CN108329311A - The tricyclic compounds alternatively adjusted under property estrogen receptor and its application - Google Patents

Abstract

The invention belongs to medicinal chemistry arts, it is related to the tricyclic compounds of conditioning agent 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 the purposes of pharmaceutical composition and these compound or compositions for treating and/or preventing the relevant disease of estrogen receptor containing these compounds.The compound of the present invention has more excellent antitumor activity, and dosing interval is longer, less side effects, promises to be very much breast cancer treatment agent.

Description

The tricyclic compounds alternatively adjusted under property estrogen receptor and its application

Technical field

The invention belongs to medicinal chemistry arts, and in particular to be adjusted (SERD) under a kind of alternatively property estrogen receptor 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 technology

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 tools：ER- α and ER- β, respectively by positioned at No. 6 of people and two different bases of No. 14 chromosome Because of coding, ER- α are limited only to the tissues such as female reproductive system and brain, bone in various tissue wide expressions, the expression of ER- β. 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 It is acted on other transcription factors to activate the transcription of target gene, in addition there are many places phosphorylation sites.The DNA being made of the domains 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 domains D are hinge area, are responsible for connection DBD and aglucon binding domain (LBD).The domains 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 of 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 combined with agonist, this conformation of H12 becomes more stable, and is suitable for association The combination of activity factor, the then transcription of activation target gene.And when ER is combined 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 being adjusted under selective estrogen receptor with 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 better efficacy, 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.

Invention content

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

Wherein,

R¹、R²Separately be selected from 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 Aminoacyl, double alkyl aminos and naphthenic base；

R³Selected from alkyl, alkyl acyl, aminoacyl, alkylaminoacyl, halogenated alkyl, hydroxy alkyl, alkenyl, cycloalkanes Base, heterocycle, aryl and heteroaryl；

R⁴、R⁵Separately it is selected from hydrogen, alkyl, alkoxy, halogen, halogenated alkyl and hydroxy alkyl；Or R⁴、R⁵With it The carbon atom that is connected form carbonyl or naphthenic base together；

R⁶、R⁷Separately it is selected from hydrogen, alkyl, alkoxy, halogen, halogenated alkyl and hydroxy alkyl；Or R⁶、R⁷With it The carbon atom that is connected form carbonyl or naphthenic base together；Or

R⁴、R⁶Carbon atom connected to them forms naphthenic base together；

Each R⁸Separately 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, naphthenic base and boric acid；

Y is selected fromWherein R⁹Selected from carboxyl, cyano, alkyl, halogenated alkyl and hydroxyl Base alkyl, R¹⁰Selected from hydrogen and halogen, R¹¹Selected from hydroxyl, amino, alkoxy and alkyl amino, ring A be selected from naphthenic base, heterocycle, Aryl and heteroaryl, the naphthenic base, heterocycle, aryl and heteroaryl can be by one or more hydrogen, halogen, hydroxyl, alkane Base, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, monoalkyl Amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos and naphthenic base substitution, R¹²Choosing 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 and Naphthenic base, n 1,2 or 3, or when n is 2, two R¹²Group carbon atom connected to them forms carbonyl, cycloalkanes together Base, heterocycle, aryl, heteroaryl, the naphthenic base, heterocycle, aryl and heteroaryl can be by one or more hydrogen, halogen Element, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, ammonia Base, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos and naphthenic base Substitution, L¹Selected from key ,-NHCO- ,-CONH- ,-NHCONH- ,-NH-, alkylidene, O, S, halogeno alkylen, hydroxy alkylidene, Asia Alkoxy, halo alkyleneoxy, hydroxyl alkylene oxide group, carbonyl and alkylidene amino；

Chemical bondIt is each independentlyOr

M is 1,2,3 or 4；

Condition is when Y isAnd R¹、R²All it is fluorine, R¹⁰For hydrogen when, R³It is selected fromAlkenyl and aryl, wherein R¹³Selected from halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxylic Base, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl ammonia Base and naphthenic base.

It is a further object to provide the compounds of formula I for preparing the present invention or its isomers, 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 the compounds of formula I comprising the present 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.

The present invention's a further object is the compounds of formula I for providing the present invention or its isomers, pharmaceutically acceptable Salt, solvate, crystallization, isostere or prodrug treatment and/or prevent the relevant disease of estrogen receptor method, with And the present invention compounds of formula I or its isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or Application of the prodrug in preparing 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 compounds represented or its isomers, pharmaceutically acceptable salt, solvent Compound, crystallization, isostere or prodrug,

Wherein,

R¹、R²Separately be selected from 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 Aminoacyl, double alkyl aminos and naphthenic base；

R³Selected from alkyl, alkyl acyl, aminoacyl, alkylaminoacyl, halogenated alkyl, hydroxy alkyl, alkenyl, cycloalkanes Base, heterocycle, aryl and heteroaryl；

R⁴、R⁵Separately it is selected from hydrogen, alkyl, alkoxy, halogen, halogenated alkyl and hydroxy alkyl；Or R⁴、R⁵With it The carbon atom that is connected form carbonyl or naphthenic base together；

R⁶、R⁷Separately it is selected from hydrogen, alkyl, alkoxy, halogen, halogenated alkyl and hydroxy alkyl；Or R⁶、R⁷With it The carbon atom that is connected form carbonyl or naphthenic base together；Or

R⁴、R⁶Carbon atom connected to them forms naphthenic base together；

Each R⁸Separately 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, naphthenic base and boric acid；

Y is selected fromWherein R⁹Selected from carboxyl, cyano, alkyl, halogenated alkyl and hydroxyl Base alkyl, R¹⁰Selected from hydrogen and halogen, R¹¹Selected from hydroxyl, amino, alkoxy and alkyl amino, ring A be selected from naphthenic base, heterocycle, Aryl and heteroaryl, the naphthenic base, heterocycle, aryl and heteroaryl can be by one or more hydrogen, halogen, hydroxyl, alkane Base, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, monoalkyl Amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos and naphthenic base substitution, R¹²Choosing 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 and Naphthenic base, n 1,2 or 3, or when n is 2, two R¹²Group carbon atom connected to them forms carbonyl, cycloalkanes together Base, heterocycle, aryl, heteroaryl, the naphthenic base, heterocycle, aryl and heteroaryl can be by one or more hydrogen, halogen Element, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, ammonia Base, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos and naphthenic base Substitution, L¹Selected from key ,-NHCO- ,-CONH- ,-NHCONH- ,-NH-, alkylidene, O, S, halogeno alkylen, hydroxy alkylidene, Asia Alkoxy, halo alkyleneoxy, hydroxyl alkylene oxide group, carbonyl and alkylidene amino；

Chemical bondIt is each independentlyOr

M is 1,2,3 or 4；

Condition is when Y isAnd R¹、R²All it is fluorine, R¹⁰For hydrogen when, R³It is selected fromAlkenyl and aryl, wherein R¹³Selected from halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxylic Base, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl ammonia Base and naphthenic base.

In some specific embodiments, the compound of the present invention is general formula IaChange Close object or its isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug.

In some specific embodiments, the compound of the present invention is general formula IbChemical combination Object or its isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug.

In some specific embodiments, the compound of the present invention is general formula Ic Compound or its isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug.

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 fluorine, chlorine, bromine, iodine, 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 and C_3-10Naphthenic base；

It is further preferred that R¹、R²Separately it is selected from fluorine, chlorine, bromine, iodine, 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 and C_3-6Naphthenic base；

It is further preferred that R¹、R²Separately it is selected from fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl It is base, trifluoromethyl, trifluoroethyl, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyls, methoxyl group, ethyoxyl, propoxyl group, different Propoxyl group, nitro, carboxyl, cyano, amino, methylamino, ethylamino, propylcarbamic, isopropylamino, dimethylamino, diethyl Amino, methylethylamine, dipropyl amino, methylpropylamino, ethylpropylamino, methylacyl amino, ethyl acyl group ammonia Base, vinyl acyl amino, methylacyl, ethyl acyl group, vinyl acyl group, aminoacyl, methylamino acyl group, ethylamino Acyl group, cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.

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 C_1-10Alkyl, C_1-10Alkyl acyl, aminoacyl, C_1-10Alkylaminoacyl, halogenated C_1-10Alkyl, hydroxyl C_1-10Alkyl, C_2-10Alkenyl, C_3-10Naphthenic base, C_3-10Heterocycle, C_6-18Aryl and C_5-18Heteroaryl, 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 and the naphthenic base substitution optionally replaced；

It is further preferred that R³Selected from C_1-6Alkyl, C_1-6Alkyl acyl, aminoacyl, C_1-6It is alkylaminoacyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_2-6Alkenyl, C_3-8Naphthenic base, C_3-8Heterocycle, C_6-12Aryl and C_5-12Heteroaryl, the group It can be by one or more halogens, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkane Oxygroup, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl amino, double C_1-6Alkyl amino and optionally substitution C_3-8Naphthenic base replaces；

It is further preferred that R³Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, amyl, isopentyl, new Amyl, hexyl, formoxyl, acetyl group, propiono, aminoacyl, methylamino acyl group, ethylamino acyl group, propylcarbamic acyl Base, trifluoromethyl, trifluoroethyl, bis- fluoropropyls of 2,2-, the fluoro- 2- methyl-propyls of 2-, the fluoro- 2- methyl-propyls of (S) -3-, methylol, Ethoxy, hydroxypropyl, 2- hydroxypropyls, vinyl, acrylic, cyclobutenyl, 3- methyl-2-butenes base, cyclopropyl, cyclobutyl, Cyclopenta, azelidinyl, azepine cyclopenta, phenyl and naphthalene, the group can be by one or more halogens, hydroxyl, C_1-3 Alkyl, 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 amino, double C_1-3Alkyl amino replaces.

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：

R⁴、R⁵Separately it is selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxy, halogen, halogenated C_1-6Alkyl and hydroxyl C_1-6Alkyl；

It is further preferred that R⁴、R⁵Separately it is selected from hydrogen, C_1-3Alkyl, C_1-3Alkoxy, halogen, halogenated C_1-3Alkyl With hydroxyl C_1-6Alkyl；

It is further preferred that R⁴、R⁵Separately it is selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, three Fluoro ethyl, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyls, methoxyl group, ethyoxyl, propoxyl group, isopropoxy and halogen.

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：

R⁴、R⁵Carbon atom connected to them forms carbonyl or C together_3-10Naphthenic base；

It is further preferred that R⁴、R⁵Carbon atom connected to them forms carbonyl, C together_3-6Naphthenic base；

It is further preferred that R⁴、R⁵Carbon atom connected to them forms carbonyl, cyclopropyl, cyclobutyl, ring together Amyl and cyclohexyl.

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：

R⁶、R⁷Separately it is selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxy, halogen, halogenated C_1-6Alkyl and hydroxyl C_1-6Alkyl；

It is further preferred that R⁶、R⁷Separately it is selected from hydrogen, C_1-3Alkyl, C_1-3Alkoxy, halogen, halogenated C_1-3Alkyl With hydroxyl C_1-6Alkyl；

It is further preferred that R⁶、R⁷Separately it is selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, three Fluoro ethyl, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyls, methoxyl group, ethyoxyl, propoxyl group, isopropoxy and halogen.

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：

R⁶、R⁷Carbon atom connected to them forms carbonyl, C together_3-10Naphthenic base；

It is further preferred that R⁶、R⁷Carbon atom connected to them forms carbonyl, C together_3-6Naphthenic base；

It is further preferred that R⁶、R⁷Carbon atom connected to them forms carbonyl, cyclopropyl, cyclobutyl, ring together Amyl and cyclohexyl.

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：

R⁴、R⁶Carbon atom connected to them forms C together_3-10Naphthenic base；

It is further preferred that R⁴、R⁶Carbon atom connected to them forms C together_3-6Naphthenic base；

It is further preferred that R⁴、R⁶Carbon atom connected to them formed together cyclopropyl, cyclobutyl, cyclopenta and Cyclohexyl.

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：

Each R⁸Separately 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_3-10Naphthenic base and boric acid；

It is further preferred that each R⁸Separately 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_3-6Cycloalkanes Base and boric acid；

It is further preferred that each R⁸Separately be selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, Isopropyl, trifluoromethyl, trifluoroethyl, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyls, 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, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and boric acid.

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：

R⁹Selected from carboxyl, cyano, C_1-6Alkyl, halogenated C_1-6Alkyl and hydroxyl C_1-6Alkyl；

It is further preferred that R⁹Selected from carboxyl, cyano, C_1-3Alkyl, halogenated C_1-3Alkyl and hydroxyl C_1-3Alkyl；

It is further preferred that R⁹Selected from carboxyl, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoro second Base, methylol, ethoxy, hydroxypropyl and 2- hydroxypropyls.

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：

R¹¹Selected from hydroxyl, amino, C_1-6Alkoxy and C_1-6Alkyl amino；

It is further preferred that R¹¹Selected from hydroxyl, amino, C_1-3Alkoxy and C_1-3Alkyl amino；

It is further preferred that R¹¹Selected from hydroxyl, amino, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, methyl ammonia Base, ethylamino, propylcarbamic and isopropylamino.

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：

R¹²Selected 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 and C_3-10Naphthenic base；

It is further preferred that R¹²Selected 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 and C_3-6Naphthenic base；

It is further preferred that R¹²Selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, fluoroform Base, trifluoroethyl, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyls, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, nitre Base, carboxyl, cyano, amino, methylamino, ethylamino, propylcarbamic, isopropylamino, dimethylamino, lignocaine, methyl Ethylamino, dipropyl amino, methylpropylamino, ethylpropylamino, methylacyl amino, ethyl acyl amino, vinyl Acyl amino, methylacyl, ethyl acyl group, vinyl acyl group, aminoacyl, methylamino acyl group, ethylamino acyl group, ring third Base, cyclobutyl, cyclopenta and cyclohexyl.

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：

When n is 2, two R¹²Carbon atom connected to them forms carbonyl, C together_3-10Naphthenic base, C_3-10Heterocycle Base, C_6-18Aryl and C_5-18Heteroaryl, the naphthenic base, heterocycle, aryl and heteroaryl 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, nitre Base, carboxyl, cyano, amino, list C_1-6Alkyl amino, double C_1-6Alkyl amino and C_3-10Naphthenic base replaces；

It is further preferred that when n is 2, two R¹²Carbon atom connected to them forms carbonyl, C together_3-6Cycloalkanes Base, C_3-6Heterocycle, C_6-12Aryl and C_5-12Heteroaryl, the naphthenic base, heterocycle, aryl and heteroaryl can by one or Multiple halogens, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, hydroxyl C_1-6 Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl amino, double C_1-6Alkyl amino and C_3-10Naphthenic base replaces；

It is further preferred that when n is 2, two R¹²Carbon atom connected to them forms carbonyl, C together_3-6Ring Alkyl, C_3-6Heterocycle, C_6-12Aryl and C_5-12Heteroaryl, the naphthenic base, heterocycle, aryl and heteroaryl can be by one Or multiple 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, carboxyl, cyano, amino, list C_1-3Alkyl amino, double C_1-3Alkyl amino and C_3-6Naphthenic base replaces.

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：

R¹³Selected from halogen, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alcoxyl Base, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl amino, C_1-6Alkyl acylamino, C_1-6Alkyl acyl Base, aminoacyl, C_1-6Alkylaminoacyl, double C_1-6Alkyl amino and C_3-10Naphthenic base；

It is further preferred that R¹³Selected from halogen, hydroxyl, C_1-3Alkyl, halogenated C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alcoxyl Base, halogenated C_1-3Alkoxy, hydroxyl C_1-3Alkoxy, nitro, carboxyl, cyano, amino, list C_1-3Alkyl amino, C_1-3Alkyl acyl Amino, C_1-3Alkyl acyl, aminoacyl, C_1-3Alkylaminoacyl, double C_1-3Alkyl amino and C_3-6Naphthenic base；

It is further preferred that R¹³Selected from fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl, trifluoromethyl, Trifluoroethyl, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyls, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, nitro, Carboxyl, cyano, amino, methylamino, ethylamino, propylcarbamic, isopropylamino, dimethylamino, lignocaine, Methylethyl Amino, dipropyl amino, methylpropylamino, ethylpropylamino, methylacyl amino, ethyl acyl amino, vinyl acyl group Amino, methylacyl, ethyl acyl group, vinyl acyl group, aminoacyl, methylamino acyl group, ethylamino acyl group, cyclopropyl, Cyclobutyl, cyclopenta and cyclohexyl.

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：

L¹Selected from key ,-NHCO- ,-CONH- ,-NHCONH- ,-NH-, Asia C_1-6Alkyl, O, S, halogenated Asia C_1-6Alkyl, hydroxyl Sub- C_1-6Alkyl, Asia C_1-6Alkoxy, halogenated Asia C_1-6Alkoxy, hydroxyl Asia C_1-6Alkoxy, carbonyl and Asia C_1-6Alkyl amino；

It is further preferred that L¹Selected from key ,-NHCO- ,-CONH- ,-NHCONH- ,-NH-, Asia C_1-3It is alkyl, O, S, halogenated Sub- C_1-3Alkyl, hydroxyl Asia C_1-3Alkyl, Asia C_1-3Alkoxy, halogenated Asia C_1-3Alkoxy, hydroxyl Asia C_1-3Alkoxy, carbonyl and Asia C_1-3Alkyl amino；

It is further preferred that L¹Selected from key ,-NHCO- ,-CONH- ,-NHCONH- ,-NH-, methylene, ethylidene, Asia Propyl, isopropylidene, O, S, halogenated methylene, halogenated ethylidene, halogenated propylidene, halogenated isopropylidene, hydroxy methylene, hydroxyl Base ethylidene, hydroxy propylidene, hydroxyl isopropylidene, hydroxy alkylidene, methylene oxygroup, inferior ethoxyl, sub- propoxyl group, sub- isopropyl Oxygroup, halogenated methylene oxygroup, halogenated inferior ethoxyl, halogenated sub- propoxyl group, halogenated sub- isopropoxy, hydroxyl-methylene oxygroup, hydroxyl Inferior ethoxyl, hydroxyl Asia propoxyl group, hydroxyl Asia isopropoxy, carbonyl, methene amido, ethyleneimino, propylidene amino and Isopropylideneamino.

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：

Ring A is selected from C_3-10Naphthenic base, C_3-10Heterocycle, C_6-18Aryl and C_5-18Heteroaryl, the naphthenic base, heterocycle, Aryl and heteroaryl can be by one or more halogens, 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, double C_1-6Alkyl ammonia Base and C_3-10Naphthenic base replaces；

It is further preferred that ring A is selected from C_3-6Naphthenic base, C_3-6Heterocycle, C_6-12Aryl and C_5-12Heteroaryl, the ring Alkyl, heterocycle, aryl and heteroaryl can be by one or more halogens, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6 Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl amino, Double C_1-6Alkyl amino and C_3-10Naphthenic base replaces；

It is further preferred that ring A be selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclopropanyl, cyclobutane base, Cyclopentenyl, cyclohexenyl group, aziridine base, azetidinyl, nafoxidine base, pyrrole radicals, piperidyl, pyrrolin Base, tetrahydro pyridyl, pyridyl group, propylene oxide base, tetrahydrofuran base, THP trtrahydropyranyl, dihydrofuryl, furyl, dihydro Pyranose, pyranose, thiirane base, vulcanization cyclobutane base, tetrahydro-thienyl, thienyl, vulcanization pentamethylene base, dihydro-thiophene Base, pyrazolidinyl, pyrazoline base, pyrazolyl, imidazolidinyl, glyoxalidine base, imidazole radicals, pyrazoline Ji, oxazolidine radicals, Dihydro-oxazole base, imidazole radicals, thiazolidinyl, dihydro-thiazolyl, thiazolyl, isoxazole alkyls, dihydro-isoxazole base, isoxazoles Base, isothiazole alkyl, dihydro isothiazolyl, isothiazolyl, hexahydropyrimidine base, tetrahydro-pyrimidine base, dihydro-pyrimidin base, pyrimidine radicals, Hexahydro-pyridazine base, tetrahydro pyridazine base, dihydrogen dazin base, pyridazinyl, piperazinyl, tetrahydrochysene pyrazinyl, dihydro pyrazine base, pyrazinyl, Morpholinyl, thio-morpholinyl, dioxane base, two sulphur, six ring group, ox sulfophenyl, bicyclic [2.2.1] heptane base, azaspiro [2.3] bicyclic [3.1.0] hexyl of hexyl, oxo, phenyl, naphthalene, anthryl, tetralyl, fluorenyl and indanyl, it is described Group optionally can be 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, carboxyl, cyano, amino, list C_1-3Alkyl amino, double C_1-3Alkyl amino and C_3-6Naphthenic base replaces.

In some specific embodiments, the compound of general formula Ia according to the present invention or its isomers pharmaceutically may be used Salt, solvate, crystallization, isostere or the prodrug of receiving, wherein R¹Selected from chlorine, methyl, ethyl, propyl, methoxyl group, second Oxygroup, propoxyl group, fluoro-methoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy and five fluorine Ethyoxyl, R²Selected from fluorine, chlorine, methyl, ethyl, propyl, methoxyl group, ethyoxyl, propoxyl group, fluoro-methoxy, difluoromethoxy, Trifluoromethoxy, fluoroethoxy, difluoroethoxy and five fluorine ethyoxyls, R³It is selected from R⁴For methyl, R⁵、R⁶、R⁷For H, R⁹For carboxyl, R¹⁰For H or fluorine.

In some specific embodiments, the compound of general formula Ib according to the present invention, wherein R¹、R²Each independently Selected from fluorine, chlorine, methyl, ethyl, propyl, methoxyl group, ethyoxyl, propoxyl group, fluoro-methoxy, difluoromethoxy, fluoroform Oxygroup, fluoroethoxy, difluoroethoxy and five fluorine ethyoxyls, R³It is selected fromR⁴For first Base, R⁵、R⁶、R⁷For H, R⁸Selected from hydrogen, methyl, ethyl, fluorine and chlorine, m 1, ring A are selected from cyclopropyl, cyclobutyl, cyclopenta, hexamethylene Base, cyclopropanyl, cyclobutane base, cyclopentenyl, cyclohexenyl group, aziridine base, azetidinyl, nafoxidine base, Pyrrole radicals, piperidyl, pyrrolin base, tetrahydro pyridyl, pyridyl group, propylene oxide base, tetrahydrofuran base, THP trtrahydropyranyl, Dihydrofuryl, furyl, dihydro pyranyl, pyranose, thiirane base, vulcanization cyclobutane base, tetrahydro-thienyl, thiophene Base, vulcanization pentamethylene base, dihydrothiophene, pyrazolidinyl, pyrazoline base, pyrazolyl, imidazolidinyl, glyoxalidine base, miaow Oxazolyl, pyrazoline Ji, oxazolidine radicals, dihydro-oxazole base, imidazole radicals, thiazolidinyl, dihydro-thiazolyl, thiazolyl, isoxazoles Alkyl, dihydro-isoxazole base, isoxazolyl, isothiazole alkyl, dihydro isothiazolyl, isothiazolyl, hexahydropyrimidine base, tetrahydrochysene are phonetic Piperidinyl, dihydro-pyrimidin base, pyrimidine radicals, hexahydro-pyridazine base, tetrahydro pyridazine base, dihydrogen dazin base, pyridazinyl, piperazinyl, tetrahydrochysene pyrrole It is piperazine base, dihydro pyrazine base, pyrazinyl, morpholinyl, thio-morpholinyl, dioxane base, two sulphur, six ring group, ox sulfophenyl, bicyclic [2.2.1] heptane base, azaspiro [2.3] hexyl, bicyclic [3.1.0] hexyl of oxo, phenyl, naphthalene, anthryl, naphthane Base, fluorenyl and indanyl, the group optionally can be 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, carboxyl, cyano, amino, list C_1-3Alkane Base amino, double C_1-3Alkyl amino and C_3-6Naphthenic base replaces, R¹¹For hydroxyl.

The present invention provides compound in detail below：

Or its isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug.

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

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

Or

Compounds of formula I can be known in the art to be used as by the b) compound of the compound of formula 1 and formula 3 and is applicable in The chemical combination of the formula of being made 4 is reacted in the presence of condition (such as in acid) that Pickett-Shi Penggele (Pictet-Spengler) reacts Object, the compound of formula 4 is reacted with suitable group to be directly made or compounds of formula I is made using other popular responses,

Wherein the compound of formula 1 can pass through formula 5Compound and formula 6Compound it is anti- It should be made,

The compound of formula 6 can pass through formula 7Compound and trifluoromethanesulfonic acid anhydride reactant be made,

The compound of formula 2, the compound of formula 3, the compound of the compound of formula 5 or formula 7 can be commercially available or Customary preparation methods as known in the art are made,

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸, m, Y as defined in formula above I, X is halogen.

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 include 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 inhibitors, 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 prevent the relevant disease of 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 are prepared by mixing into pharmaceutical preparation with pharmaceutically acceptable carrier, diluent or excipient, 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 compounds represented of the present invention or its isomers, pharmaceutically acceptable Salt, solvate, crystallization, isostere or prodrug, or preparing treatment comprising its pharmaceutical composition and/or preventing female sharp Purposes in the drug of the plain relevant disease of receptor, wherein the relevant disease of estrogen receptor or symptom includes but unlimited In：With the relevant cancer of ER- α dysfunctions (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, hepatic sclerosis 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 compounds represented or its Isomers, pharmaceutically acceptable salt, solvate, crystallization, isostere or prodrug, or include its pharmaceutical composition, Wherein the relevant disease of estrogen receptor includes but not limited to：With the relevant cancer of ER dysfunctions (such as osteocarcinoma, breast 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, angiocardiopathy, coronary artery disease, hypertension etc.), hematological deficiencies (example Such as Deep vain thrombosis), immune and inflammation disease (such as Graves disease, arthritis, multiple sclerosis, hepatic sclerosis 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 antitumor 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 ", " oxygen " in the compounds of this invention include its all isotope.Isotope, which is understood to include, to be had Same atoms number but with those of different quality number atom.For example, the isotope of hydrogen includes tritium and deuterium, the isotope of carbon Including¹³C and¹⁴The isotope of C, oxygen includes¹⁶O and¹⁸O etc..

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

" alkyl " of the present invention refers to the saturated fat hydrocarbyl group of linear chain or branched chain, preferably contain 1 to 6 carbon atom straight chain or Branched group, the linear chain or branched chain group of further preferably 1 to 3 carbon atom, non-limiting examples include methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl Propyl, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, 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 present 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 the 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 With on any workable tie point.

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

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

" alkoxy " of the present invention refers to-O- alkyl.The non-limiting examples of alkoxy include：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 present 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 present invention refers to ring carbon atom and 1 to 4 ring hetero atom (wherein each hetero atom independence Ground be selected from nitrogen, oxygen, sulphur, boron, phosphorus and silicon) 3- to 10- member non-aromatic ring systems group (" C of the invention_3-10Member is miscellaneous The meaning of ring group " and " 3-10 circle heterocyclic rings base " are identical).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 can be monocycle (" heterocycle of monocycle ") or Person be fusion, bridging or spiral shell loop system (such as second cycle line system (" heterocycles of two rings ")) and can be saturation or Can be that part is undersaturated.The loop system of two ring of heterocycle can include one or more miscellaneous originals in one or two ring Son." heterocycle " is as defined above also including loop system, wherein heterocycle, is merged with one or more carbocylic radical groups Heterocycle in (wherein tie point is in carbocylic radical or on heterocycle) or loop system, it is as defined above, be and one or more virtue Base or (wherein tie point is on heterocycle) of heteroaryl fusion, and in such cases, the number of ring members continues referred to as to exist The number of ring members in heterocyclic ring system.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 realities It applies in example, which is unsubstituted 3-10 circle heterocyclic rings base.In certain embodiments, which is substitution 3-10 circle heterocyclic ring bases.It is fused to C₆The exemplary 5- circle heterocyclic rings base group of aryl rings (herein be also referred to as 5,6- bicyclic heterocycles) includes But it is not limited to, indoline base, isoindoline base, dihydro benzo furyl, dihydrobenzo thienyl, benzoxazolinone base etc. Deng.The exemplary 6- circle heterocyclic rings base group (herein be also referred to as 6,6- bicyclic heterocycles) for being fused to aryl rings includes but not limited to four Hydrogen quinolyl, tetrahydro isoquinolyl etc..

" aryl " of the present invention refers to the aroma system that can 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 substituted, substituent group can be on any workable tie point.

" heteroaryl " of the present invention refers to the aryl that at least one carbon atom is substituted by hetero atom, and the hetero atom is O、S、N.Suitable heteroaryl includes but not limited to imidazole radicals, benzimidazolyl, imidazopyridyl, quinazoline ketone group, pyrroles Base, imidazoles ketone group, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, three Oxazolyl etc..Wherein, " heteroaryl " of the invention preferably (is referred to as " 5-18 member heteroaryls in the present invention by 5-18 atomic building Base " or " C_5-18Unit's heteroaryl "), it is further preferably made of 5-12 atom, and at least one atom is heteroatomic miscellaneous Aryl.Suitable five yuan to 12 unit's heteroaryls include but not limited to pyrimidine radicals, pyridyl group, pyrazinyl, pyridazinyl, pyrimido pyrrole Oxazolyl, pyrimido imidazole radicals etc..Heteroaryl can be optionally substituted or unsubstituted, and when substituted, substituent group can be On any workable tie point.

" isomers " of the present 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 non-overlapping mirror image 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 by 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 exist as or mixtures thereof single enantiomer.Include the mixing of the equal proportion of enantiomer Object is referred to as " racemic mixture ".

" pharmaceutically acceptable salt " of the present 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.

The present invention " solvate " 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 Replacement 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 in human body or animal body after object play.As described above, the change with chemical formula (I) Closing the internal effect of object can also be metabolized via precursor compound (" prodrug ") to play." prodrug " of the present 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, hydrochloric acid in gastric juice 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 the hydrolysis etc. of hydrochloric acid in gastric juice 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 Cracking is to generate the pharmaceutically acceptable ester of parent acid in human body or animal body.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 esters；Naphthenic base carbonyloxy group Arrcostab, such as cyclopenta carbonyl oxy-methyl ester and 1- cyclohexylcarbonyloxyethyl esters；2- oxos -1,3- dioxa cyclopentenyl (dioxolenyl) methyl ester, such as 5- methyl -2- Oxo-1,3- Dioxol-4 -yl methyl esters；And alkoxy carbonyloxy group Arrcostab, such as methoxycarbonyl-oxymethyl ester With 1- methoxycarbonyloxyethyl esters.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- alkylamides and N, N- dialkyl amides, such as N- methyl nitrosoureas, N- ethyl acyls Amine, N- propyl amides, N, N- dimethylformamides, N- ethyl-N-methyls or N, N- diethylamide.

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

The present invention " crystallization " 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 present invention refers to comprising any type compound as described herein, including corresponding isomery Forms of protection 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.

The present invention " pharmaceutically acceptable carrier " 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, including all solvents, diluent or other excipient, dispersant, surface 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.It can include, but are not limited to carbohydrate as some examples of pharmaceutically acceptable carrier, such as breast 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 present 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.

The present invention " treatment and/or prevent the relevant disease of estrogen receptor drug in purposes " 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, the relevant disease of estrogen receptor is made to be improved, or reduce risk, it is described with the relevant disease of estrogen receptor Including with the relevant disease of estrogen receptor alpha and with the relevant disease of erss, such as 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, angiocardiopathy, 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, hepatic sclerosis 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 implementation mode

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.The material used in following embodiment is commercially available unless otherwise specified.

1 1- of embodiment (bis- fluoro- 4- of 3,5- ((1R, 3R)-2- (the fluoro- 2- methyl-propyls of (S)-3-) methyl-2,3,4-3-, 9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) azetidine -3- formic acid

The synthesis of the fluoro- 2 Methylpropionic acid methyl esters of step a (S) -3-

Under protection of argon gas, toward (R) -3- hydroxy-2-methyls methyl propionate of 20mL dichloromethane dissolving (2.0g, 16.93mmol) in solution, N, N- diethyl -1,1,2,3,3,3- hexafluoro propylamine are added dropwise in room temperature.After being added dropwise, reaction mixing A hour is stirred at room temperature in object, is then heated to reflux, and stir 4 hours.Reaction mixture is cooled to room temperature again, And stir 8 hours.It waits for after reaction, reaction mixture being poured into ice water (10mL), dichloromethane is used in combination to extract, it is organic It is mutually washed with saturated sodium-chloride, is concentrated after anhydrous sodium sulfate drying.Title compound is obtained to be used directly for reacting in next step.

The synthesis of the fluoro- 2- methylpropanols of step b (S) -3-

In 500mL three-necked bottles, be added the fluoro- 2 Methylpropionic acid methyl esters (2.3g, 19.15mmol) of (S) -3-, with 100mL without Water tetrahydrofuran dissolves, and low-temp reaction device is cooled to 0 DEG C or so, is slowly added to lithium aluminium hydride (0.78g, 20.53mmol) in batches. After addition finishes, reaction mixture respectively stirs 1h at 0 DEG C and at room temperature.After reaction, ten water sulfuric acid are slowly added portionwise Sodium filters after stirring 1h, and filter cake is washed with a small amount of tetrahydrofuran, and filtrate is concentrated to dryness, and obtains title compound.

The synthesis of the fluoro- 2- methyl-propyls trifluoromethayl sulfonic acid esters of step c (S) -3-

In 250mL reaction bulbs, the fluoro- 2- methylpropanols (1.8g, 19.54mmol) of (S) -3-, 2,6- dimethyl pyrazoles is added Pyridine (2.8mL, 23.7mmol), sub-cooled is to -10 DEG C after being dissolved with 20mL dichloromethane.By trifluoromethanesulfanhydride anhydride (3.13mL, It is added dropwise in above-mentioned reaction solution after 18.63mmol) being dissolved with 10mL dichloromethane, drop finishes the reaction was continued 1h.After reaction, will Reaction solution is washed with 2N hydrochloric acid (2 × 20mL), saturated sodium bicarbonate (2 × 20mL) and saturated nacl aqueous solution (2 × 20mL) respectively It washs, anhydrous sodium sulfate drying is removed under reduced pressure dichloromethane, obtains title compound.

The synthesis of step d (S)-N- ((R) -1- (1H- indol-3-yls) propyl- 2- yls) fluoro- 2- methyl-propyls -1- amine of -3-

In 100mL reaction bulbs, the fluoro- 2- methyl-propyls trifluoromethayl sulfonic acid esters of addition (S) -3- (2.72g, 12.10mmol), (R) -1- (1H- indol-3-yls) propyl- 2- amine (1.75g, 10.04mmol) and diisopropylethylamine (3.32ml, 20.08mmol), it being dissolved with 30mL dioxane, the lower 90 DEG C of reactions 2h of argon gas protection stops reacting, concentration, column chromatography purifying, Obtain title compound.ESI-Ms m/z:249.1[M+H]⁺。

Step e (1R, 3R)-1- (the bromo- 2,6- difluorophenyls of 4-)-2- (fluoro- 2 methyl-propyls of (S)-3-) methyl-2,3-3-, The synthesis of 4,9- tetrahydrochysene -1H- pyridos [3,4-b] indoles

In 50mL single port bottles, bromo- 2, the 6- difluorobenzaldehydes (0.535g, 2.42mmol) of 4- and (S)-N- ((R)-is added 1- (1H- indol-3-yls) propyl- 2- yls) the fluoro- 2- methyl-propyls -1- amine (0.50g, 2.0mmol) of -3-, be added 4mL acetic acid and 20mL toluene, 90 DEG C of reaction 3h, concentration, column chromatography purifying obtain title compound 0.61g.ESI-Ms m/z:451.1[M+H]⁺。

Step f 1- (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of (S) -3-) -3- methyl -2,3,4,9- Tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) azetidine -3- methyl formates synthesis

In microwave reaction tank, by (1R, 3R) -1- (4- bromo- 2,6- difluorophenyl) -2- (fluoro- 2 methyl-props of (S) -3- Base) -3- methyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indoles (910mg, 2.02mmol), azetidine -3- first Acid methyl ester hydrochloride salt (367mg, 2.42mmol), tris(dibenzylideneacetone) dipalladium (370mg, 0.404mmol), 2- dicyclohexyls Phosphorus -2,4,6- tri isopropyl biphenyls (391mg, 0.82mmol) and cesium carbonate (2.0g, 6.06mmol) are added to dioxane In (20mL).After being sufficiently displaced from argon gas, which is heated to 100 DEG C of microwave reactions.After reaction terminates, filtering simultaneously will be female Liquid concentrates.The reaction product is directly used in next step.ESI-Ms m/z:486.3[M+H]⁺。

Step g 1- (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of (S) -3-) -3- methyl -2,3,4,9- Tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) azetidine -3- formic acid synthesis

In 50mL single port bottles, 1- (3,5- bis- fluoro- 4- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of (S) -3-) -3- are added Methyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) azetidine -3- methyl formates (0.62g, 1.307mmol), it is dissolved with 10mL tetrahydrofurans and 5mL methanol, 7.5M sodium hydroxide solutions (3.0mL, 22.5mmol) is added, 3h is reacted at room temperature, with 2N hydrochloric acid tune pH to 6.5, ethyl acetate extraction, saturated sodium-chloride washing is dense after anhydrous sodium sulfate drying Contracting, column chromatography obtain title compound.¹H NMR(400MHz,d6-DMSO):12.53(s,1H),10.50(s,1H),7.40(d, 1H),7.23-7.19(m,1H),7.02-6.94(m,2H),6.08(d,2H),5.02(s,1H),4.44(d,1H),4.34(d, 1H),4.01(m,2H),3.97(m,2H),2.82(dd,1H),2.50(m,3H),2.21(m,1H),2.04(m,1H),1.93 (m,1H),1.06(d,3H),0.77(d,3H).ESI-Ms m/z:472.5[M+H]⁺。

2 1- of embodiment (the fluoro- 4- of the chloro- 5- of 3- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases) phenyl) azetidine -3- formic acid

Step a：(R) synthesis of-N- (1- (1H- indol-3-yls) propyl- 2- yls) fluoro- 2- methyl propyl- 1- amine of -2-

Preparation method is similar to the preparation method of 1 step b-d of embodiment, the difference is that by the fluoro- 2- methyl of raw material (S) -3- Methyl propionate replaces with the fluoro- 2 Methylpropionic acid methyl esters of 2-, and title compound is made.ESI-Ms m/z:249.1[M+H]⁺.

Step b：1- (the fluoro- 4- of the chloro- 5- of 3- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases) phenyl) azetidine -3- formic acid synthesis

Preparation method is similar to the preparation method of 1 step e-g of embodiment, the difference is that by raw material (S)-N- ((R) -1- (1H- indol-3-yls) propyl- 2- yls) the fluoro- 2- methyl-propyls -1- amine of -3- replaces with (R)-N- (1- (1H- indol-3-yls) propyl- 2- Base) the fluoro- 2- methyl propyl- 1- amine of -2-, and bromo- 2, the 6- difluorobenzaldehydes of raw material 4- are replaced with into the chloro- 6- fluorobenzaldehydes of the bromo- 2- of 4-, Title compound is made.¹H NMR(500MHz,DMSO-d₆)δ:12.57(s,1H),10.31(s,1H),7.36(d,1H),7.18 (d,1H),6.97-6.92(m,2H),6.33(s,1H),6.20(d,1H),5.17(s,1H),4.02-3.99(m,2H),3.87- 3.85(m,2H),3.01(d,1H),2.86(t,1H),2.58-2.56(m,2H),2.33-2.30(m,2H),1.11(d,3H), 1.05(d,3H),1.00(d,3H).ESI-Ms m/z:488.2[M+H]⁺。

3 1- of embodiment (4- ((1R, 3R) -2- (bis- fluoropropyls of 2,2-) -3- methyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) -3,5- difluorophenyls) azetidine -3- formic acid

The synthesis of bis- fluoro- 2- methyl-propyls -1- alcohol of step a 2,2-

In 250mL three-necked bottles, 2,2-, bis- fluoro- 2 Methylpropionic acids (5g, 45.5mmol) are added, with the anhydrous tetrahydrochysenes of 100mL Furans dissolves, and low-temp reaction device is cooled to -10 DEG C or so, is slowly added to lithium aluminium hydride (2.1g, 54.2mmol) in batches, and maintaining should Temperature the reaction was continued 1h.After reaction, 2.1mL water, 15% sodium hydrate aqueous solutions of 2.1mL and 4.2mL water are added dropwise successively, It is filtered after stirring 15min, filter cake is washed with a small amount of tetrahydrofuran, and filtrate is concentrated to dryness, and obtains title compound.ESI-Ms m/z: 97.0[M+H]⁺。

The synthesis of two fluoropropyl -1- amine of step b (R)-N- (1- (1H- indol-3-yls) propyl- 2- yls) -2,2-

The preparation method of the preparation method is the same as that of Example 1 step c-d, unlike by the fluoro- 2- methylpropanols of raw material (S) -3- 2,2-, bis- fluoro- 2- methyl-propyls -1- alcohol is replaced with, title compound is made.ESI-Ms m/z:253.0[M+H]⁺。

Step c 1- (4- ((1R, 3R) -2- (bis- fluoropropyls of 2,2-) -3- methyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3, 4-b] indoles -1- bases) -3,5- difluorophenyls) and azetidine -3- formic acid synthesis

Preparation method is similar to the preparation method of 1 step e-g of embodiment, the difference is that by raw material (S)-N- ((R) -1- (1H- indol-3-yls) propyl- 2- yls) the fluoro- 2- methyl-propyls -1- amine of -3- replaces with (R)-N- (1- (1H- indol-3-yls) propyl- 2- Base) bis- fluoropropyl -1- amine of -2,2-, title compound is made.¹H NMR(500MHz,DMSO-d₆)δ:12.5(s,1H),10.53 (s,1H),7.42-7.40(d,1H),7.23-7.21(d,1H),7.03-6.95(m,2H),6.14-6.12(d,2H),5.12 (s,1H),4.07-4.03(m,2H),3.93-3.90(m,2H),3.57-3.53(m,1H),3.50-3.46(m,1H),3.10- 3.01(m,1H),2.91-2.88(m,1H),2.61-2.57(m,2H),1.50-1.43(t,3H),1.11-1.01(d,3H) .ESI-Ms m/z:476.20[M+H]⁺。

4 1- of embodiment (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases) phenyl) -3- methyl azetidine -3- formic acid

Preparation method is similar to the preparation method of embodiment 2, the difference is that by raw material azetidine -3- methyl formate salt Hydrochlorate replaces with 3- methyl azetidine -3- methyl formate hydrochlorides, and title compound is made.¹H NMR(500MHz, DMSO-d₆)δ:12.5(s,1H),10.46(s,1H),7.38-7.36(d,1H),7.18-7.17(d,1H),6.97-6.92(m, 2H),6.09-6.06(d,2H),5.06(s,1H),4.03-4.01(d,2H),3.64-3.61(m,2H),3.54-3.50(m, 1H),2.89-2.76(m,2H),2.55-2.54(m,1H),2.39-2.29(m,1H),1.49(s,3H),1.20-1.10(q, 6H),1.04-1.02(d,3H).ESI-Ms m/z:486.2[M+H]⁺。

5 1- of embodiment (bis- fluoro- 4- of 3,5- (the fluoro- 2- of (1R) -6- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- Tetrahydrochysene -1H- pyridines [3,4-b] indoles -1- bases) phenyl) azetidine -3- formic acid

The synthesis of step a 5- fluoro- 3- hydroxyls -3- (2- oxopropyls)-indole-2-ketone

5- fluoro indigo reds (1.65g, 10mmol) are dissolved in 50mL acetone, potassium carbonate (13mg, 1.0mmol) are added, room temperature is stirred Mix reaction 5h.Remove solvent under reduced pressure, residue with Ethyl acetate/petroleum ether recrystallization obtains title compound.ESI-Ms m/ z:224.10[M+H]⁺。

The synthesis of step b 1- (the fluoro- 1H- indol-3-yls of 5-) propyl -2- alcohol

Step a gains 5- fluoro- 3- hydroxyls -3- (2- oxopropyls)-indole-2-ketones (2.23g, 10mmol) are dissolved in In 20mL anhydrous tetrahydro furans, borine tetrahydrofuran solution (30mL, 1M, 30mmol) is added dropwise, reacts at room temperature 4h.It will reaction Liquid pours into the mixed solution of 50mL ethyl acetate and 50mL water, and water layer is extracted with 30mL ethyl acetate, merges organic layer, anhydrous Sodium sulphate is dried.It removes solvent after filtering under reduced pressure, obtains title compound.ESI-Ms m/z:194.10[M+H]⁺。

The synthesis of step c 1- (the fluoro- 1H- indol-3-yls of 5-) propyl -2- ketone

Step b gains 1- (the fluoro- 1H- indol-3-yls of 5-) propyl -2- alcohol (1.93g, 10mmol) is dissolved in 20mL dichloros In methane, 1,1,1- triacetyls oxygen -1,1- dihydro -1,2- benzenesulfonyl -3- (1H) -one (4.66g, 11mmol) is added, room temperature is anti- Answer 2h.Reaction solution uses 20mL water, 20mL saturated salt solutions extraction to wash successively, the drying of organic layer anhydrous sodium sulfate.Column chromatography is marked Inscribe compound 1.76g.ESI-Ms m/z:192.10[M+H]⁺。

The synthesis of step d 1- (the fluoro- 1H- indol-3-yls of 5-) propyl -2- amine

Step c gains 1- (the fluoro- 1H- indol-3-yls of 5-) propyl -2- ketone (1g, 5.2mmol) is dissolved in 20mL methanol, Ammonium acetate (4.45g, 57.73mmol) and sodium cyanoborohydride (0.37g, 5.9mmol) is added, reacts at room temperature 48h.1N salt is added Acid for adjusting pH removes organic solvent under reduced pressure to 2, and 50mL dichloromethane extraction is washed.Water layer with 4N sodium hydrate aqueous solutions adjust pH to 12, dichloromethane 3 × 50mL extractions merge organic layer, anhydrous sodium sulfate drying.Column chromatography obtains title compound.ESI-Ms m/z:193.10[M+H]⁺。

Step e 1- (bis- fluoro- 4- of 3,5- (the fluoro- 2- of (1R) -6- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridines [3,4-b] indoles -1- bases) phenyl) azetidine -3- carboxylic acids synthesis

Preparation method is similar to the preparation method of embodiment 2, the difference is that by raw material (R) -1- (1H- indol-3-yls) propyl- 2- amine replaces with 1- (the fluoro- 1H- indol-3-yls of 5-) propyl -2- amine obtained in step d, and by the chloro- 6- fluorine of the bromo- 2- of raw material 4- Benzaldehyde replaces with bromo- 2, the 6- difluorobenzaldehydes of 4-, and title compound is made.¹H NMR(500MHz,DMSO-d₆)δ:12.5(s, 1H),10.55(s,1H),7.16-7.10(m,2H),6.82-6.78(m,1H),6.10-6.07(d,2H),5.05(s,1H), 4.04-4.00(m,2H),3.89-3.86(m,2H),3.54-3.49(m,2H),2.87-2.77(m,2H),2.52-2.50(m, 1H),2.37-2.29(m,1H),1.19-1.11(t,6H),1.03-1.02(d,3H).ESI-Ms m/z:490.20[M+H]⁺.

6 5- of embodiment (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases) phenyl) -5- azaspiros [2.3] hexane -1- formic acid

Preparation method is similar to the preparation method of embodiment 2, the difference is that the chloro- 6- fluorobenzaldehydes of the bromo- 2- of raw material 4- are replaced Bromo- 2, the 6- difluorobenzaldehydes of 4- are changed to, and raw material azetidine -3- methyl formate hydrochlorides are replaced with into 5- azaspiros [2.3] title compound is made in hexane -1- methyl formates.¹H NMR(500MHz,DMSO-d₆)δ:12.1(s,1H),10.49 (s,1H),7.38-7.36(d,1H),7.18-7.16(d,1H),6.99-6.90(m,2H),6.22-6.19(d,1H),6.12- 6.09(d,1H),5.06-5.01(m,1H),4.23-4.22(m,1H),3.95-3.88(m,2H),3.51-3.48(m,1H), 3.25-3.19(m,2H),2.87-2.75(m,2H),2.38-2.28(m,1H),2.04-2.01(m,0.5H),1.84-1.80 (m,0.5H),1.50(s,0.5H),1.44(s,0.5H),1.39-1.36(m,0.5H),1.28-1.25(m,0.5H),1.20- 1.10(m,6H),1.03-1.01(m,3H).ESI-Ms m/z:498.3[M+H]⁺.

7 1- of embodiment (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases) phenyl) -1H- pyrazoles -4- formic acid

Preparation method is similar to the preparation method of embodiment 2, the difference is that the chloro- 6- fluorobenzaldehydes of the bromo- 2- of raw material 4- are replaced Bromo- 2, the 6- difluorobenzaldehydes of 4- are changed to, and raw material azetidine -3- methyl formate hydrochlorides are replaced with into 4- pyrazole carboxylic acid second Title compound is made in ester.¹H NMR(500MHz,DMSO-d₆)δ:12.5(s,1H),10.59(s,1H),9.14(s,1H), 8.12(s,1H),7.71-7.68(d,2H),7.43-7.40(d,1H),7.20-7.18(d,1H),7.03-6.93(m,2H), 5.23(s,1H),3.56-3.50(m,1H),2.95-2.82(m,2H),2.62-2.56(m,1H),2.44-2.32(m,1H), 1.26-1.11(t,6H),1.07-1.05(d,3H).ESI-Ms m/z:483.3[M+H]⁺.

8 1- of embodiment (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases) phenyl) -5- pyrrolidones -3- formic acid

Preparation method is similar to the preparation method of embodiment 2, the difference is that the chloro- 6- fluorobenzaldehydes of the bromo- 2- of raw material 4- are replaced Bromo- 2, the 6- difluorobenzaldehydes of 4- are changed to, and raw material azetidine -3- methyl formate hydrochlorides are replaced with into 5- pyrrolidones - Title compound is made in 3- methyl formates.¹H NMR(500MHz,DMSO-d₆)δ:12.25(s,1H),10.51(s,1H), 7.41-7.36(t,3H),7.17(d,1H),7.00-6.94(m,2H),5.16(s,1H),4.00-3.92(m,2H)3.50(m, 1H),3.24(m,1H),2.88-2.57(m,4H),2.57(d,1H),2.32(m,1H),1.21-1.09(d,3H),1.16(d, 3H),1.04(d,3H).ESI-Ms m/z:500.2[M+H]⁺.

Embodiment 9 (E)-3- (bis- fluoro- 4- of 3,5- ((1R, 3R)-2- (bis- fluoro- 2- methyl-propyls of 2,2-) methyl-2,3-3-, 4,9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) acrylic acid

The synthesis of step a (E) -3- (bis- fluoro- 4- Fonnylphenyls of 3,5-) methyl acrylate

By bromo- 2,6-, the bis- fluoro- 1- benzaldehydes (6.66g, 30mmol) of 4-, triethylamine (8.4ml, 60mmol), acid chloride (0.34g, 1.5mmol) and trimethylphenyl phosphorus (1.0g, 3.2mmol) are dissolved in n,N-Dimethylformamide (70mL), by it It is de-gassed.Then addition methyl acrylate (4.3mL, 45.0mmol), and reaction solution is heated to 80 DEG C, continue 4h.It is cooling Afterwards, which is added in water (300mL), ethyl acetate (2 × 400mL) is used in combination to extract.Combined organic matter is mutually used 2N dilute hydrochloric acid (200mL) washs, and then anhydrous sodium sulfate is dried and concentrated, and column chromatography purifying obtains title compound.ESI-Ms m/z:227.04[M+H]⁺。

Step b (E)-3- (bis- fluoro- 4- of 3,5- ((1R, 3R)-2- (bis- fluoro- 2- methyl-propyls of 2,2-) methyl-2,3,4-3-, 9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) methyl acrylate synthesis

In 100mL reaction bulbs, (R)-N- (1- (1H- indol-3-yls) propyl- 2- yls) -2 obtained in embodiment 3 is added, Bis- fluoropropyl -1- amine (0.252g, 1mmol) of 2-, (E) -3- (3,5- bis- fluoro- 4- Fonnylphenyls) methyl acrylate (0.181g, 0.8mmol) with glacial acetic acid (0.29mL, 5mmol), toluene 25mL dissolvings, 90 DEG C of reaction 6h, concentration of reaction solution, column layer are added Analysis purifying, obtains title compound.ESI-Ms m/z:461.2[M+H]⁺。

Step c (E)-3- (bis- fluoro- 4- of 3,5- ((1R, 3R)-2- (bis- fluoro- 2- methyl-propyls of 2,2-) methyl-2,3,4-3-, 9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) acrylic acid synthesis

In 50mL single-necked flasks, step b gains (E) -3- (3,5- bis- fluoro- 4- ((1R, 3R) -2- (2,2- bis- are added Fluoro- 2- methyl-propyls) -3- methyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) methyl acrylate (0.221g, 0.48mmol) is dissolved with 8mL tetrahydrofurans and 4mL methanol, addition 7.5M sodium hydrate aqueous solutions (0.64mL, 4.8mmol), 2h is reacted at room temperature, with 2N dilute hydrochloric acid tune pH to 6.5, ethyl acetate extraction, saturated sodium-chloride washing, anhydrous slufuric acid It is concentrated after sodium drying, column chromatography obtains title compound.¹H NMR(500MHz,DMSO-d₆)δ:12.29(s,1H),10.63(s, 1H),7.58-7.55(d,1H),7.49-7.47(d,2H),7.45-7.44(d,1H),7.24-7.22(d,1H),7.06-7.02 (t,1H),7.00-6.97(t,1H),6.71-6.68(d,1H),5.25(s,1H),3.40(s,1H),3.18-3.09(m,2H), 2.94-2.90(m,2H),1.54-1.46(t,3H),1.12(s,3H).ESI-Ms m/z:447.2[M+H]⁺.

Embodiment 10 (E)-3- (the fluoro- 4- of the chloro- 5- of 3- ((1R, 3R)-2- (the fluoro- 2- methyl-propyls of 2-) methyl-2,3,4-3-, 9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) acrylic acid

Preparation method is similar to the preparation method of embodiment 9, the difference is that by bromo- 2,6-, the bis- fluoro- 1- benzaldehydes of raw material 4- Replace with the chloro- 6- fluorobenzaldehydes of the bromo- 2- of 4-, and by raw material (R)-N- (1- (1H- indol-3-yls) propyl- 2- yls) -2,2- difluoros third Base -1- amine replaces with (R)-N- (1- (1H- indol-3-yls) propyl- 2- yls) fluoro- 2- methyl propyl- 1- of -2- obtained in embodiment 2 Title compound is made in amine.¹H NMR(500MHz,DMSO-d₆)δ:12.59(s,1H),10.47(s,1H),7.70(s,1H), 7.57-7.53(d,2H),7.41(d,1H),7.17(d,1H),6.99-6.94(m,2H),6.72(d,1H),5.34(s,1H), 3.65(m,1H),3.07-2.91(m,2H),2.59(d,1H),2.28-2.24(m,1H),1.14-1.03(d,3H),1.09(d, 3H),1.05(d,3H).ESI-Ms m/z:459.2[M+H]⁺.

Embodiment 11 (E) -3- (the fluoro- 4- of 3- (difluoro-methoxy) -5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- Methyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) acrylic acid

Preparation method is similar to the preparation method of embodiment 10, the difference is that the chloro- 6- fluorobenzaldehydes of the bromo- 2- of raw material 4- are replaced 4- bromo- 2- (difluoro-methoxy) -6- hydroxy benzaldehydes are changed to, title compound is made.¹H NMR(500MHz,DMSO-d₆)δ: 12.51(s,1H),10.36(s,1H),7.49(d,1H),7.39-7.38(m,3H),7.14(m,2H),6.97-6.93(m, 2H),6.60(d,1H),5.20(s,1H),3.55(m,1H),2.98(d,1H),2.85(dd,1H),2.58(m,1H),2.26 (dd,1H),1.15-0.98(m,9H).ESI-Ms m/z:491.2[M+H]⁺.

Embodiment 12 (Z)-3- (bis- fluoro- 4- of 3,5- ((1R, 3R)-2- (the fluoro- 2- methyl-propyls of 2-) methyl-2,3,4-3-, 9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) -2- perfluoroalkyl acrylates

The synthesis of step a (Z) -3- (bis- fluoro- 4- Fonnylphenyls of 3,5-) fluoro- methyl acrylates of -2-

In 100mL reaction bulbs, bromo- 2,6-, the bis- fluoro- 1- benzaldehydes (1g, 4.93mmol) of 4-, 2- perfluoroalkyl acrylate first is added Ester (1.54g, 14.77mmol), tri-o-tolyl phosphine (0.15g, 0.493mmol), palladium (0.06g, 0.247mmol) and three Ethamine (1.00g, 9.86mmol) is dissolved with 20mL n,N-Dimethylformamide, the lower 80 DEG C of reactions 6h of argon gas protection.Reaction knot Shu Hou.The stirring of 20mL ice water is added, is extracted with ethyl acetate, saturated sodium-chloride washing is concentrated under reduced pressure after anhydrous sodium sulfate drying, Column chromatography purifies, and obtains title compound.ESI-Ms m/z:245.1[M+H]⁺。

Step b (Z) -3- (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases) phenyl) -2- perfluoroalkyl acrylates synthesis

Preparation method is similar to the preparation method of 9 step b-c of embodiment, the difference is that (3,5- bis- is fluoro- by raw material (E) -3- 4- Fonnylphenyls) methyl acrylate replaces with (Z) -3- (3,5- bis- fluoro- 4- Fonnylphenyls) fluoro- methyl acrylates of -2-, and Two fluoropropyl -1- amine of raw material (R)-N- (1- (1H- indol-3-yls) propyl- 2- yls) -2,2- is replaced with into (R)-N- (1- (1H- Yin Diindyl -3- bases) propyl- 2- yls) the fluoro- 2- methyl propyl- 1- amine of -2-, title compound is made.¹H NMR(500MHz,DMSO-d₆)δ: 12.60(s,1H),10.49(s,1H),7.71(s,1H),7.61-7.58(d,1H),7.44(d,1H),7.20(d,1H), 6.99-6.95(m,2H),6.72(d,1H),5.32(s,1H),3.65(m,1H),3.07-2.91(m,2H),2.59(d,1H), 2.28-2.24(m,1H),1.14,1.04(d,3H),1.09(d,3H),1.03(d,3H).ESI-Ms m/z:461.5[M+H]⁺.

Embodiment 13 (E)-3- (bis- chloro- 4- of 3,5- ((1R, 3R)-2- (the fluoro- 2- methyl-propyls of 2-) methyl-2,3,4-3-, 9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) acrylic acid

Preparation method is similar to the preparation method of embodiment 10, the difference is that the chloro- 6- fluorobenzaldehydes of the bromo- 2- of raw material 4- are replaced Bromo- 2, the 6- dichlorobenzaldehydes of 4- are changed to, title compound is made.¹H NMR(300MHz,DMSO-d₆)δ:10.25(s,1H), 8.27(s,1H),7.79(s,1H),7.54(s,1H),7.40-7.35(m,2H),7.16-7.14(d,1H),7.00-6.90(m, 2H),6.61-6.58(d,1H),5.58(s,1H),3.67(s,1H),3.07-2.87(m,2H),2.55-2.60(s,1H), 2.29-2.14(m,1H),1.12-1.01(s,9H).ESI-Ms m/z:475.2[M+H]⁺.

Embodiment 14 (E) -3- (the fluoro- 4- of 3- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases) -5- methoxyphenyls) acrylic acid

Preparation method is similar to the preparation method of embodiment 10, the difference is that by the fluoro- benzaldehydes of the chloro- 6- of the bromo- 2- of raw material 4- The fluoro- 6- methoxybenzaldehydes of the bromo- 2- of 4- are replaced with, title compound is made.¹H NMR(300MHz,DMSO-d₆)δ:10.36(s, 1H),7.50-7.47(d,1H),7.41-7.40(d,1H),7.25(s,1H),7.19-7.17(d,1H),7.02-6.94(m, 3H),6.69-6.60(d,1H),5.35(s,1H),3.90(s,3H),3.60(m,2H),3.00-2.97(m,1H),2.88- 2.84(m,1H),2.60-2.59(d,1H),2.38-2.29(m,1H),1.20-1.09(m,9H).ESI-Ms m/z:455.3[M +H]⁺.

15 1- of embodiment (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridines [3,4-b] indoles -1- bases) phenyl) azetidine -3- formic acid

Preparation method is similar to the preparation method of embodiment 2, the difference is that the chloro- 6- fluorobenzaldehydes of the bromo- 2- of raw material 4- are replaced Bromo- 2, the 6- difluorobenzaldehydes of 4- are changed to, title compound is made.¹H NMR(500MHz,DMSO-d₆)δ:12.15(s,1H), 10.38(s,1H),7.36-7.30(d,1H),7.23-7.19(d,1H),7.02-6.85(m,2H),6.15-6.05(d,2H), 5.05(s,1H),4.15-3.98(m,2H),3.95-3.80(m,2H),3.65-3.47(m,2H),3.90-3.75(m,2H), 2.75(s,1H),2.42-2.30(m,1H),1.26-1.01(m,9H).ESI-Ms m/z:472.3[M+H]⁺.

16 1- of embodiment (the fluoro- 4- of 3- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- tetrahydrochysenes - 1H- pyridines [3,4-b] indoles -1- bases) -5- methoxyphenyls) azetidine -3- formic acid

Preparation method is similar to the preparation method of embodiment 2, the difference is that the fluoro- benzaldehydes of the chloro- 6- of the bromo- 2- of raw material 4- are replaced The fluoro- 6- methoxybenzaldehydes of the bromo- 2- of 4- are changed to, title compound is made.¹H NMR(300MHz,DMSO-d₆)δ:10.28(s, 1H),7.95-7.93(d,1H),7.34-7.32(d,1H),7.16-7.13(d,1H),6.88-6.96(m,2H),5.90(s, 1H),5.68-5.65(m,1H),5.17(s,1H),3.94-3.92(m,2H),3.83-3.82(m,2H),3.55-3.50(m, 1H),3.39-3.46(m,1H),2.93-2.87(m,1H),2.77-2.70(m,1H),2.60-2.54(d,3H),2.26-2.37 (m,1H),2.01-1.95(m,1H),1.10-1.05(m,6H),1.00(s,3H).ESI-Ms m/z:484.3[M+H]⁺.

Bis- fluoro- 4'- of embodiment 17 3', 5'- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases)-[1,1'- xenyls] -4- formic acid

The synthesis of step a 3', 5'- bis- fluoro- 4'- formoxyls-[1,1'- xenyls] -4- methyl formates

By (4- (methoxycarbonyl) phenyl) boric acid (1.97g, 11mmol), the bromo- 2,6- difluorobenzaldehydes of 4- (2.21g, 10mmol), bis- (diphenylphosphine) the propane nickel chlorides (54mg, 0.1mmol) of 1,3-, potassium phosphate (8.48g, 40mmol) and 60mL bis- Six ring of oxygen is mixed in 100mL eggplant type bottles, is warming up to 110 DEG C of stirrings under argon gas protection, is reacted 10h at identical temperature.It depressurizes dense Contracting removes organic solvent, is diluted with 100mL ethyl acetate, and 50mL saturated sodium-chloride water solutions are washed, and anhydrous sodium sulfate drying is taken out Filter, concentration.Residue is detached with silica gel column chromatography, obtains title compound.ESI-Ms m/z:277.1[M+H]⁺。

Bis- fluoro- 4'- of step b 3', 5'- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- tetrahydrochysenes - 1H- pyridos [3,4-b] indoles -1- bases)-[1,1'- xenyls] -4- formic acid synthesis

Preparation method is similar to the preparation method of 9 step b-c of embodiment, the difference is that (3,5- bis- is fluoro- by raw material (E) -3- 4- Fonnylphenyls) methyl acrylate replaces with 3' obtained in above step a, bis- fluoro- 4'- formoxyls-[1,1'- biphenyl of 5'- Base] -4- methyl formates, and bis- fluoropropyl -1- amine of raw material (R)-N- (1- (1H- indol-3-yls) propyl- 2- yls) -2,2- is replaced For (R)-N- (1- (1H- indol-3-yls) propyl- 2- yls) the fluoro- 2- methyl propyl- 1- amine of -2-, title compound is made.¹H NMR (400MHz,DMSO-d₆)δ:13.04(s,1H),10.65(s,1H),8.03–8.01(d,2H),7.91–7.89(d,2H), 7.52–7.49(d,2H),7.44–7.42(d,1H),7.21–7.19(d,1H),7.02–7.01(m,2H),5.28(s,1H), 3.33–3.32(m,1H),2.94–2.85(m,2H),2.63–2.61(m,1H),2.52–2.40(m,1H),1.22–1.01(m, 9H).ESI-Ms m/z:493.1[M+H]⁺.

Bis- fluoro- 4'- of embodiment 18 3', 5'- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases)-[1,1'- xenyls] -3- formic acid

Preparation method is similar to the preparation method of embodiment 17, the difference is that by raw material (4- (methoxycarbonyl) phenyl) boron Acid replaces with (3- (methoxycarbonyl) phenyl) boric acid, and title compound is made.¹H NMR(400MHz,DMSO-d₆)δ:12.98 (s,1H),10.63(s,1H),8.23–8.21(d,1H),7.99–7.97(m,2H),7.62–7.58(m,1H),7.46–7.41 (d,3H),7.21–7.19(d,1H),7.02–6.94(d,2H),5.28(s,1H),3.58–3.52(m,1H),2.94–2.90 (m,2H),2.62–2.46(m,2H),1.26–1.07(m,9H).ESI-Ms m/z:493.1[M+H]⁺.

19 5- of embodiment (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases) phenyl) thiazole -2- formic acid

Step a：5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) thiazole -2- Ethyl formates Synthesis

By 5- bromo thiazole -2- Ethyl formates (4.68g, 20mmol), connection pinacol borate (5.59g, 22mmol), acetic acid Potassium (5.88g, 60mmol), [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride (1.4g, 1.8mmol) are dissolved in 100mL bis- Six ring of oxygen, argon gas are protected, and 12h is stirred under the conditions of 80 DEG C, are then evaporated under reduced pressure most of solvent, 150mL ethyl acetate is added, use Saturated sodium-chloride water solution (100mL × 2) washs, and anhydrous sodium sulfate drying, column chromatography purifies to obtain target compound.ESI-Ms m/z:284.1[M+H]⁺。

Step b：The synthesis of 5- (bis- fluoro- 4- Fonnylphenyls of 3,5-) thiazole -2- Ethyl formates

By 5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) thiazole -2- Ethyl formates Bis- fluoro- 4- bromobenzaldehydes (936mg, 4.26mmol) of (1.45g, 5.1mmol), 2,6-, [1,1'- bis- (diphenylphosphinos) two cyclopentadienyl Iron] palladium chloride (62.3mg, 0.085mmol), 4.3mL aqueous sodium carbonates (2M) be dissolved in 10mL toluene, argon gas protection, It is heated to reflux 16h under the conditions of 100 DEG C, saturated sodium-chloride water solution 50mL is added, then ethyl acetate (50mL × 3) is used to extract, Merge organic phase, anhydrous sodium sulfate drying is evaporated under reduced pressure to beige solid, column chromatography for separation obtains target compound.ESI- Ms m/z:298.0[M+H]⁺。

Step c：5- (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- tetrahydrochysenes - 1H- pyridos [3,4-b] indoles -1- bases) phenyl) thiazole -2- formic acid synthesis

Preparation method is similar to the preparation method of 9 step b-c of embodiment, the difference is that (3,5- bis- is fluoro- by raw material (E) -3- 4- Fonnylphenyls) methyl acrylate replaces with 5- (bis- fluoro- 4- Fonnylphenyls of 3,5-) thiazole -2- obtained in above step Ethyl formate, and bis- fluoropropyl -1- amine of raw material (R)-N- (1- (1H- indol-3-yls) propyl- 2- yls) -2,2- is replaced with (R) - Title compound is made in N- (1- (1H- indol-3-yls) propyl- 2- yls) fluoro- 2- methyl propyl- 1- amine of -2-.¹H NMR(400MHz, DMSO-d₆)δ:10.62(s,1H),9.16(s,1H),8.06(s,1H),8.48(s,1H),7.58-7.56(d,1H),7.43- 7.41(d,1H),7.42-7.18(d,1H),7.02-6.94(m,2H),5.25(s,1H),3.53-3.52(m,1H),2.90- 2.84(m,2H),2.61-2.58(m,1H),2.50-2.48(m,1H),1.36-1.06(m,9H).ESI-Ms m/z:500.1[M +H]⁺。

The fluoro- 4'- of 20 3'- of embodiment ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- tetrahydrochysenes - 1H- pyridos [3,4-b] indoles -1- bases) -3,5'- dimethoxys-[1,1'- xenyls] -4- formic acid

Preparation method is similar to the preparation method of embodiment 17, the difference is that by raw material (4- (methoxycarbonyl) phenyl) boron Acid replaces with (3- methoxyl groups -4- (methoxycarbonyl) phenyl) boric acid and the bromo- 2,6- difluorobenzaldehydes of raw material 4- is replaced with 4- Title compound is made in bromo- 2- methoxyl groups -6- fluorobenzaldehydes.¹H NMR(400MHz,DMSO-d₆)δ:12.70(s,1H), 10.41(s,1H),8.24(s,1H),7.68(d,1H),7.40–7.37(m,2H),7.24(s,1H),7.18–7.16(m,1H), 7.07(s,1H),6.97–6.93(m,2H),5.37(s,1H),3.95(s,3H),3.92(s,3H),3.60–3.57(m,1H), 3.10–2.87(m,2H),2.59–2.55(d,1H),2.51–2.42(m,1H),1.18–1.03(m,9H).ESI-Ms m/z: 535.3[M+H]⁺.

21 1- of embodiment (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases) phenyl) azetidine -3- formamides

In 50mL single port bottles, 1- (3,5- bis- fluoro- 4- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- are sequentially added Methyl -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indoles -1- bases) phenyl) azetidine -3- methyl formates (180mg, 0.37mmol) purified with the methanol solution of 10mL ammonia, 55 DEG C of heating stirring 12h, stopping reaction, direct concentrated by rotary evaporation, column chromatography, Obtain title compound.¹H NMR(400MHz,DMSO-d₆)δ:10.47(s,1H),7.47(s,1H),7.38-7.36(d,1H), 7.18-7.17(d,1H),7.02-6.90(m,3H),6.07-6.04(d,2H),5.05(s,1H),3.97-3.93(m,2H), 3.83-3.78(m,2H),3.53-3.51(m,1H),3.44-3.42(m,1H),2.86-2.80(m,2H),2.39-2.32(m, 2H),1.20-1.02(m,9H).ESI-Ms m/z:471.2[M+H]⁺.

22 2- of embodiment (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- four Hydrogen -1H- pyridos [3,4-b] indoles -1- bases) phenyl) cyclopropane -1- formic acid

The synthesis of bis- fluoro- 4- vinylbenzaldehydes of step a 2,6-

By the bromo- 2,6- difluorobenzaldehydes (3156mg, 14.2mmol) of 4- and vinyl -1,3 4,4,5,5- tetramethyl -2-, 2- dioxaborinates (3300mg, 21.4mmol) are dissolved in the in the mixed solvent of 30mL dimethyl ether and 10mL water, and potassium carbonate is added (3897mg, 28.2mmol) and bis- (triphenylphosphine) palladium chlorides (300mg, 0.14mmol), argon gas protection, are heated to 80 DEG C, Reaction 5 hours, cooling add water and ethyl acetate to extract, and organic layer drying, concentration obtains title compound.ESI-Ms m/z: 169.1[M+H]⁺。

The synthesis of step b 2- (bis- fluoro- 4- ethenylphenyls of 2,6-) -1,3- dioxolanes

2,6-, bis- fluoro- 4- vinylbenzaldehydes (2500mg, 14.9mmol) and ethylene glycol (1670mg, 27mmol) are dissolved in In 30mL toluene, p-methyl benzenesulfonic acid 490mg is added, silica gel 2000mg is added, 113 DEG C are reacted 8 hours.Sand processed, column chromatography must be marked Inscribe compound.ESI-Ms m/z:213.1[M+H]⁺。

The synthesis of step c 2- (4- (1,3- dioxolanes -2- bases) -3,5- difluorophenyls) cyclopropane -1- carboxylic acid, ethyl esters

By 2- (2,6- bis- fluoro- 4- ethenylphenyls) -1,3-dioxolane (2120mg, 10mmol) and dimerization rhodium acetate (70mg, 0.25mmol) is dissolved in 30ml anhydrous methylene chlorides, by ethyl diazoacetate (4500mg, 40mmol) be dissolved in 30mL without In water dichloromethane and it is slowly added dropwise into 2- (bis- fluoro- 4- ethenylphenyls of 2,6-) -1,3- dioxolanes and dimerization rhodium acetate It in mixed liquor, drips off within 1 hour, reacts at room temperature 1 hour, sand processed, column chromatography obtains title compound.ESI-Ms m/z:299.1[M+ H]⁺。

The synthesis of step d 2- (bis- fluoro- 4- Fonnylphenyls of 3,5-) cyclopropane -1- carboxylic acid, ethyl esters

By 2- (4- (1,3-dioxolane -2- bases) -3,5- difluorophenyls) cyclopropane -1- carboxylic acid, ethyl esters (1700mg, 6mL trifluoroacetic acids 5.7mmol) are dissolved in, 4mL concentrated hydrochloric acids and 2mL water is added, are reacted at room temperature 1 hour, water, ethyl acetate is added to extract, Organic layer is dried, and title compound is concentrated to give.ESI-Ms m/z:255.1[M+H]⁺。

Step e 2- (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- tetrahydrochysenes - 1H- pyridos [3,4-b] indoles -1- bases) phenyl) cyclopropane -1- methyl formates synthesis

By 2- (3,5- bis- fluoro- 4- Fonnylphenyls) cyclopropane -1- Ethyl formates (254mg, 1mmol) and (R)-N- (1- (1H- indol-3-yls) propyl- 2- yls) the fluoro- 2- methyl propyl- 1- amine (248mg, 1mmol) of -2- are dissolved in 20mL toluene, 1mL vinegar is added Acid, 80 DEG C are reacted 4 hours, and water, ethyl acetate extraction, organic layer drying is added to concentrate, obtain title compound.ESI-Ms m/z: 471.1[M+H]⁺。

Step f 2- (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- tetrahydrochysenes - 1H- pyridos [3,4-b] indoles -1- bases) phenyl) cyclopropane -1- formic acid synthesis

By 2- (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- tetrahydrochysenes -1H- Pyrido [3,4-b] indoles -1- bases) phenyl) cyclopropane -1- methyl formates (470mg, 1mmol) are dissolved in 10mL tetrahydrofurans, add Enter 5mL methanol, the sodium hydrate aqueous solution 1ml of 7.5N is added, reacts at room temperature 1 hour, add 2N dilute hydrochloric acid tune pH to 5 or so, add Water and ethyl acetate extraction, organic layer are spin-dried for, and sand processed, column chromatography obtains title compound.¹H NMR(400MHz,DMSO-d₆)δ 12.61(s,1H),10.57(s,1H),7.72(s,1H),7.52(d,1H),7.46(d,1H),7.40(d,1H),7.20(d, 1H),5.21(s,1H),4.41(m,1H),3.47-3.57(m,1H),2.80-2.98(m,2H),2.53-2.63(m,2H), 2.36(dd,1H),2.21(m,1H),1.45-1.70(m,2H),1.08-1.28(m,6H),1.07(d,3H)。ESI-Ms m/z: 457.2[M+H]⁺。

23 3,5- of embodiment, bis- fluoro- 4- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- tetrahydrochysenes - 1H- pyridos [3,4-b] indoles -1- bases)-N- ((1R, 2S) -2- fluorine cyclopropyl) benzamide

The synthesis of step a 2- (the bromo- 2,6- difluorophenyls of 4-) -1,3- dioxolanes

In 1L reaction bulbs, addition 2,6-, bis- fluoro- 4- bromobenzaldehydes (17.76g, 80.7mmol), ethylene glycol (9.1mL, 162.9mmol), a water p-methyl benzenesulfonic acid (200mg, 1.1mmol) is dissolved with 250mL toluene, and 110 DEG C of reflux, water knockout drum removes Water reacts 6h.After reaction, it is cooled to room temperature, water (100mL × 3) washing, saturated sodium-chloride water solution (100mL) washing, Organic phase is dried with anhydrous sodium sulfate, filtering, and filtrate concentration obtains title compound.

The synthesis of bis- fluoro- 4- of step b 3,5- (1,3- dioxolane -2- bases)-methyl benzoate

In 100mL reaction bulbs, step a gains 2- (bromo- 2, the 6- difluorophenyls of 4-) -1,3- dioxolanes are added (1.4g, 5.3mmol), the bis- Diphenyl phosphino ferrocenes of 1,1'- (300mg, 0.5mmol) and palladium (300mg, 1.3mmol) are used The mixed solvent dissolving of 20mL methanol and 25mL n,N-Dimethylformamide composition, adds 1.18mL triethylamines, CO gas atmosphere Lower 70 DEG C of stirrings are enclosed, 3h is reacted.After reaction, it is cooled to room temperature, concentrates, the dissolving of 100mL ethyl acetate, 1N hydrochloric acid is added (100mL) is washed, water (100mL) washing, saturated sodium-chloride water solution (100mL) washing, and organic phase is dried with anhydrous sodium sulfate, Filtering, filtrate concentration, column chromatography purifying obtain title compound.ESI-Ms m/z:245.1[M+H]⁺。

The synthesis of bis- fluoro- 4- of step c 3,5- (1,3- dioxolane -2- bases)-benzoic acid

In 100mL reaction bulbs, step b gains 3, bis- fluoro- 4- of 5- (1,3- dioxolane -2- bases)-benzoic acid is added Methyl esters (244mg, 1mmol), the mixed solvent formed with 5mL methanol and 5mL tetrahydrofurans dissolve, and sodium hydroxide is added (120mg, 3mmol) aqueous solution 5ml, is stirred at room temperature 0.5h.Reaction terminates, and reaction solution is concentrated, and 25mL water dissolutions, 1N salt is added Acid adjusts pH to 2, is extracted with 25mL ethyl acetate, and organic phase is dried with anhydrous sodium sulfate, filters, and filtrate concentration obtains title compound Object.ESI-Ms m/z:231.0[M+H]⁺。

Step d 4- (1,3- dioxolanes -2- bases) -3,5- two fluoro- N- ((1S, 2R) -2- fluorine cyclopropyl) benzamide Synthesis

In 100mL reaction bulbs, step c gains 3, bis- fluoro- 4- of 5- (1,3- dioxolane -2- bases)-benzoic acid is added (230mg, 1mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (230mg, 1.2mmol) and 1- hydroxyls Benzotriazole (162mg, 1.2mmol) is dissolved with 15mL dichloromethane, and 0.41mL triethylamines are added, add (1S, 2R) -2- Fluorine cyclopropylamine tosilate (300mg, 1mmol), is stirred at room temperature 2h.After reaction, reaction solution is spin-dried for, column chromatography obtains Title compound.ESI-Ms m/z:288.1[M+H]⁺。

The synthesis of bis- fluoro- N- of step e 3,5- ((1S, 2R) -2- fluorine cyclopropyl) -4- formyl yl-benzamides

In 100mL reaction bulbs, bis- fluoro- N- of addition step d gains (1,3-dioxolane -2- bases) -3,5- ((1S, 2R) -2- fluorine cyclopropyl) benzamide (240mg, 0.84mmol), it is dissolved with 20mL dichloromethane, 1.5mL trifluoroacetic acids is added, It is stirred overnight at room temperature.After reaction, water (50mL × 2) washs, and organic phase is dried with anhydrous sodium sulfate, filters, filtrate concentration, Obtain title compound.ESI-Ms m/z:244.1[M+H]⁺。

Bis- fluoro- 4- of step f 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- tetrahydrochysenes -1H- Pyrido [3,4-b] indoles -1- bases)-N- ((1R, 2S) -2- fluorine cyclopropyl) benzamide synthesis

In 100mL reaction bulbs, 3,5- bis- fluoro- N- ((1S, 2R) -2- fluorine cyclopropyl) -4- formyl yl-benzamides are added (200mg, 0.82mmol) and (R)-N- (1- (1H- indol-3-yls) propyl- 2- yls) fluoro- 2- methyl propyl- 1- amine of -2- (200mg, 0.81mmol), it is dissolved with 5mL toluene, 0.5mL glacial acetic acid, 80 DEG C of reaction 3h is added.After reaction, reaction solution is added dropwise Enter into 50mL saturated sodium bicarbonate solutions, extracted with 50mL ethyl acetate, organic phase is dried with anhydrous sodium sulfate, filtrate mistake Filter, concentration, column chromatography obtain title compound.ESI-Ms m/z:474.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆):δ 10.57(s,1H),7.72(s,1H),7.52(d,1H),7.46(d,2H),7.40(d,1H),7.20(d,1H),6.92-7.06 (m,1H),5.21(s,1H),4.41(m,1H),3.47-3.57(m,1H),2.80-2.98(m,2H),2.53-2.58(m,2H), 2.36(dd,1H),1.08-1.28(m,6H),1.07(d,3H),0.55-0.61(m,2H).

According to the synthetic method of 1-23 of the embodiment of the present invention, the change of different marketable material synthetic example 24-31 is utilized Object is closed, the characterization parameter of these compounds is as shown in table 1：

Table 1：

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

1. experiment material

Control compound is that chemistry disclosed in WO 2014/191726 (PCT/GB2014/051607) embodiment 1 is entitled (E) -3- (bis- fluoro- 4- of 3,5- ((1R, 3R) -2- (the fluoro- 2- methyl-propyls of 2-) -3- methyl -2,3,4,9- tetrahydrochysene -1H- pyridos [3,4-b] indoles -1- bases) phenyl) acrylic acid compound (AZD9496), with reference to the method described in WO 2014/191726 It prepares and by hydrogen spectrum and Mass Spectrometric Identification.

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

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

Dimethyl sulfoxide (DMSO) (DMSO), activated carbon, Formaldehyde solution are purchased from Sigma companies；

MCF-7 cells are purchased from AATCC；

Estrogen Receptor α (D8H8) Rabbit mAb are purchased from CST companies；

Goat anti-Rabbit IgG(H+L)Secondary Antibody、AlexaConjugate, Purchased from Thermo companies；

Tween 20 is purchased from EIA GRADE companies.

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

Centrifuge is purchased from Eppendorf companies；

Cell counter is purchased from Invitrogen companies；

Inverted microscope is purchased from Olympus companies；

Multiflow is purchased from BioTeck companies；

Turbine mixer is purchased from IKA companies；

Envision is purchased from Perkin Elmer companies.

2. experimental method

2.1. the preparation of cell culture fluid and compound

The preparation of serum-free FBS：1g activated carbons are weighed to mix for 24 hours afterwards through 0.22 μM of filter membrane mistake for 4 DEG C with 50mL fetal calf serums Bacterium is filtered out, it is spare；

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

Compound prepares：The compound of the present invention and control compound prepared by above example, each compound are used After DMSO is configured to 100mM, be diluted to successively 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 are added in the cell reject culture solution of exponential phase in T75 Tissue Culture Flasks to wash once.It adds 2mL trypsin digestion cells, 37 DEG C are placed 2 minutes, and microscopically observation most cells shape is rounded, and the serum-free of 5mL is added Cell culture fluid terminate digestion, pipette is blown and beaten, cell dissociation is got off, cell suspension is made repeatedly, then adds 10mL cells Culture solution counts after mixing；Be diluted to the cell suspension of the μ L of 1500 cells/40, with Multiflow instruments by cell spread into 384 porocyte culture plates, 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 instruments, DMSO final concentrations 0.3%；Room temperature 1000rpm centrifugations 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 washes cell 1 time, with final concentration of 3.7% paraformaldehyde solution (PBS dilutions) room The fixed cell 20min of temperature；PBS washes cell 2 times, permeates 1h with final concentration of 0.5% Tween-20 (PBS dilutions) room temperature；With PBS-T (containing 0.05% Tween-20 in PBS) washes cell 2 times, and ER antibody diluents (1 are added in measuring in ER level: 1000, diluted containing 1% milk in PBS-T), it is incubated at room temperature 1.5h；PBS-T washes cell 3 times, and secondary antibody diluent is added (1:1000, diluted with 1% milk is contained in PBS) Hochest 33342 of 2 μ g/mL, it is incubated at room temperature 40min；PBS-T is washed Cell 3 times, PBS wash cell 2 times；Acumen reads the ratio of ER positive signals value and nuclear signal value.Experimental result is shown in Table 2。

Table 2

"-" expression is not surveyed

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.

2 Compound ira vitro cell activity of experimental example is evaluated

1. experiment material

Test-compound：The compound of the present invention and control compound prepared by above example, each compound are used DMSO is configured to 10mM, 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 are purchased from Progema companies of the U.S.； Paclitaxel is purchased from Sichuan Tai Chi drugmakers.

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, two multiple holes of each concentration are added per hole.In 37 DEG C, 5%CO₂Under the conditions of be incubated for 24 hours.

Plus compound 2.2.

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

2.3. fluorescence reading

To wait for gaging hole be added 50 μ LLuminescent Cell Viability Assay buffer, And it gently shakes 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 the reading of vehicle control group Number, Min are the reading of acellular control group, and Com is the reading of compound processing group, and data are fitted to obtain IC through XLfit processing₅₀, Experimental result is shown in Table 3.

Table 3

"-" expression is not surveyed

From the above experiment as can be seen that the compound of the present invention shows good inhibition to MCF-7 breast cancer cells Activity.

Pharmacokinetic Evaluation in 3 compound body of experimental example

Test-compound：The compound of the present invention and control compound prepared by above example, each compound is with molten Matchmaker is formulated as oral test sample 2mg/kg, intravenous test sample 1mg/kg.

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

Mouse oral is with 2mg/kg, after intravenous is with 1mg/kg single-doses, 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 4。

Table 4

Test-compound	T1/2(h)	Cmax(ng/ml)	AUC(h*ng/ml)	F (%)
					AZD9496	1.1	703.7	1229.9	45.5
Embodiment 1	1.3	647	1948.9	58.1
					Embodiment 2	3.2	583.4	3232.8	62.6
Embodiment 3	4.3	410.2	2413.5	86.6
					Embodiment 4	3.7	793.4	4548.4	64.3
Embodiment 5	5.7	493.7	4893.3	81.1
					Embodiment 6	3.2	1457.7	8373.5	80.5
Embodiment 7	4	255.1	2768.2	86
					Embodiment 9	5.2	474.6	3115	115.5
Embodiment 10	3.9	1102.7	4525.6	70.4
					Embodiment 12	3.4	125.4	767.9	28.8
Embodiment 13	6.9	1326.1	16451.4	88
					Embodiment 14	2.7	1023.8	2895.8	62.4
Embodiment 15	2.3	598.1	2441.3	39.9
					Embodiment 16	-	-	-	-
Embodiment 17	12.1	1277.7	16073.7	80.5
					Embodiment 20	7.6	1210.7	13602.1	79.0
Embodiment 22	6.4	1676.5	4991.7	77.5
					Embodiment 23	6.4	403.5	2100.1	41.3

"-" expression is not surveyed

Above the experimental results showed that, the half-life period (T of the compound of the present invention_1/2), Cmax (Cmax), area under the curve (AUC) and bioavilability (F) is significantly better than that control compound.When the Increased Plasma Half-life of compound, bioavilability increases When, it can be by the administration interval prolongation of compound, drug treating time extends, and the effect of compound can be improved and reduces compound Dosage, to keep drug more effective, safer.Therefore, the compound of the present invention has more excellent internal antitumor Activity, the phase will be longer between administration.

MCF-7 subcutaneous transplantation knurl model evaluating drug effects in 4 compound body of experimental example

1. cell culture

With containing 10% fetal calf serum, the MEM culture mediums of the streptomysin of the penicillin of 100U/ml and 100 μ g/ml are 37 DEG C, 5%CO₂Incubator in culture MCF-7 breast cancer cells (being purchased from triumphant base).Cell culture initial concentration is 1 × 10⁶A/ ML, every the sub-bottle passage after cell covers in 3 to 4 days.By the connecing for in-vivo tumour of the tumour cell in exponential phase Kind.

2. sustained release tablets and cell inoculation

2-3 days before cell inoculation, by beta estradiol slow release tablet, (60 days SE121 0.72mg of Estradiol-17 β, are purchased from Innovative Research of America companies) it is inoculated in the left back back of the body of every mouse.It is right 3 times a week 1 week after inoculation Animal urinates, and urinates daily to animal when necessary.

10 × 10 will be contained⁶The PBS of cell is inoculated in mouse with the Matrigel mixing (200 μ L of final volume) of 100 μ L Right back.

3. measurement of tumor and experimental index

Test-compound：The compound of the present invention and control compound prepared by above example.The compound of the present invention And control compound is by daily single (QD), successive administration three weeks (3W).

Experimental index is to investigate whether tumour growth is suppressed, delays or cures.It is swollen with vernier caliper measurement three-times-weekly Tumor diameter.The calculation formula of gross tumor volume is：V=0.5a × b², a and b indicate the major diameter and minor axis of tumour respectively.

The tumor killing effect of test-compound is evaluated with Relative tumor proliferation rate T/C (%) and tumour inhibiting rate (%).Relative tumor The calculation formula of proliferation rate T/C (%) is as follows：T/C%=T_RTV/C_RTV× 100% (T_RTV：Treatment group RTV；C_RTV：Negative control Group RTV).Relative tumour volume (relative tumor volume, RTV) is calculated according to the result of measurement of tumor, is calculated public Formula is RTV=V_t/V₀, wherein V₀(i.e. d when being grouping administration₀) measure gained gross tumor volume, V_tFor certain one-shot measurement when tumour Volume, T_RTVWith C_RTVTake same day data.Tumour inhibiting rate (%)=(1-T/C) × 100%.

Experimental result of the test-compound to the tumor suppression evaluating drug effect of human breast carcinoma cell lines MCF-7 subcutaneous transplantation knurl model As shown in table 5, corresponding T/C (%) numerical value of each embodiment compound is that each dosage group animal of each embodiment compound is based in table T/C (%) mean value that the 21st day gross tumor volume is calculated after administration.

Table 5

The experimental results showed that surprisingly, the compound of the present invention is substantially better than positive drug to the tumor killing effect of breast cancer AZD9496.The compound of the present invention, for example, embodiment 3, embodiment 10, embodiment 13, embodiment 17, embodiment 20 chemical combination Object, drug effect is significantly better than the AZD9496 of same dose under 0.6mg/kg dosage, and drug effect is much better than under 2mg/kg dosage Drug effect under AZD9496 6mg/kg dosage.In addition, the present invention part of compounds produced under 1/10th dosage with The comparable effects of positive drug AZD9496 (0.6mg/kg VS 6mg/kg).

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.The interest field of the present invention is not limited to It is described in detail made by above, and claims should be belonged to.

Claims (10)

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

Wherein,

R¹、R²Separately it is selected from halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxyl Alkoxy, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkyl amino Acyl group, double alkyl aminos and naphthenic base；

R³Selected from alkyl, alkyl acyl, aminoacyl, alkylaminoacyl, halogenated alkyl, hydroxy alkyl, alkenyl, naphthenic base, miscellaneous Ring group, aryl and heteroaryl；

R⁴、R⁵Separately it is selected from hydrogen, alkyl, alkoxy, halogen, halogenated alkyl and hydroxy alkyl；Or R⁴、R⁵Connect with them The carbon atom connect forms carbonyl or naphthenic base together；

R⁶、R⁷Separately it is selected from hydrogen, alkyl, alkoxy, halogen, halogenated alkyl and hydroxy alkyl；Or R⁶、R⁷Connect with them The carbon atom connect forms carbonyl or naphthenic base together；Or

R⁴、R⁶Carbon atom connected to them forms naphthenic base together；

Each R⁸Separately it is selected from hydrogen, halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxyl Base alkoxy, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkyl ammonia Base acyl group, double alkyl aminos, naphthenic base and boric acid；

Y is selected fromWherein R⁹Selected from carboxyl, cyano, alkyl, halogenated alkyl and hydroxyl alkane Base, R¹⁰Selected from hydrogen and halogen, R¹¹Selected from hydroxyl, amino, alkoxy and alkyl amino, ring A is selected from naphthenic base, heterocycle, aryl And heteroaryl, the naphthenic base, heterocycle, aryl and heteroaryl can be by one or more hydrogen, halogen, hydroxyl, alkyl, halogen Substituted 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 and naphthenic base substitution, R¹²Selected 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 and cycloalkanes Base, n 1,2 or 3, or when n is 2, two R¹²Group carbon atom connected to them formed together carbonyl, naphthenic base, Heterocycle, aryl, heteroaryl, the naphthenic base, heterocycle, aryl and heteroaryl can be by one or more hydrogen, halogen, hydroxyls Base, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyano, amino, list Alkyl amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos and naphthenic base substitution, L¹Selected from key ,-NHCO- ,-CONH- ,-NHCONH- ,-NH-, alkylidene, O, S, halogeno alkylen, hydroxy alkylidene, alkylene oxide Base, halo alkyleneoxy, hydroxyl alkylene oxide group, carbonyl and alkylidene amino；

Chemical bondIt is each independently

M is 1,2,3 or 4；

Condition is when Y isAnd R¹、R²All it is fluorine, R¹⁰For hydrogen when, R³It is selected fromAlkenyl and aryl, wherein R¹³Choosing From halogen, hydroxyl, alkyl, halogenated alkyl, hydroxy alkyl, alkoxy, halogenated alkoxy, hydroxy alkoxy base, nitro, carboxyl, cyanogen Base, amino, alkyl monosubstituted amino, alkyl acylamino, alkyl acyl, aminoacyl, alkylaminoacyl, double alkyl aminos and ring Alkyl.

2. compound according to claim 1 or its isomers, pharmaceutically acceptable salt, solvate, crystallization or preceding Medicine, wherein R¹、R²Separately it is selected from fluorine, chlorine, bromine, iodine, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6 Alkoxy, 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 and C_3-10Naphthenic base.

3. compound according to claim 1 or 2 or its isomers, pharmaceutically acceptable salt, solvate, crystallization or Prodrug, wherein R³Selected from C_1-10Alkyl, C_1-10Alkyl acyl, aminoacyl, C_1-10Alkylaminoacyl, halogenated C_1-10Alkyl, hydroxyl Base C_1-10Alkyl, C_2-10Alkenyl, C_3-10Naphthenic base, C_3-10Heterocycle, C_6-18Aryl and C_5-18Heteroaryl, the group can be by one A or multiple halogens, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, hydroxyl Base C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl amino, double C_1-6Alkyl amino and the C optionally replaced_3-8Ring Alkyl replaces.

4. according to any one of them compound or its isomers, pharmaceutically acceptable salt, solvation of claim 1-3 Object, crystallization or prodrug, wherein R⁴、R⁵Separately it is selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxy, halogen, halogenated C_1-6Alkyl and hydroxyl Base C_1-6Alkyl, R⁶、R⁷Separately it is selected from hydrogen, C_1-6Alkyl, C_1-6Alkoxy, halogen, halogenated C_1-6Alkyl and hydroxyl C_1-6Alkane Base.

5. according to any one of them compound or its isomers, pharmaceutically acceptable salt, solvation of claim 1-3 Object, crystallization or prodrug, wherein R⁴、R⁵Carbon atom connected to them forms carbonyl or C together_3-10Naphthenic base；Or R⁶、R⁷With it The carbon atom that is connected form carbonyl or C together_3-10Naphthenic base；Or R⁴、R⁶Carbon atom connected to them is formed together C_3-10Naphthenic base.

6. according to any one of them compound or its isomers, pharmaceutically acceptable salt, solvation of claim 1-5 Object, crystallization or prodrug, wherein each R⁸Separately it is selected from hydrogen, halogen, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6 Alkyl, 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_1-6Alkyl amino, C_3-10Naphthenic base And boric acid.

7. compound according to claim 1 or its isomers, pharmaceutically acceptable salt, solvate, crystallization or preceding Medicine, wherein

R⁹Selected from carboxyl, cyano, C_1-6Alkyl, halogenated C_1-6Alkyl and hydroxyl C_1-6Alkyl；

R¹¹Selected from hydroxyl, amino, C_1-6Alkoxy and C_1-6Alkyl amino；

Ring A is selected from C_3-10Naphthenic base, C_3-10Heterocycle, C_6-18Aryl and C_5-18Heteroaryl, the naphthenic base, heterocycle, aryl It can be by one or more halogens, hydroxyl, C with heteroaryl_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, double C_1-6Alkyl amino and C_3-10Naphthenic base replaces；

R¹²Selected from hydrogen, halogen, hydroxyl, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alcoxyl Base, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, amino, list C_1-6Alkyl amino, C_1-6Alkyl acylamino, C_1-6Alkyl acyl Base, aminoacyl, C_1-6Alkylaminoacyl, double C_1-6Alkyl amino and C_3-10Naphthenic base, n 1,2 or 3；Or when n is 2, Two R¹²Carbon atom connected to them forms carbonyl, C together_3-10Naphthenic base, C_3-10Heterocycle, C_6-18Aryl and C_5-18It is miscellaneous Aryl, the naphthenic base, heterocycle, aryl and heteroaryl can be by one or more halogens, hydroxyl, C_1-6It is alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, halogenated C_1-6Alkoxy, hydroxyl C_1-6Alkoxy, nitro, carboxyl, cyano, ammonia Base, list C_1-6Alkyl amino, double C_1-6Alkyl amino and C_3-8Naphthenic base replaces；L¹Selected from key ,-NHCO- ,-CONH- ,- NHCONH- ,-NH-, Asia C_1-6Alkyl, O, S, halogenated Asia C_1-6Alkyl, hydroxyl Asia C_1-6Alkyl, Asia C_1-6Alkoxy, halogenated Asia C_1-6 Alkoxy, hydroxyl Asia C_1-6Alkoxy, carbonyl and Asia C_1-6Alkyl amino；With

R¹³Selected from 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_1-6Alkyl acylamino, C_1-6Alkyl acyl, Aminoacyl, C_1-6Alkylaminoacyl, double C_1-6Alkyl amino and C_3-10Naphthenic base.

8. according to claim 1 compound represented 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 any one of them compound of claim 1 to 8 or its isomers, pharmaceutically Acceptable salt, solvate, crystallization or prodrug and pharmaceutical acceptable carrier.

10. any one of them compound or its isomers, pharmaceutically acceptable salt, solvate, knot of claim 1-8 Pharmaceutical composition described in brilliant or prodrug or claim 9 is being prepared for treating and/or preventing the relevant disease of estrogen receptor Application in the drug of disease.