[go: up one dir, main page]

WO2018130124A1 - Composé tricyclique utilisé en tant que régulateur sélectif du récepteur des œstrogènes et son utilisation - Google Patents

Composé tricyclique utilisé en tant que régulateur sélectif du récepteur des œstrogènes et son utilisation Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
alkoxy
hydroxy
amino
Prior art date
Application number
PCT/CN2018/071700
Other languages
English (en)
Chinese (zh)
Inventor
王勇
赵立文
王小伟
张小猛
张雁
庞司林
Original Assignee
南京圣和药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京圣和药业股份有限公司 filed Critical 南京圣和药业股份有限公司
Publication of WO2018130124A1 publication Critical patent/WO2018130124A1/fr

Links

Classifications

    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/44—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Psychiatry (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Addiction (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Vascular Medicine (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)

Abstract

La présente invention se rapporte au domaine de la chimie médicale et concerne un composé tricyclique utilisé en tant que régulateur sélectif du récepteur des œstrogènes et son utilisation. La présente invention concerne particulièrement, un composé tel que représenté par la formule I ou un isomère, un sel pharmaceutiquement acceptable, un solvate, un cristal ou un promédicament de celui-ci. L'invention concerne également, des procédés de préparation dudit composé et des compositions pharmaceutiques contenant ces composés ainsi qu'une utilisation desdits composés ou compositions pour le traitement et/ou la prévention de maladies associées au récepteur des œstrogènes. Le composé de la présente invention présente une meilleure activité antitumorale, un intervalle de dosage plus long et moins d'effets secondaires et semble être très prometteur en tant qu'agent thérapeutique contre le cancer du sein.
PCT/CN2018/071700 2017-01-11 2018-01-08 Composé tricyclique utilisé en tant que régulateur sélectif du récepteur des œstrogènes et son utilisation WO2018130124A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710019392.X 2017-01-11
CN201710019392 2017-01-11

Publications (1)

Publication Number Publication Date
WO2018130124A1 true WO2018130124A1 (fr) 2018-07-19

Family

ID=62839325

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/071700 WO2018130124A1 (fr) 2017-01-11 2018-01-08 Composé tricyclique utilisé en tant que régulateur sélectif du récepteur des œstrogènes et son utilisation

Country Status (2)

Country Link
CN (1) CN108329311B (fr)
WO (1) WO2018130124A1 (fr)

Cited By (10)

* 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
EP3442971A4 (fr) * 2016-04-01 2020-01-01 Recurium IP Holdings, LLC Modulateurs du récepteur des estrogènes
US10647724B2 (en) 2016-02-05 2020-05-12 Inventisbio Inc. Selective estrogen receptor degraders and uses thereof
WO2020132785A1 (fr) * 2018-12-24 2020-07-02 Inventisbio Shanghai Ltd. Nouveaux sels d'agents de dégradation sélectifs du récepteur des oestrogènes
WO2021253380A1 (fr) * 2020-06-19 2021-12-23 InventisBio Co., Ltd. Formulations orales et leurs utilisations
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 (fr) * 2021-12-15 2023-06-22 Recurium Ip Holdings, Llc Traitement de l'ostéoporose
US20240181066A1 (en) * 2019-05-14 2024-06-06 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
US12398121B2 (en) 2018-05-14 2025-08-26 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230019094A1 (en) * 2019-10-31 2023-01-19 Holosmedic Novel compound and pharmaceutical composition for prevention or treatment of cancer comprising same
CN114746424B (zh) * 2020-01-10 2023-06-16 江苏恒瑞医药股份有限公司 三环四氢异喹啉类衍生物、其制备方法及其在医药上的应用
CN116120316A (zh) * 2022-12-29 2023-05-16 渭南瑞联制药有限责任公司 一种氮杂三环抗菌化合物的合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010138652A1 (fr) * 2009-05-27 2010-12-02 Ptc Therapeutics, Inc. Méthodes de traitement du sarcome de kaposi
WO2010138706A1 (fr) * 2009-05-27 2010-12-02 Ptc Therapeutics, Inc. Procédés de traitement d'un cancer du sein
CN105229004A (zh) * 2013-05-28 2016-01-06 阿斯利康(瑞典)有限公司 化合物
WO2016097071A1 (fr) * 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Modulateurs du récepteur des œstrogènes et leurs utilisations

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5898067B2 (ja) * 2009-05-27 2016-04-06 ピーティーシー セラピューティクス，インコーポレーテッド がん及び非新生物性状態の治療方法
BR112018015419B1 (pt) * 2016-02-05 2024-01-30 Inventisbio Llc Degradantes seletivos de receptor de estrogênio, seus usos, e composição farmacêutica
WO2017172957A1 (fr) * 2016-04-01 2017-10-05 Kalyra Pharmaceuticals, Inc. Modulateurs du récepteur des œstrogènes
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
WO2010138652A1 (fr) * 2009-05-27 2010-12-02 Ptc Therapeutics, Inc. Méthodes de traitement du sarcome de kaposi
WO2010138706A1 (fr) * 2009-05-27 2010-12-02 Ptc Therapeutics, Inc. Procédés de traitement d'un cancer du sein
CN105229004A (zh) * 2013-05-28 2016-01-06 阿斯利康(瑞典)有限公司 化合物
WO2016097071A1 (fr) * 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Modulateurs du récepteur des œstrogènes et leurs utilisations

Cited By (24)

* 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
US12187736B2 (en) 2016-02-05 2025-01-07 Inventisbio Llc Selective estrogen receptor degraders and uses thereof
EP3442971A4 (fr) * 2016-04-01 2020-01-01 Recurium IP Holdings, LLC Modulateurs du récepteur des estrogènes
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
US11065234B2 (en) 2016-04-01 2021-07-20 Recurium Ip Holdings, Llc Estrogen receptor modulators
US12398121B2 (en) 2018-05-14 2025-08-26 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
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
US11903931B2 (en) 2018-12-24 2024-02-20 InventisBio Co., Ltd. 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
EP3902545A4 (fr) * 2018-12-24 2022-06-22 InventisBio Co., Ltd. Nouveaux sels d'agents de dégradation sélectifs du récepteur des oestrogènes
WO2020132785A1 (fr) * 2018-12-24 2020-07-02 Inventisbio Shanghai Ltd. Nouveaux sels d'agents de dégradation sélectifs du récepteur des oestrogènes
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
US12208141B2 (en) * 2019-05-14 2025-01-28 Nuvation Bio Inc. Anti-cancer nuclear hormone receptor-targeting compounds
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
WO2021254471A1 (fr) * 2020-06-19 2021-12-23 InventisBio Co., Ltd. Formulations orales et leurs utilisations
JP2023532209A (ja) * 2020-06-19 2023-07-27 インベンティスバイオ カンパニー リミテッド 経口製剤およびその用途
WO2021253380A1 (fr) * 2020-06-19 2021-12-23 InventisBio Co., Ltd. Formulations orales et leurs utilisations
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 (fr) * 2021-12-15 2023-06-22 Recurium Ip Holdings, Llc Traitement de l'ostéoporose

Also Published As

Publication number Publication date
CN108329311B (zh) 2022-02-22
CN108329311A (zh) 2018-07-27

Similar Documents

Publication Publication Date Title
WO2018130124A1 (fr) Composé tricyclique utilisé en tant que régulateur sélectif du récepteur des œstrogènes et son utilisation
CN109776445B (zh) 苯并噁二唑类化合物及其制备方法和医药用途
CN111646995B (zh) 4-氨基-嘧啶并氮杂环-苯基脲类衍生物及其制备方法和用途
JP2021512059A (ja) ブルトン型チロシンキナーゼ（ｂｔｋ）阻害剤のｅ３リガーゼリガンドとのコンジュゲーションによるｂｔｋの分解および使用方法
JP6321821B2 (ja) ２，３，４，６−４置換ベンゼン−１，５−ジアミン誘導体、その製造方法および医薬品における使用
KR20190012167A (ko) 이소퀴놀린-3-일 카르복스아마이드 및 이의 제제와 용도
JP6797923B2 (ja) Ａｌｋおよびｓｒｐｋ阻害剤ならびに使用方法
CN109641882A (zh) 作为nik抑制剂的杂芳族衍生物
CN106565706B (zh) 一种磺酰胺衍生物及其在药学中的应用
WO2016124067A1 (fr) Sulfonate hydroxyéthylique d'un inhibiteur de protéine kinase dépendant de la cycline, forme cristalline de celui-ci et leur procédé de préparation
CN102070618B (zh) 一种化合物及其晶体
TWI723480B (zh) 用作fgfr4抑制劑的稠環衍生物
WO2020143763A1 (fr) Composés d'halogénoallylamine et leur utilisation
US9724331B2 (en) Use of maleimide derivatives for preventing and treating leukemia
WO2023125928A1 (fr) Inhibiteur de ménine et son utilisation
CA3087716A1 (fr) Inhibiteurs de l'egfr et leurs procedes d'utilisation
CN108299420B (zh) 作为选择性雌激素受体下调剂的五环类化合物及其应用
WO2023036252A1 (fr) Dérivé de pyrrolopyrimidine ou de pyrrolopyridine et son utilisation médicale
CN116744920A (zh) 杂芳基并哌啶类衍生物及其药物组合物和应用
CN110407839B (zh) 含杂芳基酰胺结构的三唑并杂环类化合物的制备及应用
JP2023549187A (ja) 貧血およびがんの処置のためのｖｈｌ阻害剤としての１－（２－（４－シクロプロピル－１ｈ－１，２，３－トリアゾール－１－イル）アセチル）－４－ヒドロキシ－ｎ－（ベンジル）ピロリジンｅ－２－カルボキサミド誘導体
CN103435562B (zh) 6-取代苯并二氮卓-2,4-二酮类化合物及其用途
WO2020187292A1 (fr) Composé de formamide amino-5-pyrimidine substitué en position 4 par pyrazoleamino substitué en position 2, composition et utilisation associées
WO2019109647A1 (fr) Inhibiteur double cible parp/pi3k contenant une structure pyridopyrimidine
CN117729921A (zh) 作为pd1/pd-l1抑制剂的化合物及其方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18739131

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18739131

Country of ref document: EP

Kind code of ref document: A1