WO2013097773A1 - Nouveaux dérivés d'arylalcène et utilisation de ceux-ci en tant que modulateurs sélectifs de récepteur d'œstrogène - Google Patents

Nouveaux dérivés d'arylalcène et utilisation de ceux-ci en tant que modulateurs sélectifs de récepteur d'œstrogène Download PDF

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WO2013097773A1
WO2013097773A1 PCT/CN2012/087884 CN2012087884W WO2013097773A1 WO 2013097773 A1 WO2013097773 A1 WO 2013097773A1 CN 2012087884 W CN2012087884 W CN 2012087884W WO 2013097773 A1 WO2013097773 A1 WO 2013097773A1
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Prior art keywords
alkyl
phenyl
group
halogen
ring
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PCT/CN2012/087884
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English (en)
Inventor
Dengming Xiao
Li Zhu
Yuandong Hu
Rong Yu
Wei Hu
Na Zhao
Yong Peng
Hong Luo
Yongxin Han
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Centaurus Biopharma Co., Ltd.
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Priority claimed from CN2011104578981A external-priority patent/CN102584687A/zh
Priority claimed from CN2011104561181A external-priority patent/CN102532073A/zh
Application filed by Centaurus Biopharma Co., Ltd. filed Critical Centaurus Biopharma Co., Ltd.
Priority to KR1020147022291A priority Critical patent/KR20150039705A/ko
Priority to JP2014549345A priority patent/JP2015504049A/ja
Priority to AU2012361344A priority patent/AU2012361344A1/en
Priority to CA2861939A priority patent/CA2861939A1/fr
Priority to CN201280065593.9A priority patent/CN105658628A/zh
Priority to EP12863580.2A priority patent/EP2797889A4/fr
Priority to US14/369,936 priority patent/US9309211B2/en
Publication of WO2013097773A1 publication Critical patent/WO2013097773A1/fr

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    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/28—Halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a series of ethylene derivatives which are selective estrogen receptor modulators (SERMs), a pharmaceutical composition thereof, use thereof in the preparation of a medicament, and a method for preventing and/or treating estrogen-dependent diseases and conditions in mammals, especially humans, by using the same.
  • SERMs selective estrogen receptor modulators
  • Estrogen receptor is an important transcription factor which plays a key role in reproductive, cardiovascular and central nervous systems and bone tissue.
  • tissues or organs containing ER including for example uterus, vagina, breast, pelvic cavity (anadesma and connective tissues), skin, urocyst, urethra, ossature and brain.
  • the secretion of estrogens is dramatically decreased, and the tissues, organs and systems related to estrogen change accordingly.
  • Estrogen replacement therapy is increasingly used for the treatment of climacteric symptoms in women. Estrogen replacement therapy is also shown to be beneficial in decreasing the risk of osteoporotic bone fractures, preventing Alzheimer's disease (Henderson VW: Estrogen, cognition, and as woman 's risk of Alzheimer 's disease. Am J Med 103 (3A): 11 S-18S, 1997) and lowering LDL-cholesterol values and thus preventing cardiovascular diseases (Grodstein F, Stampfer, MJ: Estrogen for women at varying risk of coronary disease. Maturitas 30: 19-26, 1998). However, use of estrogen replacement therapy increases the risk of uterine and breast cancers (Lobo RA: Benefits and risks of estrogen replacement therapy. Am J Obstet Gynecol 173:982-990, 1995).
  • SERMs Selective estrogen receptor modulators
  • Raloxifene exhibits ER antagonism in breast and uterus and ER agonism in bone tissue and cardiovascular system.
  • Raloxifene has no advantage over Tamoxifen in terms of therapeutic effect on breast cancer, while it has adverse effects such as hot flashes, leg cramps, headache and weight gain (Davies GC, et al, Obstet Gynecol 193: 558-565(1999)).
  • R° and R 1 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen, -OH, -NH 2 , -SH, alkyl, halogenated alkyl, and alkoxy, and the carbon atoms on the ring of the cycloalkyl, the heterocyclyl and the heteroaryl are optionally oxidized;
  • ring A and ring B are each independently selected from aryl, heteroaryl and heterocyclyl, wherein the carbon atoms on the ring of the heterocyclyl and the heteroaryl are optionally oxidized;
  • R 2 and R 3 are independently selected from the group consisting of halogen, -OH, -NH 2 , -CN, -SH, -COOH, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy, alkylsulfanyl, cycloalkyloxy, heterocyclyloxy, monoalkylamino, dialkylamino, -S(0)-alkyl and -S(0)2-alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy, alkylsulfanyl, cycloalkyloxy, heterocyclyloxy, monoalkylamino, dialkylamino, -S(0)-alkyl and -S(0)2-alkyl are each optionally substituted with halogen, -OH, heterocyclyl, or -NR 4 R 5 , wherein R4 and R5 are each independently hydrogen,
  • n and n are the number of group R 2 on ring A and the number of group R 3 on ring B, respectively, and m and n are each independently 0, 1, 2 or 3,
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, for modulating estrogen activities.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, for preventing and/or treating estrogen-dependent diseases and conditions.
  • the present invention provides a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, as well as a pharmaceutically acceptable carrier.
  • the present invention provides use of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, in the manufacture of a medicament for modulating estrogen activities.
  • the present invention provides use of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, in the manufacture of a medicament for preventing and/or treating estrogen-dependent diseases and conditions.
  • the present invention provides a method for modulating estrogen activities in mammals, especially in humans, which method comprises administering to a mammal, especially a human, in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof.
  • the present invention provides a method for preventing and/or treating estrogen-dependent diseases and conditions in mammals, especially in humans, which method comprises administering to a mammal, especially a human, in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof.
  • Figure 1 shows weight change of nude mice during anti -tumor (MCF-7) test.
  • Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.
  • groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.
  • substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left.
  • -CH 2 0- is equivalent to -OCH 2 -.
  • Ci-C alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms.
  • the total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.
  • Halo or "halogen” refers to bromo, chloro, fluoro or iodo.
  • aromatic refers to a planar, cyclic or polycyclic, ring moiety having a delocalized at-electron system containing 4n+2 n electrons, where n is an integer.
  • Aromatic rings can be formed by five, six, seven, eight, nine, or more than nine atoms.
  • Aromatics can be optionally substituted and can be monocyclic or fused- ring polycyclic.
  • aromatic encompasses both all carbon containing rings (e.g., phenyl) and those rings containing one or more heteroatoms (e.g., pyridine).
  • heteroatom or “hetero” as used herein, alone or in combination, refer to an atom other than carbon and hydrogen. Heteroatoms are independently selected from among oxygen, nitrogen, sulfur, phosphor, silicon, selenium and tin but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.
  • fused refers to cyclic structures in which two or more rings share one or more bonds.
  • alkyl refers to a straight or branched mono-valent hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms and more preferably one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like.
  • alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined above.
  • alkoxy radical include, but not limited to, methoxy, ethoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
  • alkylsulfanyl refers to a radical of the formula -SR a where R a is an alkyl radical as defined above.
  • alkylsulfanyl radical include, but not limited to, methylsulfanyl, ethylsulfanyl, iso-propylsulfanyl, and the like.
  • the term "monoalkylamino" refers to a radical of the formula -NHR a where R a is an alkyl radical as defined above.
  • Examples of the monoalkylamino radical include, but not limited to, methylamino, ethylamino, iso-propylamino, and the like.
  • dialkylamino refers to a radical of the formula -NR a R b where R a and R b are each independently an alkyl radical as defined above.
  • dialkylamino radical include, but not limited to, dimethylamino, diethylamino, dipropylamino, methylethylamino, and the like.
  • alkenyl refers to a straight or branched mono-valent hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to fourteen carbon atoms, preferably from two to ten carbon atoms, more preferably form two to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-l-enyl, allyl, but-l-enyl, but-2-enyl, pent-l-enyl, penta-l,4-dienyl, and the like.
  • alkynyl refers to a straight or branched mono-valent hydrocarbon chain radical group comprising solely of carbon and hydrogen atoms, containing at least one triple bond, optionally containing more or more double bonds, having from two to fourteen carbon atoms, preferably from two to ten carbon atoms, more preferably from two to six carbon atoms, and which is attached to the rest of the molecule by a single bond, for example, ethynyl, prop-l-ynyl, but-l-ynyl, pent-l-en-4-ynyl, and the like.
  • cycloalkyl refers to a stable mono-valent non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms, preferably having from three to ten carbon atoms, more preferably having from three to eight carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond.
  • cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexanonyl, cycloheptyl, cyclooctyl, l/ -indenyl, 2,3-dihydro-indenyl, 1 ,2,3 ,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, dicyclo[2.2.1 Jheptyl, 7,7-dimethyl-dicyclo[2.2.1 Jheptyl, dicyclo[2.2.1 Jhepteny
  • the heterocyclyl comprises preferably three to eitht carbon atoms, and is more preferably cyclopentyl, cyclohexyl, cyclohexanonyl, or cycloheptyl.
  • cycloalkyl oxy refers to a radical of the formula -OR b where R b is a cycloalkyl radical as defined above.
  • heterocyclyl refers to a stable 3- to 18-membered mono-valent non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated.
  • a heterocyclyl may be connected to the rest of the molecule by a single bond via a carbon atom or a heteroatom on the ring.
  • one or more of the rings may be an aryl or heteroaryl, provided that the site for connecting to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclyl is preferably a stable 4- to 11 -membered mono-valent non-aromatic mono- or di-cyclic ring radical which comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and more preferably a stable 4- to 8-membered mono-valent non-aromatic mono-cyclic ring radical which comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • heterocyclyl radicals include, but are not limited to, azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuranyl, dihydroindolyl, dioxolanyl, 1 , 1 -dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, oxazolidinyl, 1 -oxo-thiomorpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, phthalimido, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrol
  • heterocyclyl oxy refers to a radical of the formula -OR c where 3 ⁇ 4 is a heterocyclyl radical as defined above.
  • aryl or the prefix “ar-” (such as in “aralkyl”) refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms, and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may included fused or bridged ring systems.
  • An aryl may be connected to the rest of the molecule by a single bond via an aromatic ring atom.
  • Aryl radicals include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2-benzooxazolinonyl, 2H-l,4-benzooxazon-3(4H)-on-7-yl, and the like.
  • the aryl is preferably a Ci-Cio aryl, and more preferably phenyl.
  • heteroaryl refers to a 5- to 16-membered ring system radical comprising one to fifteen carbon atoms, preferably one to ten carbon atoms, one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems, provided that the site for connection to the rest of the molecule is an aromatic ring atom.
  • the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heteroaryl is preferably a stable 4- to 11 -membered aromatic mono-cyclic ring radical which comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and more preferably a stable 5- to 8-membered aromatic mono-cyclic ring radical which comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • heteroaryl radicals include, but are not limited to, acridinyl, azepinyl, benzimidazolyl, benzindolyl, 1 ,4-benzodioxanyl, benzo[6][l,4]dioxepinyl, benzodioxinyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzo[4,6]imidazo[l,2-a]pyridinyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanonyl, furanyl, imid
  • the heteroaryl is preferably a 5- to 8-membered heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and more preferably pyridinyl, pyrimidinyl, thiazolyl, oxo-pyridinyl, l-£/-pyridin-2-on-4-yl or thienyl.
  • Optional or “optionally” as used herein means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures.
  • the present invention contemplates various stereoisomers and mixtures thereof.
  • a "tautomer” refers to an isomer resulted from a proton shift from one atom of a molecule to another atom of the same molecule.
  • the present invention includes tautomers of any said compounds.
  • polymorph or “polymorphism” as used herein refers to a compound of this invention present in different crystal lattice forms. Some of the compounds of the present invention may have more than one crystal forms, and the present invention tends to encompass all the polymorphs or mixtures thereof.
  • the compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), or (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • the term "pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, 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-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanes
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isoprop
  • solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent.
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
  • the compounds of the present invention may react in a solvent or deposit or crystallize from a solvent.
  • the solvates of the compounds of the present invention are also encompassed in the scope of the present invention.
  • the present invention also contemplates prodrugs of the compounds of the present invention.
  • “Prodrugs” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • the term “prodrug” refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism.
  • Prodrugs include amino protective groups and carboxy protective groups which are known to persons skilled in the art. Methods for preparing specific prodrugs are provided in e.g. Saulnier, M. G, et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R. B., et al., J. Med. Chem. 2000, 43, 475.
  • pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers therefor.
  • pharmaceutically acceptable refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • “Pharmaceutically acceptable carrier” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by relevant government administration as being acceptable for use in humans or domestic animals.
  • SERMs refers to selective estrogen receptor modulators, which are compounds that exhibit estrogen receptor agonism in one or more target tissues, and estrogen receptor antagonism in one or more other target tissues.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non- mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • prevention of, "prophylaxis” and “prevent” includes reducing the likelihood of a patient incurring or developing breast cancer.
  • Treating covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:
  • the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
  • an “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” as used herein, refer to a sufficient amount of at least one agent or compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • administer refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion
  • topical and rectal administration Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein, e.g., as discussed in Goodman and Oilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
  • the compounds and compositions described herein are administered orally.
  • agonist refers to a molecule such as a compound, a drug, an enzyme activator or a hormone modulator which enhances the activity of another molecule or the activity of a receptor site.
  • antagonist refers to a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone modulator, which diminishes, or prevents the action of another molecule or the activity of a receptor site.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target (up-regulate), to inhibit the activity of the target (down-regulate), to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist and an antagonist.
  • enhancement means to increase or prolong either in potency or duration of a desired effect.
  • enhancing refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • an "enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • pharmaceutical combination refers to a pharmaceutical therapy resulting from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that at least one of the compounds described herein, and at least one co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that at least one of the compounds described herein, and at least one co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient.
  • cocktail therapies e.g. the administration of three or more active ingredients.
  • co-administration are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • the compounds described herein will be co-administered with other agents.
  • These terms encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
  • the compounds of the invention and the other agent (s) are administered in a single composition.
  • metabolite refers to a derivative of a compound which is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • the term "metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism.
  • enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions
  • uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free mercapto groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
  • the present invention provides a compound of formula I,
  • R° and R 1 are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen, -OH, -NH 2 , -SH, alkyl, halogenated alkyl and alkoxy, and the carbon atoms on the ring of the cycloalkyl, the heterocyclyl and the heteroaryl are optionally oxidized;
  • ring A and ring B are each independently selected from aryl, heteroaryl and heterocyclyl, wherein the carbon atoms on the ring of the heterocyclyl and the heteroaryl are optionally oxidized;
  • R 2 and R 3 are independently selected from the group consisting of halogen, -OH, -NH 2 , -CN, -SH, -COOH, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy, alkylsulfanyl, cycloalkyloxy, heterocyclyloxy, monoalkylamino, dialkylamino, -S(0)-alkyl and -S(0)2-alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy, alkylsulfanyl, cycloalkyloxy, heterocyclyloxy, monoalkylamino, dialkylamino, -S(0)-alkyl and -S(0)2-alkyl are each optionally substituted with halogen, -OH, heterocyclyl, or -NR 4 R 5 , wherein R4 and R5 are each independently hydrogen,
  • n and n are the number of group R 2 on ring A and the number of group R 3 on ring B, respectively, and m and n are each independently 0, 1, 2 or 3,
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • R° and R 1 are independently selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen, -OH, alkyl, halogenated alkyl and alkoxy, and the carbon atoms on the ring of the cycloalkyl, the heterocyclyl, and the carbon atoms on the ring of the cycloalkyl or the heteroaryl are optionally oxidized.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • R° and R 1 are independently selected from the group consisting of alkyl, cycloalkyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl are each optionally substituted with one or more groups selected from the group consisting of halogen, -OH, alkyl and alkoxy, and the carbon atoms on the ring of the cycloalkyl or the heteroaryl are optionally oxidized.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • R° and R 1 is alkyl
  • the other of R° and R 1 is selected from the group consisting of cycloalkyl, aryl and heteroaryl, each optionally substituted with one or more groups independently selected from the group consisting of halogen, -OH, -NH 2 , -SH, alkyl, alkoxy, and halogen-substituted alkyl, wherein the carbon atoms on the ring of the cycloalkyl or the heteroaryl are optionally oxidized.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • R° and R 1 is alkyl or halogen-substituted alkyl, and the other of R° and R 1 is selected from the group consisting of:
  • 5-membered heteroaryl comprising at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen, optionally substituted with one or more groups independently selected from the group consisting of halogen, -OH, alkyl, alkoxy, and halogen-substituted alkyl; preferably thiophenyl optionally substituted with one or more halogen;
  • 6-membered heteroaryl comprising one or two heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, optionally substituted with one or more groups independently selected from the group consisting of halogen, -OH, alkyl, alkoxy, and halogen-substituted alkyl, wherein the carbon atoms on the ring of the heteroaryl are optionally oxidized; preferably pyridinyl optionally substituted with one or more -OH;
  • cycloalkyl optionally substituted with one or more groups independently selected from the group consisting of halogen, -OH, alkyl, alkoxy, and halogen-substituted alkyl, wherein the carbon atoms on the ring of the cycloalkyl are optionally oxidized; preferably cyclohexanonyl or cyclohexyl optionally substituted with one or more -OH; and
  • phenyl optionally substituted with one or more groups independently selected from the group consisting of halogen, -OH, alkyl and alkoxy.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • R° and R 1 is selected from the group consisting of hydrogen, halogen and alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -OH, -NH 2 , alkoxy; or is alkyl optionally substituted with one or more halogen; and
  • X, Y and W are each independently selected from the group consisting of C, N, O and S; and said 5-membered ring is optionally substituted with one or more groups independently selected from the group consisting of halogen, -OH, -SH, alkyl, cycloalkyl, alkoxy and alkylsulfanyl, wherein the alkyl, cycloalkyl, alkoxy and alkylsulfanyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, -OH, -NH 2 , monoalkylamino, dialkylamino and heterocyclyl.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • At least one of X, Y and W is a heteroatom selected from the group consisting of N, O and S; and said 5-membered ring is optionally substituted with one or more groups independently selected from the group consisting of halogen and alkyl;
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • Formula II is selected from:
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • ring A and ring B are each independently selected from aryl and heteroaryl, wherein the carbon atoms on the ring of the heteroaryl are optionally oxidized.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • ring A and ring B are each independently selected from aryl and a 6-membered heteroaryl comprising 1 or 2 nitrogen atoms, wherein the carbon atoms on the ring of the heteroaryl are optionally oxidized.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • ring A and ring B are each independently selected from phenyl and pyridinyl.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • R 2 and R 3 are independently selected from the group consisting of halogen, -OH, -NH 2 , -CN, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfanyl, heterocyclyloxy, monoalkylammo and dialkylamino, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylsulfanyl, heterocyclyloxy, monoalkylammo and dialkylamino are each optionally substituted with halogen, -OH, heterocyclyl or -NR ⁇ Rs, wherein R4 and R5 are each independently hydrogen, alkyl or cycloalkyl, or R4 and R5, together with the nitrogen atom to which they attach, form a heterocyclyl which is optionally substituted with alkyl.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • R 2 and R 3 are independently selected from the group consisting of halogen, -OH, -NH 2 , -CN, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfanyl, heterocyclyloxy, monoalkylammo and dialkylamino, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylsulfanyl, heterocyclyloxy, monoalkylammo and dialkylamino are each optionally substituted with heterocyclyl or -NR 4 R 5 , wherein R4 and R5 are each independently hydrogen or alkyl, or R4 and R5, together with the nitrogen atom to which they attach, form a heterocyclyl which is optionally substituted with alkyl.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • ring A is selected from phenyl and a 6-membered heteroaryl, and R 2 is at least at para-position of the phenyl or the 6-membered heteroaryl;
  • ring B is selected from phenyl and a 6-membered heteroaryl, and R 3 is at least at para-position of the phenyl or the 6-membered heteroaryl.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein:
  • n are each independently 1 or 2.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, wherein the compound is selected from the group consisting of:
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, for modulating estrogen activities.
  • the present invention provides use of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, in the manufacture of a medicament for modulating estrogen activities.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, for preventing and/or treating estrogen-dependent diseases and conditions.
  • the present invention provides use of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, in the manufacture of a medicament for preventing and/or treating estrogen-dependent diseases and conditions.
  • the present invention provides a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, as well as a pharmaceutically acceptable carrier.
  • a compound of the invention may be administered by formulating it into an appropriate pharmaceutical composition with one or more pharmaceutically acceptable carrier can.
  • the pharmaceutical composition of the invention may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • the pharmaceutical composition of the invention may be prepared by methodology well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000).
  • Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal.
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups.
  • the compound of the present invention included in these dosage forms may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; emulsions of oil-in-water type of water-in-oil type; and the like.
  • the above mentioned dosage forms may be prepared from active compounds and one or more carriers or auxiliaries through common pharmacological methods.
  • the carriers shall be compatible with the active compounds or the other auxiliaries.
  • non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid formulations include, but are not limited to, water, physiological saline, aqueous solution of glucose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound may form a solution or a suspension with the above carriers.
  • the specific route of administration and dosage form depend on the physical/chemical properties of the compound per se and the severity of the disease to be treated, and can be routinely determined by a person skilled in the art.
  • the present invention provides a method for modulating estrogen activities in mammals, especially in humans, which method comprises administering to a mammal, especially a human, in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof.
  • estrogen receptor is up-regulated by a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof in bone tissue, cardiovascular system and central nervous system, and down-regulated by a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof in tissues like breast and uterus.
  • the present invention provides a method for preventing and/or treating estrogen-dependent diseases and conditions in mammals, especially in humans, which method comprises administering to a mammal, especially a human, in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof.
  • estrogen-dependent diseases and conditions refer to diseases and conditions in which the regulation of estrogen receptor is involved.
  • estrogen-dependent diseases and conditions are selected from the group consisting of menopausal or postmenopausal disorders, vasomotor symptoms, urogenital or vulvar vaginal atrophy, atrophic vaginitis, endometriosis, female sexual dysfunction, cancers (e.g. uterine cancer, breast cancer, etc.), depressive symptoms, diabetes, bone demineralization, and osteoporosis.
  • the compound of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer or prodrug thereof, is administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.
  • a therapeutically effective daily dose is from about 0.001 mg/Kg body weight to about 100 mg/Kg body weight; preferaby a therapeutically effective dose is from about 0.01 mg/Kg body weight to about 50 mg/Kg body weight; more preferably a therapeutically effective dose is from about 1 mg/Kg body weight to about 25 mg/Kg body weight.
  • the parenteral dose of the compound of the present invention may be from about 1 mg/Kg body weight to about 100 mg/Kg body weight; the oral dose may be from about 1 mg/Kg body weight to about 500 mg/Kg body weight.
  • the total dose required for each treatment can be administered by multiple doses or in a single dose over the course of the day, if desired. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the diagnostic pharmaceutical compound or composition can be administered alone or in conjunction with other diagnostics and/or pharmaceuticals directed to the pathology, or directed to other symptoms of the pathology.
  • the recipients of administration of compounds and/or compositions of the invention can be any mammals.
  • the preferred recipients are mammals of the Orders Primate (including humans, apes and monkeys), Arteriodactyla (including horses, goats, cows, sheep, pigs), Rodenta (including mice, rats, rabbits, and hamsters), and Camivora (including cats, and dogs).
  • the most preferred recipients are humans.
  • Suitable protecting groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for mercapto include -C(0)-R" (where R" is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like.
  • Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.
  • the use of protecting groups is described in detail in Greene, T. W. and P. G. M. Wuts, Greene's Protective Groups in Organic Synthesis (2006), 4th Ed., Wiley.
  • the protecting group may also be a polymer resin.
  • McMurry coupling is carried out between compounds II and III to provides the ethylene derivative I.
  • Compounds II and III are either commercially available or may be prepared by synthetic methods appreciated by those skilled in the art.
  • Step A (6-chloropyridin-3-yl)(4-(tetrahydro-2//-pyran-2-yloxy)phenyl) methanone
  • Mg (1.67 g, 1.2 eq) was added to dry THF (50 mL). The mixture was heated to 55 °C, then I 2 was added in one lot followed by EtBr. 2-(4-Bromophenoxy)tetrahydro- 2_f/-pyran (16 g, 1.1 eq) was dissolved in THE Part of this solution was added at once to the Mg-THF mixture. After the initiation after about 30min and reflux started, the remaining above solution was added, and the resulting mixture was refluxed for 2 h to give a MgBr-THF solution, which will be used in the next step.
  • Step B (Z)-4-(l-(6-chloropyridin-3-yl)-2-phenylbut-l-enyl)phenol
  • Step C 4-(l-(4-(2-chloroethoxy)phenyl)-2-(thiophen-3-yl)but-l-enyl) phenol
  • Step D 4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-(thiophen-3-yl)but-l- enyl)phenol
  • Step A 5-chloro-N-me oxamide
  • Step B l-(5-chlorothiophen-3-yl)propan-l-one
  • step B the title compound was obtained.
  • Step C (£)-4-(l-(4-(2-chloroethoxy)phenyl)-2-(5-chlorothiophen-3-yl)- but-l-enyl)phenol
  • step B l-(5-chlorothiophen-3-yl)propan-l-one (1.5 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (2.0 g, 1.2 eq) to give 0.8 g desired product (45% yield, E).
  • Step D (£)-4-(2-(5-chlorothiophen-3-yl)-l-(4-(2-(methylamino)ethoxy)- phenyl)but-l-enyl)phenol
  • step D (ii)-4-(l-(4-(2-chloroethoxy)phenyl)-2-(5-chlorothiophen-3-yl)but-l-enyl)phenol (0.8 g, 1.0 eq) was reacted with MeNH 2 (30% wt in water, 10 mL) in MeOH (20 mL) at reflux to give 120 mg desired product (35% yield, E).
  • Step A l-(4-hydroxycyclo
  • Step B 4-(l-(4-(2-chloroethoxy)phenyl)-2-(4-hydroxycyclohexyl)but-l- enyl)phenol
  • Step C 4-(2-(4-hydroxycyclohexyl)-l-(4-(2-(methylamino)ethoxy)- phenyl)but-l-enyl)phenol
  • Step A methyl 3-bromo-4
  • Step C (3-bromo-4-(2-bromoethoxy)phenyl)(4-methoxyphenyl) methanone
  • Step D (3-bromo-4-(2-bromoethoxy)phenyl)(4-hydroxyphenyl)- methanone
  • Step E 4-(l-(3-bromo-4-(2-bromoethoxy)phenyl)-2-phenylbut-l-enyl) phenol
  • Step F 4-(l-(3-bromo-4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut- l-enyl)phenol
  • Step A (5)-pyrrolidin-2-ylmethanol
  • Step B (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-l-carboxylate
  • Step C 4-(l-(4-hydroxylphenyl)-2-phenylbut-l-enyl)phenol
  • step B propiophenone (1.9 g, 3.0 eq) was reacted with bis(4-hydroxyphenyl)- methanone (1.0 g, 1.0 eq) to give 1.3 g desired product (88% yield).
  • Step D (S)-tert-butyl 2-((4-(l-(4-hydroxyphenyl)-2-phenylbut-l-enyl)- phenoxy)methyl)pyrrolidine-l-carboxylate
  • Step E (5)-4-(2-phenyl-l-(4-(pyrrolidin-2-ylmethoxy)phenyl)but-l- enyl)phenol
  • Step A teri-butyl 3-(methylsulfonyloxy)pyrrolidine-l-carboxylate
  • Step B teri-butyl 3-(4-(4-hydroxybenzoyl)phenoxy)pyrrolidine-l- carboxylate
  • Step C 4-(2-phenyl-l-(4-(pyrrolidin-3-yloxy)phenyl)but-l-enyl)phenol
  • step B tert-butyl
  • Step A 2-methoxyphenyl propio
  • Step B l-(4-hydroxy-3-methoxyphenyl)propan-l-one
  • Step C 4-(l-(4-(2-chloroethoxy)phenyl)-l-(4-hydroxyphenyl)but-l-en-
  • step B l-(4-hydroxy-3-methoxyphenyl)propan-l-one (207 mg, 1.15 mmol) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (318 mg, 1.15 mmol) to give 188 mg desired product (38.5% yield).
  • Step D 4-(l-(4-hydroxyphenyl)-l-(4-(2-(methylamino)ethoxy)phenyl)- but-l-en-2-yl)-2-methoxyphenol
  • Step B 3-fluoro-4-hydroxybenzo
  • Step C 4-(2-bromoethoxy)-3-fl robenzonitrile
  • Step D 4-(2-bromoethoxy)-3-fluorobenzoic acid
  • Step E 4-(2-bromoethoxy)-3-fl robenzoyl chloride
  • Step F (4-(2-bromoethoxy)-3-fluorophenyl)(4-methoxyphenyl)- methanone
  • Step G (4-(2-bromoethoxy)-3-fluorophenyl)(4-hydroxyphenyl)- methanone
  • BBr 3 (0.5 mL, 5.29 mmol) was added to (4-(2-bromoethoxy)-3-fluorophenyl)(4- methoxyphenyl)methanone (930 mg, 2.63 mmol) in dichloromethane (6 niL) at 0 °C. Stirring was continued at room temperature for 2 h under a nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with dichloromethane and the white suspension was filtered off. The organic layer was washed with water and brine and then dried over sodium sulfate.
  • Step H 4-(l-(4-(2-bromoethoxy)-3-fluorophenyl)-2-phenylbut-l-enyl) phenol
  • Step I 4-(l-(3-fluoro-4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-l- enyl)phenol
  • Step A l-(3-fluoro-4-methoxyphenyl)propan-l-one
  • Step B l-(3-fluoro-4-hydroxyphenyl)propan-l-one
  • Step C 4-(l-(4-(2-chloroethoxy)phenyl)-l-(4-hydroxyphenyl)but-l-en-2- yl)-2-fluorophenol
  • step B l-(3-fluoro-4-hydroxyphenyl)propan-l-one (255 mg, 1.52 mmol) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (629 mg, 2.27 mmol) to give 549 mg desired product (88% yield).
  • Step D (Z)-2-fluoro-4-(l-(4-hydroxyphenyl)-l-(4-(2-(methylamino)- ethoxy)phenyl)but-l-en-2-yl)phenol
  • Step A 3-fuoro-4-methoxybenzoic acid
  • Step B 3-fluoro-4-methoxybenzoyl chloride
  • Step C (4-(2-chloroethoxy)phenyl)(3-fluoro-4-methoxyphenyl)- methanone
  • Step D (4-(2-chloroethoxy)phenyl)(3-fluoro-4-hydroxyphenyl)- methanone
  • Step E 4-(l-(4-(2-chloroethoxy)phenyl)-2-phenylbut-l-enyl)-2-fluoro phenol
  • step B (4-(2-chloroethoxy)phenyl)(3-fluoro-4-hydroxyphenyl)methanone (350 mg, 1.19 mmol) was reacted with propiophenone (319 mg, 2.38 mmol) to give the desired product (quant.) as a yellow solid.
  • Step F 2-fuoro-4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-l- enyl)phenol
  • Step A (5-bromopyrimidin-2-yl)(4-(tetrahydro-2//-pyran-2-yloxy)- phenyl)methanone
  • step A 2-(4-bromophenoxy)tetrahydro-2_f/-pyran (2.57 g, 10 mmol) was reacted with 5-bromopyrimidine-2-carbonitrile (0.92 g, 5 mmol) to give 910 mg desired product (50%).
  • Step B (4-(tetrahydro-2 ⁇ -pyran-2-yloxy)phenyl)(5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)methanone
  • Step C (5-hydroxypyrimidin-2-yl)(4-(tetrahydro-2//-pyran-2-yloxy)- phenyl)methanone
  • Step D (5-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)(4-(tetrahydro-2H- pyran-2-yloxy)phenyl)methanone
  • Step E (Z)-4-(l-(5-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)-2-phenyl but-l-enyl)phenol hydrochloride
  • step B (5-(2-(dimethylamino)ethoxy)pyrimidin-2-yl)(4-(tetrahydro-2_f/-pyran-2 -yloxy) phenyl)methanone (753 mg, 2 mmol) was reacted with propiophenone (800 mg, 6 mmol) to give Z/E mixed product.
  • the pure (Z) and (E) isomer were separated by preparative HPLC. Evaporation of the (Z)-isomer from 3 N HCI in MeOH to afford the title compound (16 mg).
  • Step B 5-(2-(dimethylamino ethoxy)-N-methoxy-N-methylpicolinamide
  • Step C (5-(2-(dimethylamino)ethoxy)pyridin-2-yl)(4-(tetrahydro-2S- pyran-2-yloxy)phenyl)methanone
  • Step D 4-(l-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-2-phenylbut-l- enyl)phenol
  • Step A (6-chloropyridin-3-yl)(4-methoxyphenyl)methanone
  • Step B (6-(3-(dimethylamino)prop-l-ynyl)pyridin-3-yl)(4-methoxy phenyl)methanone
  • Step C (6-(3-(dimethylamino)propyl)pyridin-3-yl)(4-methoxy-phenyl) methanone
  • Step D (6-(3-(dimethylamino)propyl)pyridin-3-yl)(4-hydroxy-phenyl) methanone
  • Step E 4-(l-(6-(3-(dimethylamino)propyl)pyridin-3-yl)-2-phenylbut- l-enyl)phenol hydrochloride
  • Step A terf-butyl 2-(4-bromophenoxy)ethyl(methyl)carbamate
  • Step B tert-butyl 2-(4-(5-hydroxypicolinoyl)phenoxy)ethyl-(methyl) carbamate
  • Mg (3.5 eq) was added to a 3 -neck round bottom flask containing 50 mL anhydrous THF. The mixture was heated to 55 °C. Iodine chips (2 grains) were added in one lot followed by addition of 0.1 mL ethyl bromide. 7ert-butyl 2-(4-bromophenoxy)ethyl(methyl)carbamate (3.0 eq) was dissolved in 30 mL anhydrous THF, 3 mL of this solution was added at once to Mg- THF suspension. The reaction was initiated after 30 min and reflux started.
  • Step C 6-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-l-enyl) pyridin-3-ol
  • Step B 6-chloro-N-methoxy-N-methylnicotinamide
  • 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 100 mL telxahydrofuran. The reaction mixture was stirred at room temperature for 1 h, and then concentrated to give a residue, which was dissolved in 50 mL dichlorom ethane.
  • Step C l-(prop-2-ynyl)pyrrolidi
  • Step D (6-chloropyridin-3-yl)(4-(tetrahydro-2//-pyran-2-yloxy)-phenyl) methanone
  • Step E (6-(3-(pyrrolidin-l-yl)prop-l-ynyl)pyridin-3-yl)(4-(tetrahydro-
  • Step F (6-(3-(pyrrolidin-l-yl)propyl)pyridin-3-yl)(4-(tetrahydro-2S- pyran-2-yloxy)phenyl)methanone
  • Raney nickel (0.3 g, 0.6 mmol, 10 mol%) was added to a solution of (6-(3 -(pyrrolidin- 1 -yl)prop- 1 -ynyl)pyridin-3 -yl)(4-(tetrahydro-2_f/-pyran-2-yloxy)phenyl)methanone (2.2 g, 5.6 mmol) in 20 mL methanol at room temperature, and the reaction mixture was stirred for 1 h under hydrogen atmosphere. The nickel was filtered off and the filtrate was concentrated in vacuo to afford the desired product as a yellow solid (1.7 g, 77.3% yield).
  • Step G 4-(2-phenyl-l-(6-( -(pyrrolidin-l-yl)propyl)pyridin-3-yl)but-l- enyl)phenol
  • Step A (4-(3-(pyrrolidin-l-yl)prop-l-ynyl)phenyl)(4-(tetrahydri pyran-2-yloxy)phenyl)methanone
  • Step B (4-(3-(pyrrolidin-l-yl)propyl)phenyl)(4-(tetrahydro-2//-pyran- 2-yloxy)phenyl)methanon
  • Step C 4-(2-phenyl-l-(4-( -(pyrrolidin-l-yl)propyl)phenyl)but-l-enyl)- phenol
  • Step B tert-butyl methyl(prop-2-ynyl)carbamate
  • Step C tert-butyl methyl(3-(5-(4-(tetrahydro-2fl-pyran-2-yloxy) benzoyl)-pyridin-2-yl)prop-2-ynyl)carbamate
  • Step D tert-butyl methyl(3-(5-(4-(tetrahydro-2//-pyran-2-yloxy) benzoyl)-pyridin-2-yl)propyl)carbamate
  • Raney nickel (2.4 mg, 0.04 mmol, 10 mol%) was added to a solution of ier ⁇ butylmethyl(3-(5-(4-(telxahydro-2_f/-pyran-2-yloxy)benzoyl)pyridin-2-yl)prop-2-ynyl)carbamate (180 mg, 0.4 mmol) in 3 mL methanol at room temperature, and the reaction mixture was stirred for 1 h under hydrogen atmosphere. The nickel was filtered off and the filtrate was concentrated in vacuo to afford the desired product as a yellow solid (100 mg, 55.6% yield).
  • Step E 4-(l-(6-(3-(methylamino)propyl)pyridin-3-yl)-2-phenylbut-l- enyl)phenol
  • Step A tert-butyl methyl(3-(4-(4-(tetrahydro-2fl-pyran-2-yloxy) benzoyl)-phenyl)prop-2-ynyl)carbamate
  • Step B terf-butyl methyl(3-(4-(4-(tetrahydro-2fl-pyran-2-yloxy) benzoyl)-phenyl)propyl)carbamate
  • Step C 4-(l-(4-(3-(methylamino)propyl)phenyl)-2-phenylbut-l-enyl)- phenol
  • Step A (4-bromo-3-fluorophenyl)(4-(tetrahydro-2//-pyran-2-yloxy)- phenyl)methanone
  • Step B (3-fluoro-4-(3-(pyrrolidin-l-yl)prop-l-ynyl)phenyl)(4-
  • Step C 4-(l-(3-fluoro-4-(3-(pyrrolidin-l-yl)prop-l-ynyl)phenyl)-2- phenylbut-l-enyl)phenol
  • step B (3 -fluoro-4-(3 -(pyrrolidin- 1 -yl)prop- 1 -ynyl)phenyl)(4-(tetrahydro-2_f/-pyran-
  • Step A triethyl 4-oxocyclohexane-l,l,3-tricarboxylate
  • Step B 4-oxocyclohexanecarboxylic acid
  • a mixture of triethyl 4-oxocyclohexane-l,l,3-tricarboxylate (31.4 g, 0.1 mol), concentrate hydrochloride acid (30 mL), and water (145 mL) was reflux ed overnight, and then extracted with ethyl acetate. The extract was concentrated and purified by silic gel chromatography (CH 2 Cl 2 :MeOH 80: l) to give the product of 4-oxocyclohexanecarboxylic acid (4.2 g, 29% yield).
  • Step C N-methoxy-N-methyl-4-oxoc clohexanecarboxamide
  • Step D N-methoxy-N-methyl-l,4-dioxaspiro[4.5]decane-8-carboxamide
  • Step E l-(l,4-dioxaspiro[4.5]decan-8-yl)propan-l-one
  • Step F (Z)-4-(l-(4-(2-chloroethoxy)phenyl)-2-(l,4-dioxaspiro[4.5]decan-
  • step B l-(l,4-dioxaspiro[4.5]decan-8-yl)propan-l-one (259 mg, 1.3 mmol) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (360 mg, 1.3 mmol) to give 90 mg title compound (Z-isomer, 16% yield) and 110 mg ii-isomer (19% yield) as well.
  • Step G (Z)-4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-(l,4-dioxaspiro-
  • Step H (Z)-4-(l-(4-hydroxyphenyl)-l-(4-(2-(methylamino)ethoxy)- phenyl)but-l-en-2-yl)cyclohexanone
  • Step B methyl l-methyl-2-oxo-l,2-dihydropyridine-4-carboxylate
  • Step C l-methyl-2-oxo-l,2-dihydropyridine-4-carboxylic acid
  • Step D N-methoxy-N,l-dimethyl ihydropyridine-4- carboxamide
  • Step E l-methyl-4-propionylpyrid -one
  • Step F 4-(l-(4-(2-chloroethoxy)phenyl)-l-(4-hydroxyphenyl)but-l-en-2- yl)-l-methylpyridin-2(l/ )-one
  • Step G (Z)-4-(l-(4-hydroxyphenyl)-l-(4-(2-(methylamino)ethoxy) phenyl)but-l-en-2-yl)-l-methylpyridin-2(l//)-one
  • Step B 2-chloro-N-methylethanamine hydrochloride
  • Step D (Z)-4-(l-(6-(2-(methylamino)ethylthio)pyridin-3-yl)-2-phenylbut- l-enyl)phenol
  • step D (£)-4-(l-(6- chloropyridin-3-yl)-2-phenylbut-l-enyl)phenol (100 mg, 1.0 eq, made from example 2) was reacted with V, V-dimethylethane-l,2-diamine (262 mg, 10.0 eq) to give the desired product.
  • Step A 6-hydroxy-N-methox -N-methylnicotinamide
  • Step B l-(6-hydroxypyridin-3-yl)propan-l-one
  • Step C (Z)-5-(l-(4-(2-chloroethoxy)phenyl)-l-(4-hydroxyphenyl)- but-l-en-2-yl)pyridin-2-ol
  • step B l-(6-hydroxypyridin-3-yl)propan-l-one (0.3 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.37 g, 2.5 eq) to give the desired Z-product (Z and E isomer can be separated via column chromatography).
  • Step D (Z)-5-(l-(4-hydroxyphenyl)-l-(4-(2-(methylamino)ethoxy)- phenyl)but-l-en-2-yl)pyridin-2-
  • step D (Z)-5-(l-(4- (2-chloroethoxy)phenyl)-l-(4-hydroxyphenyl)but-l-en-2-yl)pyridin-2-ol (0.02 g, 1.0 eq) was reacted with MeNH 2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give the desired product.
  • step A 5-hydroxypicolinic acid (6.2 g, 1.0 eq) was reacted with N, O-dimethylhydroxylamine hydrochloride (5.2 g, 1.2 eq) to get the desired product with column chromatography (4.25 g, 52% yield).
  • Step B l-(5-hydroxypyridin-2-yl)propan-l-one
  • Step B 5-hydroxy-V-methoxy- V-methylpicolinamide (0.5 g, 1.0 eq) was reacted with EtMgBr (6.0 mL, 4.0 eq) to get the desired product (0.2 g, 48% yield).
  • EtMgBr 6.0 mL, 4.0 eq
  • Step C 6-(l-(4-(2-chloroethoxy)phenyl)-l-(4-hydroxyphenyl)but-l-en-2- yl)pyridin-3-ol
  • Step D 6-(l-(4-hydroxyphenyl)-l-(4-(2-(methylamino)ethoxy)phenyl)- but-l-en-2-yl)pyridin-3-ol
  • Step A 3-chloro-N,N-dimethylpropan-l-amine hydrochloride
  • Step B N-methoxy-N-methyl-2-oxo-l,2-dihydropyridine-4-carboxamide
  • Step C l-(3-(dimethylamino)propyl)-N-methoxy-N-methyl-2-oxo-l,2- dihydropyridine-4-carboxamide
  • Step D l-(3-(dimethylamino)propyl)-4-(4-(tetrahydro-2H-pyran-2-yloxy) benzoyl)pyridin-2(lH)-one
  • reaction mixture was further reflux for 2 h., cooled to rt, l-(3-(dimethylamino)propyl)-N-methoxy-N-methyl-2-oxo-l,2-dihydro- pyridine-4-carboxamide (1.4 g, 1.0 eq ) in 20 mL THF was added dropwise at rt, stirred at rt for 30 min., quenched with sat NH 4 CI (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (1.6g, 80% yield).
  • Step E l-(3-(dimethylamino)propyl)-4-(l-(4-hydroxyphenyl)-2-phenyl but-l-enyl)pyridin-2(lH)-one
  • step B propiophenone (0.838 g, 3.0 eq) was reacted with l-(3-(dimethylamino) propyl)-4-(4-hydroxybenzoyl)pyridin-2(lH)-one (0.8 g, 1.0 eq) to give the desired product (Z was prepared by preparative HPLC).
  • Step A l-(2,3-dihydrobenzofuran-5-yl)propan-l-one
  • Step B (4-(2-chloroethoxy)phenyl)(4-methoxyphenyl)methanone
  • Step C (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone
  • Step D 4-(l-(4-(2-chloroethoxy)phenyl)-2-(2,3-dihydrobenzofuran-5-yl) but-l-enyl)phenol
  • Step E 4-(2-(2,3-dihydrobenzofuran-5-yl)-l-(4-(2-(methylamino)ethoxy)- phenyl)but-l-enyl)phenol
  • Step A methyl 4-amino-3-methylbenzoate
  • Step B 4-(methoxycarbonyl)-2-methylbenzenediazonium tetrafluoro- borate
  • Step C methyl l//-indazole-5-carboxylate
  • Step D l//-indazole-5-carboxylic acid
  • Step E N-methoxy-N-methyl-l//-indazole-5-carboxamide
  • N, 0-dimethylhydroxylamine hydrochloride 5.4 g, 1.5 eq
  • HOBt 6.0 g, 1.2 eq
  • EDCI 8.5 g, 1.2 eq
  • Et 3 N 15g, 4.0 eq
  • Step F l-(l//-indazol-5-yl)propan-l-one
  • Step G 4-(l-(4-(2-chloroethoxy)phenyl)-2-(l ⁇ -indazol-5-yl)but-l-enyl)- phenol
  • Step H (Z)-4-(2-(l ⁇ -indazol-5-yl)-l-(4-(2-(methylamino)ethoxy)- phenyl)but-l-enyl)phenol
  • Step C benzo[ ⁇ /]oxazole-5-ca
  • Step D N-methoxy-N-methylbenzo[ ⁇ /]oxazole-5-carboxamide
  • Step E l-(benzo[ ⁇ /]oxazol-5-yl)propan-l-one
  • Step F 4-(2-(benzo[ ⁇ oxazol-5-yl)-l-(4-(2-chloroethoxy)phenyl)but-l- enyl)phenol
  • Step G 4-(2-(benzo[ ⁇ oxazol-5-yl)-l-(4-(2-(methylamino)ethoxy)phe- nyl)but-l-enyl)phenol
  • Step A 3-chloro-l-(2,3-dihydrobenzofuran-5-yl)propan-l-one
  • Step B (4-hydroxyphenyl)(4-(2-(methylamino)ethoxy)phenyl)methanone
  • step E described (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (2.0 g, 1.0 eq) was reacted with MeNH 2 (30% wt in water, 30 mL) in MeOH (30 mL) under reflux to give the desired product (1.4 g, 65%).
  • Step C maybezofuran-5-yl)-l-(4-(2-(methyl- amino)ethoxy)phenyl)but-l-enyl)phenol
  • Step E 4-(2-bromoethoxy)-3-fluorobenzoyl chloride
  • Step F (4-(2-bromoethoxy)-3-fluorophenyl)(4-methoxyphenyl)methan- one
  • Step G (4-(2-bromoethoxy)-3-fluorophenyl)(4-hydroxyphenyl)methan- one
  • BBr 3 (0.5 mL, 5.29 mmol) was added to (4-(2-bromoethoxy)-3-fluorophenyl)(4- methoxyphenyl)methanone (930 mg, 2.63 mmol) in dichloromethane (6 mL) at 0 °C. Stirring was continued at room temperature for 2 h under a nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with dichloromethane.
  • Step H 4-(l-(4-(2-bromoethoxy)-3-fluorophenyl)-2-phenylbut-l-enyl)- phenol
  • Step I ran-5-yl)-l-(3-fluoro-4-(2-(methyl- amino)ethoxy)phenyl)but-l-enyl)phenol
  • Step B l-(4-amino-3-nitrophenyl)propan-l-one
  • V-(2-nitro-4-propionylphenyl)acetamide (3.36 g, 10 mmol) in 30 mL 35% HC1 was heated to reflux for 1 h and cooled. The pH was adjusted to 7 by adding aqueous ammonia under stirring. The precipitate was collected by filtration to give the desired product as a yellow solid (1.75 g, 90%).
  • Step C l-(3,4-diaminophenyl)pr
  • Step D l-(benzo[c][l,2,5]thiadiazol-5-yl)propan-l-one
  • Step E 4-(2-(benzo[c] [l,2,5]thiadiazol-5-yl)-l-(4-(2-chloroethoxy)- phenyl)but-l-enyl)phenol
  • Step F 4-(2-(benzo[c] [l,2,5]thiadiazol-5-yl)-l-(4-(2-(methylamino)- ethoxy)phenyl)but-l-enyl)phenol
  • Step C l-methyl-l//-benzo[ ⁇ /]imidazole-5-carboxylic acid
  • Step D N-methoxy-N,l-dimethyl-l//-benzo[ ⁇ imidazole-5-carboxamide
  • Step E l-(l-methyl-l//-benzo[ ⁇ /]imidazol-5-yl)propan-l-one
  • Step F (Z)-4-(l-(4-(2-chloroethoxy)phenyl)-2-(l-methyl-m-benzo[i/]- imidazol-5-yl)but-l-enyl)pheno
  • step D l-(l-methyl-l_f/-benzo[(i]imidazol-5-yl)propan-l-one (730 mg, 2.2 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (500 mg, 1.0 eq) to give the separated (Z)-isomer and (£ isomer of the product.
  • Step G (Z)-4-(2-(l-methyl-l ⁇ -benzo[i/]imidazol-5-yl)-l-(4-(2-(methyl- amino)ethoxy)phenyl)but-l-enyl)phenol
  • step E (£)-4-(l -(4-(2-chloroethoxy)phenyl)-2-(l -methyl- l_f/-benzo[(i]imidazol-5-yl)but- 1 -enyl)phenol (made by example 8, step F) was reacted with MeNH 2 (30% wt in water) in MeOH under reflux to give the desired (£)-product.
  • Step A l-(benzofuran-5-yl)propan-l-
  • Step B 4-(2-(benzofuran-5-yl)-l-(4-(2-chloroethoxy)phenyl)but-l- enyl)phenol
  • Step C 4-(2-(benzofuran-5-yl)-l-(4-(2-(methylamino)ethoxy)phenyl)- but-l-enyl)phenol
  • Step A 5-(2-ethyl-l,3-dioxola
  • Step B 2-chloro-5-(2-ethyl-l,3-dioxolan-2-yl)benzofuran
  • Step C l-(2-chlorobenzofur -5-yl)propan-l-one
  • Step D 4-(2-(2-chlorobenzofuran-5-yl)-l-(4-(2-chloroethoxy)phenyl)but- l-enyl)phenol
  • Step E 4-(2-(2-chlorobenzofuran-5-yl)-l-(4-(2-(methylamino)ethoxy) phenyl)but-l-enyl)phenol
  • Step A 2-chloro-5-(l-(4-(2-chloroethoxy)phenyl)-l-(4-methoxyphenyl)- but-l-en-2-yl)benzofuran
  • Step B n-5-yl)-l-(4-methoxyphenyl)but- l-enyl)phenoxy)-N-methylethanamine
  • step E described 2-chloro-5-(l-(4-(2-chloroethoxy)phenyl)-l-(4-methoxyphenyl)b ⁇ (440 mg, 1.0 eq) was reacted with MeNH 2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give the desired (Z)-product (Z and E isomer can be separated via column chromatography).
  • Step A (6-chloropyridi -3-yl)(4-(tetrahydro-2//-pyran-2-yloxy)phenyl)- methanone
  • Mg (1.67 g, 1.2 eq) was added to dry THF (50 mL), the mixture was heated to 55 °C, I 2 was added in one lot followed by EtBr.
  • 2-(4-Bromophenoxy)tetrahydro-2H-pyran (16 g, 1.1 eq) was dissolved in THF, and part of this solution was added at once to the Mg-THF mixture. After the reaction was Initiated, the remaining above solution was added and the mixture was reiluxed for 2 h to give the MgBr-THF solution, ready for the next step.
  • Step B 4-(l-(6-chloropyridi benzofuran-5-yl)but-l- enyl)phenol
  • Step C furan-5-yl)-l-(6-(2-(methylamino)- ethoxy)pyridin-3-yl)but-l-enyl)phenol
  • Step D 4-(2-(2-chlorobenzofuran-5-yl)-l-(6-(2-(methylamino)ethylthio)- pyridin-3-yl)but-l-enyl)phenol
  • m/z 462[M+lf.
  • Step B 6-chloro-N-methoxy-N-methylnicotinamide
  • 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 100 mL tetrahydrofuran,. The reaction mixture was stirred at room temperature for 1 h, and then concentrated in vacuo to give a residue.
  • Step C l-(prop-2-ynyl)pyrrolidine
  • Step D (6-chloropyridin-3-yl)(4-(tetrahydro-2//-pyran-2-yloxy)phenyl)- methanone
  • Step E (6-(3-(pyrrolidin-l-yl)prop-l-ynyl)pyridin-3-yl)(4-(tetrahydro-
  • Step F (6-(3-(pyrrolidin-l-yl)propyl)pyridin-3-yl)(4-(tetrahydro-
  • Step G 4-(2-(2-chlorobenzofuran-5-yl)-l-(6-(3-(pyrrolidin-l-yl)propyl)- pyridin-3-yl)but-l-enyl)phenol
  • m/z 487[M+1] + .
  • the estrogen receptor a (ERa) high expression human breast cancer MCF-7 cells (#HTB-22, A.T.C.C.) were cultured in DMEM medium supplemented by 10% fetal bovine serum (Gibco®) and 10 ⁇ g/ml bovine insulin (Sigma®). The cells were maintained in 75cm 2 cell culture flask (Corning®) filled with 15 ml medium, 95% air and 5% CO 2 . Cells were split twice a week in a single layer cell culture.
  • the final concentrations of compounds and DMSO were 3xl0 "10 ⁇ lxl0 "5 M and 0.1%. Cells were incubated at 37 °C for 7 days, medium containing E 2 and compounds were changed every two days to maintain the chemical activity.
  • the viable cell numbers were calculated by the ATP amount from the luciferase quantity measurement (Cell Titre Glo® luciferase kit, Promega®). This method can be used to evaluate the stimulating estrogenicity of estrogen dependent cell growth under the condition of E 2 free. The estrogenicity was tested by percentage compared to the maximum growth stimulation (100%) by E 2 . In this study, the percentage antagonist effects were evaluated by compared to the complete inhibition (100%) at the dose of lxl 0 "5 M. The inhibition curves were generated by the reading numbers with the program Prism® 5, IC 50 values were calculated.

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Abstract

L'invention concerne de nouveaux dérivés d'éthylène représentés par la formule I, qui peuvent être utilisés en tant que modulateurs sélectifs de récepteur d'œstrogène (SERM) et utiles dans la prophylaxie et/ou le traitement d'affections œstrogène-dépendantes ou d'affections.
PCT/CN2012/087884 2011-12-30 2012-12-28 Nouveaux dérivés d'arylalcène et utilisation de ceux-ci en tant que modulateurs sélectifs de récepteur d'œstrogène WO2013097773A1 (fr)

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JP2014549345A JP2015504049A (ja) 2011-12-30 2012-12-28 新規アリールアルケン誘導体およびその選択的エストロゲン受容体調整剤における使用
AU2012361344A AU2012361344A1 (en) 2011-12-30 2012-12-28 Novel arylalkene derivatives and use thereof as selective estrogen receptor modulators
CA2861939A CA2861939A1 (fr) 2011-12-30 2012-12-28 Nouveaux derives d'arylalcene et utilisation de ceux-ci en tant que modulateurs selectifs de recepteur d'oestrogene
CN201280065593.9A CN105658628A (zh) 2011-12-30 2012-12-28 新型芳基乙烯衍生物及其在选择性雌激素受体调节剂中的应用
EP12863580.2A EP2797889A4 (fr) 2011-12-30 2012-12-28 Nouveaux dérivés d'arylalcène et utilisation de ceux-ci en tant que modulateurs sélectifs de récepteur d' strogène
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US11117881B2 (en) 2019-12-20 2021-09-14 Landos Biopharma, Inc. Lanthionine c-like protein 2 ligands, cells prepared therewith, and therapies using same
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US11260057B2 (en) 2017-07-24 2022-03-01 Sanofi Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer
US11642342B2 (en) 2019-12-23 2023-05-09 Accutar Biotechnology Combinations of estrogen receptor degraders and cyclin-dependent kinase inhibitors for treating cancer
US11713296B2 (en) 2018-09-07 2023-08-01 Sanofi Salts of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-l-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylate and preparation process thereof
EP4159723A4 (fr) * 2020-06-02 2024-06-19 Chengdu Kanghong Pharmaceutical Co., Ltd. NOUVEL AGONISTE DU RÉCEPTEUR ß DE L'HORMONE THYROÏDIENNE

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KR20150039705A (ko) 2015-04-13
JP2015504049A (ja) 2015-02-05
CN105658628A (zh) 2016-06-08

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