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WO2018130124A1 - 作为选择性雌激素受体下调剂的三环类化合物及其应用 - Google Patents

作为选择性雌激素受体下调剂的三环类化合物及其应用 Download PDF

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Publication number
WO2018130124A1
WO2018130124A1 PCT/CN2018/071700 CN2018071700W WO2018130124A1 WO 2018130124 A1 WO2018130124 A1 WO 2018130124A1 CN 2018071700 W CN2018071700 W CN 2018071700W WO 2018130124 A1 WO2018130124 A1 WO 2018130124A1
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group
alkyl
alkoxy
hydroxy
amino
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PCT/CN2018/071700
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English (en)
French (fr)
Inventor
王勇
赵立文
王小伟
张小猛
张雁
庞司林
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南京圣和药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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Definitions

  • the invention belongs to the field of medical chemistry, and particularly relates to a compound as a selective estrogen receptor down-regulator (SERD) or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an electronic isostere or a prodrug And their preparation and pharmaceutical compositions containing these compounds and the use of these compounds or compositions for the treatment and/or prevention of estrogen receptor-related diseases.
  • SESD selective estrogen receptor down-regulator
  • the Estrogen Receptor is a ligand-activated transcriptional regulatory protein that mediates the induction of multiple biological effects through interaction with endogenous estrogens.
  • Endogenous estrogens include 17 ⁇ -estradiol and estrone.
  • ER has been found to have two isoforms: ER- ⁇ and ER- ⁇ , which are encoded by two different genes located on human chromosomes 6 and 14, respectively, and ER- ⁇ is widely expressed in various tissues, ER- The expression of ⁇ is limited to the female reproductive system and tissues such as brain and bone. Both contain 6 domains and 4 functional regions, and the N-terminal A/B functional region has a non-ligand-dependent transcriptional activation domain AF-1 with constitutive activity through basal transcription factors.
  • the DNA binding domain consisting of the C domain can specifically bind to the target DNA and contain a nuclear localization signal, and also has a dimerization interface, which plays an important role in the dimerization of the receptor.
  • the D domain is the hinge region responsible for the connection of the DBD and the ligand binding domain (LBD).
  • the C-terminal E domain constitutes LBD, which determines the specific binding of ER to ligands such as estrogen, has a ligand-dependent transcriptional activation domain AF-2, and LBD also has a strong dimerization interface, in the absence of In the case of the body, it still functions, and it is a key part of the receptor's dimerization.
  • the LBD consists of 12 alpha helices and one beta fold, forming a three-layer anti-parallel sandwich structure in which H5, H6, H9 and H10 form the intermediate layer, and H1, H2, H3, H4 and H7, H8, H11 form the outer layers respectively.
  • H12 contains AF-2 with a hydrophobic surface facing the ligand binding pocket and a hydrophilic surface facing outward.
  • the LBD of the ER is wedge-shaped, and the H12 is in the groove of the ligand binding pocket and encloses the ligand binding pocket.
  • R 1 and R 2 are each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl.
  • R 3 is selected from the group consisting of alkyl, alkyl acyl, amino acyl, alkyl amino acyl, haloalkyl, hydroxyalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl and hydroxyalkyl; or R 4 , R 5 together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl and hydroxyalkyl; or R 6 , R 7 together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group;
  • R 4 and R 6 together with the carbon atom to which they are attached form a cycloalkyl group
  • Each R 8 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl An amino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a bisalkylamino group, a cycloalkyl group, and a boronic acid;
  • Y is selected from with Wherein R 9 is selected from the group consisting of carboxyl, cyano, alkyl, haloalkyl and hydroxyalkyl, R 10 is selected from hydrogen and halogen, R 11 is selected from hydroxy, amino, alkoxy and alkylamino, and ring A is selected from cycloalkane.
  • R 12 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, Monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino and
  • n 1, 2, 3 or 4;
  • R 3 is selected from Alkenyl and aryl, wherein R 13 is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkane Alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino and cycloalkyl.
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula I according to the invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug.
  • a further object of the present invention is to provide a combination of a compound of the formula I according to the invention or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug and a pharmaceutically acceptable carrier And a composition comprising a compound of formula I of the invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug, and another drug or drugs.
  • a further object of the present invention is to provide a compound of the formula I according to the invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug for the treatment and/or prophylaxis of an estrogen receptor A method of related diseases, and a compound of the formula I according to the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, electron isostere or prodrug thereof, for use in the treatment and/or prevention of a female
  • drugs for hormone receptor-related diseases are examples of drugs for hormone receptor-related diseases.
  • the present invention provides a compound of the formula I, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug,
  • R 1 and R 2 are each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl.
  • R 3 is selected from the group consisting of alkyl, alkyl acyl, amino acyl, alkyl amino acyl, haloalkyl, hydroxyalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl and hydroxyalkyl; or R 4 , R 5 together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl and hydroxyalkyl; or R 6 , R 7 together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group;
  • R 4 and R 6 together with the carbon atom to which they are attached form a cycloalkyl group
  • Each R 8 is independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkyl An amino group, an alkyl acylamino group, an alkyl acyl group, an amino acyl group, an alkylamino acyl group, a bisalkylamino group, a cycloalkyl group, and a boronic acid;
  • Y is selected from with Wherein R 9 is selected from the group consisting of carboxyl, cyano, alkyl, haloalkyl and hydroxyalkyl, R 10 is selected from hydrogen and halogen, R 11 is selected from hydroxy, amino, alkoxy and alkylamino, and ring A is selected from cycloalkane.
  • R 12 is selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, Monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino and
  • n 1, 2, 3 or 4;
  • R 3 is selected from Alkenyl and aryl, wherein R 13 is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkane Alkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, bisalkylamino and cycloalkyl.
  • the compounds of the invention are of formula Ia a compound or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug.
  • the compounds of the invention are of formula Ib a compound or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug.
  • the compounds of the invention are of formula Ic a compound or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug.
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • R 1 and R 2 are each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy , halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C a 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino acyl group, a bis C 1-6 alkylamino group, and a C 3-10 cycloalkyl group;
  • R 1 and R 2 are each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1 -3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl An acylamino group, a C 1-3 alkyl acyl group, an amino acyl group, a C 1-3 alkylamino acyl group, a bis C 1-3 alkylamino group, and a C 3-6 cycloalkyl group;
  • R 1 and R 2 are each independently selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl Base, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, Propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, ethylene Alkylamino, methylacyl, ethylacyl, vinylacyl, aminoacyl, methylaminoacyl, methyl
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • R 3 is selected from C 1-10 alkyl, C 1-10 alkyl acyl, amino acyl, C 1-10 alkylamino acyl, halo C 1-10 alkyl, hydroxy C 1-10 alkyl, C 2 a -10 alkenyl group, a C 3-10 cycloalkyl group, a C 3-10 heterocyclic group, a C 6-18 aryl group and a C 5-18 heteroaryl group, which group may be substituted by one or more halogens, hydroxyl groups, Alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, bisalkylamino, and optionally substituted cycloalkyl Replace
  • R 3 is selected from C 1-6 alkyl, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl, halo C 1-6 alkyl, hydroxy C 1-6 alkane a group, a C 2-6 alkenyl group, a C 3-8 cycloalkyl group, a C 3-8 heterocyclic group, a C 6-12 aryl group and a C 5-12 heteroaryl group, the group may be one or more Halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1- 6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, bis C 1-6 alkylamino and optionally substituted C 3-8 cycloalkyl;
  • R 3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, formyl, acetyl, propionyl , aminoacyl, methylaminoacyl, ethylaminoacyl, propylaminoacyl, trifluoromethyl, trifluoroethyl, 2,2-difluoropropyl, 2-fluoro-2-methylpropyl, ( S)-3-fluoro-2-methylpropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, vinyl, propenyl, butenyl, 3-methyl-2-butyl Alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, azacyclopentyl, pheny
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, halogenated C 1-6 alkyl and hydroxy C 1-6 alkyl;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halogen, halogenated C 1-3 alkyl and hydroxy C 1-6 alkyl;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl Base, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy and halogen.
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • R 4 , R 5 together with the carbon atom to which they are attached form a carbonyl group or a C 3-10 cycloalkyl group;
  • R 4 , R 5 together with the carbon atom to which they are attached form a carbonyl group, a C 3-6 cycloalkyl group;
  • R 4 , R 5 together with the carbon atom to which they are attached form a carbonyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, halogenated C 1-6 alkyl and hydroxy C 1-6 alkyl;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halogen, halogenated C 1-3 alkyl and hydroxy C 1-6 alkyl;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl Base, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy and halogen.
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • R 6 and R 7 together with the carbon atom to which they are attached form a carbonyl group, a C 3-10 cycloalkyl group;
  • R 6 and R 7 together with the carbon atom to which they are attached form a carbonyl group, a C 3-6 cycloalkyl group;
  • R 6 , R 7 together with the carbon atom to which they are attached form a carbonyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • R 4 , R 6 together with the carbon atom to which they are attached form a C 3-10 cycloalkyl group
  • R 4 , R 6 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • R 4 , R 6 together with the carbon atom to which they are attached form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • Each R 8 is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1 -6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl , aminoacyl group, C 1-6 alkylamino acyl group, bis C 1-6 alkylamino group, C 3-10 cycloalkyl group and boric acid;
  • each R 8 is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, Halogen C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1- a 3- alkyl acyl group, an amino acyl group, a C 1-3 alkylamino acyl group, a bis C 1-3 alkylamino group, a C 3-6 cycloalkyl group, and a boronic acid;
  • each R 8 is independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl Base, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, Propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, ethylene Alkylamino, methylacyl, ethylacyl, vinylacyl, aminoacyl, methylaminoacyl
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • R 9 is selected from the group consisting of a carboxyl group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, and a hydroxy C 1-6 alkyl group;
  • R 9 is selected from the group consisting of a carboxyl group, a cyano group, a C 1-3 alkyl group, a halogenated C 1-3 alkyl group, and a hydroxy C 1-3 alkyl group;
  • R 9 is selected from the group consisting of carboxyl, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl and 2 - hydroxypropyl.
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • R 11 is selected from the group consisting of a hydroxyl group, an amino group, a C 1-6 alkoxy group, and a C 1-6 alkylamino group;
  • R 11 is selected from the group consisting of a hydroxyl group, an amino group, a C 1-3 alkoxy group, and a C 1-3 alkylamino group;
  • R 11 is selected from the group consisting of hydroxyl, amino, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino and isopropylamino.
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • R 12 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy a group, a hydroxy C 1-6 alkoxy group, a nitro group, a carboxyl group, a cyano group, an amino group, a mono C 1-6 alkylamino group, a C 1-6 alkyl acylamino group, a C 1-6 alkyl acyl group, an amino acyl group, a C 1-6 alkylamino acyl group, a bis C 1-6 alkylamino group, and a C 3-10 cycloalkyl group;
  • R 12 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1 -3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl An aminoacyl group, a C 1-3 alkylamino acyl group, a bis C 1-3 alkylamino group, and a C 3-6 cycloalkyl group;
  • R 12 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl Base, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, propylamino, Isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, Methyl acyl, ethyl acyl, vinyl acylamino, Methyl acyl, eth
  • the compound of the present invention is a compound of Formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • two R 12 together with the carbon atom to which they are attached form a carbonyl group, a C 3-10 cycloalkyl group, a C 3-10 heterocyclic group, a C 6-18 aryl group, and a C 5-18 heteroaryl group.
  • the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be one or more halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 Alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, double a C 1-6 alkylamino group and a C 3-10 cycloalkyl group;
  • two R 12 together with the carbon atom to which they are attached form a carbonyl group, a C 3-6 cycloalkyl group, a C 3-6 heterocyclic group, a C 6-12 aryl group and a C 5 group ; a -12heteroaryl group, said cycloalkyl group, heterocyclic group, aryl group and heteroaryl group may be one or more halogen, hydroxy group, C 1-6 alkyl group, halogenated C 1-6 alkyl group, hydroxy group C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkane a base amino group, a di C 1-6 alkylamino group and a C 3-10 cycloalkyl group;
  • n 2 R 12 together with the carbon atom to which they are attached form a carbonyl group, a C 3-6 cycloalkyl group, a C 3-6 heterocyclic group, a C 6-12 aryl group and C 5-12heteroaryl
  • said cycloalkyl, heterocyclic, aryl and heteroaryl may be substituted by one or more halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, Hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 Alkylamino, bis-C 1-3 alkylamino and C 3-6 cycloalkyl substituted.
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • R 13 is selected from the group consisting of halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, Hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1 a -6 alkylamino acyl group, a bis C 1-6 alkylamino group and a C 3-10 cycloalkyl group;
  • R 13 is selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 Alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, amino An acyl group, a C 1-3 alkylamino acyl group, a bis C 1-3 alkylamino group, and a C 3-6 cycloalkyl group;
  • R 13 is selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, Hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropyl Amino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, methyl Acyl, ethyl acyl, vinyl acyl, amino acyl, methyl amino acyl, ethyl, vinyl
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • L 1 is selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, C 1-6 alkyl, O, S, halo C 1-6 alkyl, hydroxy C 1-6 An alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkoxy group, a hydroxy C 1-6 alkoxy group, a carbonyl group and a C 1-6 alkylamino group;
  • L 1 is selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, a C 1-3 alkyl group, O, S, a halogenated C 1-3 alkyl group, a hydroxyl group C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, carbonyl and C 1-3 alkylamino;
  • L 1 is selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, methylene, ethylene, propylene, isopropylidene, O, S, halogenated Methylene, haloethylene, halopropylene, haloisopropylidene, hydroxymethylene, hydroxyethylene, hydroxypropylene, hydroxyisopropylidene, hydroxyalkylene, sub Methoxy, ethyleneoxy, propyleneoxy, isopropylideneoxy, halomethyleneoxy, haloethyleneoxy, halopropoxy, haloisopropoxy, hydroxy Methyleneoxy, hydroxyethyleneoxy, hydroxypropyleneoxy, hydroxyisidineoxy, carbonyl, methyleneamino, ethyleneamino, propyleneamino and isopropylamino.
  • the compound of the invention is a compound of formula I or an isomer thereof, a pharmaceutically acceptable salt, solvate, crystal, ortho isomer or prodrug thereof, wherein:
  • Ring A is selected from the group consisting of C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-18 aryl and C 5-18 heteroaryl, said cycloalkyl, heterocyclyl, aryl and hetero
  • the aryl group may be one or more halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, bis C 1-6 alkylamino and C 3-10 cycloalkyl substituted;
  • ring A is selected from the group consisting of C 3-6 cycloalkyl, C 3-6 heterocyclic, C 6-12 aryl and C 5-12 heteroaryl, said cycloalkyl, heterocyclic,
  • the aryl and heteroaryl groups may be substituted by one or more halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, bis C 1-6 alkylamino and C 3-10 ring Alkyl substitution
  • ring A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, aziridine, nitrogen Heterocyclic butane, tetrahydropyrrolyl, pyrrolyl, piperidinyl, dihydropyrrolyl, tetrahydropyridyl, pyridyl, propylene oxide, tetrahydrofuranyl, tetrahydropyranyl, dihydrofuranyl, Furanyl, dihydropyranyl, pyranyl, cyclothioethane, cyclobutylalkyl, tetrahydrothiophenyl, thienyl, cyclopentyl sulfide, dihydrothienyl, pyrazolidinyl, di
  • hexane phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, anthracenyl and indanyl, said group optionally being one or more halogen, hydroxy, C 1-3 alkyl , halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, Cyano, amino, mono C 1-3 alkylamino, bis C 1-3 alkylamino and C 3-6 cycloalkyl substituted.
  • the compound of formula Ia according to the invention or its isomer, pharmaceutically acceptable salt, solvate, crystalline, isosteres or prodrug thereof in which R 1 is selected from chloro, Methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethane Oxyl and pentafluoroethoxy, R 2 is selected from the group consisting of fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethoxy, difluoromethoxy , trifluoromethoxy, fluoroethoxy, difluoroethoxy and pentafluoroethoxy, R 3 is selected from R 4 is a methyl group, R 5 , R 6 and R 7 are H, R 9 is a carboxyl group, and R 10
  • compounds of Formula Ib according to the invention wherein R 1 , R 2 are each independently selected from fluoro, chloro, methyl, ethyl, propyl, methoxy, ethoxy, Propyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy and pentafluoroethoxy, R 3 is selected from with R 4 is methyl, R 5 , R 6 , and R 7 are H, R 8 is selected from the group consisting of hydrogen, methyl, ethyl, fluorine, and chlorine, m is 1, and ring A is selected from the group consisting of cyclopropyl, cyclobutyl, and ring.
  • heptyl azaspiro[2.3]hexane, oxobicyclo[3.1.0]hexane, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, anthracenyl and indane
  • the group may be optionally substituted by one or more halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, bis C 1-3 alkylamino and C 3-6 ring Alkyl is substituted and R 11 is a hydroxyl group.
  • the present invention provides the following specific compounds:
  • an isomer thereof a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug.
  • the invention provides a process for the preparation of a compound of the formula of the invention, comprising:
  • the compounds of formula I can be known in the art as a suitable compound for the Pictet-Spengler reaction (eg in the presence of an acid) by a) a compound of formula 1 and a compound of formula 2 And prepared by reacting at a suitable temperature in a suitable solvent,
  • the compounds of the formula I can be known in the art as being suitable for the Pictet-Spengler reaction conditions (eg in the presence of acids) by b) the compounds of the formula 1 and the compounds of the formula 3
  • the reaction is carried out to obtain a compound of the formula 4, and the compound of the formula 4 is directly reacted with a suitable group or further subjected to other conventional reactions to obtain a compound of the formula I.
  • the compound of formula 6 can be passed through formula 7
  • the compound is prepared by reacting with a trifluoromethanesulfonic anhydride.
  • the compound of Formula 2, the compound of Formula 3, the compound of Formula 5, or the compound of Formula 7 can be obtained by a commercially available or conventionally known method known in the art.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m, Y are as defined in the above formula I, and X is a halogen.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug, further comprising a selected from the group consisting of One or more agents in the composition group: SERD, SERM, tyrosinase inhibitor, EGFR inhibitor, VEGFR inhibitor, Bcr-Abl inhibitor, c-kit inhibitor, c-Met inhibitor, Raf Inhibitor, MEK inhibitor, histone deacetylase inhibitor, VEGF antibody, EGF antibody, HIV protein kinase inhibitor, HMG-CoA reductase inhibitor, and the like.
  • the invention provides a compound of the invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, or isoster thereof or prodrug thereof, and a compound comprising the same, or an isomer thereof, Pharmaceutical compositions of pharmaceutically acceptable salts, solvates, crystals, electron isosteres or prodrugs for use in the treatment and/or prevention of estrogen receptor related diseases.
  • the compound of the present invention or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug thereof may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation.
  • a pharmaceutically acceptable carrier diluent or excipient
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
  • the formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical.
  • orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.
  • the present invention provides a compound of the formula I of the present invention, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug thereof, or a pharmaceutical composition comprising the same Use of a medicament for the treatment and/or prevention of an estrogen receptor-related disease, wherein the estrogen receptor-associated disease or condition includes, but is not limited to, a cancer associated with ER- ⁇ dysfunction (eg, bone cancer) , breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, and uterine cancer, etc.), leiomyomas (such as uterine leiomyoma, etc.), central nervous system (CNS) defects (such as alcoholism, migraine) Etc., cardiovascular system defects (such as aortic aneurysm, myocardial infarction susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, etc.), blood system defects (such
  • the invention relates to a method of treating an estrogen receptor-related disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or an isomer thereof, pharmaceutically acceptable a salt, solvate, crystallization, electron isostere or prodrug, or a pharmaceutical composition comprising the same, wherein the estrogen receptor related diseases include, but are not limited to, cancer associated with ER dysfunction (eg, bone cancer) , breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, and uterine cancer, etc.), leiomyomas (such as uterine leiomyoma, etc.), central nervous system (CNS) defects (such as alcoholism, migraine) Etc., cardiovascular system defects (such as aortic aneurysm, myocardial infarction susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, etc.), blood system defects (such as deep vein thrombosis
  • alkyl group of the present invention means a linear or branched saturated aliphatic hydrocarbon group, preferably a linear or branched group having 1 to 6 carbon atoms, further preferably a linear or branched having 1 to 3 carbon atoms.
  • Chain groups non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and the like.
  • the alkyl group can be substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.
  • alkoxy group of the present invention means an -O-alkyl group.
  • alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy, and the like.
  • the alkoxy group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.
  • cycloalkyl group of the present invention means a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • heterocyclyl of the present invention means 3- to 10-- having a ring carbon atom and 1 to 4 ring hetero atoms each of which is independently selected from the group consisting of nitrogen, oxygen, sulfur, boron, phosphorus, and silicon.
  • a group of a non-aromatic ring system (the "C 3-10 membered heterocyclic group” of the present invention has the same meaning as the "3-10 membered heterocyclic group”).
  • the point of attachment may be a carbon or nitrogen atom as long as the valency permits.
  • the heterocyclyl group may alternatively be a monocyclic ("monocyclic heterocyclic") or a fused, bridged or spiro ring system (eg, a bicyclic system ("bicyclic heterocyclyl”)) And it can be saturated or can be partially unsaturated.
  • the heterocyclic bicyclic ring system may include one or more heteroatoms in one or both rings.
  • each instance of a heterocyclic group is independently optionally substituted, that is, unsubstituted ("unsubstituted heterocyclic") or substituted with one or more substituents ("substituted hetero Ring base").
  • the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl.
  • the heterocyclyl group is a substituted 3-10 membered heterocyclyl.
  • Exemplary 5-membered heterocyclyl groups include, but are not limited to, indolinyl, iso indolinyl, two Hydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolinyl, and the like. .
  • the "aryl” of the present invention means an aromatic system which may comprise a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic aromatic system containing from 6 to 18 carbon atoms, preferably from about 6 to about 12 carbon atoms.
  • Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, anthracenyl, indanyl.
  • the aryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.
  • heteroaryl of the present invention means an aryl group having at least one carbon atom replaced by a hetero atom, and the hetero atom is O, S, N.
  • Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazole Base, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl and the like.
  • heteroaryl group of the present invention is preferably composed of 5 to 18 atoms (abbreviated as "5-18 membered heteroaryl group” or "C 5-18 membered heteroaryl group” in the present invention), further preferably A heteroaryl group having 5-12 atoms and at least one atom being a hetero atom.
  • Suitable five- to twelve-membered heteroaryl groups include, but are not limited to, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like.
  • the heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.
  • the "isomer” of the present invention is a compound having the same molecular formula but differing in nature or on the bond sequence of its atom or in the spatial arrangement of its atoms.
  • Stereoisomers are isomers whose atoms are spatially distinct.
  • Stereoisomers that are not mirror images of each other are diastereomers and that the stereoisomers that are non-overlapping mirror images of each other are enantiomers.
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • Enantiomers are characterized by the absolute configuration of their asymmetric centers and are described by Rahn and S-sequence rules of Cahn and Prelog, or by methods of rotating the plane of polarized light by molecules and designated as right-handed or left-handed ( That is, as (+) or (-)-isomers, respectively.
  • the chiral compound can exist as a single enantiomer or a mixture thereof.
  • An equal proportion of mixtures comprising enantiomers is referred to as a "racemic mixture".
  • compositions of the present invention refer to salts of the compounds of the present invention which are safe and effective for use in mammals and which have the desired biological activity.
  • Suitable pharmaceutically acceptable prodrugs of the compound of formula I having a carboxy group are, for example, cleavable esters thereof in vivo.
  • An in vivo cleavable ester of a compound of formula I comprising a carboxyl group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically acceptable esters for carboxyl groups include alkyl esters such as methyl esters, ethyl esters and tert-butyl esters, alkoxymethyl esters such as methoxymethyl esters; alkanoyloxy groups a base such as pivaloyloxy ester; 3-decyl ester; a cycloalkylcarbonyloxyalkyl ester such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester; -Oxo-1,3-dioxolyl methyl ester, such as 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl ester And alkoxycarbonyloxyalkyl esters such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester.
  • alkyl esters such as methyl esters, ethyl esters and tert-buty
  • Suitable pharmaceutically acceptable prodrugs of the compound of formula I having a carboxy group are, for example, in vivo cleavable amides such as N-alkyl amides and N,N-dialkyl amides such as N-methyl amide, N Ethyl amide, N-propyl amide, N,N-dimethyl amide, N-ethyl-N-methyl amide or N,N-diethyl amide.
  • bioisostere of the present invention (or simply "e-isostere") is used to define that one or more of the atoms (or radicals) have been similarly spatially and/or electronically characterized by those atoms to which they are substituted.
  • e-isostere A generally recognized term in the art for replacing a drug analog substituted with an atom (or group of atoms).
  • the "crystallization" of the present invention means that the internal structure is a solid formed by regularly repeating constituent atoms (or a group thereof) in three dimensions, and is different from an amorphous solid having an internal structure not having such a regularity.
  • a "pharmaceutical composition” is meant to include any one of the compounds described herein, including the corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or A mixture of a plurality of pharmaceutically acceptable carriers.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • the compositions are typically used in the manufacture of a medicament for the treatment and/or prevention of a disease mediated by one or more kinases.
  • the "pharmaceutically acceptable carrier” of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersing agents, Surfactant isotonicity agent, thickener or emulsifier, preservative, solid binder, lubricant, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • Excipients can include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
  • the "use in a medicament for treating and/or preventing an estrogen receptor-associated disease" of the present invention means that an estrogen receptor-related disease can be improved, and growth, development and/or inhibition of an estrogen receptor-related disease can be suppressed. Or transferring, or reducing the risk of an estrogen receptor-related disease, primarily administering a therapeutically and/or prophylactically effective amount of a compound of the invention to a human or animal in need thereof to inhibit, slow or reverse the estrogen receptor in the subject
  • a body-related disease that improves or reduces the risk of estrogen receptor-related diseases, including diseases associated with estrogen receptor alpha and Diseases associated with estrogen receptor beta, such as cancers associated with estrogen receptor dysfunction (eg, bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, and uterine cancer), smoothing Fibroids (eg uterine leiomyoma, etc.), central nervous system (CNS) defects (eg alcoholism, migraine, etc.), cardiovascular system
  • CNS central
  • methyl (S)-3-fluoro-2-methylpropanoate (2.3 g, 19.15 mmol) was added, dissolved in 100 mL of anhydrous tetrahydrofuran, and the reactor was cooled to about 0 ° C in a low temperature reactor.
  • Lithium aluminum hydride (0.78 g, 20.53 mmol) was slowly added. After the addition was completed, the reaction mixture was stirred at 0 ° C and room temperature for 1 h each. After the reaction was completed, sodium sulfate decahydrate was added portionwise, and the mixture was stirred for 1 hr.
  • Step a Synthesis of (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine
  • the preparation method is similar to the preparation method of the step eg of Example 1, except that the starting material (S)-N-((R)-1-(1H-indol-3-yl)propan-2-yl)-3- Replacement of fluoro-2-methylpropyl-1-amine with (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropane- 1-amine, and the starting material 4-bromo-2,6-difluorobenzaldehyde was replaced with 4-bromo-2-chloro-6-fluorobenzaldehyde to give the title compound.
  • the preparation method is similar to the preparation method of the step eg of Example 1, except that the starting material (S)-N-((R)-1-(1H-indol-3-yl)propan-2-yl)-3- Replacement of fluoro-2-methylpropyl-1-amine with (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2,2-difluoropropyl-1 -Amine to give the title compound.
  • the 5-fluoro-3-hydroxy-3-(2-oxopropyl)-indololin-2-one (2.23 g, 10 mmol) obtained in the step a was dissolved in 20 mL of anhydrous tetrahydrofuran, and borane was added dropwise. Tetrahydrofuran solution (30 mL, 1 M, 30 mmol) was reacted at room temperature for 4 h. The reaction mixture was poured into a mixed solution of 50 mL of ethyl acetate and 50 mL of water. After filtration, the solvent was evaporated under reduced pressure tolu ESI-Ms m/z: 194.10 [M+H] + .
  • the preparation method is similar to the preparation method of Example 2, except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde is replaced with 4-bromo-2,6-difluorobenzaldehyde, and the raw material nitrogen heterocycle is used.
  • the butane-3-carboxylic acid methyl ester hydrochloride was replaced with methyl 5-azaspiro[2.3]hexane-1-carboxylate to give the title compound.
  • the preparation method is similar to the preparation method of Example 2, except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde is replaced with 4-bromo-2,6-difluorobenzaldehyde, and the raw material nitrogen heterocycle is used.
  • the title compound was obtained by substituting methyl butane-3-carboxylate hydrochloride with ethyl 4-pyrazolecarboxylate.
  • step b In a 50 mL single-necked flask, the product obtained in step b (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2,2-difluoro-2-methylpropyl) Methyl 3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (0.221 g, 0.48 mmol), Dissolve with 8 mL of tetrahydrofuran and 4 mL of methanol, add 7.5 M aqueous sodium hydroxide solution (0.64 mL, 4.8 mmol), react at room temperature for 2 h, adjust pH to 6.5 with 2N diluted hydrochloric acid, extract with ethyl acetate, wash with saturated sodium chloride, anhydrous sulfuric acid The sodium was dried and concentrated to give the title compound.
  • the preparation method is similar to the preparation method of Example 9, except that the starting material 4-bromo-2,6-difluoro-1-benzaldehyde is replaced with 4-bromo-2-chloro-6-fluorobenzaldehyde, and the raw materials are used.
  • (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2,2-difluoropropyl-1-amine was replaced with (R) obtained in Example 2.
  • -N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine gave the title compound.
  • the preparation method was similar to the preparation method of Example 10 except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde was replaced with 4-bromo-2-(difluoromethoxy)-6-hydroxybenzaldehyde. The title compound was obtained.
  • step a (Z)-3-(3,5-difluoro-4-formylphenyl)-2-fluoro-methyl acrylate
  • Step b (Z)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4 Synthesis of 9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-2-fluoroacrylic acid
  • the preparation method is similar to the preparation method of the step bc of Example 9, except that the starting material (E) methyl 3-(3,5-difluoro-4-formylphenyl)acrylate is replaced with (Z)-3- (3,5-Difluoro-4-formylphenyl)-2-fluoro-methyl acrylate, and the starting material (R)-N-(1-(1H-indol-3-yl)propan-2- Substituting -2,2-difluoropropyl-1-amine for (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methyl The propyl-1-amine gave the title compound.
  • the preparation method is similar to the preparation method of Example 10 except that the starting material 4-bromo-2-chloro-6-fluoro-benzaldehyde is replaced by 4-bromo-2-fluoro-6-methoxybenzaldehyde. Title compound.
  • the preparation method was similar to the preparation method of Example 2 except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde was replaced with 4-bromo-2,6-difluorobenzaldehyde to give the title compound.
  • the preparation method is similar to the preparation method of Example 2, except that the starting material 4-bromo-2-chloro-6-fluoro-benzaldehyde is replaced by 4-bromo-2-fluoro-6-methoxybenzaldehyde. Title compound.
  • Step b 3',5'-Difluoro-4'-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetra Synthesis of hydrogen-1H-pyrido[3,4-b]indol-1-yl)-[1,1'-biphenyl]-4-carboxylic acid
  • the preparation method is similar to the preparation method of the step bc of Example 9, except that the starting material (E) methyl 3-(3,5-difluoro-4-formylphenyl)acrylate is replaced by the above step a.
  • Methyl 3',5'-difluoro-4'-formyl-[1,1'-biphenyl]-4-carboxylate, and the starting material (R)-N-(1-(1H- ⁇ ) -3-yl)propan-2-yl)-2,2-difluoropropyl-1-amine is replaced by (R)-N-(1-(1H-indol-3-yl)propan-2-yl 2-fluoro-2-methylpropan-1-amine to give the title compound.
  • the preparation method was similar to the preparation method of Example 17, except that the starting material (4-(methoxycarbonyl)phenyl)boronic acid was replaced by (3-(methoxycarbonyl)phenyl)boronic acid to give the title compound.
  • Step a Synthesis of ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole-2-carboxylate
  • Step b Synthesis of ethyl 5-(3,5-difluoro-4-formylphenyl)thiazole-2-carboxylate
  • Step c 5-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- Synthesis of tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)thiazole-2-carboxylic acid
  • the preparation method is similar to the preparation method of the step bc of Example 9, except that the starting material (E) methyl 3-(3,5-difluoro-4-formylphenyl)acrylate is replaced by the above step.
  • Ethyl 5-(3,5-difluoro-4-formylphenyl)thiazole-2-carboxylate, and the starting material (R)-N-(1-(1H-indol-3-yl)propane-2 -yl)-2,2-difluoropropyl-1-amine was replaced by (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2- Methyl propan-1-amine gave the title compound.
  • the preparation method was similar to the preparation method of Example 17, except that the starting material (4-(methoxycarbonyl)phenyl)boronic acid was replaced with (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid.
  • the title compound was obtained by substituting 4-bromo-2,6-difluorobenzaldehyde as 4-bromo-2-methoxy-6-fluorobenzaldehyde.
  • 2-(2,6-Difluoro-4-vinylphenyl)-1,3-dioxolane (2120 mg, 10 mmol) and diammonium acetate (70 mg, 0.25 mmol) were dissolved in 30 ml of anhydrous dichloride.
  • methane ethyl diazoacetate (4500 mg, 40 mmol) was dissolved in 30 mL of anhydrous dichloromethane and 2-(2,6-difluoro-4-vinylphenyl)-1,3-di was slowly added dropwise.
  • a mixture of oxylanol and bismuth diacetate was added dropwise over 1 hour, and the mixture was reacted at room temperature for 1 hour to obtain a title compound.
  • step a 2-(4-bromo-2,6-difluorophenyl)-1,3-dioxolane (1.4 g, 5.3 mmol), 1,1'-double Diphenylphosphinoferrocene (300 mg, 0.5 mmol) and palladium acetate (300 mg, 1.3 mmol) were dissolved in a mixed solvent of 20 mL of methanol and 25 mL of N,N-dimethylformamide, and then 1.18 mL of triethylamine was added. The mixture was stirred at 70 ° C under a CO gas atmosphere for 3 hours.
  • step b 3,5-difluoro-4-(1,3-dioxolan-2-yl)-benzoic acid methyl ester (244 mg, 1 mmol), using 5 mL methanol and 5 mL
  • the mixed solvent of tetrahydrofuran was dissolved, and 5 ml of an aqueous solution of sodium hydroxide (120 mg, 3 mmol) was added, and the mixture was stirred at room temperature for 0.5 h.
  • the reaction mixture was concentrated, evaporated, evaporated, evaporated, evaporated ESI-Ms m/z: 231.0 [M+H] + .
  • Step d Synthesis of 4-(1,3-dioxolan-2-yl)-3,5-difluoro-N-((1S,2R)-2-fluorocyclopropyl)benzamide
  • step c 3,5-difluoro-4-(1,3-dioxolan-2-yl)-benzoic acid (230 mg, 1 mmol), 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (230 mg, 1.2 mmol) and 1-hydroxybenzotriazole (162 mg, 1.2 mmol) were dissolved in 15 mL dichloromethane. Further, (1S, 2R)-2-fluorocyclopropylamine p-toluenesulfonate (300 mg, 1 mmol) was added and stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was evaporated to dryness. ESI-Ms m/z: 288.1 [M+H] + .
  • step d In the 100 mL reaction flask, the product obtained in step d (1,3-dioxolan-2-yl)-3,5-difluoro-N-((1S,2R)-2-fluorocyclopropyl)benzene was added.
  • Formamide (240 mg, 0.84 mmol) was dissolved in 20 mL of dichloromethane, and 1.5 mL of trifluoroacetic acid was added and stirred at room temperature overnight. After the reaction was completed, water (50 mL ⁇ 2) was evaporated.
  • the control compound is the chemical name (E)-3-(3,5-difluoro-4-((1R,3R)-2-)) disclosed in Example 1 of WO 2014/191726 (PCT/GB2014/051607). -fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid
  • the compound (AZD9496) was prepared by the method described in WO 2014/191726 and identified by hydrogen spectroscopy and mass spectrometry.
  • phosphate buffer (DPBS), trypan blue, PolarScreen ER Alpha competitor Assay purchased from Invitrogen;
  • DMSO dimethyl sulfoxide
  • activated carbon Trimethyl sulfoxide (DMSO), activated carbon, Formaldehyde solution, purchased from Sigma;
  • MCF-7 cells purchased from AATCC
  • Estrogen Receptor alpha (D8H8) Rabbit mAb, purchased from CST;
  • Vortex mixer purchased from IKA;
  • Preparation of cell culture medium 50 mL of FBS, 5 mL of penicillin-streptomycin was added to 445 mL of DMEM, and mixed for use. Serum-free FBS was used in the preparation of serum-free cell culture media.
  • the cell-discarded culture medium in the logarithmic growth phase of the T75 cell culture flask was washed once with 10 mL of DPBS. Add 2 mL of trypsin-digested cells, and place at 37 ° C for 2 minutes. Observe most of the cells in a round shape under microscope. Add 5 mL of serum-free cell culture solution to stop digestion. Pipette repeatedly and digest the cells to make cell suspension. Add 10 mL of cell culture solution, mix and count, dilute to 1500 cells/40 ⁇ L of cell suspension, and place the cells into a 384-well cell culture plate with a Multiflow instrument, 40 ⁇ L/well; equilibrate at room temperature for 20 min. Incubate in a 37 ° C cell culture incubator for 24 h.
  • the compound was added to the cell culture plate with Acho instrument at a final concentration of 0.3% DMSO; it was centrifuged at 1000 rpm for 1 min at room temperature, and then cultured in a 37 ° C cell culture incubator for 24 h.
  • the cell culture medium was aspirated, the cells were washed once with PBS, and the cells were fixed with a final concentration of 3.7% paraformaldehyde solution (diluted in PBS) for 20 min at room temperature; the cells were washed twice with PBS and diluted with a final concentration of 0.5% Tween-20 (PBS).
  • the compounds of the present invention have a good inhibitory activity against ER levels based on cellular levels.
  • Test compound The compound of the present invention and the control compound prepared in the above examples, each compound was formulated into 10 mM with DMSO, and then diluted 3 times to 100.00 nM, 33.33 nM, 11.11 nM, 3.70 nM, 1.23 nM, 0.41 nM, 0.14 nM, 0.045 nM, 0.015 nM.
  • the breast cancer cell line MCF-7 was purchased from Nanjing Kaiji Biotechnology Co., Ltd.
  • MEM MEM, FBS, Trypsin-EDTA, Penicillin-Streptomycin, purchased from GIBCO, USA; Luminescent Cell Viability Assay Kit, purchased from Progema, USA; Paclitaxel, purchased from Sichuan Tai Chi Pharmaceutical Company.
  • Cultured expanded MCF-7 cells were trypsinized, resuspended in fresh medium and counted. The resuspended cells were adjusted to 2 ⁇ 10 4 cells/mL, and 96-well cell culture plates were added, and 100 ⁇ L of each well was added to each well. Incubate for 24 h at 37 ° C, 5% CO 2 .
  • the compound was formulated into 200 ⁇ working solution in DMSO, diluted to 2 ⁇ working solution with the culture solution, and then transferred to 100 ⁇ L to the test well, and incubated at 37° C. under 5% CO 2 for 96 h.
  • the compounds of the present invention showed good inhibitory activity against MCF-7 breast cancer cells.
  • Test compound The compound of the present invention and the control compound prepared in the above examples were prepared in an amount of 2 mg/kg for oral administration and 1 mg/kg for the test sample.
  • Balb/c mice were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd.
  • mice were orally administered with 2 mg/kg, and after a single dose of 1 mg/kg intravenously, blood was collected from the orbital venous plexus at 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 6 h, 10 h, 24 h, and centrifuged for plasma treatment.
  • the LC-MS/MS was used for the detection, and the measured blood concentration at each time point was plotted as a drug concentration-time curve, and the pharmacokinetic parameters were calculated.
  • Table 4 The experimental results are shown in Table 4.
  • MCF-7 breast cancer cells (purchased from KGI) were cultured in an ELISA medium containing 10% fetal calf serum, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin in a 37 ° C, 5% CO 2 incubator. .
  • the initial concentration of the cell culture was 1 ⁇ 10 6 /mL, and the cells were subcultured every 3 to 4 days after the cells were over. Tumor cells in the logarithmic growth phase are used for inoculation of tumors in vivo.
  • a beta-estradiol sustained release tablet (Estradiol-17 ⁇ 60 days SE121 0.72 mg, purchased from Innovative Research of America) was inoculated into the left back of each mouse.
  • a beta-estradiol sustained release tablet (Estradiol-17 ⁇ 60 days SE121 0.72 mg, purchased from Innovative Research of America) was inoculated into the left back of each mouse.
  • the animals were urinated three times a week, and if necessary, the animals were urinated daily.
  • a PBS containing 10 ⁇ 10 6 cells was mixed with 100 ⁇ L of Matrigel (final volume 200 ⁇ L) to inoculate the right rear side of the mouse. 3.
  • Test compound The compound of the present invention and the control compound prepared in the above examples.
  • the compound of the present invention and the control compound were administered once daily (QD) for three weeks (3 W).
  • the experimental indicator is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured with vernier calipers three times a week.
  • T/C T RTV / C RTV ⁇ 100% (T RTV : treatment group RTV; C RTV : negative control group RTV).
  • Tumor inhibition rate (%) (1-T/C) ⁇ 100%.
  • the experimental results of the antitumor efficacy evaluation of the test compound on the human breast cancer cell line MCF-7 subcutaneous xenograft model are shown in Table 5.
  • the corresponding T/C (%) values of the compounds of the examples in the table are the respective examples.
  • the T/C (%) mean of the tumor volume calculated on the 21st day after administration of the animals in each dose group of the compound.
  • the experimental results show that, unexpectedly, the compound of the present invention has a significantly better antitumor effect against breast cancer than the positive drug AZD9496.
  • the compounds of the present invention such as the compounds of Example 3, Example 10, Example 13, Example 17, and Example 20, are significantly more effective than the same dose of AZD9496 at a dose of 0.6 mg/kg at a dose of 2 mg/kg.
  • the efficacy is much better than the AZD9496 6mg/kg dose.
  • some of the compounds of the present invention produced an effect equivalent to the positive drug AZD9496 (0.6 mg/kg VS 6 mg/kg) at a tenth dose.

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Abstract

本发明属于医药化学领域，涉及一类作为选择性雌激素受体下调节剂的三环类化合物及其应用，具体地，本发明提供式I所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，它们的制备方法以及含有这些化合物的药物组合物和这些化合物或组合物用于治疗和/或预防雌激素受体相关的疾病的用途。本发明的化合物具有更加优异的抗肿瘤活性，给药间隔更长，副作用更小，非常有希望成为乳腺癌治疗剂。

Description

作为选择性雌激素受体下调剂的三环类化合物及其应用 技术领域
本发明属于医药化学领域，具体涉及一类作为选择性雌激素受体下调剂(SERD)的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，它们的制备方法以及含有这些化合物的药物组合物和这些化合物或组合物用于治疗和/或预防雌激素受体相关的疾病的用途。
背景技术
雌激素受体(Estrogen Receptor，ER)是配体激活的转录调节蛋白，它通过与内源性雌激素的相互作用介导多种生物效应的诱导。内源性雌激素包括17β-雌二醇和雌酮。已发现ER具有两种同种型：ER-α和ER-β，其分别由位于人的6号和14号染色体的两个不同的基因编码，ER-α在各种组织广泛表达，ER-β的表达仅局限于女性生殖系统和脑、骨骼等组织。二者均包含6个结构域和4个功能区，N端的A/B功能区具有非配体依赖的转录激活功能域AF-1，具有组成性激活活性(constitutive activity)，通过与基础转录因子、协激活因子和其他转录因子作用来激活靶标基因的转录，此外还有多处磷酸化位点。由C域组成的DNA结合域(DBD)能特异性地结合在靶标DNA上，并包含着核定位信号，同时还具有二聚化界面，对受体的二聚化起着重要的作用。D域为铰链区，负责连接DBD和配基结合域(LBD)。C端E域组成LBD，该域决定ER与雌激素等配体的特异性结合，具有配体依赖的转录激活功能域AF-2，而且LBD还具有很强的二聚化界面，在没有配体的情况下仍能发挥作用，是受体发生二聚化的关键部位。LBD由12条α螺旋和一个β折叠组成，形成三层反向平行的三明治结构，其中H5、H6、H9和H10组成中间层，H1、H2、H3、H4和H7、H8、H11分别组成外面两层，其中H12含有AF-2，其疏水表面朝向配体结合口袋，而亲水表面朝外。ER的LBD呈楔形，H12处于配体结合口袋的凹槽中，并封住配体结合口袋。当ER与激动剂结合时，H12这一构象变得更加稳定，适于协激活因子的结合，继而激活靶基因的转录。而当ER与拮抗剂结合时，H12的位置发生改变并占据协激活因子的结合部位，进而产生雌激素拮抗作用。
对于靶向雌激素受体的药物研究已进行了多年，临床上取得了一些成功，特别是近来发现选择性雌激素受体下调剂具有更加强的抗雌性激素作用，如干扰雌性激素受体的稳定性并导致其降解。不过，仍然需要开发更多的雌激素受体下调剂，尤其是选择性雌激素受体下调剂，使得所述药物具有更加优异的特性，例如疗效更好，副作用更小，给药间隔更长等，从而更好地用于预防或治疗雌激素受体相关的疾病。
发明内容
本发明的一个目的是提供通式I所示的一类具有选择性雌激素受体下调活性的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，
Figure PCTCN2018071700-appb-000001
其中，
R 1、R 2分别独立地选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；
R 3选自烷基、烷基酰基、氨基酰基、烷基氨基酰基、卤代烷基、羟基烷基、烯基、环烷基、杂环基、芳基和杂芳基；
R 4、R 5分别独立地选自氢、烷基、烷氧基、卤素、卤代烷基和羟基烷基；或R 4、R 5与它们所连接的碳原子一起形成羰基或环烷基；
R 6、R 7分别独立地选自氢、烷基、烷氧基、卤素、卤代烷基和羟基烷基；或R 6、R 7与它们所连接的碳原子一起形成羰基或环烷基；或者
R 4、R 6与它们所连接的碳原子一起形成环烷基；
各R 8分别独立地选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、环烷基和硼酸；
Y选自
Figure PCTCN2018071700-appb-000002
和
Figure PCTCN2018071700-appb-000003
其中R 9选自羧基、氰基、烷基、卤代烷基和羟基烷基，R 10选自氢和卤素，R 11选自羟基、氨基、烷氧基和烷基氨基，环A选自环烷基、杂环基、芳基和杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基取代，R 12选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基，n为1、2或3，或者当n为2时，两个R 12基团与它们所连接的碳原子一起形成羰基、环烷基、杂环基、芳基、杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个氢、卤素、羟基、烷基、卤代烷基、羟基烷 基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基取代，L 1选自键、-NHCO-、-CONH-、-NHCONH-、-NH-、亚烷基、O、S、卤代亚烷基、羟基亚烷基、亚烷氧基、卤代亚烷氧基、羟基亚烷氧基、羰基和亚烷基氨基；
化学键
Figure PCTCN2018071700-appb-000004
各自独立地为
Figure PCTCN2018071700-appb-000005
或
Figure PCTCN2018071700-appb-000006
m为1、2、3或4；
条件是当Y为
Figure PCTCN2018071700-appb-000007
且R 1、R 2都为氟，R 10为氢时，R 3选自
Figure PCTCN2018071700-appb-000008
烯基和芳基，其中R 13选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基。
本发明的另一个目的是提供制备本发明的通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药的方法。
本发明的再一个目的是提供包含本发明的通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药和药学可接受的载体的组合物，以及包含本发明的通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药和另一种或多种药物的组合物。
本发明的还一个目的是提供本发明的通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药治疗和/或预防雌激素受体相关的疾病的方法，以及本发明的通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药在制备用于治疗和/或预防雌激素受体相关的疾病的药物中的应用。
针对上述目的，本发明提供以下技术方案：
第一方面，本发明提供通式I所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，
Figure PCTCN2018071700-appb-000009
其中，
R 1、R 2分别独立地选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；
R 3选自烷基、烷基酰基、氨基酰基、烷基氨基酰基、卤代烷基、羟基烷基、烯基、环烷基、杂 环基、芳基和杂芳基；
R 4、R 5分别独立地选自氢、烷基、烷氧基、卤素、卤代烷基和羟基烷基；或R 4、R 5与它们所连接的碳原子一起形成羰基或环烷基；
R 6、R 7分别独立地选自氢、烷基、烷氧基、卤素、卤代烷基和羟基烷基；或R 6、R 7与它们所连接的碳原子一起形成羰基或环烷基；或者
R 4、R 6与它们所连接的碳原子一起形成环烷基；
各R 8分别独立地选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、环烷基和硼酸；
Y选自
Figure PCTCN2018071700-appb-000010
和
Figure PCTCN2018071700-appb-000011
其中R 9选自羧基、氰基、烷基、卤代烷基和羟基烷基，R 10选自氢和卤素，R 11选自羟基、氨基、烷氧基和烷基氨基，环A选自环烷基、杂环基、芳基和杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基取代，R 12选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基，n为1、2或3，或者当n为2时，两个R 12基团与它们所连接的碳原子一起形成羰基、环烷基、杂环基、芳基、杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基取代，L 1选自键、-NHCO-、-CONH-、-NHCONH-、-NH-、亚烷基、O、S、卤代亚烷基、羟基亚烷基、亚烷氧基、卤代亚烷氧基、羟基亚烷氧基、羰基和亚烷基氨基；
化学键
Figure PCTCN2018071700-appb-000012
各自独立地为
Figure PCTCN2018071700-appb-000013
或
Figure PCTCN2018071700-appb-000014
m为1、2、3或4；
条件是当Y为
Figure PCTCN2018071700-appb-000015
且R 1、R 2都为氟，R 10为氢时，R 3选自
Figure PCTCN2018071700-appb-000016
烯基和芳基，其中R 13选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基。
在一些具体的实施方案中，本发明的化合物为通式Ia
Figure PCTCN2018071700-appb-000017
的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药。
在一些具体的实施方案中，本发明的化合物为通式Ib
Figure PCTCN2018071700-appb-000018
的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药。
在一些具体的实施方案中，本发明的化合物为通式Ic
Figure PCTCN2018071700-appb-000019
的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 1、R 2分别独立地选自氟、氯、溴、碘、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基和C 3-10环烷基；
进一步优选地，R 1、R 2分别独立地选自氟、氯、溴、碘、羟基、C 1-3烷基、卤代C 1-3烷基、羟基C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、羟基C 1-3烷氧基、硝基、羧基、氰基、氨基、单C 1-3烷基氨基、C 1-3烷基酰基氨基、C 1-3烷基酰基、氨基酰基、C 1-3烷基氨基酰基、双C 1-3烷基氨基和C 3-6环烷基；
更进一步优选地，R 1、R 2分别独立地选自氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基、硝基、羧基、氰基、氨基、甲氨基、乙基氨基、丙基氨基、异丙基氨基、二甲氨基、二乙氨基、甲基 乙基氨基、二丙氨基、甲基丙基氨基、乙基丙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、环丙基、环丁基、环戊基和环己基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 3选自C 1-10烷基、C 1-10烷基酰基、氨基酰基、C 1-10烷基氨基酰基、卤代C 1-10烷基、羟基C 1-10烷基、C 2-10烯基、C 3-10环烷基、C 3-10杂环基、C 6-18芳基和C 5-18杂芳基，所述基团可以被一个或多个卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、双烷基氨基和任选取代的环烷基取代；
进一步优选地，R 3选自C 1-6烷基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、卤代C 1-6烷基、羟基C 1-6烷基、C 2-6烯基、C 3-8环烷基、C 3-8杂环基、C 6-12芳基和C 5-12杂芳基，所述基团可以被一个或多个卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、双C 1-6烷基氨基和任选取代的C 3-8环烷基取代；
更进一步优选地，R 3选自甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基、新戊基、己基、甲酰基、乙酰基、丙酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、丙基氨基酰基、三氟甲基、三氟乙基、2,2-二氟丙基、2-氟-2-甲基丙基、(S)-3-氟-2-甲基丙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、乙烯基、丙烯基、丁烯基、3-甲基-2-丁烯基、环丙基、环丁基、环戊基、氮杂环丁基、氮杂环戊基、苯基和萘基，所述基团可以被一个或多个卤素、羟基、C 1-3烷基、卤代C 1-3烷基、羟基C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、羟基C 1-3烷氧基、硝基、羧基、氰基、氨基、单C 1-3烷基氨基、双C 1-3烷基氨基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 4、R 5分别独立地选自氢、C 1-6烷基、C 1-6烷氧基、卤素、卤代C 1-6烷基和羟基C 1-6烷基；
进一步优选地，R 4、R 5分别独立地选自氢、C 1-3烷基、C 1-3烷氧基、卤素、卤代C 1-3烷基和羟基C 1-6烷基；
更进一步优选地，R 4、R 5分别独立地选自氢、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基和卤素。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 4、R 5与它们所连接的碳原子一起形成羰基或C 3-10环烷基；
进一步优选地，R 4、R 5与它们所连接的碳原子一起形成羰基、C 3-6环烷基；
更进一步优选地，R 4、R 5与它们所连接的碳原子一起形成羰基、环丙基、环丁基、环戊基和环己基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 6、R 7分别独立地选自氢、C 1-6烷基、C 1-6烷氧基、卤素、卤代C 1-6烷基和羟基C 1-6烷基；
进一步优选地，R 6、R 7分别独立地选自氢、C 1-3烷基、C 1-3烷氧基、卤素、卤代C 1-3烷基和羟基C 1-6烷基；
更进一步优选地，R 6、R 7分别独立地选自氢、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基和卤素。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 6、R 7与它们所连接的碳原子一起形成羰基、C 3-10环烷基；
进一步优选地，R 6、R 7与它们所连接的碳原子一起形成羰基、C 3-6环烷基；
更进一步优选地，R 6、R 7与它们所连接的碳原子一起形成羰基、环丙基、环丁基、环戊基和环己基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 4、R 6与它们所连接的碳原子一起形成C 3-10环烷基；
进一步优选地，R 4、R 6与它们所连接的碳原子一起形成C 3-6环烷基；
更进一步优选地，R 4、R 6与它们所连接的碳原子一起形成环丙基、环丁基、环戊基和环己基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
各R 8分别独立地选自氢、卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基、C 3-10环烷基和硼酸；
进一步优选地，各R 8分别独立地选自氢、卤素、羟基、C 1-3烷基、卤代C 1-3烷基、羟基C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、羟基C 1-3烷氧基、硝基、羧基、氰基、氨基、单C 1-3烷基氨基、C 1-3烷基酰基氨基、C 1-3烷基酰基、氨基酰基、C 1-3烷基氨基酰基、双C 1-3烷基氨基、C 3-6环烷基和硼酸；
更进一步优选地，各R 8分别独立地选自氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙 氧基、硝基、羧基、氰基、氨基、甲氨基、乙基氨基、丙基氨基、异丙基氨基、二甲氨基、二乙氨基、甲基乙基氨基、二丙氨基、甲基丙基氨基、乙基丙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、环丙基、环丁基、环戊基、环己基和硼酸。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 9选自羧基、氰基、C 1-6烷基、卤代C 1-6烷基和羟基C 1-6烷基；
进一步优选地，R 9选自羧基、氰基、C 1-3烷基、卤代C 1-3烷基和羟基C 1-3烷基；
更进一步优选地，R 9选自羧基、氰基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基和2-羟基丙基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 11选自羟基、氨基、C 1-6烷氧基和C 1-6烷基氨基；
进一步优选地，R 11选自羟基、氨基、C 1-3烷氧基和C 1-3烷基氨基；
更进一步优选地，R 11选自羟基、氨基、甲氧基、乙氧基、丙氧基、异丙氧基、甲基氨基、乙基氨基、丙基氨基和异丙基氨基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 12选自氢、卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基和C 3-10环烷基；
进一步优选地，R 12选自氢、卤素、羟基、C 1-3烷基、卤代C 1-3烷基、羟基C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、羟基C 1-3烷氧基、硝基、羧基、氰基、氨基、单C 1-3烷基氨基、C 1-3烷基酰基氨基、C 1-3烷基酰基、氨基酰基、C 1-3烷基氨基酰基、双C 1-3烷基氨基和C 3-6环烷基；
更进一步优选地，R 12选自氢、氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基、硝基、羧基、氰基、氨基、甲氨基、乙基氨基、丙基氨基、异丙基氨基、二甲氨基、二乙氨基、甲基乙基氨基、二丙氨基、甲基丙基氨基、乙基丙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、环丙基、环丁基、环戊基和环己基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、 溶剂化物、结晶、电子等排体或前药，其中：
当n为2时，两个R 12与它们所连接的碳原子一起形成羰基、C 3-10环烷基、C 3-10杂环基、C 6-18芳基和C 5-18杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、双C 1-6烷基氨基和C 3-10环烷基取代；
进一步优选地，当n为2时，两个R 12与它们所连接的碳原子一起形成羰基、C 3-6环烷基、C 3-6杂环基、C 6-12芳基和C 5-12杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、双C 1-6烷基氨基和C 3-10环烷基取代；
更进一步优选地，当n为2时，两个R 12与它们所连接的碳原子一起形成羰基、C 3-6环烷基、C 3-6杂环基、C 6-12芳基和C 5-12杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个卤素、羟基、C 1-3烷基、卤代C 1-3烷基、羟基C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、羟基C 1-3烷氧基、硝基、羧基、氰基、氨基、单C 1-3烷基氨基、双C 1-3烷基氨基和C 3-6环烷基取代。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
R 13选自卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基和C 3-10环烷基；
进一步优选地，R 13选自卤素、羟基、C 1-3烷基、卤代C 1-3烷基、羟基C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、羟基C 1-3烷氧基、硝基、羧基、氰基、氨基、单C 1-3烷基氨基、C 1-3烷基酰基氨基、C 1-3烷基酰基、氨基酰基、C 1-3烷基氨基酰基、双C 1-3烷基氨基和C 3-6环烷基；
更进一步优选地，R 13选自氟、氯、溴、碘、羟基、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、羟甲基、羟乙基、羟丙基、2-羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基、硝基、羧基、氰基、氨基、甲氨基、乙基氨基、丙基氨基、异丙基氨基、二甲氨基、二乙氨基、甲基乙基氨基、二丙氨基、甲基丙基氨基、乙基丙基氨基、甲基酰基氨基、乙基酰基氨基、乙烯基酰基氨基、甲基酰基、乙基酰基、乙烯基酰基、氨基酰基、甲基氨基酰基、乙基氨基酰基、环丙基、环丁基、环戊基和环己基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
L 1选自键、-NHCO-、-CONH-、-NHCONH-、-NH-、亚C 1-6烷基、O、S、卤代亚C 1-6烷基、羟基亚C 1-6烷基、亚C 1-6烷氧基、卤代亚C 1-6烷氧基、羟基亚C 1-6烷氧基、羰基和亚C 1-6烷基氨基；
进一步优选地，L 1选自键、-NHCO-、-CONH-、-NHCONH-、-NH-、亚C 1-3烷基、O、S、卤代亚C 1-3烷基、羟基亚C 1-3烷基、亚C 1-3烷氧基、卤代亚C 1-3烷氧基、羟基亚C 1-3烷氧基、羰基和亚C 1-3烷基氨基；
更进一步优选地，L 1选自键、-NHCO-、-CONH-、-NHCONH-、-NH-、亚甲基、亚乙基、亚丙基、亚异丙基、O、S、卤代亚甲基、卤代亚乙基、卤代亚丙基、卤代亚异丙基、羟基亚甲基、羟基亚乙基、羟基亚丙基、羟基亚异丙基、羟基亚烷基、亚甲氧基、亚乙氧基、亚丙氧基、亚异丙氧基、卤代亚甲氧基、卤代亚乙氧基、卤代亚丙氧基、卤代亚异丙氧基、羟基亚甲氧基、羟基亚乙氧基、羟基亚丙氧基、羟基亚异丙氧基、羰基、亚甲基氨基、亚乙基氨基、亚丙基氨基和亚异丙基氨基。
在一些优选的实施方案中，本发明的化合物为通式I的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，其中：
环A选自C 3-10环烷基、C 3-10杂环基、C 6-18芳基和C 5-18杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、双C 1-6烷基氨基和C 3-10环烷基取代；
进一步优选地，环A选自C 3-6环烷基、C 3-6杂环基、C 6-12芳基和C 5-12杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、双C 1-6烷基氨基和C 3-10环烷基取代；
更进一步优选地，环A选自环丙基、环丁基、环戊基、环己基、环丙烯基、环丁烯基、环戊烯基、环己烯基、氮杂环丙烷基、氮杂环丁烷基、四氢吡咯基、吡咯基、哌啶基、二氢吡咯基、四氢吡啶基、吡啶基、环氧丙烷基、四氢呋喃基、四氢吡喃基、二氢呋喃基、呋喃基、二氢吡喃基、吡喃基、环硫乙烷基、硫化环丁烷基、四氢噻吩基、噻吩基、硫化环戊烷基、二氢噻吩基、吡唑烷基、二氢吡唑基、吡唑基、咪唑烷基、二氢咪唑基、咪唑基、二氢吡唑基、噁唑烷基、二氢噁唑基、咪唑基、噻唑烷基、二氢噻唑基、噻唑基、异噁唑烷基、二氢异噁唑基、异噁唑基、异噻唑烷基、二氢异噻唑基、异噻唑基、六氢嘧啶基、四氢嘧啶基、二氢嘧啶基、嘧啶基、六氢哒嗪基、四氢哒嗪基、二氢哒嗪基、哒嗪基、哌嗪基、四氢吡嗪基、二氢吡嗪基、吡嗪基、吗啉基、硫代吗啉基、二氧六环基、二硫六环基、牛磺胺基、双环[2.2.1]庚烷基、氮杂螺[2.3]己烷基、氧代双环[3.1.0]己烷基、苯基、萘基、蒽基、四氢萘基、芴基和茚满基，所述的基团任选可以被一个或多个卤素、羟基、C 1-3烷基、卤代C 1-3烷基、羟基C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、羟基C 1-3烷氧基、硝基、羧基、氰基、氨基、单C 1-3烷基氨基、双C 1-3烷基氨基和C 3-6环烷基取代。
在一些具体的实施方案中，根据本发明的通式Ia的化合物或其异构体、药学上可接受的盐、溶 剂化物、结晶、电子等排体或前药，其中R 1选自氯、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、二氟代甲氧基、三氟甲氧基、氟代乙氧基、二氟代乙氧基和五氟乙氧基，R 2选自氟、氯、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、二氟代甲氧基、三氟甲氧基、氟代乙氧基、二氟代乙氧基和五氟乙氧基，R 3选自
Figure PCTCN2018071700-appb-000020
R 4为甲基，R 5、R 6、R 7为H，R 9为羧基，R 10为H或氟。
在一些具体的实施方案中，根据本发明的通式Ib的化合物，其中R 1、R 2各自独立地选自氟、氯、甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、二氟代甲氧基、三氟甲氧基、氟代乙氧基、二氟代乙氧基和五氟乙氧基，R 3选自
Figure PCTCN2018071700-appb-000021
和
Figure PCTCN2018071700-appb-000022
R 4为甲基，R 5、R 6、R 7为H，R 8选自氢、甲基、乙基、氟和氯，m为1，环A选自环丙基、环丁基、环戊基、环己基、环丙烯基、环丁烯基、环戊烯基、环己烯基、氮杂环丙烷基、氮杂环丁烷基、四氢吡咯基、吡咯基、哌啶基、二氢吡咯基、四氢吡啶基、吡啶基、环氧丙烷基、四氢呋喃基、四氢吡喃基、二氢呋喃基、呋喃基、二氢吡喃基、吡喃基、环硫乙烷基、硫化环丁烷基、四氢噻吩基、噻吩基、硫化环戊烷基、二氢噻吩基、吡唑烷基、二氢吡唑基、吡唑基、咪唑烷基、二氢咪唑基、咪唑基、二氢吡唑基、噁唑烷基、二氢噁唑基、咪唑基、噻唑烷基、二氢噻唑基、噻唑基、异噁唑烷基、二氢异噁唑基、异噁唑基、异噻唑烷基、二氢异噻唑基、异噻唑基、六氢嘧啶基、四氢嘧啶基、二氢嘧啶基、嘧啶基、六氢哒嗪基、四氢哒嗪基、二氢哒嗪基、哒嗪基、哌嗪基、四氢吡嗪基、二氢吡嗪基、吡嗪基、吗啉基、硫代吗啉基、二氧六环基、二硫六环基、牛磺胺基、双环[2.2.1]庚烷基、氮杂螺[2.3]己烷基、氧代双环[3.1.0]己烷基、苯基、萘基、蒽基、四氢萘基、芴基和茚满基，所述的基团任选可以被一个或多个卤素、羟基、C 1-3烷基、卤代C 1-3烷基、羟基C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、羟基C 1-3烷氧基、硝基、羧基、氰基、氨基、单C 1-3烷基氨基、双C 1-3烷基氨基和C 3-6环烷基取代，R 11为羟基。
本发明提供以下具体化合物：
Figure PCTCN2018071700-appb-000023
Figure PCTCN2018071700-appb-000024
Figure PCTCN2018071700-appb-000025
或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药。
另一方面，本发明提供本发明的通式化合物的制备方法，包括：
通式I的化合物可以通过a)式1的化合物和式2的化合物在本领域中已知作为适用于皮克特-施彭格勒(Pictet-Spengler)反应的条件(如在酸)的存在下并且在一种合适的溶剂中以合适的温度下反应制得，
Figure PCTCN2018071700-appb-000026
或者
通式I的化合物可以通过b)式1的化合物和式3的化合物在本领域中已知作为适用于皮克特-施彭格勒(Pictet-Spengler)反应的条件(如在酸)的存在下反应制得式4的化合物，式4的化合物与合适的基团反应直接制得或再经过其它常规反应制得通式I的化合物，
Figure PCTCN2018071700-appb-000027
其中式1的化合物可以通过式5
Figure PCTCN2018071700-appb-000028
的化合物和式6
Figure PCTCN2018071700-appb-000029
的化合物反应制得，
式6的化合物可以通过式7
Figure PCTCN2018071700-appb-000030
的化合物与三氟甲磺酸酐反应制得，
式2的化合物、式3的化合物、式5的化合物或式7的化合物可以通过商购得到或者本领域中已知的常规制备方法制得，
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、m、Y如以上通式I中所定义，X为卤素。
第三方面，本发明提供药物组合物，其包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药。
在一些实施方案中，本发明提供药物组合物，其包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，还包含选自下列组成的组中的一种或多种药剂：SERD、SERM、酪氨酸蛋白酶抑制剂、EGFR抑制剂、VEGFR抑制剂、Bcr-Abl抑制剂、c-kit抑制剂、c-Met抑制剂、Raf抑制剂、MEK抑制剂、组蛋白去乙酰酶抑制剂、VEGF抗体、EGF抗体、HIV蛋白激酶抑制剂、HMG-CoA还原酶抑制剂等。
在一些实施方案中，本发明提供本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药及包含本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药的药物组合物，所述化合物或药物组合物用于治疗和/或预防雌激素受体相关的疾病。
可以将本发明的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药与药学上可接受的载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。
第四方面，本发明提供本发明通式I所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，或包含其的药物组合物在制备治疗和/或预防雌激素受体相关的疾病的药 物中的用途，其中所述的雌激素受体相关的疾病或病状包括但不限于：与ER-α功能障碍相关的癌症(例如骨癌、乳腺癌、结直肠癌、子宫内膜癌、前列腺癌、卵巢癌和子宫癌等)、平滑肌瘤(例如子宫平滑肌瘤等)、中枢神经系统(CNS)缺陷(例如酒精中毒、偏头痛等)、心血管系统缺陷(例如主动脉瘤、心肌梗死易感性、主动脉瓣硬化、心血管疾病、冠状动脉疾病、高血压等)、血液系统缺陷(例如深静脉血栓形成等)、免疫及炎症疾病(例如格雷夫斯病、关节炎、多发性硬化、肝硬化等)、感染易感性(例如乙型肝炎、慢性肝病等)、代谢缺陷(例如骨密度、胆汁淤积、尿道下裂、肥胖症、骨关节炎、骨质减少、骨质疏松症等)、神经缺陷(例如阿尔茨海默病、帕金森病、偏头痛、眩晕等)、精神缺陷(例如神经性厌食、注意力缺陷伴多动障碍(ADHD)、痴呆、严重抑郁障碍、精神病等)和生殖缺陷(例如月经初潮年龄异常、子宫内膜异位症、不育症等)等。在一些实施方案中，本发明涉及一种治疗雌激素受体相关的疾病的方法，其包括给予所需患者治疗有效量的通式I所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶、电子等排体或前药，或包含其的药物组合物，其中所述的雌激素受体相关的疾病包括但不限于：与ER功能障碍相关的癌症(例如骨癌、乳腺癌、结直肠癌、子宫内膜癌、前列腺癌、卵巢癌和子宫癌等)、平滑肌瘤(例如子宫平滑肌瘤等)、中枢神经系统(CNS)缺陷(例如酒精中毒、偏头痛等)、心血管系统缺陷(例如主动脉瘤、心肌梗死易感性、主动脉瓣硬化、心血管疾病、冠状动脉疾病、高血压等)、血液系统缺陷(例如深静脉血栓形成等)、免疫及炎症疾病(例如格雷夫斯病、关节炎、多发性硬化、肝硬化等)、感染易感性(例如乙型肝炎、慢性肝病等)、代谢缺陷(例如骨密度、胆汁淤积、尿道下裂、肥胖症、骨关节炎、骨质减少、骨质疏松症等)、神经缺陷(例如阿尔茨海默病、帕金森病、偏头痛、眩晕等)、精神缺陷(例如神经性厌食、注意力缺陷伴多动障碍(ADHD)、痴呆、严重抑郁障碍、精神病等)和生殖缺陷(例如月经初潮年龄异常、子宫内膜异位症、不育症等)等。
本发明的化合物具有更加优异的抗肿瘤活性，给药间隔更长，副作用更小。
术语说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明化合物中的“氢”、“碳”、“氧”包括其所有同位素。同位素应理解为包括具有相同原子数但具有不同质量数的那些原子。举例来说，氢的同位素包括氚和氘，碳的同位素包括 13C和 14C，氧的同位素包括 16O和 18O等。
本发明的“卤素”是指氟、氯、溴、碘。本发明的“卤代”是指被氟、氯、溴或碘取代。
本发明的“烷基”指直链或支链的饱和脂肪烃基团，优选含1至6个碳原子的直链或支链基团，进一步优选含有1至3个碳原子的直链或支链基团，非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1- 乙基丙基、2-甲基丁基、3-甲基丁基、正己基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。
本发明的“亚烷基”是指烷基从形式上去掉一个氢原子所剩下的基团，如亚甲基(-CH 2-)，亚乙基(-CH 2-CH 2-)，亚丙基(-CH 2-CH 2-CH 2-)等，在本文中，所述的“亚C 1-10烷基”是指C 1-10烷基从形式上去掉一个氢原子所剩下的基团，所述的“亚C 1-6烷基”是指C 1-6烷基从形式上去掉一个氢原子所剩下的基团。亚烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。
本发明的“卤代烷基”是指至少被一个卤素取代的烷基。
本发明的“羟基烷基”是指至少被一个羟基取代的烷基。
本发明的“烷氧基”是指-O-烷基。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、正丙氧基、异丙氧基、异丁氧基、仲丁氧基等。烷氧基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。
本发明的“环烷基”是指环状的饱和烃基。合适的环烷基可以为取代或未取代的具有3-10个碳原子的单环、二环或三环饱和烃基，例如环丙基、环丁基、环戊基、环己基。
本发明的“杂环基”是指具有环碳原子以及1至4个环杂原子(其中每个杂原子独立地选自氮、氧、硫、硼、磷以及硅)的3-至10-元非芳香族环系统的基团(本发明的“C 3-10元杂环基”的含义和“3-10元杂环基”相同)。在包含一个或多个氮原子的杂环基基团中，连接点可以是碳或氮原子，只要化合价许可。杂环基基团或者可以是单环的(“单环的杂环基”)或者是融合的、桥联的或螺的环系统(例如二环系统(“二环的杂环基”))并且可以是饱和的或可以是部分不饱和的。杂环基二环的环系统可以在一个或两个环中包括一个或多个杂原子。“杂环基”也包括环系统，其中杂环，如以上定义的，是与一个或多个碳环基基团融合的(其中连接点在碳环基或在杂环上)，或环系统中的杂环，如以上定义的，是与一个或多个芳基或杂芳基融合的(其中连接点在杂环上)，并且在此类情况下，环成员的数目继续称作在杂环系统中的环成员的数目。除非另有规定，杂环基的每个实例是独立地任选取代地，即，未取代的(“未取代的杂环基”)或用一个或多个取代基取代的(“取代的杂环基”)。在某些实施例中，该杂环基基团是未取代的3-10元杂环基。在某些实施例中，该杂环基基团是取代的3-10元杂环基。融合至C 6芳基环(在此也称为5,6-二环杂环)的示例性5-元杂环基基团包括但不限于，吲哚啉基、异吲哚啉基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基等等。融合至芳基环的示例性6-元杂环基基团(在此也称为6,6-二环杂环)包括但不限于，四氢喹啉基、四氢异喹啉基等等。
本发明的“芳基”是指可以包含单环或稠合多环的芳香体系，优选包含单环或稠合双环的芳香体系，其含有6个至18个碳原子，优选含有约6至约12个碳原子。合适的芳基包括但不限于苯基、萘基、蒽基、四氢萘基、芴基、茚满基。芳基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。
本发明的“杂芳基”是指至少有一个碳原子被杂原子替代的芳基，所述的杂原子为O、S、N。合适的杂芳基包括但不限于咪唑基、苯并咪唑基、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、三唑基等。其中，本发明的“杂芳基”优选由5-18个原子构成(在本发明中简称为“5-18元杂芳基”或“C 5-18元杂芳基”)，进一步优选由5-12个原子组成，且至少有一个原子为杂原子的杂芳基。合适的五元至十二元杂芳基包括但不限于嘧啶基、吡啶基、吡嗪基、哒嗪基、嘧啶并吡唑基、嘧啶并咪唑基等。杂芳基可以是任选取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上。
本发明的“异构体”是具有相同分子式的但在性质上或在其原子的键序列上或在其原子的空间排列上不同的化合物。立体异构体是其原子在空间排列上不同的异构体。彼此不成镜像的立体异构体是非对映体并且互相是非重叠的镜像的立体异构体是对映体。当化合物具有不对称中心时，例如，它被键合到四个不同的基团，一对对映体是可能的。对映体以其不对称中心的绝对构型为特征并且通过Cahn和Prelog的R-和S-测序规则，或通过分子旋转偏振光的平面的方法被描述并指定作为右旋的或左旋的(即分别作为(+)或(-)-异构体)。手性化合物可以作为单一的对映体或其混合物存在。包含对映体的相等比例的混合物称作“外消旋混合物”。
本发明的“药学上可接受的盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本发明的“溶剂化物”在常规意义上是指溶质(如活性化合物、活性化合物的盐)和溶剂(如水)组合形成的复合物。溶剂是指本领域的技术人员所知的或容易确定的溶剂。如果是水，则溶剂化物通常被称作水合物，例如半水合物、一水合物、二水合物、三水合物或其替代量等。
具有化学式(I)的化合物的体内作用可以部分地由在给予具有化学式(I)的化合物之后在人体或动物体内形成的一种或多种代谢物来发挥。如上所述，具有化学式(I)的化合物的体内作用也可以经由前体化合物(“前药”)代谢来发挥。本发明的“前药”是指在生物体中的生理条件下，由于与酶、胃酸等反应而转化成式(I)的化合物的化合物，即通过酶的氧化、还原、水解等转化成式(I)的化合物的化合物和/或通过胃酸等的水解反应等转化成式(I)的化合物的化合物等。具有羧基的具有化学式I的化合物的适合的药学上可接受的前药为例如其体内可裂解的酯。包含羧基的具有化学式I的化合物的体内可裂解的酯为例如在人体或动物体内裂解以产生母体酸的药学上可接受的酯。对于羧基的适合的药学上可接受的酯包括烷基酯，如甲基酯、乙基酯和叔丁基酯、烷氧基甲基酯如甲氧基甲基酯；链烷酰氧基甲基酯，如新戊酰氧基酯；3-酞基酯；环烷基羰氧基烷基酯，如环戊基羰氧基甲基酯和1-环己基羰氧基乙基酯；2-氧代-1,3-二氧杂环戊烯基(dioxolenyl)甲基酯，如5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基甲基酯；以及烷氧基羰氧基烷基酯，如甲氧基羰氧基甲基酯和1-甲氧基羰氧基乙基酯。具有羧基的具有化学式I的化合物的适合的药学上可接受的前药为例如体内可裂解的酰胺，诸如N-烷基酰胺和N,N-二 烷基酰胺，如N-甲基酰胺、N-乙基酰胺、N-丙基酰胺、N,N-二甲基酰胺、N-乙基-N-甲基酰胺或N,N-二乙基酰胺。
本发明生物电子等排体(或简称“电子等排体”)是用于定义其中一个或多个原子(或原子团)已被具有与它们所置换的那些原子具有相似空间和/或电子特征的置换原子(或原子团)所取代的药物类似物的本领域中一般公认的术语。
本发明的“结晶”是指其内部结构是在三维上规律地重复构成原子(或其集团)而形成的固体，有别于不具有这种规律的内部结构的无定形固体。
本发明的“药物组合物”是指包含任何一种本文所述的化合物，包括对应的异构体、前药、溶剂化物、药学上可接受的盐或其化学的保护形式，和一种或多种药学上可接受载体的混合物。药用组合物的目的是促进化合物对生物体的给药。所述组合物通常用于制备治疗和/或预防由一种或多种激酶介导的疾病的药物。
本发明的“药学上可接受的载体”是指对有机体不引起明显刺激性和不干扰所给予化合物的生物活性和性质的载体，包含所有的溶剂、稀释剂或其它赋形剂、分散剂、表面活性剂等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。除非任何常规载体介质与本发明化合物不相容。可以作为药学上可接受的载体的一些实例包括，但不限于糖类，如乳糖、葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，如羧甲基纤维素钠、以及纤维素和乙酸纤维素；麦芽、明胶等。
本发明的“赋形剂”指加入到药用组合物中以进一步促进给予化合物的惰性物质。赋形剂可以包括碳酸钙、磷酸钙、多种糖类和多种类型的淀粉、纤维素衍生物、明胶、植物油、聚乙二醇。
本发明的“治疗和/或预防雌激素受体相关的疾病的药物中的用途”是指可以使雌激素受体相关的疾病得到改善，抑制雌激素受体相关的疾病的生长、发展和/或转移，或降低雌激素受体相关的疾病的风险，主要向所需要的人或动物给予治疗和/或预防有效量的本发明的化合物以抑制、减慢或逆转受治疗者中雌激素受体相关的疾病的生长、发展或扩散，使雌激素受体相关的疾病得到改善，或降低患病风险，所述的与雌激素受体相关的疾病包括与雌激素受体α相关的疾病及与雌激素受体β相关的疾病，例如与雌激素受体功能障碍相关的癌症(例如骨癌、乳腺癌、结直肠癌、子宫内膜癌、前列腺癌、卵巢癌和子宫癌等)、平滑肌瘤(例如子宫平滑肌瘤等)、中枢神经系统(CNS)缺陷(例如酒精中毒、偏头痛等)、心血管系统缺陷(例如主动脉瘤、心肌梗死易感性、主动脉瓣硬化、心血管疾病、冠状动脉疾病、高血压等)、血液系统缺陷(例如深静脉血栓形成等)、免疫及炎症疾病(例如格雷夫斯病、关节炎、多发性硬化、肝硬化等)、感染易感性(例如乙型肝炎、慢性肝病等)、代谢缺陷(例如骨密度、胆汁淤积、尿道下裂、肥胖症、骨关节炎、骨质减少、骨质疏松症等)、神经缺陷(例如阿尔茨海默病、帕金森病、偏头痛、眩晕等)、精神缺陷(例如神经性厌食、注意力缺陷伴多动障碍(ADHD)、痴呆、严重抑郁障碍、精神病等)和生殖缺陷(例如月经初潮年龄异常、子宫内膜异位症、不育症等)等。
具体实施方式
下面代表性的实施例是为了更好地说明本发明，而非用于限制本发明的保护范围。以下实施例中使用的材料如无特殊说明均为商购获得。
实施例1 1-(3,5-二氟-4-((1R,3R)-2-((S)-3-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氮杂环丁烷-3-甲酸
Figure PCTCN2018071700-appb-000031
步骤a (S)-3-氟-2-甲基丙酸甲酯的合成
Figure PCTCN2018071700-appb-000032
在氩气保护下，往20mL二氯甲烷溶解的(R)-3-羟基-2-甲基丙酸甲酯(2.0g，16.93mmol)溶液中，室温滴加N,N-二乙基-1,1,2,3,3,3-六氟丙胺。滴加完毕后，反应混合物在室温下搅拌一个小时，然后加热至回流，并搅拌4个小时。反应混合物重新冷却至室温，并搅拌8个小时。待反应结束后，将反应混合物倒入冰水(10mL)中，并用二氯甲烷萃取，有机相用饱和氯化钠洗涤，无水硫酸钠干燥后浓缩。得到标题化合物直接使用于下一步反应。
步骤b (S)-3-氟-2-甲基丙醇的合成
Figure PCTCN2018071700-appb-000033
在500mL三颈瓶中，加入(S)-3-氟-2-甲基丙酸甲酯(2.3g，19.15mmol)，用100mL无水四氢呋喃溶解，低温反应器冷却至0℃左右，分批缓慢加入氢化锂铝(0.78g，20.53mmol)。加入完毕以后，反应混合物在0℃和室温下各搅拌1h。反应结束后，缓慢分批加入十水硫酸钠，搅拌1h后过滤，滤饼用少量四氢呋喃洗涤，滤液浓缩至干，得标题化合物。
步骤c (S)-3-氟-2-甲基丙基三氟甲烷磺酸酯的合成
Figure PCTCN2018071700-appb-000034
在250mL反应瓶中，加入(S)-3-氟-2-甲基丙醇(1.8g，19.54mmol)、2,6-二甲基吡啶(2.8mL，23.7mmol)，用20mL二氯甲烷溶解后低温冷却至-10℃。将三氟甲磺酸酐(3.13mL，18.63mmol)用10mL二氯甲烷溶解后滴加入上述反应液中，滴毕继续反应1h。反应结束后，将反应液分别用2N盐酸(2×20mL)、饱和碳酸氢钠(2×20mL)和饱和氯化钠溶液(2×20mL)洗涤，无水硫酸钠干燥，减压除去二氯甲烷，得标 题化合物。
步骤d (S)-N-((R)-1-(1H-吲哚-3-基)丙-2-基)-3-氟-2-甲基丙基-1-胺的合成
Figure PCTCN2018071700-appb-000035
在100mL反应瓶中，加入(S)-3-氟-2-甲基丙基三氟甲烷磺酸酯(2.72g，12.10mmol)、(R)-1-(1H-吲哚-3-基)丙-2-胺(1.75g，10.04mmol)和二异丙基乙胺(3.32ml，20.08mmol)，用30mL二氧六环溶解，氩气保护下90℃反应2h，停止反应，浓缩，柱层析纯化，得标题化合物。ESI-Ms m/z:249.1[M+H] +。
步骤e (1R,3R)-1-(4-溴-2,6-二氟苯基)-2-((S)-3-氟-2甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚的合成
Figure PCTCN2018071700-appb-000036
在50mL单口瓶中，加入4-溴-2,6-二氟苯甲醛(0.535g，2.42mmol)和(S)-N-((R)-1-(1H-吲哚-3-基)丙-2-基)-3-氟-2-甲基丙基-1-胺(0.50g，2.0mmol)，加入4mL醋酸和20mL甲苯，90℃反应3h，浓缩，柱层析纯化，得标题化合物0.61g。ESI-Ms m/z:451.1[M+H] +。
步骤f 1-(3,5-二氟-4-((1R,3R)-2-((S)-3-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氮杂环丁烷-3-甲酸甲酯的合成
Figure PCTCN2018071700-appb-000037
在微波反应罐中，将(1R,3R)-1-(4-溴-2,6-二氟苯基)-2-((S)-3-氟-2甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(910mg，2.02mmol)、氮杂环丁烷-3-甲酸甲酯盐酸盐(367mg，2.42mmol)、三(二亚苄基丙酮)二钯(370mg,0.404mmol)、2-二环己基磷-2,4,6-三异丙基联苯(391mg，0.82mmol)以及碳酸铯(2.0g，6.06mmol)加入到二氧六环(20mL)中。充分置换氩气后，将该混合物加热至100℃微波反应。反应结束以后，过滤并将母液浓缩。该反应产物直接用于下一步。ESI-Ms m/z:486.3[M+H] +。
步骤g 1-(3,5-二氟-4-((1R,3R)-2-((S)-3-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氮杂环丁烷-3-甲酸的合成
在50mL单口瓶中，加入1-(3,5-二氟-4-((1R,3R)-2-((S)-3-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氮杂环丁烷-3-甲酸甲酯(0.62g，1.307mmol)，用10mL四氢呋喃和5mL 甲醇溶解，加入7.5M氢氧化钠溶液(3.0mL，22.5mmol)，室温反应3h，用2N盐酸调pH至6.5，乙酸乙酯萃取，饱和氯化钠洗涤，无水硫酸钠干燥后浓缩，柱层析得标题化合物。 1H NMR(400MHz,d6-DMSO):12.53(s,1H),10.50(s,1H),7.40(d,1H),7.23-7.19(m,1H),7.02-6.94(m,2H),6.08(d,2H),5.02(s,1H),4.44(d,1H),4.34(d,1H),4.01(m,2H),3.97(m,2H),2.82(dd,1H),2.50(m,3H),2.21(m,1H),2.04(m,1H),1.93(m,1H),1.06(d,3H),0.77(d,3H).ESI-Ms m/z:472.5[M+H] +。
实施例2 1-(3-氯-5-氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氮杂环丁烷-3-甲酸
Figure PCTCN2018071700-appb-000038
步骤a：(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2-氟-2-甲基丙-1-胺的合成
Figure PCTCN2018071700-appb-000039
制备方法类似于实施例1步骤b-d的制备方法，不同的是将原料(S)-3-氟-2-甲基丙酸甲酯替换为2-氟-2-甲基丙酸甲酯，制得标题化合物。ESI-Ms m/z:249.1[M+H] +.
步骤b：1-(3-氯-5-氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氮杂环丁烷-3-甲酸的合成
制备方法类似于实施例1步骤e-g的制备方法，不同的是将原料(S)-N-((R)-1-(1H-吲哚-3-基)丙-2-基)-3-氟-2-甲基丙基-1-胺替换为(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2-氟-2-甲基丙-1-胺，且将原料4-溴-2,6-二氟苯甲醛替换为4-溴-2-氯-6-氟苯甲醛，制得标题化合物。 1H NMR(500MHz,DMSO-d 6)δ:12.57(s,1H),10.31(s,1H),7.36(d,1H),7.18(d,1H),6.97-6.92(m,2H),6.33(s,1H),6.20(d,1H),5.17(s,1H),4.02-3.99(m,2H),3.87-3.85(m,2H),3.01(d,1H),2.86(t,1H),2.58-2.56(m,2H),2.33-2.30(m,2H),1.11(d,3H),1.05(d,3H),1.00(d,3H).ESI-Ms m/z:488.2[M+H] +。
实施例3 1-(4-((1R,3R)-2-(2,2-二氟丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)氮杂环丁烷-3-甲酸
Figure PCTCN2018071700-appb-000040
步骤a 2,2-二氟-2-甲基丙基-1-醇的合成
Figure PCTCN2018071700-appb-000041
在250mL三颈瓶中，加入2,2-二氟-2-甲基丙酸(5g，45.5mmol)，用100mL无水四氢呋喃溶解，低温反应器冷却至-10℃左右，分批缓慢加入氢化锂铝(2.1g，54.2mmol)，维持该温度继续反应1h。反应结束后，依次滴加2.1mL水，2.1mL 15％氢氧化钠水溶液和4.2mL水，搅拌15min后过滤，滤饼用少量四氢呋喃洗涤，滤液浓缩至干，得标题化合物。ESI-Ms m/z:97.0[M+H] +。
步骤b (R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2,2-二氟丙基-1-胺的合成
Figure PCTCN2018071700-appb-000042
制备方法同实施例1步骤c-d的制备方法，不同的是将原料(S)-3-氟-2-甲基丙醇替换为2,2-二氟-2-甲基丙基-1-醇，制得标题化合物。ESI-Ms m/z:253.0[M+H] +。
步骤c 1-(4-((1R,3R)-2-(2,2-二氟丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5-二氟苯基)氮杂环丁烷-3-甲酸的合成
制备方法类似于实施例1步骤e-g的制备方法，不同的是将原料(S)-N-((R)-1-(1H-吲哚-3-基)丙-2-基)-3-氟-2-甲基丙基-1-胺替换为(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2,2-二氟丙基-1-胺，制得标题化合物。
1H NMR(500MHz,DMSO-d 6)δ:12.5(s,1H),10.53(s,1H),7.42-7.40(d,1H),7.23-7.21(d,1H),7.03-6.95(m,2H),6.14-6.12(d,2H),5.12(s,1H),4.07-4.03(m,2H),3.93-3.90(m,2H),3.57-3.53(m,1H),3.50-3.46(m,1H),3.10-3.01(m,1H),2.91-2.88(m,1H),2.61-2.57(m,2H),1.50-1.43(t,3H),1.11-1.01(d,3H).ESI-Ms m/z:476.20[M+H] +。
实施例4 1-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-3-甲基氮杂环丁烷-3-甲酸
Figure PCTCN2018071700-appb-000043
制备方法类似于实施例2的制备方法，不同的是将原料氮杂环丁烷-3-甲酸甲酯盐酸盐替换为3-甲基氮杂环丁烷-3-甲酸甲酯盐酸盐，制得标题化合物。 1H NMR(500MHz,DMSO-d 6)δ:12.5(s,1H),10.46(s,1H),7.38-7.36(d,1H),7.18-7.17(d,1H),6.97-6.92(m,2H),6.09-6.06(d,2H),5.06(s,1H),4.03-4.01(d,2H),3.64-3.61(m,2H),3.54-3.50(m,1H),2.89-2.76(m,2H),2.55-2.54(m,1H),2.39-2.29(m,1H),1.49(s,3H),1.20-1.10(q,6H),1.04-1.02(d,3H).ESI-Ms m/z:486.2[M+H] +。
实施例5 1-(3,5-二氟-4-((1R)-6-氟-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)氮杂环丁烷-3-甲酸
Figure PCTCN2018071700-appb-000044
步骤a 5-氟-3-羟基-3-(2-氧代丙基)-吲哚啉-2-酮的合成
Figure PCTCN2018071700-appb-000045
将5-氟靛红(1.65g，10mmol)溶于50mL丙酮，加入碳酸钾(13mg，1.0mmol)，室温搅拌反应5h。减压蒸除溶剂，残留物用乙酸乙酯/石油醚重结晶，得到标题化合物。ESI-Ms m/z:224.10[M+H] +。
步骤b 1-(5-氟-1H-吲哚-3-基)丙基-2-醇的合成
Figure PCTCN2018071700-appb-000046
将步骤a所得物5-氟-3-羟基-3-(2-氧代丙基)-吲哚啉-2-酮(2.23g，10mmol)溶于20mL无水四氢呋喃中，逐滴加入硼烷四氢呋喃溶液(30mL，1M，30mmol)，室温反应4h。将反应液倒入50mL乙酸乙酯和50mL水的混合溶液中，水层用30mL乙酸乙酯萃取，合并有机层，无水硫酸钠干燥。过滤后减压蒸除溶剂，得到标题化合物。ESI-Ms m/z:194.10[M+H] +。
步骤c 1-(5-氟-1H-吲哚-3-基)丙基-2-酮的合成
Figure PCTCN2018071700-appb-000047
将步骤b所得物1-(5-氟-1H-吲哚-3-基)丙基-2-醇(1.93g，10mmol)溶于20mL二氯甲烷中，加入1,1,1-三乙酰氧-1,1-二氢-1,2-苯碘酰-3-(1H)-酮(4.66g，11mmol)，室温反应2h。反应液依次用20mL水，20mL饱和食盐水萃洗，有机层无水硫酸钠干燥。柱层析得到标题化合物1.76g。ESI-Ms m/z:192.10[M+H] +。
步骤d 1-(5-氟-1H-吲哚-3-基)丙基-2-胺的合成
Figure PCTCN2018071700-appb-000048
将步骤c所得物1-(5-氟-1H-吲哚-3-基)丙基-2-酮(1g，5.2mmol)溶于20mL甲醇，加入乙酸胺(4.45g，57.73mmol)和氰基硼氢化钠(0.37g，5.9mmol)，室温反应48h。加入1N盐酸调节pH至2，减压蒸除有机溶剂，50mL二氯甲烷萃洗。水层用4N氢氧化钠水溶液调节pH至12，二氯甲烷3×50mL萃取，合并有机层，无水硫酸钠干燥。柱层析得到标题化合物。ESI-Ms m/z:193.10[M+H] +。
步骤e 1-(3,5-二氟-4-((1R)-6-氟-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)氮杂环丁烷-3-羧酸的合成
制备方法类似于实施例2的制备方法，不同的是将原料(R)-1-(1H-吲哚-3-基)丙-2-胺替换为步骤d中制得的1-(5-氟-1H-吲哚-3-基)丙基-2-胺，且将原料4-溴-2-氯-6-氟苯甲醛替换为4-溴-2,6-二氟苯甲醛，制得标题化合物。 1H NMR(500MHz,DMSO-d 6)δ:12.5(s,1H),10.55(s,1H),7.16-7.10(m,2H),6.82-6.78(m,1H),6.10-6.07(d,2H),5.05(s,1H),4.04-4.00(m,2H),3.89-3.86(m,2H),3.54-3.49(m,2H),2.87-2.77(m,2H),2.52-2.50(m,1H),2.37-2.29(m,1H),1.19-1.11(t,6H),1.03-1.02(d,3H).ESI-Ms m/z:490.20[M+H] +.
实施例6 5-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-5-氮杂螺[2.3]己烷-1-甲酸
Figure PCTCN2018071700-appb-000049
制备方法类似于实施例2的制备方法，不同的是将原料4-溴-2-氯-6-氟苯甲醛替换为4-溴-2,6-二氟苯甲醛，且将原料氮杂环丁烷-3-甲酸甲酯盐酸盐替换为5-氮杂螺[2.3]己烷-1-甲酸甲酯，制得标题化合物。 1H NMR(500MHz,DMSO-d 6)δ:12.1(s,1H),10.49(s,1H),7.38-7.36(d,1H),7.18-7.16(d,1H),6.99-6.90(m,2H),6.22-6.19(d,1H),6.12-6.09(d,1H),5.06-5.01(m,1H),4.23-4.22(m,1H),3.95-3.88(m,2H),3.51-3.48(m,1H),3.25-3.19(m,2H),2.87-2.75(m,2H),2.38-2.28(m,1H),2.04-2.01(m,0.5H),
1.84-1.80(m,0.5H),1.50(s,0.5H),1.44(s,0.5H),1.39-1.36(m,0.5H),1.28-1.25(m,0.5H),1.20-1.10(m,6H),1.03-1.01(m,3H).ESI-Ms m/z:498.3[M+H] +.
实施例7 1-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-1H-吡唑-4-甲酸
Figure PCTCN2018071700-appb-000050
制备方法类似于实施例2的制备方法，不同的是将原料4-溴-2-氯-6-氟苯甲醛替换为4-溴-2,6-二氟苯甲醛，且将原料氮杂环丁烷-3-甲酸甲酯盐酸盐替换为4-吡唑甲酸乙酯，制得标题化合物。 1H NMR(500MHz,DMSO-d 6)δ:12.5(s,1H),10.59(s,1H),9.14(s,1H),8.12(s,1H),7.71-7.68(d,2H),7.43-7.40(d,1H),7.20-7.18(d,1H),7.03-6.93(m,2H),5.23(s,1H),3.56-3.50(m,1H),2.95-2.82(m,2H),2.62-2.56(m,1H),2.44-2.32(m,1H),1.26-1.11(t,6H),1.07-1.05(d,3H).ESI-Ms m/z:483.3[M+H] +.
实施例8 1-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-5-吡咯烷酮-3-甲酸
Figure PCTCN2018071700-appb-000051
制备方法类似于实施例2的制备方法，不同的是将原料4-溴-2-氯-6-氟苯甲醛替换为4-溴-2,6-二氟苯甲醛，且将原料氮杂环丁烷-3-甲酸甲酯盐酸盐替换为5-吡咯烷酮-3-甲酸甲酯，制得标题化合物。 1H NMR(500MHz,DMSO-d 6)δ:12.25(s,1H),10.51(s,1H),7.41-7.36(t,3H),7.17(d,1H),7.00-6.94(m,2H),5.16(s,1H),4.00-3.92(m,2H)3.50(m,1H),3.24(m,1H),2.88-2.57(m,4H),2.57(d,1H),2.32(m,1H),1.21-1.09(d,3H),1.16(d,3H),1.04(d,3H).ESI-Ms m/z:500.2[M+H] +.
实施例9 (E)-3-(3,5-二氟-4-((1R,3R)-2-(2,2-二氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸
Figure PCTCN2018071700-appb-000052
步骤a (E)-3-(3,5-二氟-4-甲酰基苯基)丙烯酸甲酯的合成
Figure PCTCN2018071700-appb-000053
将4-溴-2,6-二氟-1-苯甲醛(6.66g，30mmol)、三乙胺(8.4ml，60mmol)、乙酸钯(0.34g，1.5mmol)和三甲苯基磷(1.0g，3.2mmol)溶解在N,N-二甲基甲酰胺(70mL)中，将其进行脱气。然后添加丙烯酸甲酯(4.3mL，45.0mmol)，并将反应液加热至80℃，持续4h。冷却后，将该混合物添加到水(300mL)中，并用乙酸乙酯(2×400mL)萃取。将合并的有机物相用2N稀盐酸(200mL)洗涤，然后无水硫酸钠干燥并浓缩，柱层析纯化，得标题化合物。ESI-Ms m/z:227.04[M+H] +。
步骤b (E)-3-(3,5-二氟-4-((1R,3R)-2-(2,2-二氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯的合成
Figure PCTCN2018071700-appb-000054
在100mL反应瓶中，加入实施例3中制得的(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2,2-二氟丙基-1-胺(0.252g，1mmol)、(E)-3-(3,5-二氟-4-甲酰基苯基)丙烯酸甲酯(0.181g，0.8mmol)和冰醋酸(0.29mL，5mmol)，再加入甲苯25mL溶解，90℃反应6h，浓缩反应液，柱层析纯化，得标题化合物。ESI-Ms m/z:461.2[M+H] +。
步骤c (E)-3-(3,5-二氟-4-((1R,3R)-2-(2,2-二氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸的合成
Figure PCTCN2018071700-appb-000055
在50mL单口烧瓶中，加入步骤b所得物(E)-3-(3,5-二氟-4-((1R,3R)-2-(2,2-二氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸甲酯(0.221g，0.48mmol)，用8mL四氢呋喃和4mL甲醇溶解，加入7.5M氢氧化钠水溶液(0.64mL，4.8mmol)，室温反应2h，用2N稀盐酸调pH至6.5，乙酸乙酯萃取，饱和氯化钠洗涤，无水硫酸钠干燥后浓缩，柱层析得标题化合物。 1H NMR(500MHz,DMSO-d 6)δ:12.29(s,1H),10.63(s,1H),7.58-7.55(d,1H),7.49-7.47(d,2H),7.45-7.44(d,1H),7.24-7.22(d,1H),7.06-7.02(t,1H),7.00-6.97(t,1H),6.71-6.68(d,1H),5.25(s,1H),3.40(s,1H),3.18-3.09(m,2H), 2.94-2.90(m,2H),1.54-1.46(t,3H),1.12(s,3H).ESI-Ms m/z:447.2[M+H] +.
实施例10 (E)-3-(3-氯-5-氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸
Figure PCTCN2018071700-appb-000056
制备方法类似于实施例9的制备方法，不同的是将原料4-溴-2,6-二氟-1-苯甲醛替换为4-溴-2-氯-6-氟苯甲醛，且将原料(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2,2-二氟丙基-1-胺替换为实施例2中制得的(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2-氟-2-甲基丙-1-胺，制得标题化合物。 1H NMR(500MHz,DMSO-d 6)δ:12.59(s,1H),10.47(s,1H),7.70(s,1H),7.57-7.53(d,2H),7.41(d,1H),7.17(d,1H),6.99-6.94(m,2H),6.72(d,1H),5.34(s,1H),3.65(m,1H),3.07-2.91(m,2H),2.59(d,1H),2.28-2.24(m,1H),1.14-1.03(d,3H),1.09(d,3H),1.05(d,3H).ESI-Ms m/z:459.2[M+H] +.
实施例11 (E)-3-(3-(二氟甲氧基)-5-氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸
Figure PCTCN2018071700-appb-000057
制备方法类似于实施例10的制备方法，不同的是将原料4-溴-2-氯-6-氟苯甲醛替换为4-溴-2-(二氟甲氧基)-6-羟基苯甲醛，制得标题化合物。 1H NMR(500MHz,DMSO-d 6)δ:12.51(s,1H),10.36(s,1H),7.49(d,1H),7.39-7.38(m,3H),7.14(m,2H),6.97-6.93(m,2H),6.60(d,1H),5.20(s,1H),3.55(m,1H),2.98(d,1H),2.85(dd,1H),2.58(m,1H),2.26(dd,1H),1.15-0.98(m,9H).ESI-Ms m/z:491.2[M+H] +.
实施例12 (Z)-3-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-2-氟丙烯酸
Figure PCTCN2018071700-appb-000058
步骤a (Z)-3-(3,5-二氟-4-甲酰基苯基)-2-氟-丙烯酸甲酯的合成
Figure PCTCN2018071700-appb-000059
在100mL反应瓶中，加入4-溴-2,6-二氟-1-苯甲醛(1g，4.93mmol)、2-氟丙烯酸甲酯(1.54g，14.77mmol)、三邻甲苯基膦(0.15g，0.493mmol)、醋酸钯(0.06g，0.247mmol)和三乙胺(1.00g，9.86mmol)，用20mL N,N-二甲基甲酰胺溶解，氩气保护下80℃反应6h。反应结束后。加入20mL冰水搅拌，用乙酸乙酯萃取，饱和氯化钠洗涤，无水硫酸钠干燥后减压浓缩，柱层析纯化，得标题化合物。ESI-Ms m/z:245.1[M+H] +。
步骤b (Z)-3-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)-2-氟丙烯酸的合成
制备方法类似于实施例9步骤b-c的制备方法，不同的是将原料(E)-3-(3,5-二氟-4-甲酰基苯基)丙烯酸甲酯替换为(Z)-3-(3,5-二氟-4-甲酰基苯基)-2-氟-丙烯酸甲酯，且将原料(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2,2-二氟丙基-1-胺替换为(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2-氟-2-甲基丙-1-胺，制得标题化合物。 1H NMR(500MHz,DMSO-d 6)δ:12.60(s,1H),10.49(s,1H),7.71(s,1H),7.61-7.58(d,1H),7.44(d,1H),7.20(d,1H),6.99-6.95(m,2H),6.72(d,1H),5.32(s,1H),3.65(m,1H),3.07-2.91(m,2H),2.59(d,1H),2.28-2.24(m,1H),1.14,1.04(d,3H),1.09(d,3H),1.03(d,3H).ESI-Ms m/z:461.5[M+H] +.
实施例13 (E)-3-(3,5-二氯-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸
Figure PCTCN2018071700-appb-000060
制备方法类似于实施例10的制备方法，不同的是将原料4-溴-2-氯-6-氟苯甲醛替换为4-溴-2,6-二氯苯甲醛，制得标题化合物。 1H NMR(300MHz,DMSO-d 6)δ:10.25(s,1H),8.27(s,1H),7.79(s,1H),7.54(s,1H),7.40-7.35(m,2H),7.16-7.14(d,1H),7.00-6.90(m,2H),6.61-6.58(d,1H),5.58(s,1H),3.67(s,1H),3.07-2.87(m,2H),2.55-2.60(s,1H),2.29-2.14(m,1H),1.12-1.01(s,9H).ESI-Ms m/z:475.2[M+H] +.
实施例14 (E)-3-(3-氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-5-甲氧基苯基)丙烯酸
Figure PCTCN2018071700-appb-000061
制备方法类似于实施例10的制备方法，不同的是将原料4-溴-2-氯-6-氟-苯甲醛替换为4-溴-2-氟-6-甲氧基苯甲醛，制得标题化合物。 1H NMR(300MHz,DMSO-d 6)δ:10.36(s,1H),7.50-7.47(d,1H),7.41-7.40(d,1H),7.25(s,1H),7.19-7.17(d,1H),7.02-6.94(m,3H),6.69-6.60(d,1H),5.35(s,1H),3.90(s,3H),3.60(m,2H),3.00-2.97(m,1H),2.88-2.84(m,1H),2.60-2.59(d,1H),2.38-2.29(m,1H),1.20-1.09(m,9H).ESI-Ms m/z:455.3[M+H] +.
实施例15 1-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)氮杂环丁烷-3-甲酸
Figure PCTCN2018071700-appb-000062
制备方法类似于实施例2的制备方法，不同的是将原料4-溴-2-氯-6-氟苯甲醛替换为4-溴-2,6-二氟苯甲醛，制得标题化合物。 1H NMR(500MHz,DMSO-d 6)δ:12.15(s,1H),10.38(s,1H),7.36-7.30(d,1H),7.23-7.19(d,1H),7.02-6.85(m,2H),6.15-6.05(d,2H),5.05(s,1H),4.15-3.98(m,2H),3.95-3.80(m,2H),3.65-3.47(m,2H),3.90-3.75(m,2H),2.75(s,1H),2.42-2.30(m,1H),1.26-1.01(m,9H).ESI-Ms m/z:472.3[M+H] +.
实施例16 1-(3-氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)-5-甲氧基苯基)氮杂环丁烷-3-甲酸
Figure PCTCN2018071700-appb-000063
制备方法类似于实施例2的制备方法，不同的是将原料4-溴-2-氯-6-氟-苯甲醛替换为4-溴-2-氟-6-甲氧基苯甲醛，制得标题化合物。 1H NMR(300MHz,DMSO-d 6)δ:10.28(s,1H),7.95-7.93(d,1H), 7.34-7.32(d,1H),7.16-7.13(d,1H),6.88-6.96(m,2H),5.90(s,1H),5.68-5.65(m,1H),5.17(s,1H),3.94-3.92(m,2H),3.83-3.82(m,2H),3.55-3.50(m,1H),3.39-3.46(m,1H),2.93-2.87(m,1H),2.77-2.70(m,1H),2.60-2.54(d,3H),2.26-2.37(m,1H),2.01-1.95(m,1H),1.10-1.05(m,6H),1.00(s,3H).ESI-Ms m/z:484.3[M+H] +.
实施例17 3',5'-二氟-4'-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-[1,1'-联苯基]-4-甲酸
Figure PCTCN2018071700-appb-000064
步骤a 3',5'-二氟-4'-甲酰基-[1,1'-联苯基]-4-甲酸甲酯的合成
Figure PCTCN2018071700-appb-000065
将(4-(甲氧基羰基)苯基)硼酸(1.97g,11mmol)、4-溴-2,6-二氟苯甲醛(2.21g,10mmol)、1,3-双(二苯基膦)丙烷氯化镍(54mg,0.1mmol)、磷酸钾(8.48g,40mmol)和60mL二氧六环混合于100mL茄型瓶中，氩气保护下升温至110℃搅拌，相同温度下反应10h。减压浓缩，去除有机溶剂，用100mL乙酸乙酯稀释，50mL饱和氯化钠水溶液洗，无水硫酸钠干燥，抽滤，浓缩。残渣用硅胶柱层析分离，得标题化合物。ESI-Ms m/z:277.1[M+H] +。
步骤b 3',5'-二氟-4'-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-[1,1'-联苯基]-4-甲酸的合成
制备方法类似于实施例9步骤b-c的制备方法，不同的是将原料(E)-3-(3,5-二氟-4-甲酰基苯基)丙烯酸甲酯替换为以上步骤a中制得的3',5'-二氟-4'-甲酰基-[1,1'-联苯基]-4-甲酸甲酯，且将原料(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2,2-二氟丙基-1-胺替换为(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2-氟-2-甲基丙-1-胺，制得标题化合物。 1H NMR(400MHz,DMSO-d 6)δ:13.04(s,1H),10.65(s,1H),8.03–8.01(d,2H),7.91–7.89(d,2H),7.52–7.49(d,2H),7.44–7.42(d,1H),7.21–7.19(d,1H),7.02–7.01(m,2H),5.28(s,1H),3.33–3.32(m,1H),2.94–2.85(m,2H),2.63–2.61(m,1H),2.52–2.40(m,1H),1.22–1.01(m,9H).ESI-Ms m/z:493.1[M+H] +.
实施例18 3',5'-二氟-4'-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1- 基)-[1,1'-联苯基]-3-甲酸
Figure PCTCN2018071700-appb-000066
制备方法类似于实施例17的制备方法，不同的是将原料(4-(甲氧基羰基)苯基)硼酸替换为(3-(甲氧基羰基)苯基)硼酸，制得标题化合物。 1H NMR(400MHz,DMSO-d 6)δ:12.98(s,1H),10.63(s,1H),8.23–8.21(d,1H),7.99–7.97(m,2H),7.62–7.58(m,1H),7.46–7.41(d,3H),7.21–7.19(d,1H),7.02–6.94(d,2H),5.28(s,1H),3.58–3.52(m,1H),2.94–2.90(m,2H),2.62–2.46(m,2H),1.26–1.07(m,9H).ESI-Ms m/z:493.1[M+H] +.
实施例19 5-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)噻唑-2-甲酸
Figure PCTCN2018071700-appb-000067
步骤a：5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)噻唑-2-甲酸乙酯的合成
Figure PCTCN2018071700-appb-000068
将5-溴噻唑-2-甲酸乙酯(4.68g，20mmol)、联硼酸频哪醇酯(5.59g，22mmol)、乙酸钾(5.88g，60mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.4g，1.8mmol)溶于100mL二氧六环，氩气保护，80℃条件下搅拌12h，然后减压蒸馏大部分溶剂，加入150mL乙酸乙酯，用饱和氯化钠水溶液(100mL×2)洗涤，无水硫酸钠干燥，柱层析纯化得目标化合物。ESI-Ms m/z:284.1[M+H] +。
步骤b：5-(3,5-二氟-4-甲酰基苯基)噻唑-2-甲酸乙酯的合成
Figure PCTCN2018071700-appb-000069
将5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)噻唑-2-甲酸乙酯(1.45g，5.1mmol)、2,6-二氟-4-溴苯甲醛(936mg，4.26mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(62.3mg，0.085mmol)、4.3mL碳酸钠水溶液(2M)溶于10mL甲苯中，氩气保护，100℃条件下加热回流16h，加入饱和氯化钠水溶液50mL，然后用乙酸乙酯(50mL×3)萃取，合并有机相，无水硫酸钠干燥，减压蒸馏得灰褐色固体，柱层析分离得到目标化合物。ESI-Ms m/z:298.0[M+H] +。
步骤c：5-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)噻唑-2-甲酸的合成
Figure PCTCN2018071700-appb-000070
制备方法类似于实施例9步骤b-c的制备方法，不同的是将原料(E)-3-(3,5-二氟-4-甲酰基苯基)丙烯酸甲酯替换为以上步骤中制得的5-(3,5-二氟-4-甲酰基苯基)噻唑-2-甲酸乙酯，且将原料(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2,2-二氟丙基-1-胺替换为(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2-氟-2-甲基丙-1-胺，制得标题化合物。 1H NMR(400MHz,DMSO-d 6)δ:10.62(s,1H),9.16(s,1H),8.06(s,1H),8.48(s,1H),7.58-7.56(d,1H),7.43-7.41(d,1H),7.42-7.18(d,1H),7.02-6.94(m,2H),5.25(s,1H),3.53-3.52(m,1H),2.90-2.84(m,2H),2.61-2.58(m,1H),2.50-2.48(m,1H),1.36-1.06(m,9H).ESI-Ms m/z:500.1[M+H] +。
实施例20 3'-氟-4'-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-3,5'-二甲氧基-[1,1'-联苯基]-4-甲酸
Figure PCTCN2018071700-appb-000071
制备方法类似于实施例17的制备方法，不同的是将原料(4-(甲氧基羰基)苯基)硼酸替换为(3-甲氧基-4-(甲氧基羰基)苯基)硼酸、且将原料4-溴-2,6-二氟苯甲醛替换为4-溴-2-甲氧基-6-氟苯甲醛，制得标题化合物。 1H NMR(400MHz,DMSO-d 6)δ:12.70(s,1H),10.41(s,1H),8.24(s,1H),7.68(d,1H),7.40–7.37(m,2H),7.24(s,1H),7.18–7.16(m,1H),7.07(s,1H),6.97–6.93(m,2H),5.37(s,1H),3.95(s,3H),3.92(s,3H),3.60–3.57(m,1H),3.10–2.87(m,2H),2.59–2.55(d,1H),2.51–2.42(m,1H),1.18–1.03(m,9H).ESI-Ms m/z:535.3[M+H] +.
实施例21 1-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)氮杂环丁烷-3-甲酰胺
Figure PCTCN2018071700-appb-000072
在50mL单口瓶中，依次加入1-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-1-基)苯基)氮杂环丁烷-3-甲酸甲酯(180mg，0.37mmol)和10mL氨的甲醇溶液，55℃加热搅拌12h，停止反应，直接旋蒸浓缩，柱层析纯化，得标题化合物。 1H NMR(400MHz,DMSO-d 6)δ:10.47(s,1H),7.47(s,1H),7.38-7.36(d,1H),7.18-7.17(d,1H),7.02-6.90(m,3H),6.07-6.04(d,2H),5.05(s,1H),3.97-3.93(m,2H),3.83-3.78(m,2H),3.53-3.51(m,1H),3.44-3.42(m,1H),2.86-2.80(m,2H),2.39-2.32(m,2H),1.20-1.02(m,9H).ESI-Ms m/z:471.2[M+H] +.
实施例22 2-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)环丙烷-1-甲酸
Figure PCTCN2018071700-appb-000073
步骤a 2,6-二氟-4-乙烯基苯甲醛的合成
Figure PCTCN2018071700-appb-000074
将4-溴-2,6-二氟苯甲醛(3156mg,14.2mmol)和4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧杂硼烷(3300mg，21.4mmol)溶于30mL二甲醚和10mL水的混合溶剂中，加入碳酸钾(3897mg，28.2mmol)和双(三苯基膦)二氯化钯(300mg，0.14mmol)，氩气保护，加热到80℃，反应5小时，降温，加水和乙酸乙酯萃取，有机层干燥，浓缩，得标题化合物。ESI-Ms m/z:169.1[M+H] +。
步骤b 2-(2,6-二氟-4-乙烯基苯基)-1,3-二氧戊环的合成
Figure PCTCN2018071700-appb-000075
将2,6-二氟-4-乙烯基苯甲醛(2500mg，14.9mmol)和乙二醇(1670mg，27mmol)溶于30mL甲苯中，加入对甲苯磺酸490mg，加入硅胶2000mg，113℃反应8小时。制砂，柱层析得标题化合物。ESI-Ms m/z:213.1[M+H] +。
步骤c 2-(4-(1,3-二氧戊环-2-基)-3,5-二氟苯基)环丙烷-1-羧酸乙酯的合成
Figure PCTCN2018071700-appb-000076
将2-(2,6-二氟-4-乙烯基苯基)-1,3-二氧戊环(2120mg，10mmol)和二聚醋酸铑(70mg，0.25mmol)溶于30ml无水二氯甲烷中，将重氮乙酸乙酯(4500mg，40mmol)溶于30mL无水二氯甲烷中并缓慢滴加入2-(2,6-二氟-4-乙烯基苯基)-1,3-二氧戊环和二聚醋酸铑的混合液中，1小时滴完，室温反应1小时，制砂，柱层析得标题化合物。ESI-Ms m/z:299.1[M+H] +。
步骤d 2-(3,5-二氟-4-甲酰基苯基)环丙烷-1-羧酸乙酯的合成
Figure PCTCN2018071700-appb-000077
将2-(4-(1,3-二氧戊环-2-基)-3,5-二氟苯基)环丙烷-1-羧酸乙酯(1700mg，5.7mmol)溶于6mL三氟乙酸，加入4mL浓盐酸和2mL水，室温反应1小时，加水，乙酸乙酯萃取，有机层干燥，浓缩得标题化合物。ESI-Ms m/z:255.1[M+H] +。
步骤e 2-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)环丙烷-1-甲酸甲酯的合成
Figure PCTCN2018071700-appb-000078
将2-(3,5-二氟-4-甲酰基苯基)环丙烷-1-甲酸乙酯(254mg，1mmol)和(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2-氟-2-甲基丙-1-胺(248mg，1mmol)溶于20mL甲苯，加入1mL醋酸，80℃反应4小时，加水，乙酸乙酯萃取，有机层干燥，浓缩，得标题化合物。ESI-Ms m/z:471.1[M+H] +。
步骤f 2-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)环丙烷-1-甲酸的合成
将2-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)环丙烷-1-甲酸甲酯(470mg，1mmol)溶于10mL四氢呋喃，加入5mL甲醇，加入7.5N的氢氧化钠水溶液1ml，室温反应1小时，加2N稀盐酸调pH至5左右，加水和乙酸乙酯萃取，有机层旋干，制砂，柱层析得标题化合物。 1H NMR(400MHz,DMSO-d 6)δ12.61(s,1H),10.57(s,1H),7.72(s,1H),7.52(d,1H),7.46(d,1H),7.40(d,1H),7.20(d,1H),5.21(s,1H),4.41(m,1H),3.47-3.57(m,1H),2.80-2.98(m,2H),2.53-2.63(m,2H),2.36(dd,1H),2.21(m,1H),1.45-1.70(m,2H),1.08-1.28(m,6H),1.07(d,3H)。ESI-Ms m/z:457.2[M+H] +。
实施例23 3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-N-((1R,2S)-2-氟环丙基)苯甲酰胺
Figure PCTCN2018071700-appb-000079
步骤a 2-(4-溴-2,6-二氟苯基)-1,3-二氧戊烷的合成
Figure PCTCN2018071700-appb-000080
在1L反应瓶中，加入2,6-二氟-4-溴苯甲醛(17.76g，80.7mmol)，乙二醇(9.1mL,162.9mmol)，一水对甲苯磺酸(200mg，1.1mmol)，用250mL甲苯溶解，110℃回流，分水器除水，反应6h。反应结束后，冷却至室温，水(100mL×3)洗涤，饱和氯化钠水溶液(100mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩，得标题化合物。
步骤b 3,5-二氟-4-(1,3-二氧戊烷-2-基)-苯甲酸甲酯的合成
Figure PCTCN2018071700-appb-000081
在100mL反应瓶中，加入步骤a所得物2-(4-溴-2,6-二氟苯基)-1,3-二氧戊烷(1.4g，5.3mmol)、1,1'-双二苯基膦二茂铁(300mg，0.5mmol)和醋酸钯(300mg，1.3mmol)，用20mL甲醇和25mL N,N-二甲基甲酰胺组成的混合溶剂溶解，再加入1.18mL三乙胺，CO气体氛围下70℃搅拌，反应3h。反应结束后，冷却至室温，浓缩，加入100mL乙酸乙酯溶解，1N盐酸(100mL)洗涤，水(100mL)洗涤，饱和氯化钠水溶液(100mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩，柱层析纯化，得标题化合物。ESI-Ms m/z:245.1[M+H] +。
步骤c 3,5-二氟-4-(1,3-二氧戊烷-2-基)-苯甲酸的合成
Figure PCTCN2018071700-appb-000082
在100mL反应瓶中，加入步骤b所得物3,5-二氟-4-(1,3-二氧戊烷-2-基)-苯甲酸甲酯(244mg，1mmol)，用5mL甲醇和5mL四氢呋喃组成的混合溶剂溶解，加入氢氧化钠(120mg，3mmol)水溶液5ml，室温搅拌0.5h。反应结束，将反应液浓缩，加入25mL水溶解，1N盐酸调pH至2，用25mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩，得标题化合物。ESI-Ms m/z:231.0[M+H] +。步骤d 4-(1,3-二氧戊环-2-基)-3,5-二氟-N-((1S,2R)-2-氟环丙基)苯甲酰胺的合成
Figure PCTCN2018071700-appb-000083
在100mL反应瓶中，加入步骤c所得物3,5-二氟-4-(1,3-二氧戊烷-2-基)-苯甲酸(230mg，1mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(230mg，1.2mmol)和1-羟基苯并三唑(162mg，1.2mmol)，用15mL二氯甲烷溶解，加入0.41mL三乙胺，再加入(1S,2R)-2-氟环丙胺对甲苯磺酸盐(300mg，1mmol)，室温搅拌2h。反应结束后，将反应液旋干，柱层析得标题化合物。ESI-Ms m/z:288.1[M+H] +。
步骤e 3,5-二氟-N-((1S,2R)-2-氟环丙基)-4-甲酰基苯甲酰胺的合成
Figure PCTCN2018071700-appb-000084
在100mL反应瓶中，加入步骤d所得物(1,3-二氧戊环-2-基)-3,5-二氟-N-((1S,2R)-2-氟环丙基)苯甲酰胺(240mg，0.84mmol)，用20mL二氯甲烷溶解，加入1.5mL三氟乙酸，室温搅拌过夜。反应结束后，水(50mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩，得标题化合物。ESI-Ms m/z:244.1[M+H] +。
步骤f 3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)-N-((1R,2S)-2-氟环丙基)苯甲酰胺的合成
在100mL反应瓶中，加入3,5-二氟-N-((1S,2R)-2-氟环丙基)-4-甲酰基苯甲酰胺(200mg，0.82mmol)和(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2-氟-2-甲基丙-1-胺(200mg，0.81mmol)，用5mL甲苯溶解，加入0.5mL冰醋酸，80℃反应3h。反应结束后，将反应液逐滴加入到50mL饱和碳酸氢钠溶液中，用50mL乙酸乙酯萃取，有机相用无水硫酸钠干燥，滤液过滤，浓缩，柱层析得标题化合物。ESI-Ms m/z:474.2 [M+H] +。 1H NMR(400MHz,DMSO-d 6):δ10.57(s,1H),7.72(s,1H),7.52(d,1H),7.46(d,2H),7.40(d,1H),7.20(d,1H),6.92-7.06(m,1H),5.21(s,1H),4.41(m,1H),3.47-3.57(m,1H),2.80-2.98(m,2H),2.53-2.58(m,2H),2.36(dd,1H),1.08-1.28(m,6H),1.07(d,3H),0.55-0.61(m,2H).
按照本发明实施例1-23的合成方法，利用不同的市售原料合成实施例24-31的化合物，这些化合物的表征参数如表1所示：
表1：
Figure PCTCN2018071700-appb-000085
实验例1 化合物体外基于细胞水平的ER level活性评价
1.实验材料
对照化合物为WO 2014/191726(PCT/GB2014/051607)实施例1中公开的化学名为(E)-3-(3,5-二氟-4-((1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-1-基)苯基)丙烯酸的化合物(AZD9496)，参照WO 2014/191726中描述的方法制备并通过氢谱和质谱鉴定。
试剂：磷酸盐缓冲液(DPBS)、台盼蓝、PolarScreen ER Alpha competitor Assay，购自于Invitrogen公司；
胎牛血清(FBS)、胰酶、DMEM、青霉素-链霉素(Pen/Strep)，购自于GIBCO公司；
二甲基亚砜(DMSO)、活性炭、Formaldehyde solution，购自于Sigma公司；
MCF-7细胞，购自于AATCC；
Estrogen Receptorα(D8H8)Rabbit mAb，购自于CST公司；
Goat anti-Rabbit IgG(H+L)Secondary Antibody、Alexa Fluor
Figure PCTCN2018071700-appb-000086
488 conjugate，购自于Thermo公司；Tween 20，购自于EIA GRADE公司。
仪器：生物安全柜、CO 2培养箱，购自于Thermo Scientific公司；
离心机，购自于Eppendorf公司；
细胞计数仪，购自于Invitrogen公司；
倒置显微镜，购自于Olympus公司；
Multiflow，购自于BioTeck公司；
涡旋混合器，购自于IKA公司；
Envision，购自于Perkin Elmer公司。
2.实验方法
2.1.细胞培养液及化合物的准备
无血清FBS的制备：称取1g活性炭与50mL胎牛血清4℃混合24h后经0.22μM滤膜过滤除菌，备用；
细胞培养液配制：将50mL FBS、5mL的青霉素-链霉素加入到445mL的DMEM中，混匀备用。无血清的细胞培养液配制时使用无血清的FBS。
化合物准备：以上实施例制备的本发明的化合物和对照化合物，每个化合物用DMSO配制成100mM后，依次稀释至10nM、3.33nM、1.11nM、0.37nM、0.123nM、0.041nM、0.014nM、0.0045nM、0.0015nM、0.0005nM。
2.2.接种细胞
将T75细胞培养瓶中对数生长期的细胞弃除培养液加入10mL DPBS洗一次。再加入2mL胰酶消化细胞，37℃放置2分钟，显微镜下观察大部分细胞形状变圆，加入5mL的无血清的细胞培养液 终止消化，移液管反复吹打，将细胞消化下来制成细胞悬液，再补加10mL细胞培养液，混匀后计数；稀释成1500个细胞/40μL的细胞悬液，用Multiflow仪器将细胞铺入384孔细胞培养板，40μL/孔；室温平衡20min后置于37℃细胞培养箱内培养24h。
2.3.加化合物
用Acho仪器将化合物加入细胞培养板中，DMSO终浓度0.3％；室温1000rpm离心1min后置于37℃细胞培养箱内培养24h。
2.4.免疫荧光实验
吸出细胞培养基，PBS洗细胞1次，用终浓度为3.7％的多聚甲醛溶液(PBS稀释)室温固定细胞20min；PBS洗细胞2次，用终浓度为0.5％的Tween-20(PBS稀释)室温渗透1h；用PBS-T(PBS中含有0.05％的Tween-20)洗细胞2次，ER level测定中加入ER抗体稀释液(1:1000，用PBS-T中含有1％的milk稀释)，室温孵育1.5h；PBS-T洗细胞3次，加入二抗稀释液(1:1000，用PBS中含有1％的milk稀释)2μg/mL的Hochest 33342，室温孵育40min；PBS-T洗细胞3次，PBS洗细胞2次；Acumen读取ER阳性信号值与细胞核信号值的比率。实验结果见表2。
表2
Figure PCTCN2018071700-appb-000087
“-”表示未测
从以上实验结果可以看出，本发明的化合物对基于细胞水平的ER level具有好的抑制活性。
实验例2 化合物体外细胞活性评价
1.实验材料
受试化合物：以上实施例制备的本发明的化合物及对照化合物，每个化合物用DMSO配制成10mM，然后依次3倍稀释为100.00nM、33.33nM、11.11nM、3.70nM、1.23nM、0.41nM、0.14nM、0.045nM、0.015nM。
乳腺癌细胞株MCF-7购自于南京凯基生物公司。
试剂：MEM，FBS，Trypsin-EDTA，Penicillin-Streptomycin，购自于美国GIBCO公司；
Figure PCTCN2018071700-appb-000088
Luminescent Cell Viability Assay Kit，购自于美国Progema公司；Paclitaxel，购自于四川Tai Chi制药公司。
2.实验方法
2.1.细胞接种
培养扩增的MCF-7细胞用胰蛋白酶消化，使用新鲜培养基重悬并计数。将重悬的细胞调整至2×10 4个细胞/mL，并加入96孔细胞培养板，每孔加入100μL，每个浓度两复孔。于37℃、5％CO 2条件下孵育24h。
2.2.加化合物
化合物用DMSO配制成200×工作液，用培养液稀释成2×工作液，再转移100μL到实验孔，于37℃、5％CO 2条件下孵育96h。
2.3.荧光读数
向待测孔加入50μL
Figure PCTCN2018071700-appb-000089
Luminescent Cell Viability Assay buffer，并轻轻摇匀。10分钟后，置于Envison上读取荧光读数，并计算细胞存活率(cell survive(％))，计算公式为cell survive(％)＝(Com-Min)/(Max-Min)，其中Max为溶媒对照组的读数，Min为无细胞对照组的读数，Com为化合物处理组的读数，数据经XLfit处理，拟合得IC 50，实验结果见表3。
表3
Figure PCTCN2018071700-appb-000090
“-”表示未测
从以上实验可以看出，本发明的化合物对MCF-7乳腺癌细胞表现出了良好的抑制活性。
实验例3 化合物体内药代动力学评价
受试化合物：以上实施例制备的本发明的化合物及对照化合物，每个化合物用溶媒配制为口服供试品2mg/kg，静注供试品1mg/kg。
Balb/c小鼠，购自于北京维通利华实验动物有限公司。
小鼠口服以2mg/kg，静注以1mg/kg单次给药后，分别于2min,5min,15min,30min,1h,2h,6h,10h,24h自眼眶静脉丛采血，离心取血浆处理后，使用LC-MS/MS进行检测，将测得的各时间点的血药浓度绘制成药物浓度-时间曲线，并计算药代动力学参数。实验结果见表4。
表4
受试化合物 T 1/2(h) Cmax(ng/ml) AUC(h*ng/ml) F(％)
AZD9496 1.1 703.7 1229.9 45.5
实施例1 1.3 647 1948.9 58.1
实施例2 3.2 583.4 3232.8 62.6
实施例3 4.3 410.2 2413.5 86.6
实施例4 3.7 793.4 4548.4 64.3
实施例5 5.7 493.7 4893.3 81.1
实施例6 3.2 1457.7 8373.5 80.5
实施例7 4 255.1 2768.2 86
实施例9 5.2 474.6 3115 115.5
实施例10 3.9 1102.7 4525.6 70.4
实施例12 3.4 125.4 767.9 28.8
实施例13 6.9 1326.1 16451.4 88
实施例14 2.7 1023.8 2895.8 62.4
实施例15 2.3 598.1 2441.3 39.9
实施例16 - - - -
实施例17 12.1 1277.7 16073.7 80.5
实施例20 7.6 1210.7 13602.1 79.0
实施例22 6.4 1676.5 4991.7 77.5
实施例23 6.4 403.5 2100.1 41.3
“-”表示未测
以上实验结果表明，本发明的化合物的半衰期(T 1/2)、峰浓度(Cmax)、曲线下面积(AUC)及生物利用度(F)均明显优于对照化合物。当化合物的半衰期延长，生物利用度增加时，可将化合物的给药 间期延长，药物作用时间延长，可提高化合物的疗效以及降低化合物的给药量，从而使药物更有效、更安全。因此，本发明的化合物具有更加优异的体内抗肿瘤活性，给药间期将更长。
实验例4 化合物体内MCF-7皮下移植瘤模型药效评价
1.细胞培养
用含有10％胎牛血清，100U/ml的青霉素和100μg/ml的链霉素的MEM培养基在37℃、5％CO 2的培养箱中培养MCF-7乳腺癌细胞(购自凯基)。细胞培养起始浓度为1×10 6个/mL，每隔3至4天待细胞长满后分瓶传代。将处于对数生长期的肿瘤细胞用于体内肿瘤的接种。
2.缓释片及细胞接种
细胞接种前2-3天，将β-雌二醇缓释药片(Estradiol-17β60天SE121 0.72mg，购自Innovative Research of America公司)接种于每只小鼠的左后背。接种后1周，每周3次对动物进行排尿，必要时每天对动物进行排尿。
将含有10×10 6细胞的PBS同100μL的Matrigel混合(终体积200μL)接种于小鼠的右后边。3.肿瘤测量和实验指标
受试化合物：以上实施例制备的本发明的化合物及对照化合物。本发明的化合物以及对照化合物每日给药一次(QD)，连续给药三周(3W)。
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周三次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
受试化合物的抑瘤效果用相对肿瘤增殖率T/C(％)和抑瘤率(％)评价。相对肿瘤增殖率T/C(％)的计算公式如下：T/C％＝T RTV/C RTV×100％(T RTV：治疗组RTV；C RTV：阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝V t/V 0，其中V 0是分组给药时(即d 0)测量所得肿瘤体积，V t为某一次测量时的肿瘤体积，T RTV与C RTV取同一天数据。抑瘤率(％)＝(1-T/C)×100％。
受试化合物对人乳腺癌细胞系MCF-7皮下移植瘤模型的抑瘤药效评价的实验结果如表5所示，表中各实施例化合物对应的T/C(％)数值为各实施例化合物各剂量组动物基于给药后第21天肿瘤体积计算得到的T/C(％)均值。
表5
Figure PCTCN2018071700-appb-000091
Figure PCTCN2018071700-appb-000092
实验结果表明，意料不到地，本发明的化合物对乳癌的抑瘤效果明显优于阳性药AZD9496。本发明的化合物，例如实施例3、实施例10、实施例13、实施例17、实施例20的化合物，在0.6mg/kg剂量下药效显著优于相同剂量的AZD9496，在2mg/kg剂量下药效远好于AZD9496 6mg/kg剂量下的药效。另外，本发明的部分化合物在十分之一的剂量下产生了与阳性药AZD9496相当的效果(0.6mg/kg VS 6mg/kg)。
尽管以上已经对本发明作了详细描述，但是本领域技术人员理解，在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述，而应归属于权利要求书。

Claims (10)

  1. 一种通式I所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，
    Figure PCTCN2018071700-appb-100001
    其中，
    R 1、R 2分别独立地选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基；
    R 3选自烷基、烷基酰基、氨基酰基、烷基氨基酰基、卤代烷基、羟基烷基、烯基、环烷基、杂环基、芳基和杂芳基；
    R 4、R 5分别独立地选自氢、烷基、烷氧基、卤素、卤代烷基和羟基烷基；或R 4、R 5与它们所连接的碳原子一起形成羰基或环烷基；
    R 6、R 7分别独立地选自氢、烷基、烷氧基、卤素、卤代烷基和羟基烷基；或R 6、R 7与它们所连接的碳原子一起形成羰基或环烷基；或者
    R 4、R 6与它们所连接的碳原子一起形成环烷基；
    各R 8分别独立地选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基、环烷基和硼酸；
    Y选自
    Figure PCTCN2018071700-appb-100002
    其中R 9选自羧基、氰基、烷基、卤代烷基和羟基烷基，R 10选自氢和卤素，R 11选自羟基、氨基、烷氧基和烷基氨基，环A选自环烷基、杂环基、芳基和杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基取代，R 12选自氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基，n为1、2或3，或者当n为2时，两个R 12基团与它们所连接的碳原子一起形成羰基、环烷基、杂环基、芳基、杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个氢、卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基取代，L 1选自键、-NHCO-、-CONH-、-NHCONH-、 -NH-、亚烷基、O、S、卤代亚烷基、羟基亚烷基、亚烷氧基、卤代亚烷氧基、羟基亚烷氧基、羰基和亚烷基氨基；
    化学键
    Figure PCTCN2018071700-appb-100003
    各自独立地为
    Figure PCTCN2018071700-appb-100004
    m为1、2、3或4；
    条件是当Y为
    Figure PCTCN2018071700-appb-100005
    且R 1、R 2都为氟，R 10为氢时，R 3选自
    Figure PCTCN2018071700-appb-100006
    烯基和芳基，其中R 13选自卤素、羟基、烷基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、羟基烷氧基、硝基、羧基、氰基、氨基、单烷基氨基、烷基酰基氨基、烷基酰基、氨基酰基、烷基氨基酰基、双烷基氨基和环烷基。
  2. 根据权利要求1所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中R 1、R 2分别独立地选自氟、氯、溴、碘、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基和C 3-10环烷基。
  3. 根据权利要求1或2所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中R 3选自C 1-10烷基、C 1-10烷基酰基、氨基酰基、C 1-10烷基氨基酰基、卤代C 1-10烷基、羟基C 1-10烷基、C 2-10烯基、C 3-10环烷基、C 3-10杂环基、C 6-18芳基和C 5-18杂芳基，所述基团可以被一个或多个卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、双C 1-6烷基氨基和任选取代的C 3-8环烷基取代。
  4. 根据权利要求1-3之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中R 4、R 5分别独立地选自氢、C 1-6烷基、C 1-6烷氧基、卤素、卤代C 1-6烷基和羟基C 1-6烷基，R 6、R 7分别独立地选自氢、C 1-6烷基、C 1-6烷氧基、卤素、卤代C 1-6烷基和羟基C 1-6烷基。
  5. 根据权利要求1-3之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中R 4、R 5与它们所连接的碳原子一起形成羰基或C 3-10环烷基；或R 6、R 7与它们所连接的碳原子一起形成羰基或C 3-10环烷基；或R 4、R 6与它们所连接的碳原子一起形成C 3-10环烷基。
  6. 根据权利要求1-5之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中各R 8分别独立地选自氢、卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基、C 3-10环烷基和硼酸。
  7. 根据权利要求1所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中
    R 9选自羧基、氰基、C 1-6烷基、卤代C 1-6烷基和羟基C 1-6烷基；
    R 11选自羟基、氨基、C 1-6烷氧基和C 1-6烷基氨基；
    环A选自C 3-10环烷基、C 3-10杂环基、C 6-18芳基和C 5-18杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、双C 1-6烷基氨基和C 3-10环烷基取代；
    R 12选自氢、卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基和C 3-10环烷基，n为1、2或3；或者当n为2时，两个R 12与它们所连接的碳原子一起形成羰基、C 3-10环烷基、C 3-10杂环基、C 6-18芳基和C 5-18杂芳基，所述的环烷基、杂环基、芳基和杂芳基可以被一个或多个卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、双C 1-6烷基氨基和C 3-8环烷基取代；L 1选自键、-NHCO-、-CONH-、-NHCONH-、-NH-、亚C 1-6烷基、O、S、卤代亚C 1-6烷基、羟基亚C 1-6烷基、亚C 1-6烷氧基、卤代亚C 1-6烷氧基、羟基亚C 1-6烷氧基、羰基和亚C 1-6烷基氨基；和
    R 13选自卤素、羟基、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基C 1-6烷氧基、硝基、羧基、氰基、氨基、单C 1-6烷基氨基、C 1-6烷基酰基氨基、C 1-6烷基酰基、氨基酰基、C 1-6烷基氨基酰基、双C 1-6烷基氨基和C 3-10环烷基。
  8. 根据权利要求1所示的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药，其中所述化合物为选自以下的化合物：
    Figure PCTCN2018071700-appb-100007
    Figure PCTCN2018071700-appb-100008
    Figure PCTCN2018071700-appb-100009
  9. 一种药物组合物，其包含权利要求1至8之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药和可药用载体。
  10. 权利要求1-8之任一项所述的化合物或其异构体、药学上可接受的盐、溶剂化物、结晶或前药或权利要求9所述的药物组合物在制备用于治疗和/或预防雌激素受体相关的疾病的药物中的应用。
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053542A (zh) * 2018-07-25 2018-12-21 南通大学 一种6-溴-5-羟基异吲哚啉-1-酮的化学合成方法
EP3442971A1 (en) * 2016-04-01 2019-02-20 Zeno Royalties & Milestones, LLC Estrogen receptor modulators
US10647724B2 (en) 2016-02-05 2020-05-12 Inventisbio Inc. Selective estrogen receptor degraders and uses thereof
WO2020132785A1 (en) * 2018-12-24 2020-07-02 Inventisbio Shanghai Ltd. Novel salts of selective estrogen receptor degraders
WO2021253380A1 (en) * 2020-06-19 2021-12-23 InventisBio Co., Ltd. Oral formulations and uses thereof
US11278532B2 (en) 2019-08-06 2022-03-22 Recurium Ip Holdings, Llc Estrogen receptor modulators for treating mutants
US11339162B1 (en) 2020-12-23 2022-05-24 Recurium Ip Holdings, Llc Estrogen receptor modulators
WO2023114874A1 (en) * 2021-12-15 2023-06-22 Recurium Ip Holdings, Llc Treating osteoporosis
US20240181066A1 (en) * 2019-05-14 2024-06-06 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114630830A (zh) * 2019-10-31 2022-06-14 治愈医药社株式会社 新型化合物及包含其的用于预防或治疗癌症的药物组合物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010138706A1 (en) * 2009-05-27 2010-12-02 Ptc Therapeutics, Inc. Methods for treating breast cancer
WO2010138652A1 (en) * 2009-05-27 2010-12-02 Ptc Therapeutics, Inc. Methods for treating kaposi sarcoma
CN105229004A (zh) * 2013-05-28 2016-01-06 阿斯利康(瑞典)有限公司 化合物
WO2016097071A1 (en) * 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Estrogen receptor modulators and uses thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9351964B2 (en) * 2009-05-27 2016-05-31 Ptc Therapeutics, Inc. Methods for treating cancer and non-neoplastic conditions
CN113004273A (zh) * 2016-02-05 2021-06-22 益方生物科技(上海)股份有限公司 选择性雌激素受体降解物及其用途
CN113717170A (zh) * 2016-04-01 2021-11-30 里科瑞尔姆Ip控股有限责任公司 雌激素受体调节剂
CN109415361B (zh) * 2016-06-29 2022-03-08 浙江海正药业股份有限公司 丙烯酸类衍生物及其制备方法和其在医药上的用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010138706A1 (en) * 2009-05-27 2010-12-02 Ptc Therapeutics, Inc. Methods for treating breast cancer
WO2010138652A1 (en) * 2009-05-27 2010-12-02 Ptc Therapeutics, Inc. Methods for treating kaposi sarcoma
CN105229004A (zh) * 2013-05-28 2016-01-06 阿斯利康(瑞典)有限公司 化合物
WO2016097071A1 (en) * 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Estrogen receptor modulators and uses thereof

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10647724B2 (en) 2016-02-05 2020-05-12 Inventisbio Inc. Selective estrogen receptor degraders and uses thereof
US11014936B2 (en) 2016-02-05 2021-05-25 Inventisbio Llc Selective estrogen receptor degraders and uses thereof
US11065234B2 (en) 2016-04-01 2021-07-20 Recurium Ip Holdings, Llc Estrogen receptor modulators
EP3442971A1 (en) * 2016-04-01 2019-02-20 Zeno Royalties & Milestones, LLC Estrogen receptor modulators
EP3442971A4 (en) * 2016-04-01 2020-01-01 Recurium IP Holdings, LLC ESTROGEN RECEPTOR MODULATORS
US10959989B2 (en) 2016-04-01 2021-03-30 Recurium Ip Holdings, Llc Estrogen receptor modulators
US11065233B2 (en) 2016-04-01 2021-07-20 Recurium Ip Holdings, Llc Estrogen receptor modulators
CN109053542A (zh) * 2018-07-25 2018-12-21 南通大学 一种6-溴-5-羟基异吲哚啉-1-酮的化学合成方法
EP3902545A4 (en) * 2018-12-24 2022-06-22 InventisBio Co., Ltd. NOVEL SALTS OF SELECTIVE ESTROGEN RECEPTOR DEGRADERS
CN113164467A (zh) * 2018-12-24 2021-07-23 益方生物科技(上海)股份有限公司 选择性雌激素受体降解剂的新型盐
US11241418B2 (en) 2018-12-24 2022-02-08 InventisBio Co., Ltd. Salts of selective estrogen receptor degraders
WO2020132785A1 (en) * 2018-12-24 2020-07-02 Inventisbio Shanghai Ltd. Novel salts of selective estrogen receptor degraders
CN113164467B (zh) * 2018-12-24 2023-12-26 益方生物科技(上海)股份有限公司 选择性雌激素受体降解剂的新型盐
US11903931B2 (en) 2018-12-24 2024-02-20 InventisBio Co., Ltd. Salts of selective estrogen receptor degraders
US20240181066A1 (en) * 2019-05-14 2024-06-06 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US11278532B2 (en) 2019-08-06 2022-03-22 Recurium Ip Holdings, Llc Estrogen receptor modulators for treating mutants
WO2021253380A1 (en) * 2020-06-19 2021-12-23 InventisBio Co., Ltd. Oral formulations and uses thereof
WO2021254471A1 (en) * 2020-06-19 2021-12-23 InventisBio Co., Ltd. Oral formulations and uses thereof
US11339162B1 (en) 2020-12-23 2022-05-24 Recurium Ip Holdings, Llc Estrogen receptor modulators
US11999728B2 (en) 2020-12-23 2024-06-04 Recurium Ip Holdings, Llc Estrogen receptor modulators
WO2023114874A1 (en) * 2021-12-15 2023-06-22 Recurium Ip Holdings, Llc Treating osteoporosis

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