogen-dependent cell growth under conditions that do not contain estrogen can be evaluated. The maximum stimulation with E ₂ as 100%, it is possible to calculate the percentage of stimulation. In the test, when calculating the percentage of the antagonistic effect, the suppression (inhibition) at the compound concentration of 1 × 10 ⁻⁵ M is regarded as complete suppression (100%). Suppression curves and suppression IC ₅₀ values are obtained by the software Prism® 5.

Biological data of selected compounds The preferred compounds prepared above were analyzed by the biological methods described herein. The results are shown in the following table.

  The compounds disclosed by the present invention show strong antiestrogenic activity against MCF-7.

Toxicity Further studies have confirmed that the compounds of the present invention have relatively weak toxicity.

As is apparent from the drawings and the table below, nude mice were given tamoxifen (TAMifen, TAM) (20 mg / kg) for 21 days, the body weight was reduced by 20%, and representative compounds of the present invention (CT When administered at a high dose of 30 mg / kg, the body weight increased by 7%.

PO: oral (per os);
QD: once a day (quapua die);
TGI: Target Group Index (Target Group Index);
BW: Weight (Body Weight)

  Although several embodiments of the present invention have been described in detail in the above examples, the scope of the claims of the present invention is not limited by these embodiments. For those skilled in the art, various changes and improvements can be made without departing from the scope of the present invention. It is obvious that all such changes and improvements belong to the protection scope of the present invention. Therefore, the claims of the present invention should be based on the appended claims.

Claims (13)

Compound represented by formula (I):

(In the formula (I),
R ⁰ and R ¹ are each independently selected from hydrogen, halogen, alkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein alkyl group, cycloalkyl group, heterocyclic group , Aryl groups and heteroaryl groups are independently optionally substituted with one or more groups selected from halogen, —OH, —NH ₂ , —SH, alkyl groups, halogenated alkyl groups, and alkoxy groups. And carbon atoms of the cycloalkyl group, heterocyclic group and heteroaryl group may optionally be oxidized,
A ring and B ring are each independently selected from an aryl group, a heteroaryl group and a heterocyclic group, and the carbon atoms of the heterocyclic 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 heterocyclic group, an alkoxy group, An alkylthio group, a cycloalkoxy group, a heterocycloalkoxy group, a monoalkylamino group, a dialkylamino group, a —S (O) -alkyl group, and a —S (O) ₂ -alkyl group, wherein the alkyl group , Alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, alkoxy group, alkylthio group, cycloalkoxy group, heterocycloalkoxy group, monoalkylamino group, dialkylamino group, -S (O) -alkyl group, and- S _{(O) 2} - alkyl group is optionally independently halogen, -OH, a heterocyclic group, or, May be substituted with NR ⁴ R ^5, therein, ^{R 4} and ^{R 5} are each independently hydrogen, an alkyl group, selected from cycloalkyl, or, ^{R 4} and ^{R 5} are attached thereto Together with the nitrogen atom, a heterocyclic group may be optionally substituted with an alkyl group;
m and n are respectively 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 . )
Or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof. A compound according to claim 1 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 heterocyclic group, an aryl group and a heteroaryl group, and the alkyl group, cycloalkyl group, heterocyclic group, aryl group and hetero group The aryl group may optionally be substituted with one or more groups selected from halogen, —OH, alkyl group, halogenated alkyl group, and alkoxy group, and the cycloalkyl group, hetero The carbon atoms of the ring group and heteroaryl group may optionally be 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, heterocyclic group, aryl group, and heteroaryl group are independently May be substituted with one or more groups selected from halogen, —OH, alkyl groups, and alkoxy groups, and carbon atoms of the cycloalkyl groups and heteroaryl groups may be optionally oxidized. Well or
One of R ⁰ and R ¹ is an alkyl group or an alkyl halide, 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 is optionally selected from halogen, —OH, alkyl groups, alkoxy groups and alkyl halides A thienyl group optionally substituted with one or more halogens, which may be substituted with one or more groups
b) a 6-membered heteroaryl group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, wherein said heteroaryl group is optionally halogen, —OH, alkyl group, alkoxy group and halogenated One or more groups selected from alkyl may be substituted, and the carbon atom in the heteroaryl group may be optionally oxidized, preferably, optionally substituted with one or more —OH. A pyridinyl group,
c) a 5- or 6-membered cycloalkyl group, wherein the cycloalkyl group is independently optionally substituted with one or more groups selected from halogen, —OH, alkyl groups, alkoxy groups and alkyl halides And the carbon atom in the cycloalkyl group may be optionally oxidized, preferably a cyclohexanone group or a cyclohexyl group, optionally substituted with one or more —OH,
d) a phenyl group, wherein the phenyl group may optionally be substituted with one or more groups selected from halogen, —OH, alkyl groups and alkoxy groups. A compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof,
One of R ⁰ and R ¹ is selected from hydrogen, halogen and an alkyl group, wherein the alkyl group may independently be optionally substituted with a halogen, —OH, NH ₂ or alkoxy group; Or an alkyl group optionally substituted with one or more halogens, and
Another of R ⁰ and R ¹ has the structure represented by the general formula (II),

In the structure represented by the general formula (II), a dotted line indicates that a 5-membered ring composed of X, Y and W and a carbon atom bonded thereto is saturated or unsaturated,
Here, X, Y and W are each independently selected from C, N, O and S, and the 5-membered ring is optionally halogen, —OH, —SH, an alkyl group, a cycloalkyl group, an alkoxy group. And may be substituted with one or more groups selected from a group and an alkylthio group, in which the alkyl group, cycloalkyl group, alkoxy group and alkylthio group may independently be optionally halogen, —OH, —NH ₂ , may be substituted with one or more groups selected from a monoalkylalkyl group, a dialkylamino group and a heterocyclic group, or
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 with one or more groups selected from a halogen and an alkyl group. Well or
Formula (II) is selected from the following structures:
A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or prodrug thereof,
The A ring and the B ring are each independently selected from an aryl group and a heteroaryl group, wherein carbon atoms of the heteroaryl group may be optionally oxidized, or
The A ring and B ring are each independently selected from an aryl group and a 6-membered heteroaryl group containing one or two nitrogen atoms, wherein the carbon atoms of the heteroaryl group are optionally oxidized. Or
The A ring and B ring are each independently selected from phenyl and pyridinyl groups. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or prodrug thereof,
R ² and R ³ are each independently halogen, —OH, —NH ₂ , —CN, alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, heterocycloalkoxy group, monoalkylamino group, And a dialkylamino group, wherein the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, heterocycloalkoxy group, monoalkylamino group, and dialkylamino group are independently optionally substituted with halogen, -OH , A heterocyclic group, or substituted with —NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are each independently selected from hydrogen, alkyl groups, and cycloalkyl groups, or R ⁴ and R ⁵ Together with the nitrogen atom bonded to them form one heterocyclic group, Group may be substituted with an alkyl group, or,
R ² and R ³ are each independently halogen, —OH, —NH ₂ , —CN, alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, heterocycloalkoxy group, monoalkylamino group, And 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 are each independently an optionally substituted heterocyclic group, Or may be substituted with —NR ⁴ R ⁵ , in which R ⁴ and R ⁵ are each independently selected from a halogen or an alkyl group, or are bonded to R ⁴ and R ⁵ with them. Together with the nitrogen atom, a heterocyclic group is optionally formed It may be substituted with kill group. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or prodrug thereof,
The ring A is selected from a phenyl group and a 6-membered heteroaryl group, and has at least one R ² group in the para-coordination of the phenyl group or the 6-membered heteroaryl group, or
The ring B is selected from a phenyl group and a 6-membered heteroaryl group, and has at least one R ³ group in the para-coordination of the phenyl group or the para-coordination of the 6-membered heteroaryl group. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or prodrug thereof,
The m and n are each independently selected from 1 or 2. A compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or prodrug thereof,
The compound is selected from the following:




  9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorph, tautomer, or for modulating estrogenic activity, or Prodrug.   The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline polymorphism thereof for preventing and / or treating estrogen-dependent diseases and symptoms. Form, tautomer, or prodrug.   9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or prodrug thereof, and a pharmaceutically acceptable. A pharmaceutical composition comprising a carrier.   A pharmaceutically effective amount of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, solvate, crystal polymorph, tautomer, or prodrug thereof. A method of preventing and / or treating an estrogen-dependent disease and condition in a mammal, particularly a human, comprising administering to the mammal, especially a human in need.   Estrogen-dependent diseases and diseases include menopause or postmenopausal disorders, vasomotor symptoms, urinary genital or vulvar atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, cancer, depression, diabetes, bone 13. The method of claim 12, wherein the method is selected from the group consisting of decalcification and osteoporosis.