CN108864080A

CN108864080A - Four cyclics alternatively adjusted under property estrogen receptor and its application

Info

Publication number: CN108864080A
Application number: CN201810429737.3A
Authority: CN
Inventors: 王勇; 赵立文; 王小伟; 钮嘉辉; 程青; 庞司林; 王辉; 肖学兵
Original assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Current assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Priority date: 2017-05-09
Filing date: 2018-05-08
Publication date: 2018-11-23
Anticipated expiration: 2038-05-08
Also published as: CN108864080B

Abstract

The invention belongs to medicinal chemistry arts, it is related to four cyclics of regulator and its application under a kind of alternatively property estrogen receptor, specifically, the present invention provides Formulas I compound represented or its isomers, pharmaceutically acceptable salt, solvate, crystallization or prodrug, their preparation method and pharmaceutical composition containing these compounds and these compound or compositions are for treating and/or preventing the purposes of the relevant disease of estrogen receptor.The compound of the present invention has more excellent anti-tumor activity, promises to be very much breast cancer treatment agent.

Description

Four cyclics alternatively adjusted under property estrogen receptor and its application

Technical field

The invention belongs to medicinal chemistry arts, and in particular to adjust under a kind of alternatively property estrogen receptor (SERD) Compound or its isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug, their preparation side Method and pharmaceutical composition containing these compounds and these compound or compositions for treat and/or prevent estrogen by The purposes of the relevant disease of body.

Background technique

Estrogen receptor (Estrogen Receptor, ER) is the transcript regutation protein of ligand activation, it by with it is endogenous Property estrogen interaction mediate the inductions of a variety of biological effects.Endogenous estrogen includes 17 beta estradiols and oestrone.? It was found that there are two types of isotypes for ER tool：ER- α and ER- β, respectively by being located at No. 6 of people and two different bases of No. 14 chromosome Because of coding, for ER- α in various tissue wide expressions, the expression of ER- β is limited only to the tissue such as female reproductive system and brain, bone. The two includes 6 structural domains and 4 functional areas, and the functional areas A/B of N-terminal have the transcriptional activation function domain of non-ligand-dependent AF-1, has that constitutively activated is active (constitutive activity), by with basal transcription factor, association's activity factor The transcription to activate target gene is acted on other transcription factors, in addition there are many places phosphorylation sites.The DNA being made of the domain C Binding domain (DBD) can be specifically incorporated on target DNA, and include nuclear localization signal, while also have dimerization interface, It plays an important role to the dimerization of receptor.The domain D is hinge area, is responsible for connection DBD and aglucon binding domain (LBD).The domain C-terminal E LBD is formed, which determines the specific binding of the ligands such as ER and estrogen, the transcriptional activation function domain AF- with ligand-dependent 2, and LBD also has very strong dimerization interface, remains to play a role in the case where no ligand, is that dimerization occurs for receptor The key position of change.LBD is made of 12 α spirals and a β-pleated sheet, forms three layers of antiparallel sandwich structure, wherein H5, H6, H9 and H10 form middle layer, and H1, H2, H3, H4 and H7, H8, H11 separately constitute two outside layers, and wherein H12 contains AF- 2, hydrophobic surface is towards ligand binding pocket, and water-wetted surface is outwardly.The LBD of ER is wedge shaped, and H12 is in ligand binding pocket Groove in, and seal ligand binding pocket.When ER is in conjunction with agonist, this conformation of H12 is become more stable, and is suitable for association The combination of activity factor, the then transcription of activation target gene.And when ER is in conjunction with antagonist, the position of H12 changes simultaneously The binding site of association's activity factor is occupied, and then generates estrogen antagonism effect.

Drug research for targeting estrogen receptor has been carried out for many years, clinically achieves some successes, especially It has recently found that adjusting under selective estrogen receptor has the anti-female hormone effect more reinforced, such as interference estrogen receptor Stability simultaneously leads to its degradation.But, it is still desirable to develop under more estrogen receptor and adjust, especially selective estrogen Receptor down-regulated agent, so that the drug has more excellent characteristic, such as curative effect is better, and less side effects, dosing interval is more It is long etc., to be preferably applied to prevent or treat the relevant disease of estrogen receptor.

Summary of the invention

It is an object of the present invention to provide one kind shown in general formula I, and there is selective estrogen receptor to lower activeization Object or its isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug are closed,

Wherein,

X¹、X²、X⁴, each X³Separately it is selected from C (R¹R²)、N(R³), O, S, sulfone and sulfoxide；

R¹、R²Separately it is selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, haloalkoxy Base, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, Alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base, heterocycle, heteroaryl and aryl；Or R¹、R²It is connected to it Carbon atom is formed together carbonyl；R³Selected from hydrogen, alkyl acyl, aminoacyl, alkylaminoacyl, alkyl, halogenated alkyl, hydroxyl Alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, heteroaryl and aryl, the group can by one or more halogens, hydroxyl, Alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, single alkane Base amino, double alkyl aminos, naphthenic base, heterocycle, aryl and heteroaryl replace；

R⁴Selected from hydrogen, alkyl acyl, aminoacyl, alkylaminoacyl, alkyl, halogenated alkyl, hydroxy alkyl, alkenyl, Alkynyl, naphthenic base, heterocycle, heteroaryl and aryl, the group can be by one or more halogens, hydroxyl, alkyl, alkyl halides Base, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double alkane Base amino, naphthenic base, heterocycle, aryl and heteroaryl replace；

R⁵Selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy Base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkyl amino acyl Base, double alkyl aminos, alkenyl, alkynyl and naphthenic base；

Each R⁶, each R⁷Separately selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated Alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl Base, alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base and boric acid；

Y is selected from alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl, heteroarylalkoxy, alkyl ammonia Base, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkyl amino, naphthenic base, heterocycle, virtue Base, heteroaryl, alkenyl and alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl, heteroaryl Alkoxy, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkyl amino, ring Alkyl, heterocycle, aryl, heteroaryl, alkenyl and alkynyl can be by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxyls Base alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acyl ammonia Base, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base, heterocycle and oxo base Group replaces；With

M, n, o are each independently 1,2,3 or 4.

It is a further object to provide prepare compounds of formula I or its isomers of the invention, pharmaceutically may be used The salt of receiving, solvate, crystallization, isostere or prodrug method.

It is also another object of the present invention to provide comprising compounds of formula I of the invention or its isomers, pharmaceutically may be used Salt, solvate, crystallization, isostere or the prodrug of receiving and the composition of pharmaceutically acceptable carrier, and include this The compounds of formula I of invention or its isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug With the composition of one or more drugs.

Of the invention a further object is provides compounds of formula I or its isomers of the invention, pharmaceutically acceptable Salt, solvate, crystallization, isostere or prodrug treatment and/or the relevant disease of prevention estrogen receptor method, with And compounds of formula I or its isomers of the invention, pharmaceutically acceptable salt, solvate, crystallization, isostere or Prodrug is preparing the application in the drug for treating and/or preventing the relevant disease of estrogen receptor.

For above-mentioned purpose, the present invention provides following technical scheme：

In a first aspect, the present invention provides general formula I compound represented or its isomers, pharmaceutically acceptable salt, solvent Compound, crystallization, isostere or prodrug,

Wherein,

M, n, o are each independently 1,2,3 or 4.

In some specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically Acceptable salt, solvate, crystallization, isostere or prodrug, wherein when o is 1, X¹、X²、X³、X⁴In have one for C (R¹R²), excess-three is N (R³), O, S, sulfone or sulfoxide.

In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy Upper acceptable salt, solvate, crystallization, isostere or prodrug, wherein when o is 1, X¹、X²、X³、X⁴In there are two being C(R¹R²), other two is N (R³), O, S, sulfone or sulfoxide.

In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy Upper acceptable salt, solvate, crystallization, isostere or prodrug, wherein when o is 1, X¹、X²、X³、X⁴In there are three being C(R¹R²), remaining one is N (R³), O, S, sulfone or sulfoxide.

In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy Acceptable salt, solvate, crystallization, isostere or prodrug are gone up, wherein X¹、X², each X³It is C (R¹R²), X⁴For N (R³), O, S, sulfone or sulfoxide.

In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically Acceptable salt, solvate, crystallization, isostere or prodrug, wherein：

R¹、R²Separately it is selected from hydrogen, halogen, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkane Oxygroup, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl amino, C_1-6Alkyl acyl Base amino, C_1-6Alkyl acyl, aminoacyl, C_1-6Alkylaminoacyl, double C_1-6Alkyl amino, C_2-10Alkenyl, C_2-10Alkynyl, C_3-10Naphthenic base, C_1-10Heterocycle, C_6-18Aryl and C_1-18Heteroaryl；

It is further preferred that R¹、R²Separately it is selected from hydrogen, halogen, hydroxyl, C_1-3Alkyl, halogenated C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkoxy, halogenated C_1-3Alkoxy, hydroxyl C_1-3Alkoxy, nitro, carboxyl, cyano, amino, list C_1-3Alkyl ammonia Base, C_1-3Alkyl acylamino, C_1-3Alkyl acyl, aminoacyl, C_1-3Alkylaminoacyl, double C_1-3Alkyl amino, C_2-6Alkene Base, C_2-6Alkynyl, C_3-8Naphthenic base, C_1-8Heterocycle, C_6-12Aryl and C_1-12Heteroaryl；

It is further preferred that R¹、R²Separately selected from hydrogen, halogen, hydroxyl, methyl, ethyl, propyl, isopropyl, Trifluoromethyl, trifluoroethyl, pentafluoroethyl group, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyl, methoxyl group, ethyoxyl, the third oxygen Base, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, propylcarbamic, isopropylamino, dimethylamino, Lignocaine, methylethylamine, dipropyl amino, methylpropylamino, ethylpropylamino, methylacyl amino, ethyl acyl Base amino, vinyl acyl amino, methylacyl, ethyl acyl group, vinyl acyl group, aminoacyl, methylamino acyl group, ethyl Aminoacyl, vinyl, acrylic, allyl, cyclobutenyl, alkene butyl, 3- methyl-2-butene base, acetenyl, propinyl, alkynes Propyl, butynyl, alkynes butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, C_1-6Heterocycle, C_6-10Aryl and C_1-10Heteroaryl.

In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically Acceptable salt, solvate, crystallization, isostere or prodrug, wherein：R¹、R²Carbon atom connected to it is formed together carbonyl Base.

In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically Acceptable salt, solvate, crystallization, isostere or prodrug, wherein R³Selected from hydrogen, C_1-10Alkyl acyl, aminoacyl, C_1-10Alkylaminoacyl, C_1-10Alkyl, halogenated C_1-10Alkyl, hydroxyl C_1-10Alkyl, C_2-10Alkenyl, C_2-10Alkynyl, C_3-10Cycloalkanes Base, C_1-10Heterocycle, C_6-18Aryl and C_1-18Heteroaryl, the group can be by one or more halogens, hydroxyl, alkyl, halogenated It is alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double Alkyl amino, naphthenic base, heterocycle, aryl and heteroaryl replace；

It is further preferred that R³Selected from separately selected from hydrogen, C_1-6Alkyl acyl, aminoacyl, C_1-6Alkyl amino Acyl group, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_1-8Heterocycle, C_6-12 Aryl and C_1-12Heteroaryl, the group can be by one or more halogens, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl ammonia Base, double C_1-6Alkyl amino, C_3-10Naphthenic base, C_1-10Heterocycle, C_6-18Aryl and C_1-18Heteroaryl replaces；

It is further preferred that R³Selected from hydrogen, formoxyl, acetyl group, propiono, aminoacyl, methylamino acyl group, second Base aminoacyl, propylcarbamic acyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, amyl, isopentyl, neopentyl, Hexyl, trifluoromethyl, trifluoroethyl, bis- fluoropropyl of 2,2-, the fluoro- 2- methyl-propyl of 2-, the fluoro- 2- methyl-propyl of (S) -3-, hydroxyl first Base, ethoxy, hydroxypropyl, 2- hydroxypropyl, vinyl, acrylic, cyclobutenyl, 3- methyl-2-butene base, C_2-6Alkynyl, C_3-6 Naphthenic base, C_3-6Heterocycle, C_6-10Aryl and C_5-10Heteroaryl, the group can be by one or more halogens, hydroxyl, C_1-3Alkane Base, halogenated C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkoxy, halogenated C_1-3Alkoxy, hydroxyl C_1-3Alkoxy, nitro, carboxyl, cyanogen Base, amino, list C_1-3Alkyl amino, double C_1-3Alkyl amino, C_3-6Naphthenic base, C_1-6Heterocycle, C_6-10Aryl and C_1-10Heteroaryl takes Generation.

R⁴Selected from hydrogen, C_1-10Alkyl acyl, aminoacyl, C_1-10Alkylaminoacyl, C_1-10Alkyl, halogenated C_1-10Alkyl, Hydroxyl C_1-10Alkyl, C_2-10Alkenyl, C_2-10Alkynyl, C_3-10Naphthenic base, C_1-10Heterocycle, C_6-18Aryl and C_1-18Heteroaryl, it is described Group can be by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxyl alkane Oxygroup, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double alkyl aminos, naphthenic base, heterocycle, aryl and heteroaryl take Generation；

It is further preferred that R⁴Selected from separately selected from hydrogen, C_1-6Alkyl acyl, aminoacyl, C_1-6Alkyl amino Acyl group, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_1-8Heterocycle, C_6-12 Aryl and C_1-12Heteroaryl, the group can be by one or more halogens, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl ammonia Base, double C_1-6Alkyl amino, C_3-10Naphthenic base, C_1-10Heterocycle, C_6-18Aryl and C_1-18Heteroaryl replaces；

It is further preferred that R⁴Selected from hydrogen, formoxyl, acetyl group, propiono, aminoacyl, methylamino acyl group, second Base aminoacyl, propylcarbamic acyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, amyl, isopentyl, neopentyl, Hexyl, trifluoromethyl, trifluoroethyl, bis- fluoropropyl of 2,2-, the fluoro- 2- methyl-propyl of 2-, the fluoro- 2- methyl-propyl of (S) -3-, hydroxyl first Base, ethoxy, hydroxypropyl, 2- hydroxypropyl, vinyl, acrylic, cyclobutenyl, 3- methyl-2-butene base, C_2-6Alkynyl, C_3-6 Naphthenic base, C_3-6Heterocycle, C_6-10Aryl and C_5-10Heteroaryl, the group can be by one or more halogens, hydroxyl, C_1-3Alkane Base, halogenated C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkoxy, halogenated C_1-3Alkoxy, hydroxyl C_1-3Alkoxy, nitro, carboxyl, cyanogen Base, amino, list C_1-3Alkyl amino, double C_1-3Alkyl amino, C_3-6Naphthenic base, C_1-6Heterocycle, C_6-10Aryl and C_1-10Heteroaryl takes Generation.

R⁵Selected from hydrogen, halogen, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6 Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl amino, C_1-6Alkyl acylamino, C_1-6Alkane Base acyl group, aminoacyl, C_1-6Alkylaminoacyl, double C_1-6Alkyl amino, C_2-10Alkenyl, C_2-10Alkynyl and C_3-10Naphthenic base；

It is further preferred that R⁵Selected from hydrogen, halogen, hydroxyl, C_1-3Alkyl, halogenated C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkane Oxygroup, halogenated C_1-3Alkoxy, hydroxyl C_1-3Alkoxy, nitro, carboxyl, cyano, amino, list C_1-3Alkyl amino, C_1-3Alkyl acyl Base amino, C_1-3Alkyl acyl, aminoacyl, C_1-3Alkylaminoacyl, double C_1-3Alkyl amino, C_2-6Alkenyl, C_2-6Alkynyl and C_3-8Naphthenic base；

It is further preferred that R⁵Selected from hydrogen, halogen, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoro Ethyl, pentafluoroethyl group, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, Nitro, carboxyl, cyano, amino, methylamino, ethylamino, propylcarbamic, isopropylamino, dimethylamino, lignocaine, first Base ethylamino, dipropyl amino, methylpropylamino, ethylpropylamino, methylacyl amino, ethyl acyl amino, ethylene Base acyl amino, methylacyl, ethyl acyl group, vinyl acyl group, aminoacyl, methylamino acyl group, ethylamino acyl group, second Alkenyl, acrylic, allyl, cyclobutenyl, alkene butyl, 3- methyl-2-butene base, acetenyl, propinyl, propargyl, butynyl, Alkynes butyl, cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.

Each R⁶, each R⁷Separately it is selected from hydrogen, halogen, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl amino, C_1-6Alkane Base acyl amino, C_1-6Alkyl acyl, aminoacyl, C_1-6Alkylaminoacyl, double C_1-6Alkyl amino, C_2-10Alkenyl, C_2-10Alkynes Base, C_3-10Naphthenic base and boric acid；

It is further preferred that each R⁶, each R⁷Separately it is selected from hydrogen, halogen, hydroxyl, C_1-3Alkyl, halogenated C_1-3Alkyl, Hydroxyl C_1-3Alkyl, C_1-3Alkoxy, halogenated C_1-3Alkoxy, hydroxyl C_1-3Alkoxy, nitro, carboxyl, cyano, amino, list C_1-3Alkane Base amino, C_1-3Alkyl acylamino, C_1-3Alkyl acyl, aminoacyl, C_1-3Alkylaminoacyl, double C_1-3Alkyl amino, C_2-6 Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base and boric acid；

It is further preferred that each R⁶, each R⁷Separately it is selected from hydrogen, halogen, hydroxyl, methyl, ethyl, propyl, isopropyl Base, trifluoromethyl, trifluoroethyl, pentafluoroethyl group, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyl, methoxyl group, ethyoxyl, Propoxyl group, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, propylcarbamic, isopropylamino, diformazan Amino, lignocaine, methylethylamine, dipropyl amino, methylpropylamino, ethylpropylamino, methylacyl amino, second Base acyl amino, vinyl acyl amino, methylacyl, ethyl acyl group, vinyl acyl group, aminoacyl, methylamino acyl group, Ethylamino acyl group, vinyl, acrylic, allyl, cyclobutenyl, alkene butyl, 3- methyl-2-butene base, acetenyl, propine Base, propargyl, butynyl, alkynes butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and boric acid.

Y is selected from C_1-6Alkoxy, C_3-10Naphthenic base C_1-6Alkoxy, C_1-10Heterocycle C_1-6Alkoxy, C_6-18Aryl C_1-6Alcoxyl Base, C_1-18Heteroaryl C_1-6Alkoxy, C_1-6Alkyl amino, C_3-10Naphthenic base C_1-6Alkyl amino, C_1-10Heterocycle C_1-6Alkyl ammonia Base, C_6-18Aryl C_1-6Alkyl amino, C_1-18Heteroaryl C_1-6Alkyl amino, C_3-10Naphthenic base, C_1-10Heterocycle, C_6-18Aryl, C_1-18Heteroaryl, C_2-10Alkenyl and C_2-10Alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, arylalkoxy Base, heteroarylalkoxy, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkane Base amino, naphthenic base, heterocycle, aryl, heteroaryl, alkenyl and alkynyl can be by one or more halogens, hydroxyl, C_1-6Alkyl, Halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, Amino, list C_1-6Alkyl amino, C_1-6Alkyl acylamino, C_1-6Alkyl acyl, aminoacyl, C_1-6Alkylaminoacyl, double C_1-6 Alkyl amino, C_2-10Alkenyl, C_2-10Alkynyl, C_1-10Heterocycle, C_3-10Naphthenic base and oxo group replace；

It is further preferred that Y is selected from C_1-3Alkoxy, C_3-8Naphthenic base C_1-3Alkoxy, C_1-8Heterocycle C_1-3Alkoxy, C_6-12Aryl C_1-3Alkoxy, C_1-12Heteroaryl C_1-3Alkoxy, C_1-3Alkyl amino, C_3-8Naphthenic base C_1-3Alkyl amino, C_1-8Heterocycle Base C_1-3Alkyl amino, C_6-12Aryl C_1-3Alkyl amino, C_1-8Heteroaryl C_1-3Alkyl amino, C_3-8Naphthenic base, C_1-8Heterocycle, C_6-12Aryl, C_1-12Heteroaryl, C_2-6Alkenyl and C_2-6Alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, virtue It is base alkoxy, heteroarylalkoxy, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, miscellaneous Aryl-alkyl amino, naphthenic base, heterocycle, aryl, heteroaryl, alkenyl and alkynyl can by one or more halogens, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxylic Base, cyano, amino, list C_1-6Alkyl amino, C_1-6Alkyl acylamino, C_1-6Alkyl acyl, aminoacyl, C_1-6Alkyl amino acyl Base, double C_1-6Alkyl amino, C_2-10Alkenyl, C_2-10Alkynyl, C_1-10Heterocycle, C_3-10Naphthenic base and oxo group replace；

It is further preferred that Y is selected from C_1-3Alkoxy, C_3-8Naphthenic base C_1-3Alkoxy, C_1-8Heterocycle C_1-3Alkoxy, C_6-12Aryl C_1-3Alkoxy, C_1-12Heteroaryl C_1-3Alkoxy, C_1-3Alkyl amino, C_3-8Naphthenic base C_1-3Alkyl amino, C_1-8Heterocycle Base C_1-3Alkyl amino, C_6-12Aryl C_1-3Alkyl amino, C_1-8Heteroaryl C_1-3Alkyl amino, C_3-8Naphthenic base, C_1-8Heterocycle, C_6-12Aryl, C_1-12Heteroaryl, C_2-6Alkenyl and C_2-6Alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, virtue It is base alkoxy, heteroarylalkoxy, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, miscellaneous Aryl-alkyl amino, naphthenic base, heterocycle, aryl, heteroaryl, alkenyl and alkynyl can by one or more halogens, hydroxyl, C_1-3Alkyl, halogenated C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkoxy, halogenated C_1-3Alkoxy, hydroxyl C_1-3Alkoxy, nitro, carboxylic Base, cyano, amino, list C_1-3Alkyl amino, C_1-3Alkyl acylamino, C_1-3Alkyl acyl, aminoacyl, C_1-3Alkyl amino acyl Base, double C_1-3Alkyl amino, C_2-6Alkenyl, C_2-6Alkynyl, C_3-8Naphthenic base, C_1-8Heterocycle and oxo group replace.

In some specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically Acceptable salt, solvate, crystallization, isostere or prodrug, wherein Y be

In some preferred embodiments, the compound of the present invention is the compound or its isomers, pharmacy of general formula Ia Upper acceptable salt, solvate, crystallization, isostere or prodrug,

Wherein, each R⁶, each R⁷、R⁴, m, n be as defined in general formula I.

In some specific embodiments, the compound or its isomers of general formula Ia according to the present invention pharmaceutically may be used Salt, solvate, crystallization, isostere or the prodrug of receiving, wherein each R⁶, each R⁷It is each independently selected from fluorine, chlorine, bromine, first Base, ethyl, propyl, methoxyl group, ethyoxyl, propoxyl group, fluoro-methoxy, difluoromethoxy, trifluoromethoxy, fluoro ethoxy Base, difluoroethoxy, R⁴It is selected from

The present invention provides compound or its isomers, pharmaceutically acceptable salt, solvate, crystallization, electricity in detail below Sub- isostere or prodrug：

On the other hand, the present invention provides the preparation method of general formula compound of the invention, including：

Compounds of formula I can be known in the art as being suitable for by the compound of formula 1 and the compound of formula 2 In the presence of condition (such as in acid) of Pickett-Shi Penggele (Pictet-Spengler) reaction and a kind of suitable molten It is made in agent with being reacted at suitable temperature,

Wherein the compound of formula 1 can pass through formula 3Compound and formula 4Change It closes object reaction to be made, the compound of formula 4 can pass through formula 5Compound and trifluoromethanesulfonic acid anhydride reactant be made, formula 2 Compound, the compound of formula 3, formula 5 compound can be commercially available or customary preparation methods as known in the art It is made,

X¹、X²、X³、X⁴、R⁴、R⁵、R⁶、R⁷, m, n, o, Y be as defined in formula above I.

The third aspect, the present invention provide pharmaceutical composition, it includes the compound of the present invention or its isomers, pharmaceutically may be used Salt, solvate, crystallization, isostere or the prodrug of receiving.

In some embodiments, the present invention provides pharmaceutical composition, it includes the compound of the present invention or its isomers, Pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug, also comprising one in the group selected from following composition Kind or various medicaments：SERD, SERM, tyrosine protein enzyme inhibitor, EGFR inhibitor, VEGFR inhibitor, Bcr-Abl inhibit Agent, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, mek inhibitor, inhibitors of histone deacetylase, VEGF antibody, EGF antibody, HIV kinases inhibitor, HMG-CoA reductase inhibitor etc..

In some embodiments, the present invention provide the compound of the present invention or its isomers, pharmaceutically acceptable salt, Solvate, crystallization, isostere or prodrug and include the compound of the present invention or its isomers, pharmaceutically acceptable Salt, solvate, crystallization, isostere or prodrug pharmaceutical composition, the compound or pharmaceutical composition are for treating And/or the relevant disease of prevention estrogen receptor.

It can be by the compound of the present invention or its isomers, pharmaceutically acceptable salt, solvate, crystallization, electronics etc. Isostere or prodrug and pharmaceutically acceptable carrier, diluent or excipient are prepared by mixing into pharmaceutical preparation, oral to be suitable for Or parenteral.Medication includes, but are not limited to that intradermal, intramuscular, peritonaeum is interior, intravenous, subcutaneous, intranasal and oral way Diameter.The preparation can be applied by any approach, such as by being transfused or injecting, by transepithelial or it is mucocutaneous (such as Oral mucosa or rectum etc.) absorb approach application.Administration can be whole body or local.The example packet of oral administration preparation Solid or liquid dosage form are included, specifically, including tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspension etc.. The preparation can be prepared by methods known in the art, and include the conventional use of carrier of field of pharmaceutical preparations, diluent or Excipient.

Fourth aspect, the present invention provide general formula I compound represented of the present invention or its isomers, pharmaceutically acceptable Salt, solvate, crystallization, isostere or prodrug, or comprising its pharmaceutical composition preparation treatment and/or prevent it is female swash Purposes in the drug of the relevant disease of plain receptor, wherein the relevant disease of estrogen receptor or symptom includes but unlimited In：Relevant to ER- α dysfunction cancer (such as osteocarcinoma, breast cancer, colorectal cancer, carcinoma of endometrium, prostate cancer, ovary Cancer and uterine cancer etc.), liomyoma (such as leiomyoma of uterus etc.), central nervous system (CNS) defect is (such as in alcohol Poison, migraine etc.), cardiovascular system defect (such as aortic aneurysm, myocardial infarction neurological susceptibility, aortic valve sclerosis, cardiovascular disease Disease, coronary artery disease, hypertension etc.), hematological deficiencies (such as Deep vain thrombosis etc.), immune and inflammation disease (such as Graves disease, arthritis, multiple sclerosis, cirrhosis etc.), susceptibility infection (such as hepatitis B, chronic liver disease Deng), metabolic deficiency (such as bone density, cholestasis, hypospadia, obesity, osteoarthritis, sclerotin reduce, osteoporosis Deng), neurologically handicapped (such as Alzheimer disease, Parkinson's disease, migraine, dizziness etc.), mental defect (such as detest by nerve Food, Attention deficit hyperactivity disorder (ADHD), dementia, major depressive disorder, mental disease etc.) and genetic defect (such as menstruation Age of menarche exception, endometriosis, sterility etc.) etc..In some embodiments, the present invention relates to it is a kind of treat it is female The method of the relevant disease of hormone receptor comprising give required bacterium general formula I compound represented or its Isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug, or comprising its pharmaceutical composition, Wherein the relevant disease of estrogen receptor includes but is not limited to：Relevant to ER dysfunction cancer (such as osteocarcinoma, cream Gland cancer, colorectal cancer, carcinoma of endometrium, prostate cancer, oophoroma and uterine cancer etc.), liomyoma (such as leiomyoma of uterus Deng), central nervous system (CNS) defect (such as alcoholism, migraine etc.), cardiovascular system defect (such as aortic aneurysm, Myocardial infarction neurological susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension etc.), hematological deficiencies (example Such as Deep vain thrombosis), immune and inflammation disease (such as Graves disease, arthritis, multiple sclerosis, cirrhosis Deng), susceptibility infection (such as hepatitis B, chronic liver disease etc.), metabolic deficiency is (such as under bone density, cholestasis, urethra Split, the reduction of obesity, osteoarthritis, sclerotin, osteoporosis etc.), neurologically handicapped (such as Alzheimer disease, Parkinson's disease, Migraine, dizziness etc.), mental defect (such as anorexia nervosa, Attention deficit hyperactivity disorder (ADHD), dementia, serious suppression Strongly fragrant obstacle, mental disease etc.) and genetic defect (such as Menarcheal Age exception, endometriosis, sterility etc.) etc..

The compound of the present invention has more excellent anti-tumor activity, and dosing interval is longer, less side effects.

Term explanation

Unless stated to the contrary, the term used in the specification and in the claims has following meanings.

" hydrogen ", " carbon " in the compounds of this invention include its all isotope.Isotope is understood to include with identical Atomicity but there is those of different quality number atom.For example, the isotope of hydrogen includes tritium and deuterium, the isotope packet of carbon It includes¹³C and¹⁴C。

" halogen " of the invention refers to fluorine, chlorine, bromine, iodine." halogenated " of the invention refers to be replaced by fluorine, chlorine, bromine or iodine.

" alkyl " of the invention refers to the saturated fat hydrocarbyl group of linear chain or branched chain, preferably the straight chain containing 1 to 6 carbon atom or Branched group, the linear chain or branched chain group of further preferably 1 to 3 carbon atom, non-limiting example include methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl Propyl, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl etc..Alkyl can be substitution Or it is unsubstituted, when substituted, substituent group can be on any workable tie point.

" alkylidene " of the invention refers to that alkyl formally removes group remained by a hydrogen atom, as methylene (- CH₂), ethylidene (- CH₂-CH₂), propylidene (- CH₂-CH₂-CH₂) etc., herein, " the sub- C_1-10Alkyl " refers to C_1-10Alkyl formally removes group remained by a hydrogen atom, " the sub- C_1-6Alkyl " refers to C_1-6Alkyl is from form On remove group remained by a hydrogen atom.Alkylidene can be substituted or unsubstituted, and when substituted, substituent group can On any workable tie point.

" halogenated alkyl " of the invention refers to the alkyl at least replaced by a halogen.

" hydroxy alkyl " of the invention refers to the alkyl at least replaced by a hydroxyl.

" alkoxy " of the invention refers to-O- alkyl.The non-limiting example of alkoxy includes：Methoxyl group, ethyoxyl, third Oxygroup, positive propoxy, isopropoxy, isobutoxy, sec-butoxy etc..Alkoxy can be optionally it is substituted or unsubstituted, When substituted, substituent group can be on any workable tie point.

" naphthenic base " of the invention refers to cricoid saturated hydrocarbyl.Suitable naphthenic base can be substituted or unsubstituted tool There are the monocyclic, bicyclic or tricyclic saturated hydrocarbyl of 3-10 carbon atom, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl.

" heterocycle " of the invention refers to ring carbon atom (preferably containing 1-10 carbon atom i.e. C_1-10) and 1 to 4 3- to the 12- member non-aromatic ring system of ring hetero atom (wherein each hetero atom is independently selected from nitrogen, oxygen, sulphur, boron, phosphorus and silicon) The group (" 3-12 circle heterocyclic ring base ") of system.In the heterocyclyl groups comprising one or more nitrogen-atoms, tie point can be carbon Or nitrogen-atoms, as long as chemical valence is permitted.Heterocyclyl groups or (" heterocycle of monocycle ") that can be monocycle either merge , bridging or spiral shell loop system (such as second cycle line system (" heterocycles of two rings ")) and can be saturation or can be portion Divide unsaturated.The loop system of two ring of heterocycle can include one or more hetero atoms in one or two ring." heterocycle Base " also includes loop system, and wherein heterocycle, as defined above, is to merge (wherein to connect with one or more carbocylic radical groups Point in carbocylic radical or on heterocycle) or loop system in heterocycle, it is as defined above, be and one or more aryl or heteroaryl (wherein tie point is on heterocycle) of base fusion, and in such cases, the number of ring members continues referred to as in heterocyclic ring system In ring members number.Unless otherwise prescribed, each example of heterocycle is independently optionally to replace ground, that is, unsubstituted (" unsubstituted heterocycle ") or (" the substituted heterocycle ") replaced with one or more substituent groups.In certain embodiments, The heterocyclyl groups are unsubstituted 3-10 circle heterocyclic ring bases.In certain embodiments, which is the 3-10 member replaced Heterocycle.It is fused to C₆The exemplary 5- circle heterocyclic ring base group of aryl rings (herein be also referred to as 5,6- bicyclic heterocycles) includes but unlimited In indoline base, isoindoline base, dihydro benzo furyl, dihydrobenzo thienyl, benzoxazolinone base etc..Fusion Exemplary 6- circle heterocyclic ring base group (herein be also referred to as 6,6- bicyclic heterocycles) to aryl rings includes but is not limited to tetrahydroquinoline Base, tetrahydro isoquinolyl etc..

" aryl " of the invention refers to the aroma system that may include monocycle or fused polycycle, preferably comprises monocycle or condensed Bicyclic aroma system contains 6 to 18 carbon atoms, preferably comprises from about 6 to about 12 carbon atoms.Suitable aryl includes But it is not limited to phenyl, naphthalene, anthryl, tetralyl, fluorenyl, indanyl.Aryl can be optionally it is substituted or unsubstituted, when When being substituted, substituent group can be on any workable tie point.

" heteroaryl " of the invention refers to the aryl that at least one carbon atom is substituted by hetero atom, by 5-20 atom structure At being further preferably made of 5-12 atom, the hetero atom is O, S, N, and suitable heteroaryl preferably contains 1-18 carbon Atom (i.e. C_1-18), including but not limited to imidazole radicals, benzimidazolyl, imidazopyridyl, quinazoline ketone group, pyrrole radicals, miaow Oxazolone base, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, Pyrimidine radicals, pyridyl group, pyrazinyl, pyridazinyl, pyrimido pyrazolyl, pyrimido imidazole radicals etc..Heteroaryl can be optional substitution Or it is unsubstituted, when substituted, substituent group can be on any workable tie point.

" isomers " of the invention be there is identical molecular formula but in nature or on the key sequence of its atom or Different compound on the space arrangement of its atom.Stereoisomer is its atom isomers different on space arrangement.That This stereoisomer not being mirrored into is diastereomer and be the stereoisomer of mirror image of non-overlap is mutually enantiomer.When When compound has asymmetric center, for example, it is bonded to four different groups, a pair of of enantiomer is possible.Mapping Rule is sequenced characterized by the absolute configuration of its asymmetric center and through the R- and S- of Cahn and Prelog in body, or by dividing The method of the plane of sub- rotatory polarization light is described and specifies as dextrorotation or left-handed (i.e. different respectively as (+) or (-)- Structure body).Chipal compounds can be used as the presence of or mixtures thereof single enantiomer.The mixing of equal proportion comprising enantiomer Object is referred to as " racemic mixture ".

" pharmaceutically acceptable salt " of the invention refers to the salt of the compounds of this invention, and this kind of salt is in the mammalian body When have safety and validity, and have due bioactivity.

" solvate " of the invention refer in a conventional sense solute (such as salt of reactive compound, reactive compound) and The compound that solvent (such as water) combination is formed.Solvent refers to the solvent of known to those of skill in the art or easy determination.Such as Fruit is water, then solvate is commonly referred to as hydrate, for example, semihydrate, monohydrate, dihydrate, trihydrate or its Substitution amount etc..

The internal effect of compound with chemical formula (I) can be partly by giving the chemical combination with chemical formula (I) One or more metabolins for being formed after object in human body or animal body play.As described above, having the change of chemical formula (I) The internal effect for closing object can also be metabolized to play via precursor compound (" prodrug ")." prodrug " of the invention refers in biology Under physiological condition in body, due to reacting and converting the compound of the compound of an accepted way of doing sth (I) with enzyme, gastric acid etc., that is, pass through enzyme Oxidation, reduction, hydrolysis etc. convert the compound of the compound of an accepted way of doing sth (I) and/or are converted to by hydrolysis of gastric acid etc. etc. The compound etc. of the compound of formula (I).The compound with Formula I with carboxyl it is suitable it is pharmaceutically acceptable before Medicine is the ester of such as its internal cleavable.The ester for wrapping the internal cleavable of the carboxylic compound with Formula I is for example It is cracked in human body or animal body to generate the pharmaceutically acceptable ester of parent acid.Suitable for carboxyl can pharmaceutically connect The ester received includes Arrcostab, such as methyl ester, ethyl ester and tertiary butyl ester, alkoxy methyl ester such as methoxymethyl ester；Alkane acyl Oxygroup methyl ester, such as new pentane acyloxy ester；3- phthalidyl ester；Naphthenic base carbonyloxy group Arrcostab, such as cyclopenta carbonyl oxy-methyl ester and 1- cyclohexylcarbonyloxyethyl ester；2- oxo -1,3- dioxa cyclopentenyl (dioxolenyl) methyl ester, such as 5- methyl -2- Oxo-1,3- Dioxol-4 -yl methyl ester；And alkoxy carbonyloxy group Arrcostab, such as methoxycarbonyl-oxymethyl ester With 1- methoxycarbonyloxyethyl ester.The compound with Formula I with carboxyl it is suitable it is pharmaceutically acceptable before Medicine is the amide of for example internal cleavable, such as N- alkylamide and N, N- dialkyl amide, such as N- methyl nitrosourea, N- ethyl acyl Amine, N- propyl amides, N, N- dimethylformamide, N- ethyl-N-methyl or N, N- diethylamide.

Bioisostere (or abbreviation " isostere ") of the present invention is for defining wherein one or more atoms (or atomic group) is by with those of replacing the displaced atom that atom has similar spatial and/or electronic characteristic with them The term generally acknowledged generally in the art of drug analogue replaced (or atomic group).

" crystallization " of the invention refer to its internal structure be in three-dimensional regularly repeat constituting atom (or its group) and The solid of formation is different from the amorphous solid of the internal structure without this rule.

" pharmaceutical composition " of the invention refers to comprising any compound as described herein, including corresponding isomery Protection form and one or more pharmaceutically acceptable of body, prodrug, solvate, pharmaceutically acceptable salt or its chemistry The mixture of carrier.The purpose of Pharmaceutical composition is to promote the administration of compound on organism body.The composition is commonly used in system It is standby to treat and/or prevent the drug by one or more kinase mediated diseases.

" pharmaceutically acceptable carrier " of the invention refer to obvious irritation is not caused to organism and do not interfere to The bioactivity of compound and the carrier of property are given, all solvents, diluent or other excipient, dispersing agent, surface are included Activating agent isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant etc..Unless any conventional carrier medium with The compounds of this invention is incompatible.The some examples that can be used as pharmaceutically acceptable carrier include, but are not limited to carbohydrate, such as cream Sugar, dextrose and saccharose；Starch, such as cornstarch and potato starch；Cellulose and its derivates, such as carboxymethyl cellulose Sodium and cellulose and cellulose acetate；Malt, gelatin etc..

" excipient " of the invention, which refers to, to be added in Pharmaceutical composition with the further inert substance for promoting to give compound. Excipient may include calcium carbonate, calcium phosphate, various saccharides and a plurality of types of starch, cellulose derivative, gelatin, plant Oil, polyethylene glycol.

Of the invention " purposes in the drug for the treatment of and/or the relevant disease of prevention estrogen receptor " refer to can make it is female The relevant disease of hormone receptor is improved, and growth, development and/or the transfer of the relevant disease of estrogen receptor, or drop are inhibited The risk of the relevant disease of low estrogen receptor mainly gives treatment and/or prevention effective dose to required human or animal The compound of the present invention is to inhibit, slow down or reverse growth, development or the expansion of the relevant disease of estrogen receptor in subject It dissipates, improves the relevant disease of estrogen receptor, or reduce risk, the disease relevant to estrogen receptor Including disease relevant to estrogen receptor alpha and disease relevant with erss, for example, with estrogen receptor dysfunction Relevant cancer (such as osteocarcinoma, breast cancer, colorectal cancer, carcinoma of endometrium, prostate cancer, oophoroma and uterine cancer etc.) is put down Sliding myomata (such as leiomyoma of uterus etc.), central nervous system (CNS) defect (such as alcoholism, migraine etc.), painstaking effort Guard system defect (such as aortic aneurysm, myocardial infarction neurological susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease, Hypertension etc.), hematological deficiencies (such as Deep vain thrombosis etc.), immune and inflammation disease (such as Graves disease, close Save inflammation, multiple sclerosis, cirrhosis etc.), susceptibility infection (such as hepatitis B, chronic liver disease etc.), metabolic deficiency (such as bone Density, cholestasis, hypospadia, obesity, osteoarthritis, sclerotin reduction, osteoporosis etc.), neurologically handicapped (such as Ah Alzheimer's disease, Parkinson's disease, migraine, dizziness etc.), (such as anorexia nervosa, attention deficit are with more dynamic barriers for mental defect Hinder (ADHD), dementia, major depressive disorder, mental disease etc.) and genetic defect (such as Menarcheal Age is abnormal, endometrium Endometriosis, sterility etc.) etc..

Specific embodiment

Representative embodiment is protection model and is not intended to limit the present invention in order to better illustrate the present invention below It encloses.Material used in the following embodiment is commercially available unless otherwise specified.

Embodiment 1 (E) -3- (the fluoro- 4- of 3,5- bis- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6, 10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) acrylic acid

The synthesis of step a 2- (1H- indol-3-yl) cyclopenta -1- ketone

In the mono- neck bottle of 100mL, indoles (1.98g, 16.9mmol) and dichloro cyclopentanone (2g, 16.9mmol) is added, The dissolution of 35mL trifluoroethanol, is stirred at room temperature, and is added natrium carbonicum calcinatum (2.15g, 20.28mmol), maintaining the temperature, the reaction was continued 48h.After reaction, it successively filters, be concentrated, column chromatographs to obtain title product.ESI-Ms m/z:200.1[M+H]⁺。

The synthesis of step b 2- (1H- indol-3-yl) cyclopenta -1- amine

In the mono- neck bottle of 200mL, 2- (1H- indol-3-yl) cyclopenta -1- ketone (4.78g, 24.02mmol), 60mL is added Methanol dissolution, weighs ammonium acetate (20.18g, 262mmol), sodium cyanoborohydride (1.67g, 26.42mmol) addition, and room temperature is stirred Mix 48h.Then 50mL water is added in 2M HCl% tune pH to 2, concentrated solvent, the extraction of 40mL methylene chloride collects water phase, then use 4M sodium hydroxide solution tune pH to 12 is extracted with 3 × 60mL methylene chloride, merges organic phase, washing, saturated common salt washing are dense Contract to obtain title product.ESI-Ms m/z:201.13[M+H]⁺。

The synthesis of the fluoro- 2- methyl-propyl trifluoromethayl sulfonic acid ester of step c 2-

In 250mL reaction flask, the fluoro- 2- methyl propyl- 1- alcohol (7.25g, 78.75mmol) of 2-, 2,6- dimethyl pyrazole is added Pyridine (12.75mL, 110.25mmol), with sub-cooled after the dissolution of 60mL methylene chloride to -10 DEG C.By trifluoromethanesulfanhydride anhydride (14.58mL, 86.75mmol) is added dropwise in above-mentioned reaction solution after being dissolved with 20mL methylene chloride, and drop finishes the reaction was continued 1h.Reaction After, reaction solution is used respectively 2N hydrochloric acid (2 × 20mL), saturated sodium bicarbonate aqueous solution (2 × 20mL) and saturated salt solution (2 × 20mL) washing, anhydrous sodium sulfate is dry, and methylene chloride is removed under reduced pressure and obtains title compound.ESI-Ms m/z:225.1[M+ H]⁺。

The synthesis of step d N- (the fluoro- 2- methyl-propyl of 2-) -2- (1H- indol-3-yl) cyclopenta -1- amine

In 250mL reaction flask, the addition fluoro- 2- methyl-propyl trifluoromethayl sulfonic acid ester of step c gains 2- (5g, 22.32mmol), 2- (1H- indol-3-yl) cyclopenta -1- amine (3.5g, 17.5mmol) and diisopropylethylamine (4.52g, 35mmol), it is dissolved with 50mL dioxane, argon gas protects lower 90 DEG C of reactions 2h, stops reaction, concentration, and column chromatographic purifying must be marked Inscribe compound 1.7g.ESI-Ms m/z:275.19[M+H]⁺.Step e (E) -3- (4- carbonyl -3,5- difluorophenyl) propyl- 2- alkene The synthesis of sour methyl esters

By the fluoro- 1- benzaldehyde (6.66g, 30mmol) of the bromo- 2,6- bis- of 4-, triethylamine (8.4mL, 60mmol), acid chloride (0.34g, 1.5mmol) and trimethylphenyl phosphorus (1.0g, 3.2mmol) are dissolved in DMF (70mL), are de-gassed.Then The reactant is simultaneously heated to 80 DEG C of lasting 4h by addition methyl acrylate (4.3mL, 45.0mmol).After cooling, by the mixture It is added in water (300mL), and is extracted with ethyl acetate (2 × 400mL).Combined organic matter is used into 2N HCl in succession (200mL) washing, then anhydrous sodium sulfate is dried and concentrated, which is obtained title compound.ESI-Ms m/z:227.04[M+H]⁺。

Step f (E) -3- (the fluoro- 4- of 3,5- bis- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6,10c- Octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) methyl acrylate synthesis

In 100mL reaction flask, addition step d gains (300mg, 1.1mmol), (3,5- bis- is fluoro- by (E)-methyl -3- 4- Fonnylphenyl) methyl acrylate (251mg, 1.1mmol) and glacial acetic acid (0.6mL, 11mmol), it is molten to add toluene 25mL Solution, 90 DEG C of reaction 6h, concentration of reaction solution, column chromatographic purifying obtain title compound.ESI-Ms m/z:483.2[M+H]⁺。

Step g (E) -3- (the fluoro- 4- of 3,5- bis- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6,10c- Octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) acrylic acid synthesis

Weigh step f gains (E) -3- (the fluoro- 4- of 3,5- bis- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6,10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) methyl acrylate (215mg, 0.45mmol) in 100mL single port bottle, tetrahydrofuran/methanol (10mL/5mL) dissolution instills 7.5M NaOH% solution 2h is stirred at room temperature in (0.5mL), and fully reacting is concentrated under reduced pressure, and instills 1M HCl%, adjusts pH value to 6.5,15mL water is added, with 3 The extraction of × 15mL ethyl acetate merges organic phase, concentration, and column, which chromatographs, is made title compound.¹H-NMR(400MHz,DMSO-d₆) δ:12.17(s,1H),10.16(s,1H),7.55(s,1H),7.51-7.15(m,4H),7.18-7.16(d,1H),7.02- 6.92(m,1H),6.71-6.67(d,1H),5.20(s,1H),3.15-3.12(m,1H),2.39-2.28(m,1H),2.15- 2.13(m,1H),2.08(s,1H),1.91-1.77(m,1H),1.65-1.49(m,1H),1.15(s,2H),1.09(s,6H), 1.01(s,2H).ESI-Ms m/z:469.2[M+H]⁺。

Embodiment 2 (E) -3- (the fluoro- 4- of the chloro- 5- of 3- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6, 10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) acrylic acid

Step a：(E) synthesis of -3- (the fluoro- 4- Fonnylphenyl of the chloro- 5- of 3-) methyl acrylate

In 100mL reaction flask, the fluoro- benzaldehyde of the chloro- 6- of the bromo- 2- of 4- (2.37g, 10mmol), methyl acrylate is added (1.72g, 20mmol), three (adjacent toluene) phosphines (0.33g, 1.0mmol), acid chloride (0.13g, 0.5mmol) and triethylamine (1.99g, 20mmol) is dissolved with 25mL DMF, and argon gas protects lower 80 DEG C of reactions 6h.After reaction.20mL ice water is added to stir It mixes, is extracted with ethyl acetate, saturated sodium-chloride washing is concentrated under reduced pressure after anhydrous sodium sulfate is dry, and column chromatographic purifying obtains titled Close object.ESI-Ms m/z:243.0[M+H]⁺。

Step b：(E) -3- (the fluoro- 4- of the chloro- 5- of 3- (and (5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6, 10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) acrylic acid synthesis

By the method for step f-g in embodiment 1, with step d gains N- (the fluoro- 2- methyl-propyl of 2-) -2- (1H- indoles - 3- yl) cyclopenta -1- amine, embodiment 2 step a gains (E) -3- (the fluoro- 4- Fonnylphenyl of the chloro- 5- of 3-) methyl acrylate be Title compound is made in raw material.¹H-NMR(400MHz,DMSO-d₆)δ:12.23(s,1H),10.38(s,1H),8.07(s, 1H),7.92-7.45(m,4H),7.01-6.92(m,2H),6.77-6.69(m,1H),5.41(s,1H),3.95-3.89(m, 1H),3.03-2.95(m,1H),2.18-1.93(m,1H),1.91-1.52(m,2H),1.65-1.49(m,1H),1.31-0.99 (m,10H).ESI-Ms m/z:485.2[M+H]⁺。

Embodiment 3 (E) -3- (the fluoro- 4- of 3- ((5R) -4- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6,10c- eight Hydrogen cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) -5- methoxyphenyl) acrylic acid

Preparation method is similar to the preparation method of embodiment 1, the difference is that by the fluoro- 1- benzaldehyde of bromo- 2, the 6- bis- of raw material 4- The fluoro- 6- methoxybenzaldehyde of the bromo- 2- of 4- is replaced with, title compound is made.

¹H-NMR(400MHz,DMSO-d₆)δ:12.24(s,1H),10.23(s,1H),7.55-7.47(m,2H),7.29- 7.14(m,2H),7.06-7.03(m,1H),6.96-6.91(m,2H),6.68-6.64(d,1H),5.35(s,1H),3.91(s, 3H),2.89(m,1H),2.32-2.29(m,1H),2.20-1.91(m,2H),1.60-1.55(m,2H),1.36-1.17(m, 4H),1.08-1.01(m,6H).ESI-Ms m/z:481.3[M+H]⁺。

Embodiment 4 (E) -3- (the fluoro- 4- of 3,5- bis- (the fluoro- 4- of (5R) -9- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5, 6,10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) phenyl) acrylic acid

Preparation method is similar to the preparation method of embodiment 1, the difference is that indoles, which is replaced with the fluoro- indoles of 5-, is made title Compound.

¹H-NMR(400MHz,DMSO-d₆)δ:12.50(s,1H),10.60(s,1H),7.22-7.0(m,5H),6.85- 6.80(dd,1H),6.50-6.45(d,1H),5.16(s,1H),3.94-3.35(m,1H),3.01-2.75(m,1H),2.39- 2.27(m,1H),2.35-2.27(m,1H),2.09-2.03(m,1H),1.82-1.75(m,1H),1.68-1.51(m,1H), 1.38-1.24(m,1H),1.13(s,2H),1.09-1.08(d,5H),1.01(s,1H).ESI-Ms m/z:487.2[M+H]⁺。

Embodiment 5 (E) -3- (the fluoro- 4- of 3- (the fluoro- 4- of (5R) -9- (the fluoro- 2- methyl-propyl of 2-) -1,2,3,3a, 4,5,6, 10c- octahydro cyclopentadiene [5,6] pyrido [3,4-b] indoles -5- base) -5- methoxyphenyl) acrylic acid

Preparation method is similar to the preparation method of embodiment 1, unlike indoles replaced with into the fluoro- indoles of 5- and by 4- The fluoro- 1- benzaldehyde of bromo- 2,6- bis- replaces with the fluoro- 6- methoxybenzaldehyde of the bromo- 2- of 4-, and title compound is made.

¹H-NMR(400MHz,DMSO-d₆)δ:12.48(s,1H),10.35(s,1H),7.59-7.55(d,1H),7.31 (s,1H),7.20-7.07(m,3H),6.82-6.80(m,1H),6.70-6.66(d,1H),5.35(s,1H),3.91(s,3H), 3.41-3.37(t,2H),2.89-2.86(t,1H),2.38-2.26(t,1H),2.07-2.01(m,1H),1.92-1.71(m, 2H),1.59-1.52(m,2H),1.41-1.21(m,1H),1.09-1.01(q,6H).ESI-Ms m/z:499.3[M+H]⁺。

ER level activity rating of 1 Compound ira vitro of experimental example based on cellular level

1. experimental material

Reagent：Phosphate buffer (DPBS), trypan blue, PolarScreen ER Alpha competitor Assay, Purchased from Invitrogen company；

Fetal calf serum (FBS), pancreatin, DMEM, Pen .- Strep (Pen/Strep) are purchased from GIBCO company；

Dimethyl sulfoxide (DMSO), active carbon, Formaldehyde solution are purchased from Sigma company；

MCF-7 cell is purchased from ATCC；

Estrogen Receptor α (D8H8) Rabbit mAb is purchased from CST company；

Goat anti-Rabbit IgG(H+L)Secondary Antibody(Alexa 488conjugate), it is purchased from Thermo company；

Tween 20 is purchased from EIA GRADE company.

Instrument：Biohazard Safety Equipment, CO₂Incubator is purchased from Thermo Scientific company；

Centrifuge is purchased from Eppendorf company；

Cell counter is purchased from Invitrogen company；

Inverted microscope is purchased from Olympus company；

Multiflow is purchased from BioTeck company；

Turbine mixer is purchased from IKA company；

Envision is purchased from Perkin Elmer company.

2. experimental method

2.1. the preparation of cell culture fluid and compound

The preparation of Charcoal-stripped FBS：It weighs 1g active carbon and is mixed with 4 DEG C of 50mL fetal calf serum and passed through afterwards for 24 hours 0.22 μM of membrane filtration degerming, it is spare；

Cell culture fluid is prepared：The Pen .- Strep of 50mL FBS, 5mL are added in the DMEM of 445mL, mixed It is spare.Charcoal-stripped FBS is used when cell culture fluid is prepared.

Compound prepares：After the compound of the present invention of above embodiments preparation is configured to 100mM with DMSO, successively dilute To 10nM, 3.33nM, 1.11nM, 0.37nM, 0.123nM, 0.041nM, 0.014nM, 0.0045nM, 0.0015nM, 0.0005nM。

2.2. inoculating cell

10mL DPBS is added in the cell reject culture solution of logarithmic growth phase in T75 Tissue Culture Flask to wash once.It adds 2mL trypsin digestion cell, 37 DEG C are placed 2 minutes, and microscopically observation most cells shape is rounded, and the cell training of 5mL is added Nutrient solution terminates digestion, and pipette is blown and beaten repeatedly, cell dissociation got off, cell suspension is made, then adds 10mL cell culture fluid, It is counted after mixing；It is diluted to 1500 cells/40 μ L cell suspension, is spread cell into 384 hole cells with Multiflow instrument Culture plate, 40 holes μ L/；Equilibrium at room temperature 20min is placed in 37 DEG C of cell incubators and cultivates for 24 hours.

Plus compound 2.3.

Compound is added in tissue culture plate with Acho instrument, DMSO final concentration 0.3%；Room temperature 1000rpm centrifugation 1min is placed in 37 DEG C of cell incubators and cultivates for 24 hours.

2.4. immunofluorescence experiment

Cell culture medium is sucked out, PBS is washed cell 1 time, with final concentration of 3.7% paraformaldehyde solution (PBS dilution) room The fixed cell 20min of temperature；PBS is washed cell 2 times, permeates 1h with final concentration of 0.5% Tween-20 (PBS dilution) room temperature；With PBS-T (in PBS containing 0.05% Tween-20) is washed cell 2 times, and Estrogen Receptor is added in ER level measurement α (D8H8) Rabbit mAb dilution (1:1000, diluted with the milk in PBS-T containing 1%), it is incubated at room temperature 1.5h；PBS-T It washes cell 3 times, Goat anti-Rabbit IgG (H+L) Secondary Antibody dilution (1 is added:1000, use PBS In diluted containing 1% milk) Hochest 33342 of 2 μ g/mL, be incubated at room temperature 40min；PBS-T is washed cell 3 times, and PBS is washed Cell 2 times；The ratio of Acumen reading ER positive signal value and nuclear signal value.

Table 1

It can be seen that the compound of the present invention had had the ER level based on cellular level from the above experimental result Inhibitory activity promises to be the higher cancer therapeutic agent of curative effect very much.

The evaluation of 2 Compound ira vitro cell activity of experimental example

1. experimental material

Test-compound：The compound of the present invention of above embodiments preparation, each compound are configured to 10mM with DMSO, Then successively 3 times be diluted to 100.00nM, 33.33nM, 11.11nM, 3.70nM, 1.23nM, 0.41nM, 0.14nM, 0.045nM、0.015nM。

Breast cancer cell line mcf-7 is purchased from company of Nanjing Keygen Biotech.

Reagent：MEM, FBS, Trypsin-EDTA, Penicillin-Streptomycin, it is public purchased from U.S. GIBCO Department；Luminescent Cell Viability Assay Kit is purchased from U.S. Progema company； Paclitaxel is purchased from Sichuan Tai Chi drugmaker.

2. experimental method

2.1. cell inoculation

The MCF-7 for cultivating amplification is cells trypsinised, is resuspended and is counted using fresh culture.By the thin of resuspension Born of the same parents adjust to 2 × 10⁴A cell/mL, and 96 porocyte culture plates are added, 100 μ L, each two multiple holes of concentration are added in every hole.In 37 DEG C, 5%CO₂Under the conditions of be incubated for for 24 hours.

Plus compound 2.2.

Compound is configured to 200 × working solution with DMSO, is diluted to 2 × working solution with culture solution, retransfers 100 μ L in fact It verifies, in 37 DEG C, 5%CO₂Under the conditions of be incubated for 96h.

2.3. fluorescence reading

50 μ L are added to gaging hole Luminescent Cell Viability Assay Buffer, and gently shake up.After ten minutes, it is placed on Envison and reads fluorescence reading, and calculate cell survival rate (cell Survive (%)), calculation formula is cell survive (%)=(Com-Min)/(Max-Min), and wherein Max is blank pair According to the reading of group, Min is the reading of cell-free control group, and Com is the reading of compound processing group, and data are handled through XLfit, is intended Close to obtain IC₅₀, experimental result is shown in Table 2.

Table 2

From the above experiment as can be seen that the compound of the present invention shows good suppression to MCF-7 breast cancer cell System activity, promises to be breast cancer treatment agent very much.

Pharmacokinetic Evaluation in 3 compound body of experimental example

Test-compound：The compound of the present invention of above embodiments preparation, each compound solvent (2% Solutol, 98% physiological saline) it is formulated as oral test sample 2mg/kg, intravenous test sample 1mg/kg.

Balb/c mouse ties up experimental animal Co., Ltd of tonneau China purchased from Beijing.

Mouse oral is with 2mg/kg, after intravenous is with 1mg/kg single-dose, respectively at 2min, 5min, 15min, 30min, 1h, 2h, 6h, 10h take a blood sample from orbital venous plexus for 24 hours, after centrifuging and taking plasma treatment, are detected, will be measured using LC-MS/MS The blood concentration at each time point be depicted as pharmaceutical concentration-time curve, and calculate pharmacokinetic parameter.Experimental result is shown in Table 3。

Table 3

Test-compound	T_1/2(h)	C_max(ng/mL)	AUC(h*ng/mL)	F (%)
					Embodiment 1	0.9	143.2	187.6	45.6
Embodiment 2	2.5	288.8	142.5	68.9
					Embodiment 3	2.6	211.0	685.4	48.7
Embodiment 4	4.3	267.8	2022.2	100.1
					Embodiment 5	3.2	321.0	1573.5	72.4

The experimental results showed that, the compound of the present invention has good exposed amount, oral bio benefit in Mice Body above Expenditure is high, can be used for being administered orally.

Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair The present invention can be carry out various modifications and be changed under the premise of bright spirit and scope.Interest field of the invention is not limited to Detailed description made by above, and claims should be belonged to.

Claims

1. a kind of general formula I compound represented or its isomers, pharmaceutically acceptable salt, solvate, crystallization or prodrug,

Wherein,

X¹、X²、X⁴, each X³Separately it is selected from C (R¹R²)、N(R³), O, S, sulfone and sulfoxide, wherein R¹、R²Separately select From hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, Cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos, Alkenyl, alkynyl, naphthenic base, heterocycle, heteroaryl and aryl；Or R¹、R²Carbon atom connected to it is formed together carbonyl；R³Choosing From hydrogen, alkyl acyl, aminoacyl, alkylaminoacyl, alkyl, halogenated alkyl, hydroxy alkyl, alkenyl, alkynyl, naphthenic base, Heterocycle, heteroaryl and aryl, the group can by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, Alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double alkyl aminos, cycloalkanes Base, heterocycle, aryl and heteroaryl replace；

R⁴Selected from hydrogen, alkyl acyl, aminoacyl, alkylaminoacyl, alkyl, halogenated alkyl, hydroxy alkyl, alkenyl, alkynyl, Naphthenic base, heterocycle, heteroaryl and aryl, the group can be by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxyls Base alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double alkyl ammonia Base, naphthenic base, heterocycle, aryl and heteroaryl replace；

R⁵Selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitre Base, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkane Base amino, alkenyl, alkynyl and naphthenic base；

Each R⁶, each R⁷Separately it is selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, haloalkoxy Base, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, Alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base and boric acid；

Y is selected from alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl, heteroarylalkoxy, alkyl amino, ring It is alkalkylamino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkyl amino, naphthenic base, heterocycle, aryl, miscellaneous Aryl, alkenyl and alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl, heteroarylalkoxy Base, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, heteroaryl alkyl amino, naphthenic base, Heterocycle, aryl, heteroaryl, alkenyl and alkynyl can be by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxyl alkane Base, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, Alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos, alkenyl, alkynyl, naphthenic base, heterocycle and oxo group take Generation；With

M, n, o are each independently 1,2,3 or 4.

2. compound according to claim 1 or its isomers, pharmaceutically acceptable salt, solvate, crystallization or preceding Medicine, wherein X¹、X², each X³It is C (R¹R²), X⁴For N (R³), O, S, sulfone or sulfoxide.

3. compound according to claim 1 or its isomers, pharmaceutically acceptable salt, solvate, crystallization or preceding Medicine, wherein R¹、R²Separately it is selected from hydrogen, halogen, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alcoxyl Base, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl amino, C_1-6Alkyl acyl Amino, C_1-6Alkyl acyl, aminoacyl, C_1-6Alkylaminoacyl, double C_1-6Alkyl amino, C_2-10Alkenyl, C_2-10Alkynyl, C_3-10 Naphthenic base, C_1-10Heterocycle, C_6-18Aryl and C_1-18Heteroaryl；Or R¹、R²Carbon atom connected to it is formed together carbonyl；R³Choosing From hydrogen, C_1-10Alkyl acyl, aminoacyl, C_1-10Alkylaminoacyl, C_1-10Alkyl, halogenated C_1-10Alkyl, hydroxyl C_1-10Alkyl, C_2-10Alkenyl, C_2-10Alkynyl, C_3-10Naphthenic base, C_1-10Heterocycle, C_6-18Aryl and C_1-18Heteroaryl, the group can be by one Or multiple halogens, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxylic Base, cyano, amino, alkyl monosubstituted amino, double alkyl aminos, naphthenic base, heterocycle, aryl and heteroaryl replace.

4. -3 described in any item compounds or its isomers, pharmaceutically acceptable salt, solvation according to claim 1 Object, crystallization or prodrug, wherein R⁴Selected from hydrogen, C_1-10Alkyl acyl, aminoacyl, C_1-10Alkylaminoacyl, C_1-10Alkyl, halogen For C_1-10Alkyl, hydroxyl C_1-10Alkyl, C_2-10Alkenyl, C_2-10Alkynyl, C_3-10Naphthenic base, C_1-10Heterocycle, C_6-18Aryl and C_1-18It is miscellaneous Aryl, the group can be by one or more halogens, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, haloalkoxies Base, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, double alkyl aminos, naphthenic base, heterocycle, aryl and Heteroaryl replaces；R⁵Selected from hydrogen, halogen, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6It is alkoxy, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl amino, C_1-6Alkyl acylamino, C_1-6 Alkyl acyl, aminoacyl, C_1-6Alkylaminoacyl, double C_1-6Alkyl amino, C_2-10Alkenyl, C_2-10Alkynyl and C_3-10Naphthenic base.

5. -4 described in any item compounds or its isomers, pharmaceutically acceptable salt, solvation according to claim 1 Object, crystallization or prodrug, wherein each R⁶, each R⁷Separately it is selected from hydrogen, halogen, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl ammonia Base, C_1-6Alkyl acylamino, C_1-6Alkyl acyl, aminoacyl, C_1-6Alkylaminoacyl, double C_1-6Alkyl amino, C_2-10Alkene Base, C_2-10Alkynyl, C_3-10Naphthenic base and boric acid.

6. -5 described in any item compounds or its isomers, pharmaceutically acceptable salt, solvation according to claim 1 Object, crystallization or prodrug, wherein Y is selected from C_1-6Alkoxy, C_3-10Naphthenic base C_1-6Alkoxy, C_1-10Heterocycle C_1-6Alkoxy, C_6-18 Aryl C_1-6Alkoxy, C_1-18Heteroaryl C_1-6Alkoxy, C_1-6Alkyl amino, C_3-10Naphthenic base C_1-6Alkyl amino, C_1-10Heterocycle C_1-6Alkyl amino, C_6-18Aryl C_1-6Alkyl amino, C_1-18Heteroaryl C_1-6Alkyl amino, C_3-10Naphthenic base, C_1-10Heterocycle, C_6-18Aryl, C_1-18Heteroaryl, C_2-10Alkenyl and C_2-10Alkynyl, the alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, Alkoxy aryl, heteroarylalkoxy, alkyl amino, cycloalkyl alkyl amino, heterocyclylalkylamino, aryl-alkyl amino, Heteroaryl alkyl amino, naphthenic base, heterocycle, aryl, heteroaryl, alkenyl and alkynyl can by one or more halogens, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxylic Base, cyano, amino, list C_1-6Alkyl amino, C_1-6Alkyl acylamino, C_1-6Alkyl acyl, aminoacyl, C_1-6Alkyl amino acyl Base, double C_1-6Alkyl amino, C_2-10Alkenyl, C_2-10Alkynyl, C_1-10Heterocycle, C_3-10Naphthenic base and carbonyl replace.

7. -6 described in any item compounds or its isomers, pharmaceutically acceptable salt, solvation according to claim 1 Object, crystallization or prodrug, formula of I have the structure of following general formula Ia,

Wherein R⁴, each R⁶, each R⁷, m, n such as -6 formula of I according to claim 1 define.

8. compound according to claim 1 or its isomers, pharmaceutically acceptable salt, solvate, crystallization or preceding Medicine, wherein the compound is compound selected from the following：

9. a kind of pharmaceutical composition, it includes described in any item compounds of claim 1 to 8 or its isomers, pharmaceutically Acceptable salt, solvate, crystallization or prodrug and pharmaceutical acceptable carrier.

10. the described in any item compounds or its isomers, pharmaceutically acceptable salt, solvate, knot of claim 1-8 Brilliant or prodrug or pharmaceutical composition as claimed in claim 9 are being prepared for treating and/or preventing the relevant disease of estrogen receptor Application in the drug of disease.