CN108329311B

CN108329311B - Tricyclic compound as selective estrogen receptor down-regulator and application thereof

Info

Publication number: CN108329311B
Application number: CN201810021871.XA
Authority: CN
Inventors: 王勇; 赵立文; 王小伟; 张小猛; 张雁; 庞司林
Original assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Current assignee: Nanjing Sanhome Pharmaceutical Co Ltd
Priority date: 2017-01-11
Filing date: 2018-01-10
Publication date: 2022-02-22
Anticipated expiration: 2038-01-10
Also published as: WO2018130124A1; CN108329311A

Abstract

The invention belongs to the field of medicinal chemistry, and relates to tricyclic compounds serving as selective estrogen receptor down-regulating agents and application thereof, in particular to a compound shown as a formula I or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound or the composition in treating and/or preventing estrogen receptor related diseases. The compound of the invention has more excellent antitumor activity, longer administration interval and less side effect, and is very hopeful to become a breast cancer therapeutic agent.

Description

Tricyclic compound as selective estrogen receptor down-regulator and application thereof

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a compound serving as a selective estrogen receptor down-regulator (SERD) or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound or the composition in treating and/or preventing estrogen receptor related diseases.

Background

Estrogen Receptors (ER) are ligand-activated transcriptional regulators that mediate the induction of a variety of biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17 β -estradiol and estrone. ER has been found to have two isoforms: ER- α and ER- β, which are encoded by two different genes located on human chromosomes 6 and 14, respectively, are widely expressed in various tissues, and ER- β expression is limited to female reproductive system and tissues such as brain and bone. Both of them contain 6 domains and 4 functional regions, and the N-terminal A/B functional region has a ligand-independent transcriptional activation domain AF-1, constitutive activation activity (constitutive activity), and activates transcription of a target gene by interacting with a basal transcription factor, a co-activator, and other transcription factors, and further has multiple phosphorylation sites. The DNA Binding Domain (DBD) consisting of the C domain specifically binds to the target DNA and contains a nuclear localization signal, while also having a dimerization interface that plays an important role in receptor dimerization. The D domain is a hinge region responsible for connecting the DBD and the Ligand Binding Domain (LBD). The C-terminal E domain constitutes LBD, which determines the specific binding of ER and estrogen and other ligands, has a ligand-dependent transcription activation functional domain AF-2, and has a strong dimerization interface, can still play a role in the absence of a ligand, and is a key part for receptor dimerization. LBD consists of 12 alpha helices and one beta sheet, forming a three-layer antiparallel sandwich structure, where H5, H6, H9 and H10 constitute the middle layer, and H1, H2, H3, H4 and H7, H8, H11 constitute the outer two layers, respectively, where H12 contains AF-2 with its hydrophobic surface facing the ligand binding pocket and its hydrophilic surface facing outward. The LBD of ER is wedge-shaped, H12 is in the groove of the ligand binding pocket and seals the ligand binding pocket. When ER binds to an agonist, the conformation of H12 becomes more stable, suitable for binding of co-activators, which in turn activate transcription of target genes. When ER binds to the antagonist, H12 changes its position and occupies the binding site of the co-activator, resulting in estrogen antagonism.

Studies on drugs targeting estrogen receptors have been carried out for many years with some clinical success, particularly recently it has been found that selective estrogen receptor down-modulators have more potentiated anti-estrogen effects, such as interfering with and causing degradation of estrogen receptors. However, there is still a need to develop more estrogen receptor down-regulators, especially selective estrogen receptor down-regulators, so that the drug has more excellent properties, such as better therapeutic effect, less side effects, longer administration interval, etc., and thus is better used for preventing or treating estrogen receptor-related diseases.

Disclosure of Invention

One object of the present invention is to provide a class of compounds having selective estrogen receptor down-regulation activity represented by general formula I, or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof,

wherein the content of the first and second substances,

R¹、R²each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylaminoalkyl, and cycloalkyl;

R³selected from the group consisting of alkyl, alkanoyl, aminoacyl, alkylaminoacyl, haloalkyl, hydroxyalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R⁴、R⁵each independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, and hydroxyalkyl; or R⁴、R⁵Together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group;

R⁶、R⁷are respectively and independentlySelected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl, and hydroxyalkyl; or R⁶、R⁷Together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group; or

R⁴、R⁶Together with the carbon atom to which they are attached form a cycloalkyl group;

each R⁸Each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylaminoalkyl, cycloalkyl, and boronic acid;

y is selected from

Wherein R is⁹Selected from the group consisting of carboxy, cyano, alkyl, haloalkyl and hydroxyalkyl, R¹⁰Selected from hydrogen and halogen, R¹¹Selected from the group consisting of hydroxy, amino, alkoxy and alkylamino, ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, which may be substituted with one or more of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkanoylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylaminoacyl and cycloalkyl, R is selected from the group consisting of hydroxy, amino, alkoxy and alkylamino, and ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein R is substituted with one or more of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkanoylamino, alkanoyl, aminoacyl, dialkylaminoacyl and cycloalkyl, R is substituted with one or more hydrogen, halogen, hydroxy, alkyl, amino, or dialkylamino, R is substituted with one or more hydrogen, halogen¹²Selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkanoylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl, n is 1,2 or 3, or when n is 2, two R are¹²The groups together with the carbon atoms to which they are attached form a carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be substituted with one or more of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyCyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl substitutions, L¹Selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, alkylene, O, S, haloalkylene, hydroxyalkylene, alkyleneoxy, haloalkyleneoxy, hydroxyalkyleneoxy, carbonyl, and alkyleneamino;

chemical bond(s)

Each independently is

Or

m is 1,2,3 or 4;

provided that when Y is

And R is¹、R²Are both fluorine, R¹⁰When it is hydrogen, R³Is selected from

Alkenyl and aryl, wherein R¹³Selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamino, and cycloalkyl.

It is another object of the present invention to provide a process for preparing the compounds of formula I of the present invention or their isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs.

It is a further object of the present invention to provide compositions comprising a compound of formula I of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug and a pharmaceutically acceptable carrier, and compositions comprising a compound of formula I of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug and another drug or drugs.

Still another object of the present invention is to provide a method for treating and/or preventing estrogen receptor related diseases by using the compound of the general formula I or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug, and the use of the compound of the general formula I or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug in preparing a medicament for treating and/or preventing estrogen receptor related diseases.

Aiming at the above purpose, the invention provides the following technical scheme:

in a first aspect, the present invention provides a compound of formula I or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug thereof,

wherein the content of the first and second substances,

R⁶、R⁷each independently selected from hydrogen, alkyl, and alkaneOxy, halogen, haloalkyl, and hydroxyalkyl; or R⁶、R⁷Together with the carbon atom to which they are attached form a carbonyl or cycloalkyl group; or

y is selected from

Wherein R is⁹Selected from the group consisting of carboxy, cyano, alkyl, haloalkyl and hydroxyalkyl, R¹⁰Selected from hydrogen and halogen, R¹¹Selected from the group consisting of hydroxy, amino, alkoxy and alkylamino, ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, which may be substituted with one or more of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkanoylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylaminoacyl and cycloalkyl, R is selected from the group consisting of hydroxy, amino, alkoxy and alkylamino, and ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein R is substituted with one or more of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkanoylamino, alkanoyl, aminoacyl, dialkylaminoacyl and cycloalkyl, R is substituted with one or more hydrogen, halogen, hydroxy, alkyl, amino, or dialkylamino, R is substituted with one or more hydrogen, halogen¹²Selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkanoylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl, n is 1,2 or 3, or when n is 2, two R are¹²The groups together with the carbon atoms to which they are attached form a carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl group may be substituted with one or more hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, mono-or poly-alkoxy groupsAlkylamino, alkanoylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl substitution, L¹Selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, alkylene, O, S, haloalkylene, hydroxyalkylene, alkyleneoxy, haloalkyleneoxy, hydroxyalkyleneoxy, carbonyl, and alkyleneamino;

chemical bond(s)

Each independently is

Or

m is 1,2,3 or 4;

provided that when Y is

In some particular embodiments, the compounds of the present invention are of formula Ia

Or an isomer, a pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof.

In some particular embodiments, the compounds of the present invention are of formula Ib

In some embodiments, the compounds of the invention are of formula Ic

In some preferred embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein:

R¹、R²each independently selected from fluorine, chlorine, bromine, iodine, hydroxyl and C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6Alkylaminoacyl, di-C_1-6Alkylamino and C_3-10A cycloalkyl group;

further preferably, R¹、R²Each independently selected from fluorine, chlorine, bromine, iodine, hydroxyl and C_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy, hydroxy C_1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-3Alkylamino radical, C_1-3Alkylacylamino group, C_1-3Alkyl acyl, amino acyl, C_1-3Alkylaminoacyl, di-C_1-3Alkylamino and C_3-6A cycloalkyl group;

even more preferably, R¹、R²Each independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl, isopropyl,Trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxyl, cyano, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacylamino, vinylacylamino, methylacyl, ethylaccyl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

R³is selected from C_1-10Alkyl radical, C_1-10Alkyl acyl, amino acyl, C_1-10Alkylaminoacyl, halogeno C_1-10Alkyl, hydroxy C_1-10Alkyl radical, C_2-10Alkenyl radical, C_3-10Cycloalkyl radical, C_3-10Heterocyclic group, C_6-18Aryl and C_5-18Heteroaryl, which groups may be substituted with one or more halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, dialkylamino and optionally substituted cycloalkyl groups;

further preferably, R³Is selected from C_1-6Alkyl radical, C_1-6Alkyl acyl, amino acyl, C_1-6Alkylaminoacyl, halogeno C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Cycloalkyl radical, C_3-8Heterocyclic group, C_6-12Aryl and C_5-12Heteroaryl, said group being optionally substituted by one or more halogens, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-6Alkyl ammoniaBasic, di-C_1-6Alkylamino and optionally substituted C_3-8Cycloalkyl substitution;

even more preferably, R³Selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, formyl, acetyl, propionyl, aminoacyl, methylaminoacyl, ethylaminoacyl, propylaminoyl, trifluoromethyl, trifluoroethyl, 2-difluoropropyl, 2-fluoro-2-methylpropyl, (S) -3-fluoro-2-methylpropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, ethenyl, propenyl, butenyl, 3-methyl-2-butenyl, cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, aziridinyl, phenyl and naphthyl, which groups may be substituted by one or more of halogen, hydroxy, C, N_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy, hydroxy C_1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-3Alkylamino, di-C_1-3Alkyl amino substitution.

R⁴、R⁵each independently selected from hydrogen and C_1-6Alkyl radical, C_1-6Alkoxy, halogen, halogeno C_1-6Alkyl and hydroxy C_1-6An alkyl group;

further preferably, R⁴、R⁵Each independently selected from hydrogen and C_1-3Alkyl radical, C_1-3Alkoxy, halogen, halogeno C_1-3Alkyl and hydroxy C_1-6An alkyl group;

even more preferably, R⁴、R⁵Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, and halogen.

R⁴、R⁵together with the carbon atom to which they are attached form a carbonyl group or C_3-10A cycloalkyl group;

further preferably, R⁴、R⁵Together with the carbon atom to which they are attached form a carbonyl group, C_3-6A cycloalkyl group;

even more preferably, R⁴、R⁵Together with the carbon atom to which they are attached form carbonyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

R⁶、R⁷each independently selected from hydrogen and C_1-6Alkyl radical, C_1-6Alkoxy, halogen, halogeno C_1-6Alkyl and hydroxy C_1-6An alkyl group;

further preferably, R⁶、R⁷Each independently selected from hydrogen and C_1-3Alkyl radical, C_1-3Alkoxy, halogen, halogeno C_1-3Alkyl and hydroxy C_1-6An alkyl group;

even more preferably, R⁶、R⁷Each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, and halogen.

R⁶、R⁷together with the carbon atom to which they are attached form a carbonyl group, C_3-10A cycloalkyl group;

further preferably, R⁶、R⁷Together with the carbon atom to which they are attached form a carbonyl group, C_3-6A cycloalkyl group;

even more preferably, R⁶、R⁷Together with the carbon atom to which they are attached form carbonyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

R⁴、R⁶together with the carbon atom to which they are attached form C_3-10A cycloalkyl group;

further preferably, R⁴、R⁶Together with the carbon atom to which they are attached form C_3-6A cycloalkyl group;

even more preferably, R⁴、R⁶Together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

each R⁸Each independently selected from hydrogen, halogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6Alkylaminoacyl, di-C_1-6Alkylamino radical, C_3-10Cycloalkyl and boronic acids;

further preferably, each R⁸Each independently selected from hydrogen, halogen, hydroxy, C_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy, hydroxy C_1-3Alkoxy, nitro, carboxyl, cyano, ammoniaRadical, mono C_1-3Alkylamino radical, C_1-3Alkylacylamino group, C_1-3Alkyl acyl, amino acyl, C_1-3Alkylaminoacyl, di-C_1-3Alkylamino radical, C_3-6Cycloalkyl and boronic acids;

even more preferably, each R⁸Each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacrylamino, vinylacylamino, methylacyl, ethylacryl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and boronic acid.

R⁹selected from carboxyl, cyano, C_1-6Alkyl, halo C_1-6Alkyl and hydroxy C_1-6An alkyl group;

further preferably, R⁹Selected from carboxyl, cyano, C_1-3Alkyl, halo C_1-3Alkyl and hydroxy C_1-3An alkyl group;

even more preferably, R⁹Selected from the group consisting of carboxy, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl and 2-hydroxypropyl.

R¹¹selected from hydroxy, amino, C_1-6Alkoxy and C_1-6An alkylamino group;

further preferably, R¹¹Selected from hydroxy, amino, C_1-3Alkoxy and C_1-3An alkylamino group;

even more preferably, R¹¹Selected from the group consisting of hydroxy, amino, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, propylamino and isopropylamino.

R¹²selected from hydrogen, halogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6Alkylaminoacyl, di-C_1-6Alkylamino and C_3-10A cycloalkyl group;

further preferably, R¹²Selected from hydrogen, halogen, hydroxy, C_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy, hydroxy C_1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-3Alkylamino radical, C_1-3Alkylacylamino group, C_1-3Alkyl acyl, amino acyl, C_1-3Alkylaminoacyl, di-C_1-3Alkylamino and C_3-6A cycloalkyl group;

even more preferably, R¹²Selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylaminoAmino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacrylamino, vinylacylamino, methylacyl, ethylacyl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

when n is 2, two R¹²Together with the carbon atom to which they are attached form a carbonyl group, C_3-10Cycloalkyl radical, C_3-10Heterocyclic group, C_6-18Aryl and C_5-18Heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be substituted with one or more halogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-6Alkylamino, di-C_1-6Alkylamino and C_3-10Cycloalkyl substitution;

further preferably, when n is 2, two R are¹²Together with the carbon atom to which they are attached form a carbonyl group, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-12Aryl and C_5-12Heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be substituted with one or more halogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-6Alkylamino, di-C_1-6Alkylamino and C_3-10Cycloalkyl substitution;

even more preferably, when n is 2, two R are¹²Together with the carbon atom to which they are attached form a carbonyl group, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-12Aryl and C_5-12Heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be substituted with one or more halogen, hydroxy, C_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy, hydroxy C_1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-3Alkylamino, di-C_1-3Alkylamino and C_3-6Cycloalkyl is substituted.

R¹³selected from halogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-6Alkylamino radical, C_1-6Alkylacylamino group, C_1-6Alkyl acyl, amino acyl, C_1-6Alkylaminoacyl, di-C_1-6Alkylamino and C_3-10A cycloalkyl group;

further preferably, R¹³Selected from halogen, hydroxy, C_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy, hydroxy C_1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-3Alkylamino radical, C_1-3Alkylacylamino group, C_1-3Alkyl acyl, amino acyl, C_1-3Alkylaminoacyl, di-C_1-3Alkylamino and C_3-6A cycloalkyl group;

even more preferably, R¹³Selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, methoxy, ethoxy, propoxy, isopropoxy, nitro, carboxy, cyano, amino, methylamino, ethylamino, propylamino, isopropylAmino, dimethylamino, diethylamino, methylethylamino, dipropylamino, methylpropylamino, ethylpropylamino, methylacylamino, ethylacrylamino, vinylacylamino, methylacyl, ethylacoyl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

L¹selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, and-C_1-6Alkyl radical O, S, halogeno-substituted imino C_1-6Alkyl, hydroxy-imino C_1-6Alkyl, alkylene C_1-6Alkoxy, halogeno-substituted imino C_1-6Alkoxy, hydroxy-imino C_1-6Alkoxy, carbonyl and C_1-6An alkylamino group;

further preferably, L¹Selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, and-C_1-3Alkyl radical O, S, halogeno-substituted imino C_1-3Alkyl, hydroxy-imino C_1-3Alkyl, alkylene C_1-3Alkoxy, halogeno-substituted imino C_1-3Alkoxy, hydroxy-imino C_1-3Alkoxy, carbonyl and C_1-3An alkylamino group;

even more preferably, L¹Selected from the group consisting of a bond, -NHCO-, -CONH-, -NHCONH-, -NH-, methylene, ethylene, propylene, isopropylene, O, S, halomethylene, haloethylene, halopropylene, haloisopropylene, hydroxymethylene, hydroxyethylene, hydroxypropylene, hydroxyalkylene, methyleneoxy, ethyleneoxy, propyleneoxy, isopropyleneoxy, haloethyleneoxy, halopropyleneoxy, haloisopropyleneoxy, hydroxymethyleneoxy, hydroxyethyleneoxy, hydroxyethyleneisopropoxy, carbonyl, methyleneamino, ethyleneamino, propyleneamino, and isopropylaminoamino.

ring A is selected from C_3-10Cycloalkyl radical, C_3-10Heterocyclic group, C_6-18Aryl and C_5-18Heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be substituted with one or more halogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-6Alkylamino, di-C_1-6Alkylamino and C_3-10Cycloalkyl substitution;

further preferably, ring A is selected from C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-12Aryl and C_5-12Heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be substituted with one or more halogen, hydroxy, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-6Alkylamino, di-C_1-6Alkylamino and C_3-10Cycloalkyl substitution;

still more preferably, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, aziridinyl, azetidinyl, tetrahydropyrrolyl, pyrrolyl, piperidinyl, dihydropyrrolyl, tetrahydropyridinyl, pyridinyl, glycidyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrofuranyl, furanyl, dihydropyranyl, pyranyl, thiiranyl, sulfocyclobutyl, tetrahydrothienyl, thienyl, sulfocyclopentyl, dihydrothienyl, pyrazolidinyl, dihydropyrazolyl, pyrazolyl, imidazolidinyl, dihydroimidazolyl, imidazolyl, dihydropyrazolyl, oxazolidinyl, dihydrooxazolyl, imidazolyl, thiazolidinyl, dihydrothiazolyl, thiazolyl, isoxazolidinyl, dihydroisoxazolyl, isoxazolyl, isothiazolidinyl, di-and/or tri-substituted arylthio.Hydroisothiazolyl, isothiazolyl, hexahydropyrimidyl, tetrahydropyrimidinyl, dihydropyrimidyl, pyrimidinyl, hexahydropyridazinyl, tetrahydropyridazinyl, dihydropyridazinyl, pyridazinyl, piperazinyl, tetrahydropyrazinyl, dihydropyrazinyl, pyrazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithiohexacyclic, taurylamino, bicyclo [2.2.1 ] bicyclo]Heptylalkyl, azaspiro [2.3]]Hexalkyl, oxobicyclo [3.1.0]Hexyl, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, fluorenyl and indanyl, said radicals optionally being optionally substituted by one or more halogen, hydroxy, C_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy, hydroxy C_1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-3Alkylamino, di-C_1-3Alkylamino and C_3-6Cycloalkyl is substituted.

In some particular embodiments, the compounds of formula Ia according to the present invention or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof, wherein R¹Selected from the group consisting of chloro, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy and pentafluoroethoxy, R²Selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy and pentafluoroethoxy, R³Is selected from

R⁴Is methyl, R⁵、R⁶、R⁷Is H, R⁹Is a carboxyl group, R¹⁰Is H or fluorine.

In some particular embodiments, the compounds of formula Ib according to the invention, wherein R is¹、R²Each independently selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, ethoxy, methoxy, ethoxy, propoxy, butoxy, and butoxy, and butoxy, and/or butoxy,Difluoroethoxy and pentafluoroethoxy, R³Is selected from

R⁴Is methyl, R⁵、R⁶、R⁷Is H, R⁸Selected from the group consisting of hydrogen, methyl, ethyl, fluorine and chlorine, m is 1, ring A is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, aziridinyl, azetidinyl, tetrahydropyrrolyl, pyrrolyl, piperidinyl, dihydropyrrolyl, tetrahydropyridinyl, pyridinyl, glycidyl, tetrahydrofuryl, tetrahydropyranyl, dihydrofuranyl, furanyl, dihydropyranyl, pyranyl, thienylethyl, sulfocyclobutyl, tetrahydrothienyl, thienyl, sulfocyclopentyl, dihydrothienyl, pyrazolidinyl, dihydropyrazolyl, pyrazolyl, imidazolidinyl, dihydroimidazolyl, dihydropyrazolyl, oxazolidinyl, dihydrooxazolyl, imidazolyl, thiazolidinyl, dihydrothiazolyl, thiazolyl, isoxazolyl, dihydroisoxazolyl, isoxazolyl, and the like, Isothiazolidinyl, dihydroisothiazolyl, isothiazolyl, hexahydropyrimidyl, tetrahydropyrimidinyl, dihydropyrimidyl, pyrimidinyl, hexahydropyridazinyl, tetrahydropyridazinyl, dihydropyridazinyl, pyridazinyl, piperazinyl, tetrahydropyrazinyl, dihydropyrazinyl, pyrazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithiohexacyclic, taurylamino, bicyclo [2.2.1]Heptylalkyl, azaspiro [2.3]]Hexalkyl, oxobicyclo [3.1.0]Hexyl, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, fluorenyl and indanyl, said radicals optionally being optionally substituted by one or more halogen, hydroxy, C_1-3Alkyl, halo C_1-3Alkyl, hydroxy C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy, hydroxy C_1-3Alkoxy, nitro, carboxyl, cyano, amino, mono C_1-3Alkylamino, di-C_1-3Alkylamino and C_3-6Cycloalkyl substituted, R¹¹Is a hydroxyl group.

The present invention provides the following specific compounds:

In another aspect, the present invention provides a process for the preparation of a compound of the general formula of the present invention, comprising:

the compounds of formula I may be prepared by a) reacting a compound of formula 1 with a compound of formula 2 in the presence of a suitable solvent and in a suitable solvent at a suitable temperature, as conditions known in the art to be suitable for a Pictet-Spengler reaction,

or

Compounds of formula I the compounds of formula 4 may be prepared by b) reacting a compound of formula 1 with a compound of formula 3 in the presence of conditions known in the art as being suitable for a Pictet-Schpengler (Pictet-Spengler) reaction, e.g. in the presence of an acid, reacting a compound of formula 4 with a suitable group directly or via other conventional reactions to prepare a compound of formula I,

wherein the compound of formula 1 can be prepared by the reaction of formula 5

And a compound of formula 6

The compound (A) is reacted to obtain the compound,

the compound of formula 6 can be represented by formula 7

The compound of (A) is reacted with trifluoromethanesulfonic anhydride to obtain,

the compound of formula 2, the compound of formula 3, the compound of formula 5, or the compound of formula 7 may be prepared by a commercially available or conventional preparation method known in the art,

R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸m, Y are as defined above for formula I, X is halogen.

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof.

In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, further comprising one or more agents selected from the group consisting of: SERD, SERM, tyrosine protease inhibitor, EGFR inhibitor, VEGFR inhibitor, Bcr-Abl inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, MEK inhibitor, histone deacetylase inhibitor, VEGF antibody, EGF antibody, HIV protein kinase inhibitor, HMG-CoA reductase inhibitor, and the like.

In some embodiments, the present invention provides a compound of the present invention or an isomer, a pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, and a pharmaceutical composition comprising the compound of the present invention or the isomer, the pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, for treating and/or preventing an estrogen receptor related disease.

The compound of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.

In a fourth aspect, the present invention provides a use of a compound represented by general formula I, or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and/or preventing an estrogen receptor related disease, wherein the estrogen receptor related disease or condition includes but is not limited to: cancers associated with ER-alpha dysfunction (e.g., bone, breast, colorectal, endometrial, prostate, ovarian, and uterine cancers, etc.), leiomyoma (e.g., uterine leiomyoma, etc.), Central Nervous System (CNS) deficiencies (e.g., alcoholism, migraine, etc.), cardiovascular system deficiencies (e.g., aortic aneurysm, myocardial infarction susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, etc.), hematologic deficiencies (e.g., deep vein thrombosis, etc.), immune and inflammatory diseases (e.g., Graves 'disease, arthritis, multiple sclerosis, liver cirrhosis, etc.), infection susceptibility (e.g., hepatitis B, chronic liver disease, etc.), metabolic deficiencies (e.g., bone density, cholestasis, hypospadiae, obesity, osteoarthritis, osteopenia, osteoporosis, etc.), neurological deficiencies (e.g., Alzheimer's disease, diabetes mellitus, osteoporosis, etc.), neurological deficiencies (e.g., bone density, bone loss, liver damage, diabetes, obesity, diabetes, obesity, diabetes, obesity, diabetes, obesity, diabetes, and other diabetes, and other diabetes, diabetes, Parkinson's disease, migraine, vertigo, etc.), mental deficiency (e.g., anorexia nervosa, Attention Deficit Hyperactivity Disorder (ADHD), dementia, major depressive disorder, psychosis, etc.), and reproductive deficiency (e.g., abnormal menstrual onset age, endometriosis, infertility, etc.), etc. In some embodiments, the present invention relates to a method of treating an estrogen receptor related disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug, or a pharmaceutical composition comprising the same, wherein the estrogen receptor related disorder includes, but is not limited to: cancers associated with ER dysfunction (e.g., bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, etc.), leiomyomas (e.g., uterine leiomyoma, etc.), Central Nervous System (CNS) defects (e.g., alcoholism, migraine, etc.), cardiovascular system defects (e.g., aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, etc.), hematologic defects (e.g., deep vein thrombosis, etc.), immune and inflammatory diseases (e.g., Graves 'disease, arthritis, multiple sclerosis, liver cirrhosis, etc.), susceptibility to infection (e.g., hepatitis B, chronic liver disease, etc.), metabolic defects (e.g., bone density, cholestasis, hypospadiasis, obesity, osteoarthritis, osteopenia, osteoporosis, etc.), neurological defects (e.g., Alzheimer's disease, and the like, Parkinson's disease, migraine, vertigo, etc.), mental deficiency (e.g., anorexia nervosa, Attention Deficit Hyperactivity Disorder (ADHD), dementia, major depressive disorder, psychosis, etc.), and reproductive deficiency (e.g., abnormal menstrual onset age, endometriosis, infertility, etc.), etc.

The compound of the invention has more excellent antitumor activity, longer administration interval and less side effect.

Description of the terms

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The "hydrogen", "carbon" and "oxygen" in the compounds of the present invention include all isotopes thereof. Isotopes are understood to include those atoms having the same atomic number but different mass numbers. Lifting deviceFor example, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include¹³C and¹⁴c, isotopes of oxygen including¹⁶O and¹⁸o, and the like.

The "halogen" in the present invention means fluorine, chlorine, bromine and iodine. "halo" in the context of the present invention means substituted by fluorine, chlorine, bromine or iodine.

"alkyl" in the present invention means a straight-chain or branched saturated aliphatic hydrocarbon group, preferably a straight-chain or branched group having 1 to 6 carbon atoms, further preferably a straight-chain or branched group having 1 to 3 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

"alkylene" in the context of the present invention refers to a radical of an alkyl group which is formally left after removal of one hydrogen atom, such as methylene (-CH)₂-, ethylene (-CH)₂-CH₂-, propylene (-CH)₂-CH₂-CH₂-) etc., as used herein, said "C-ene_1-10Alkyl "means C_1-10Alkyl radicals formally leaving one hydrogen atom removed, said "C-ene_1-6Alkyl "means C_1-6Alkyl formally removes a hydrogen atom from the remaining radical. The alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

"haloalkyl" in the context of the present invention means an alkyl group substituted with at least one halogen.

"hydroxyalkyl" in the context of the present invention means an alkyl group substituted with at least one hydroxyl group.

"alkoxy" in the context of the present invention means-O-alkyl. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy and the like. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.

The "cycloalkyl group" in the present invention means a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

"Heterocyclyl" in the context of the present invention refers to a group ("C" in the context of the present invention) having a ring carbon atom and a 3-to 10-membered non-aromatic ring system of 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon_3-10The meaning of the "heterocyclic group having a valence of 3 to 10) is the same as that of the" heterocyclic group having a valence of 3 to 10 "). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. The heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system (e.g., a bicyclic system ("bicyclic heterocyclyl")) and can be saturated or can be partially unsaturated. The heterocyclic bicyclic ring system may include one or more heteroatoms in one or both rings. "heterocyclyl" also includes ring systems in which a heterocycle, as defined above, is fused to one or more carbocyclyl groups (in which the point of attachment is on the carbocyclyl or on the heterocycle), or in which a heterocycle, as defined above, is fused to one or more aryl or heteroaryl groups (in which the point of attachment is on the heterocycle), and in such cases the number of ring members continues to be referred to as the number of ring members in the heterocyclic system. Unless otherwise specified, each instance of a heterocyclyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl. Fusion to C₆Exemplary 5-membered heterocyclyl groups for aryl rings (also referred to herein as 5, 6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolonyl, and the like. Exemplary fused to aryl Ring6-membered heterocyclyl groups (also referred to herein as 6, 6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

"aryl" as used herein refers to an aromatic system which may comprise a single ring or fused polycyclic ring, preferably a single ring or fused bicyclic ring, having from 6 to 18 carbon atoms, preferably from about 6 to about 12 carbon atoms. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, fluorenyl, indanyl. Aryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.

The term "heteroaryl" as used herein refers to an aryl group having at least one carbon atom replaced by a heteroatom, said heteroatom being O, S, N. Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridinyl, quinazolinyl, pyrrolyl, imidazolonyl, furanyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, and the like. Among them, the "heteroaryl group" in the present invention is preferably composed of 5 to 18 atoms (in the present invention, simply referred to as "5-to 18-membered heteroaryl group" or "C_5-18A heteroaromatic group ") consisting of 5 to 12 atoms, at least one atom of which is a heteroatom. Suitable five-to twelve-membered heteroaryl groups include, but are not limited to, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents may be at any available point of attachment.

"isomers" of the present invention are compounds having the same molecular formula but differing in nature or in the bond sequence of their atoms or in the spatial arrangement of their atoms. Stereoisomers are isomers whose atoms differ in their spatial arrangement. Stereoisomers that are not mirror images of each other are diastereomers and stereoisomers that are non-overlapping mirror images of each other are enantiomers. When the compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers are characterized by the absolute configuration of their asymmetric centers and are described and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers, respectively) by the R-and S-sequencing rules of Cahn and Prelog, or by methods in which molecules rotate the plane of polarized light. The chiral compound may exist as a single enantiomer or a mixture thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures".

The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

"solvate" of the present invention refers in the conventional sense to a complex of a solute (e.g., active compound, salt of active compound) and a solvent (e.g., water) in combination. Solvent means a solvent known or readily determined by one skilled in the art. If water, the solvate is often referred to as a hydrate, e.g., a hemihydrate, monohydrate, dihydrate, trihydrate or a substitute amount thereof, and the like.

The in vivo effect of the compound of formula (I) may be exerted in part by one or more metabolites formed in the human or animal body after administration of the compound of formula (I). As mentioned above, the in vivo effect of the compounds of formula (I) may also be exerted via metabolism of the precursor compounds ("prodrugs"). The "prodrug" of the present invention refers to a compound which is converted into a compound of the formula (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound which is converted into a compound of the formula (I) by oxidation, reduction, hydrolysis or the like by an enzyme, a compound which is converted into a compound of the formula (I) by a hydrolysis reaction of gastric acid or the like, or the like. Suitable pharmaceutically acceptable prodrugs of compounds of formula I having a carboxy group are, for example, in vivo cleavable esters thereof. An in vivo cleavable ester of a compound of formula I comprising a carboxy group is a pharmaceutically acceptable ester which is cleaved, for example, in the human or animal body to yield the parent acid. Suitable pharmaceutically acceptable esters for the carboxy group include alkyl esters such as methyl, ethyl and tert-butyl esters, alkoxymethyl esters such as methoxymethyl esters; alkanoyloxymethyl esters such as pivaloyloxyester; 3-phthalidyl ester; cycloalkylcarbonyloxyalkyl esters such as cyclopentylcarbonyloxymethyl ester and 1-cyclohexylcarbonyloxyethyl ester; 2-oxo-1, 3-dioxolyl (dioxolyl) methyl ester, such as 5-methyl-2-oxo-1, 3-dioxol-4-ylmethyl ester; and alkoxycarbonyloxyalkyl esters such as methoxycarbonyloxymethyl ester and 1-methoxycarbonyloxyethyl ester. Suitable pharmaceutically acceptable prodrugs of compounds of formula I having a carboxyl group are, for example, in vivo cleavable amides such as N-alkyl amides and N, N-dialkyl amides, e.g. N-methyl amide, N-ethyl amide, N-propyl amide, N-dimethyl amide, N-ethyl-N-methyl amide or N, N-diethyl amide.

Bioisosteres (or simply "isosteres") of the invention are terms commonly accepted in the art for defining pharmaceutical analogs in which one or more atoms (or groups of atoms) have been replaced with replacement atoms (or groups of atoms) having similar steric and/or electronic characteristics as those atoms with which they are replaced.

The "crystal" in the present invention is a solid whose internal structure is formed by repeating constituent atoms (or groups thereof) regularly in three dimensions, and is different from an amorphous solid having no such regular internal structure.

The "pharmaceutical composition" of the present invention is meant to comprise a mixture of any of the compounds described herein, including the corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts, or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The compositions are generally useful for the preparation of medicaments for the treatment and/or prevention of diseases mediated by one or more kinases.

By "pharmaceutically acceptable carrier" herein is meant a carrier that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, including all solvents, diluents or other excipients, dispersants, surfactant isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like. Unless any conventional carrier medium is incompatible with the compounds of the present invention. Some examples of carriers that may be pharmaceutically acceptable include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, and cellulose acetate; malt, gelatin, and the like.

"excipient" in the context of the present invention refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the compound. Excipients may include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.

The term "use in a medicament for treating and/or preventing an estrogen receptor related disease" of the present invention means that the estrogen receptor related disease, including estrogen receptor alpha related diseases and estrogen receptor beta related diseases, such as cancers associated with estrogen receptor dysfunction (e.g., bone cancer, breast cancer, colorectal cancer, etc.), can be ameliorated, inhibited, growth, development and/or metastasis of the estrogen receptor related disease is inhibited, or the risk of the estrogen receptor related disease is reduced by administering to a human or animal in need thereof a therapeutically and/or prophylactically effective amount of a compound of the present invention to inhibit, slow down or reverse the growth, development or spread of the estrogen receptor related disease in the subject, ameliorate the estrogen receptor related disease, or reduce the risk of the estrogen receptor related disease, Endometrial, prostate, ovarian, and uterine cancers, etc.), leiomyoma (e.g., uterine leiomyoma, etc.), Central Nervous System (CNS) deficiency (e.g., alcoholism, migraine, etc.), cardiovascular system deficiency (e.g., aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, etc.), blood system deficiency (e.g., deep vein thrombosis, etc.), immune and inflammatory disease (e.g., graves ' disease, arthritis, multiple sclerosis, liver cirrhosis, etc.), susceptibility to infection (e.g., hepatitis b, chronic liver disease, etc.), metabolic deficiency (e.g., bone density, cholestasis, hypospadiaspadia, obesity, osteoarthritis, osteopenia, osteoporosis, etc.), neurological deficiency (e.g., alzheimer's disease, parkinson's disease, migraine, vertigo, etc.), mental deficiency (e.g., anorexia nervosa, urinary tract, hypospae.g., obesity, osteoarthritis, osteoporosis, etc.), mental deficiency (e.g., anorexia nervosa, diabetes, etc.) Attention Deficit Hyperactivity Disorder (ADHD), dementia, major depressive disorder, psychosis, etc.), and reproductive deficiencies (e.g., age-abnormality in menstrual onset, endometriosis, infertility, etc.).

Detailed Description

The following representative examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention. The materials used in the following examples are all commercially available unless otherwise specified.

Example 11- (3, 5-difluoro-4- ((1R,3R) -2- ((S) -3-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) azetidine-3-carboxylic acid

Step a (S) -Synthesis of methyl 3-fluoro-2-methylpropionate

To a solution of methyl (R) -3-hydroxy-2-methylpropionate (2.0g, 16.93mmol) dissolved in 20mL of dichloromethane was added dropwise N, N-diethyl-1, 1,2,3,3, 3-hexafluoropropylamine at room temperature under an argon atmosphere. After the addition was complete, the reaction mixture was stirred at room temperature for one hour, then heated to reflux and stirred for 4 hours. The reaction mixture was cooled again to room temperature and stirred for 8 hours. After completion of the reaction, the reaction mixture was poured into ice water (10mL) and extracted with dichloromethane, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated. The title compound was obtained and used directly in the next reaction.

Step b (S) -Synthesis of 3-fluoro-2-methylpropanol

In a 500mL three-necked flask, (S) -methyl 3-fluoro-2-methylpropionate (2.3g, 19.15mmol) was added, dissolved in 100mL of anhydrous tetrahydrofuran, cooled to about 0 ℃ in a low-temperature reactor, and slowly added in portions with lithium aluminum hydride (0.78g, 20.53 mmol). After the addition was complete, the reaction mixture was stirred at 0 ℃ and room temperature for 1h each. After the reaction is finished, sodium sulfate decahydrate is slowly added in batches, the mixture is stirred for 1 hour and then filtered, a filter cake is washed by a small amount of tetrahydrofuran, and the filtrate is concentrated to be dry to obtain the title compound.

Step c Synthesis of (S) -3-fluoro-2-methylpropyl trifluoromethanesulfonate

In a 250mL reaction flask, (S) -3-fluoro-2-methylpropanol (1.8g, 19.54mmol), 2, 6-lutidine (2.8mL, 23.7mmol) were added, dissolved in 20mL of dichloromethane and then cooled to-10 ℃ with cooling. Trifluoromethanesulfonic anhydride (3.13mL, 18.63mmol) was dissolved in 10mL of dichloromethane and added dropwise to the reaction mixture, and the reaction was continued for 1h after completion of the dropwise addition. After completion of the reaction, the reaction mixture was washed with 2N hydrochloric acid (2X 20mL), saturated sodium bicarbonate (2X 20mL) and saturated sodium chloride solution (2X 20mL), respectively, dried over anhydrous sodium sulfate, and dichloromethane was removed under reduced pressure to give the title compound.

Step d Synthesis of (S) -N- ((R) -1- (1H-indol-3-yl) propan-2-yl) -3-fluoro-2-methylpropyl-1-amine

In a 100mL reaction flask, (S) -3-fluoro-2-methylpropyl trifluoromethanesulfonate (2.72g, 12.10mmol), (R) -1- (1H-indol-3-yl) propan-2-amine (1.75g, 10.04mmol) and diisopropylethylamine (3.32mL, 20.08mmol) were added, dissolved in 30mL dioxane, reacted at 90 ℃ under argon for 2H, stopped, concentrated, purified by column chromatography to give the title compound. ESI-Ms M/z 249.1[ M + H ]]⁺。

Step e Synthesis of (1R,3R) -1- (4-bromo-2, 6-difluorophenyl) -2- ((S) -3-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole

In a 50mL single neck flask, 4-bromo-2, 6-difluorobenzaldehyde (0.535g, 2.42mmol) and (S) -N- ((R) -1- (1H-indol-3-yl) propan-2-yl) -3-fluoro-2-methylpropyl-1-amine (0.50g, 2.0mmol) were added, 4mL acetic acid and 20mL toluene were added, reacted at 90 ℃ for 3H, concentrated, and purified by column chromatography to give the title compound 0.61 g. ESI-Ms M/z 451.1[ M + H ]]⁺。

Step f synthesis of methyl 1- (3, 5-difluoro-4- ((1R,3R) -2- ((S) -3-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) azetidine-3-carboxylate

(1R,3R) -1- (4-bromo-2, 6-difluorophenyl) -2- ((S) -3-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] in a microwave retort]Indole (910mg, 2.02mmol), azetidine-3-carboxylic acid methyl ester hydrochloride (367mg, 2.42mmol), tris (dibenzylideneacetone) dipalladium (370mg,0.404mmol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (391mg, 0.82mmol), and cesium carbonate (2.0g, 6.06mmol) were added to dioxane (20 mL). After sufficient replacement of argon, the mixture was heated to 100 ℃ for microwave reaction. After the reaction was completed, filtration was carried out and the mother liquor was concentrated. The reaction product was used directly in the next step. ESI-Ms M/z 486.3[ M + H ]]⁺。

Step g Synthesis of 1- (3, 5-difluoro-4- ((1R,3R) -2- ((S) -3-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) azetidine-3-carboxylic acid

In a 50mL single-necked bottle, 1- (3, 5-difluoro-4- ((1R,3R) -2- ((S) -3-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] was added]Indol-1-yl) phenyl) azetidine-3-carboxylic acid methyl ester (0.62g, 1.307mmol), dissolved in 10mL tetrahydrofuran and 5mL methanol, 7.5M sodium hydroxide solution (3.0mL, 22.5mmol) was added,reacting at room temperature for 3h, adjusting the pH value to 6.5 by using 2N hydrochloric acid, extracting by using ethyl acetate, washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, concentrating, and carrying out column chromatography to obtain the 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]⁺。

Example 21- (3-chloro-5-fluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) azetidine-3-carboxylic acid

Step a: synthesis of (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2-fluoro-2-methylpropan-1-amine

The preparation was carried out in analogy to the preparation of example 1 steps b-d, except that the starting material methyl (S) -3-fluoro-2-methylpropionate was replaced by methyl 2-fluoro-2-methylpropionate to give the title compound. ESI-Ms M/z 249.1[ M + H ]]⁺.

Step b: synthesis of 1- (3-chloro-5-fluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) azetidine-3-carboxylic acid

Preparation was analogous to the preparation of example 1, steps e-g, except that the starting material (S) -N- ((R) -1- (1H-indol-3-yl) propan-2-yl) -3-fluoro-2-methylpropyl-1-amine was replaced with (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2-fluoro-2-methylpropan-1-amine, and the starting material 4-bromo-2, 6-difluorobenzaldehyde was replaced with 4-bromo-2-chloro-6-fluorobenzaldehyde to give the title compound.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]⁺。

Example 31- (4- ((1R,3R) -2- (2, 2-difluoropropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) -3, 5-difluorophenyl) azetidine-3-carboxylic acid

Step a Synthesis of 2, 2-difluoro-2-methylpropyl-1-ol

2, 2-difluoro-2-methylpropanoic acid (5g, 45.5mmol) was added to a 250mL three-necked flask, dissolved in 100mL anhydrous tetrahydrofuran, cooled to about-10 ℃ in a low temperature reactor, and lithium aluminum hydride (2.1g, 54.2mmol) was added slowly in portions and the reaction was continued for 1h while maintaining the temperature. After the reaction was completed, 2.1mL of water, 2.1mL of 15% aqueous sodium hydroxide solution and 4.2mL of water were sequentially added dropwise, the mixture was stirred for 15min, then filtered, the filter cake was washed with a small amount of tetrahydrofuran, and the filtrate was concentrated to dryness to give the title compound. ESI-Ms M/z 97.0[ M + H ]]⁺。

Step b Synthesis of (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2, 2-difluoropropyl-1-amine

Preparation method the title compound was prepared according to the preparation method of example 1, steps c-d, except that the starting material (S) -3-fluoro-2-methylpropanol was replaced with 2, 2-difluoro-2-methylpropyl-1-ol. ESI-Ms M/z 253.0[ M + H ]]⁺。

Step c Synthesis of 1- (4- ((1R,3R) -2- (2, 2-difluoropropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) -3, 5-difluorophenyl) azetidine-3-carboxylic acid

Preparation methodThe title compound was prepared in analogy to the preparation of example 1, steps e-g, except that the starting material (S) -N- ((R) -1- (1H-indol-3-yl) propan-2-yl) -3-fluoro-2-methylpropyl-1-amine was replaced with (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2, 2-difluoropropyl-1-amine.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]⁺。

Example 41- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) -3-methylazetidine-3-carboxylic acid

The preparation was carried out in analogy to the preparation of example 2, except that the starting material azetidine-3-carboxylic acid methyl ester hydrochloride was replaced by 3-methylazetidine-3-carboxylic acid methyl ester hydrochloride to give the title compound.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]⁺。

Example 51- (3, 5-difluoro-4- ((1R) -6-fluoro-2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indol-1-yl) phenyl) azetidine-3-carboxylic acid

Step a Synthesis of 5-fluoro-3-hydroxy-3- (2-oxopropyl) -indolin-2-one

5-Fluoroisatin (1.65g, 10mmol) was dissolved in 50mL of acetone, potassium carbonate (13mg, 1.0mmol) was added, and the reaction was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate/petroleum ether to give the title compound. ESI-Ms M/z 224.10[ M + H ]]⁺。

Step b Synthesis of 1- (5-fluoro-1H-indol-3-yl) propyl-2-ol

The product of step a, 5-fluoro-3-hydroxy-3- (2-oxopropyl) -indolin-2-one (2.23g, 10mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, borane tetrahydrofuran solution (30mL, 1M, 30mmol) was added dropwise, and the reaction was carried out at room temperature for 4 h. The reaction solution was poured into a mixed solution of 50mL of ethyl acetate and 50mL of water, the aqueous layer was extracted with 30mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give the title compound. ESI-Ms M/z 194.10[ M + H ]]⁺。

Step c Synthesis of 1- (5-fluoro-1H-indol-3-yl) propyl-2-one

The product 1- (5-fluoro-1H-indol-3-yl) propyl-2-ol (1.93g, 10mmol) from step b was dissolved in 20mL of dichloromethane, and 1,1, 1-triacetoxy-1, 1-dihydro-1, 2-benziodo-3- (1H) -one (4.66g, 11mmol) was added and reacted at room temperature for 2H. The reaction mixture was washed with 20mL of water and 20mL of saturated saline in this order, and the organic layer was dried over anhydrous sodium sulfate. Column chromatography gave 1.76g of the title compound. ESI-Ms M/z 192.10[ M + H ]]⁺。

Step d Synthesis of 1- (5-fluoro-1H-indol-3-yl) propyl-2-amine

Dissolve 1- (5-fluoro-1H-indol-3-yl) propyl-2-one (1g, 5.2mmol) obtained in step c in 20mL of methanol, add amine acetate (4.45g, 57.73mmol) and sodium cyanoborohydride (0.37g, 5.9mmol), and react at room temperature for 48H. 1N hydrochloric acid was added to adjust pH to 2, the organic solvent was distilled off under reduced pressure, and 50mL of methylene chloride was washed with ethanol. The aqueous layer was adjusted to pH 12 with 4N aqueous sodium hydroxide solution, extracted with 3X 50mL of dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. Column chromatography gave the title compound. ESI-Ms M/z 193.10[ M + H ]]⁺。

Step e synthesis of 1- (3, 5-difluoro-4- ((1R) -6-fluoro-2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indol-1-yl) phenyl) azetidine-3-carboxylic acid

The preparation was carried out in analogy to the preparation of example 2, except that the starting material (R) -1- (1H-indol-3-yl) propan-2-amine was replaced with 1- (5-fluoro-1H-indol-3-yl) propyl-2-amine prepared in step d and the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde was replaced with 4-bromo-2, 6-difluorobenzaldehyde to give the title compound.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]⁺.

Example 65- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) -5-azaspiro [2.3] hexane-1-carboxylic acid

The preparation was similar to that of example 2, except that the starting 4-bromo-2-chloro-6-fluorobenzaldehyde was replaced with 4-bromo-2, 6-difluorobenzaldehyde and the starting azetidine-3-carboxylic acid methyl ester hydrochloride was replaced with 5-azaspiro [2.3]]Hexane-1-carboxylic acid methyl ester to give the title compound.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]⁺.

Example 71- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) -1H-pyrazole-4-carboxylic acid

The preparation was carried out in analogy to the preparation of example 2, except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde was replaced by 4-bromo-2, 6-difluorobenzaldehyde and the starting material azetidine-3-carboxylic acid methyl ester hydrochloride was replaced by 4-pyrazolecarboxylic acid ethyl ester to give the title compound.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]⁺.

Example 81- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) -5-pyrrolidone-3-carboxylic acid

The preparation process was similar to that of example 2 except that the starting material 4-bromo-2-chloro-6-fluorobenzaldehyde was replaced with 4-bromo-2, 6-difluorobenzaldehyde and the starting material azetidine-3-carboxylic acid methyl ester hydrochloride was replaced with 5-pyrrolidone-3-carboxylic acid methyl ester to give the title compound.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]⁺.

Example 9(E) -3- (3, 5-difluoro-4- ((1R,3R) -2- (2, 2-difluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) acrylic acid

Step a Synthesis of methyl (E) -3- (3, 5-difluoro-4-formylphenyl) acrylate

4-bromo-2, 6-difluoro-1-benzaldehyde (6.66g, 30mmol), triethylamine (8.4mL, 60mmol), palladium acetate (0.34g, 1.5mmol) and trimethylphosphine (1.0g, 3.2mmol) were dissolved in N, N-dimethylformamide (70mL) and degassed. Methyl acrylate (4.3mL, 45.0mmol) was then added and the reaction was heated to 80 ℃ for 4 h. After cooling, the mixture was added to water (300mL) and extracted with ethyl acetate (2X 400 mL). The combined organic phases were washed with 2N dilute hydrochloric acid (200mL), then dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography to afford the title compound. ESI-Ms M/z 227.04[ M + H ]]⁺。

Step b Synthesis of methyl (E) -3- (3, 5-difluoro-4- ((1R,3R) -2- (2, 2-difluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) acrylate

Into a 100mL reaction flask were charged (R) -methyl N- (1- (1H-indol-3-yl) propan-2-yl) -2, 2-difluoropropyl-1-amine (0.252g, 1mmol) prepared in example 3, methyl (E) -3- (3, 5-difluoro-4-formylphenyl) acrylate (0.181g, 0.8mmol) and glacial acetic acidAcid (0.29mL, 5mmol), toluene (25 mL) were added and dissolved, reaction was carried out at 90 ℃ for 6h, the reaction solution was concentrated, and column chromatography purification was carried out to give the title compound. ESI-Ms M/z 461.2[ M + H ]]⁺。

Step c Synthesis of (E) -3- (3, 5-difluoro-4- ((1R,3R) -2- (2, 2-difluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) acrylic acid

In a 50mL single-neck flask, the product of step b (E) -3- (3, 5-difluoro-4- ((1R,3R) -2- (2, 2-difluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] was added]Indol-1-yl) phenyl) acrylic acid methyl ester (0.221g, 0.48mmol), dissolved in 8mL of tetrahydrofuran and 4mL of methanol, added with 7.5M aqueous sodium hydroxide (0.64mL, 4.8mmol), reacted at room temperature for 2h, adjusted to pH 6.5 with 2N dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give the 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]⁺.

Example 10(E) -3- (3-chloro-5-fluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) acrylic acid

The procedure is analogous to that of example 9, except that the starting 4-bromo-2, 6-difluoro-1-benzaldehyde is replaced by 4-bromo-2-chloro-6-fluorobenzaldehyde and the starting (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2, 2-difluoropropyl-1-amine is replaced by (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2-fluoro-2-methylpropan-1-amine prepared in example 2 to give the title compound.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]⁺.

Example 11(E) -3- (3- (difluoromethoxy) -5-fluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) acrylic acid

The title compound was obtained in a similar manner to the preparation of example 10 except that the starting 4-bromo-2-chloro-6-fluorobenzaldehyde was replaced with 4-bromo-2- (difluoromethoxy) -6-hydroxybenzaldehyde.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]⁺.

Example 12(Z) -3- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) -2-fluoroacrylic acid

Step a Synthesis of (Z) -3- (3, 5-difluoro-4-formylphenyl) -2-fluoro-acrylic acid methyl ester

In a 100mL reaction flask, 4-bromo-2, 6-difluoro-1-benzaldehyde (1g, 4.93mmol), methyl 2-fluoroacrylate (1.54g, 14.77mmol), tri-o-tolylphosphine (0.15g, 0.493mmol), palladium acetate (0.06g, 0.247mmol) and triethylamine (1.00g, 9.86mmol) were added, followed by 2Dissolving 0mL of N, N-dimethylformamide, and reacting at 80 ℃ for 6 hours under the protection of argon. After the reaction is finished. Adding 20mL of ice water, stirring, extracting with ethyl acetate, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain the title compound. ESI-Ms M/z 245.1[ M + H ]]⁺。

Step b Synthesis of (Z) -3- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) -2-fluoroacrylic acid

The preparation is analogous to that of example 9, steps b-c, except that the starting material (E) -methyl 3- (3, 5-difluoro-4-formylphenyl) acrylate is replaced by (Z) -methyl 3- (3, 5-difluoro-4-formylphenyl) -2-fluoro-acrylate and the starting material (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2, 2-difluoropropyl-1-amine is replaced by (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2-fluoro-2-methylpropan-1-amine, the title compound was obtained.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]⁺.

Example 13(E) -3- (3, 5-dichloro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) acrylic acid

The title compound was obtained in a similar manner to the preparation of example 10 except that the starting material, 4-bromo-2-chloro-6-fluorobenzaldehyde, was replaced with 4-bromo-2, 6-dichlorobenzaldehyde.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]⁺.

Example 14(E) -3- (3-fluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) -5-methoxyphenyl) acrylic acid

The title compound was obtained in a similar manner to the preparation of example 10 except that the starting material 4-bromo-2-chloro-6-fluoro-benzaldehyde was replaced with 4-bromo-2-fluoro-6-methoxybenzaldehyde.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]⁺.

Example 151- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indol-1-yl) phenyl) azetidine-3-carboxylic acid

The preparation process was similar to that of example 2 except that 4-bromo-2-chloro-6-fluorobenzaldehyde, which is a starting material, was replaced with 4-bromo-2, 6-difluorobenzaldehyde to prepare the title compound.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]⁺.

Example 161- (3-fluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indol-1-yl) -5-methoxyphenyl) azetidine-3-carboxylic acid

The title compound was prepared in analogy to the preparation of example 2, except that the starting material 4-bromo-2-chloro-6-fluoro-benzaldehyde was replaced with 4-bromo-2-fluoro-6-methoxybenzaldehyde.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]⁺.

Example 173 ',5' -difluoro-4 '- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) - [1,1' -biphenyl ] -4-carboxylic acid

Step a Synthesis of methyl 3',5' -difluoro-4 '-formyl- [1,1' -biphenyl ] -4-carboxylate

(4- (methoxycarbonyl) phenyl) boronic acid (1.97g,11mmol), 4-bromo-2, 6-difluorobenzaldehyde (2.21g,10mmol), 1, 3-bis (diphenylphosphino) propanenickel chloride (54mg,0.1mmol), potassium phosphate (8.48g,40mmol) and 60mL dioxane were mixed in a 100mL eggplant-shaped flask, heated to 110 ℃ under argon protection and stirred, and reacted at the same temperature for 10 h. Concentrating under reduced pressure, removing organic solvent, diluting with 100mL ethyl acetate, washing with 50mL saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering, and concentrating. The residue was chromatographed on silica gel to give the title compound. ESI-Ms M/z 277.1[ M + H ]]⁺。

Step b Synthesis of 3',5' -difluoro-4 '- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) - [1,1' -biphenyl ] -4-carboxylic acid

The preparation is analogous to that of example 9, steps b-c, but withoutSimilarly, the raw material (E) -3- (3, 5-difluoro-4-formylphenyl) acrylic acid methyl ester is replaced by the 3',5' -difluoro-4 '-formyl- [1,1' -biphenyl ] prepared in the step a]-4-carboxylic acid methyl ester and starting material (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2, 2-difluoropropyl-1-amine was replaced with (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2-fluoro-2-methylpropan-1-amine to give the title compound.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]⁺.

Example 183 ',5' -difluoro-4 '- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) - [1,1' -biphenyl ] -3-carboxylic acid

The preparation method was similar to that of example 17, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with (3- (methoxycarbonyl) phenyl) boronic acid to give the title compound.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]⁺.

Example 195- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) thiazole-2-carboxylic acid

Step a: synthesis of ethyl 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole-2-carboxylate

Ethyl 5-bromothiazole-2-carboxylate (4.68g, 20mmol), pinacol diboron diborate (5.59g, 22mmol), potassium acetate (5.88g, 60mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (1.4g, 1.8mmol) is dissolved in 100mL dioxane, argon is used for protection, stirring is carried out at 80 ℃ for 12h, most of solvent is distilled under reduced pressure, 150mL ethyl acetate is added, and the mixture is washed by saturated sodium chloride aqueous solution (100mL multiplied by 2), dried by anhydrous sodium sulfate and purified by column chromatography to obtain the target compound. ESI-Ms M/z 284.1[ M + H ]]⁺。

Step b: synthesis of ethyl 5- (3, 5-difluoro-4-formylphenyl) thiazole-2-carboxylate

Ethyl 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole-2-carboxylate (1.45g, 5.1mmol), 2, 6-difluoro-4-bromobenzaldehyde (936mg, 4.26mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Dissolving palladium dichloride (62.3mg, 0.085mmol) and 4.3mL of sodium carbonate aqueous solution (2M) in 10mL of toluene, heating and refluxing for 16h at 100 ℃ under the protection of argon, adding 50mL of saturated sodium chloride aqueous solution, extracting with ethyl acetate (50mL multiplied by 3), combining organic phases, drying with anhydrous sodium sulfate, distilling under reduced pressure to obtain a dark brown solid, and carrying out column chromatography to separate to obtain the target compound. ESI-Ms M/z 298.0[ M + H ]]⁺。

Step c: synthesis of 5- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) thiazole-2-carboxylic acid

The preparation is analogous to that of example 9, steps b-c, except that the starting material (E) -3- (3, 5-difluoro-4-formylphenyl)The title compound was prepared by replacing methyl acrylate with ethyl 5- (3, 5-difluoro-4-formylphenyl) thiazole-2-carboxylate prepared in the above procedure and replacing the starting material (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2, 2-difluoropropyl-1-amine with (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2-fluoro-2-methylpropan-1-amine.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]⁺。

Example 203 '-fluoro-4' - ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) -3,5 '-dimethoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation process was similar to that of example 17, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with (3-methoxy-4- (methoxycarbonyl) phenyl) boronic acid and the starting material 4-bromo-2, 6-difluorobenzaldehyde was replaced with 4-bromo-2-methoxy-6-fluorobenzaldehyde, to give the title compound.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]⁺.

Example 211- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) azetidine-3-carboxamide

In a 50mL single-neck flask, 1- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-)Methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyridine [3,4-b]Indol-1-yl) phenyl) azetidine-3-carboxylic acid methyl ester (180mg, 0.37mmol) and 10mL of ammonia in methanol were heated at 55 ℃ and stirred for 12h, the reaction was stopped, directly concentrated by rotary evaporation, purified by column chromatography to give the 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]⁺.

Example 222- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) cyclopropane-1-carboxylic acid

Step a Synthesis of 2, 6-difluoro-4-vinylbenzaldehyde

4-bromo-2, 6-difluorobenzaldehyde (3156mg,14.2mmol) and 4,4,5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborane (3300mg, 21.4mmol) were dissolved in a mixed solvent of 30mL dimethyl ether and 10mL water, potassium carbonate (3897mg, 28.2mmol) and bis (triphenylphosphine) palladium dichloride (300mg, 0.14mmol) were added under argon protection, heated to 80 ℃ for reaction for 5 hours, cooled, extracted with water and ethyl acetate, the organic layer was dried and concentrated to give the title compound. ESI-Ms M/z 169.1[ M + H ]]⁺。

Step b Synthesis of 2- (2, 6-difluoro-4-vinylphenyl) -1, 3-dioxolane

2, 6-difluoro-4-vinylbenzaldehyde (2500mg, 14.9mmol) and ethylene glycol (1670mg, 27mmol) was dissolved in 30mL of toluene, 490mg of p-toluenesulfonic acid was added, 2000mg of silica gel was added, and reaction was carried out at 113 ℃ for 8 hours. And preparing sand and performing column chromatography to obtain a title compound. ESI-Ms M/z 213.1[ M + H ]]⁺。

Step c Synthesis of ethyl 2- (4- (1, 3-dioxolan-2-yl) -3, 5-difluorophenyl) cyclopropane-1-carboxylate

Dissolving 2- (2, 6-difluoro-4-vinylphenyl) -1, 3-dioxolane (2120mg, 10mmol) and rhodium diacetate dimer (70mg, 0.25mmol) in 30mL of anhydrous dichloromethane, dissolving ethyl diazoacetate (4500mg, 40mmol) in 30mL of anhydrous dichloromethane, slowly dripping into a mixed solution of 2- (2, 6-difluoro-4-vinylphenyl) -1, 3-dioxolane and rhodium diacetate, dripping for 1 hour, reacting at room temperature for 1 hour, preparing sand, and performing column chromatography to obtain the title compound. ESI-Ms M/z 299.1[ M + H ]]⁺。

Step d Synthesis of ethyl 2- (3, 5-difluoro-4-formylphenyl) cyclopropane-1-carboxylate

Ethyl 2- (4- (1, 3-dioxolan-2-yl) -3, 5-difluorophenyl) cyclopropane-1-carboxylate (1700mg, 5.7mmol) was dissolved in 6mL of trifluoroacetic acid, 4mL of concentrated hydrochloric acid and 2mL of water were added, reaction was carried out at room temperature for 1 hour, water was added, extraction was carried out with ethyl acetate, the organic layer was dried, and concentration was carried out to obtain the title compound. ESI-Ms M/z 255.1[ M + H ]]⁺。

Step e Synthesis of methyl 2- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) cyclopropane-1-carboxylate

Ethyl 2- (3, 5-difluoro-4-formylphenyl) cyclopropane-1-carboxylate (254mg, 1 m)mol) and (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2-fluoro-2-methylpropan-1-amine (248mg, 1mmol) were dissolved in 20mL of toluene, 1mL of acetic acid was added, reaction was carried out at 80 ℃ for 4 hours, water was added, ethyl acetate was added for extraction, the organic layer was dried and concentrated to give the title compound. ESI-Ms M/z 471.1[ M + H ]]⁺。

Step f Synthesis of 2- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) cyclopropane-1-carboxylic acid

2- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indol-1-yl) phenyl) cyclopropane-1-carboxylic acid methyl ester (470mg, 1mmol) is dissolved in 10mL of tetrahydrofuran, 5mL of methanol is added, 1mL of 7.5N aqueous sodium hydroxide solution is added, reaction is carried out at room temperature for 1 hour, 2N dilute hydrochloric acid is added to adjust the pH to about 5, water and ethyl acetate are added for extraction, the organic layer is dried by spinning, sand preparation and column chromatography are carried out to obtain the title compound.¹H NMR(400MHz,DMSO-d₆)δ12.61(s,1H),10.57(s,1H),7.72(s,1H),7.52(d,1H),7.46(d,1H),7.40(d,1H),7.20(d,1H),5.21(s,1H),4.41(m,1H),3.47-3.57(m,1H),2.80-2.98(m,2H),2.53-2.63(m,2H),2.36(dd,1H),2.21(m,1H),1.45-1.70(m,2H),1.08-1.28(m,6H),1.07(d,3H)。ESI-Ms m/z:457.2[M+H]⁺。

Example 233, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) -N- ((1R,2S) -2-fluorocyclopropyl) benzamide

Step a Synthesis of 2- (4-bromo-2, 6-difluorophenyl) -1, 3-dioxolane

In a 1L reaction flask, 2, 6-difluoro-4-bromobenzaldehyde (17.76g, 80.7mmol), ethylene glycol (9.1mL,162.9mmol), p-toluenesulfonic acid monohydrate (200mg, 1.1mmol) were added, dissolved in 250mL of toluene, refluxed at 110 ℃ with water being removed from the trap and reacted for 6 h. After the reaction was complete, it was cooled to room temperature, washed with water (100 mL. times.3), washed with saturated aqueous sodium chloride (100mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound.

Step b Synthesis of methyl 3, 5-difluoro-4- (1, 3-dioxolan-2-yl) -benzoate

In a 100mL reaction flask, the product of step a, 2- (4-bromo-2, 6-difluorophenyl) -1, 3-dioxolane (1.4g, 5.3mmol), 1' -bisdiphenylphosphinoferrocene (300mg, 0.5mmol) and palladium acetate (300mg, 1.3mmol) were added, dissolved in a mixed solvent composed of 20mL of methanol and 25mL of N, N-dimethylformamide, and 1.18mL of triethylamine was added thereto, followed by stirring at 70 ℃ under a CO gas atmosphere for 3 hours. After the reaction was completed, it was cooled to room temperature, concentrated, dissolved in 100mL of ethyl acetate, washed with 1N hydrochloric acid (100mL), washed with water (100mL), and washed with a saturated aqueous solution of sodium chloride (100mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the title compound. ESI-Ms M/z 245.1[ M + H ]]⁺。

Step c Synthesis of 3, 5-difluoro-4- (1, 3-dioxolan-2-yl) -benzoic acid

In a 100mL reaction flask, methyl 3, 5-difluoro-4- (1, 3-dioxolan-2-yl) -benzoate (244mg, 1mmol) obtained in step b was added, dissolved in a mixed solvent composed of 5mL of methanol and 5mL of tetrahydrofuran, and 5mL of an aqueous solution of sodium hydroxide (120mg, 3mmol) was added and stirred at room temperature for 0.5 h. After the reaction, the reaction mixture was concentrated, dissolved in 25mL of water, adjusted to pH 2 with 1N hydrochloric acid, extracted with 25mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound. ESI-Ms M/z 231.0[ M + H ]]⁺。

Step d Synthesis of 4- (1, 3-Dioxolan-2-yl) -3, 5-difluoro-N- ((1S,2R) -2-fluorocyclopropyl) benzamide

In a 100mL reaction flask, the product of step c, 3, 5-difluoro-4- (1, 3-dioxolan-2-yl) -benzoic acid (230mg, 1mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (230mg, 1.2mmol) and 1-hydroxybenzotriazole (162mg, 1.2mmol) were added, dissolved in 15mL dichloromethane, 0.41mL triethylamine was added, and (1S,2R) -2-fluorocyclopropylamine p-toluenesulfonate (300mg, 1mmol) was added and stirred at room temperature for 2 h. After the reaction is finished, the reaction liquid is dried by spinning and subjected to column chromatography to obtain the title compound. ESI-Ms M/z 288.1[ M + H ]]⁺。

Step e Synthesis of 3, 5-difluoro-N- ((1S,2R) -2-fluorocyclopropyl) -4-formylbenzamide

In a 100mL reaction flask, the product from step d (1, 3-dioxolan-2-yl) -3, 5-difluoro-N- ((1S,2R) -2-fluorocyclopropyl) benzamide (240mg, 0.84mmol) was added, dissolved in 20mL of dichloromethane, and 1.5mL of trifluoroacetic acid was added and stirred at room temperature overnight. After the reaction was complete, the reaction mixture was washed with water (50 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound. ESI-Ms M/z 244.1[ M + H ]]⁺。

Step f Synthesis of 3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) -N- ((1R,2S) -2-fluorocyclopropyl) benzamide

In a 100mL reaction flask, 3, 5-difluoro-N- ((1S,2R) -2-fluorocyclopropyl) -4-formylbenzamide (200mg, 0.82mmol) and (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2-fluoro-2-methylpropan-1-amine (200mg, 0.81mmol) were added, dissolved in 5mL toluene, and 0.5mL glacial acetic acid was added and reacted at 80 ℃ for 3H. After the reaction, the reaction mixture was added dropwise to 50mL of saturated sodium bicarbonate solution, extracted with 50mL of ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and filteredThe solution was filtered, concentrated and column chromatographed to give the title compound. ESI-Ms M/z 474.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆):δ10.57(s,1H),7.72(s,1H),7.52(d,1H),7.46(d,2H),7.40(d,1H),7.20(d,1H),6.92-7.06(m,1H),5.21(s,1H),4.41(m,1H),3.47-3.57(m,1H),2.80-2.98(m,2H),2.53-2.58(m,2H),2.36(dd,1H),1.08-1.28(m,6H),1.07(d,3H),0.55-0.61(m,2H).

According to the synthesis of examples 1 to 23 of the present invention, the compounds of examples 24 to 31 were synthesized using different commercially available starting materials, the characterization parameters of which are shown in Table 1:

table 1:

experimental example 1 evaluation of cell-level-based ER level Activity of Compounds in vitro

1. Experimental Material

The control compound was compound (AZD9496) disclosed in WO 2014/191726(PCT/GB2014/051607) example 1 under the chemical name (E) -3- (3, 5-difluoro-4- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) phenyl) acrylic acid, prepared with reference to the method described in WO 2014/191726 and identified by hydrogen and mass spectrometry.

Reagent: phosphate Buffered Saline (DPBS), Trypan blue, Polarscreen ER Alpha modifier Assay, available from Invitrogen;

fetal Bovine Serum (FBS), pancreatin, DMEM, penicillin-streptomycin (Pen/Strep), purchased from GIBCO;

dimethyl sulfoxide (DMSO), activated charcoal, formaldehydesolution, available from Sigma;

MCF-7 cells, purchased from AATCC;

estrogen Receptor alpha (D8H8) Rabbit mAb, available from CST corporation;

Goat anti-Rabbit IgG(H+L)Secondary Antibody、Alexa

conjugate, available from Thermo corporation;

tween 20, available from EIA GRADE.

The instrument comprises the following steps: biological safety cabinet, CO₂Incubator, purchased from Thermo Scientific;

centrifuge, available from Eppendorf corporation;

a cell counter, available from Invitrogen corporation;

inverted microscope, available from Olympus;

multiflow, available from BioTeck;

vortex mixer, available from IKA corporation;

envision, available from Perkin Elmer.

2. Experimental methods

2.1. Preparation of cell culture fluid and Compound

Preparation of serum-free FBS: weighing 1g of activated carbon, mixing with 50mL of fetal calf serum at 4 ℃ for 24h, and filtering and sterilizing through a 0.22 mu M filter membrane for later use;

preparing a cell culture solution: 50mL of FBS and 5mL of penicillin-streptomycin were added to 445mL of DMEM and mixed until use. Serum-free FBS was used for preparation of the serum-free cell culture medium.

Preparation of compound: the compounds of the present invention and the control compounds prepared in the above examples were each formulated to 100mM in DMSO and then diluted to 10nM, 3.33nM, 1.11nM, 0.37nM, 0.123nM, 0.041nM, 0.014nM, 0.0045nM, 0.0015nM, 0.0005nM, in that order.

2.2. Seeding cells

Cells in logarithmic growth phase in T75 cell culture flasks were discarded by adding 10mL of DPBS once. Adding 2mL of pancreatin digested cells, standing at 37 ℃ for 2 minutes, observing most of the cells under a microscope to be rounded, adding 5mL of serum-free cell culture solution to stop digestion, repeatedly blowing and beating a pipette, digesting the cells to prepare cell suspension, adding 10mL of cell culture solution, uniformly mixing, and counting; diluted to 1500 cells/40 u L cell suspension, using the Multiflow instrument cell spread into 384 holes cell culture plate, 40 u L/hole; after being balanced for 20min at room temperature, the mixture is placed in a cell culture box at 37 ℃ for 24 h.

2.3. Addition compound

Compounds were added to the cell culture plates using an Acho instrument at a final DMSO concentration of 0.3%; centrifuging at 1000rpm for 1min at room temperature, and culturing in a cell culture box at 37 deg.C for 24 h.

2.4. Immunofluorescence assay

Sucking out cell culture medium, washing cells with PBS for 1 time, and fixing cells with 3.7% paraformaldehyde solution (PBS for 20 min); the cells were washed 2 times with PBS and permeabilized with Tween-20(PBS diluted) at a final concentration of 0.5% for 1h at room temperature; washing cells with PBS-T (0.05% Tween-20 in PBS) for 2 times, adding ER antibody diluent (1:1000, diluted with 1% mil in PBS-T) in ER level determination, and incubating at room temperature for 1.5 h; PBS-T washing cells for 3 times, adding secondary antibody diluent (1:1000, diluted with 1% mil k in PBS) 2 μ g/mL Hochest 33342, and incubating at room temperature for 40 min; PBS-T washing cells 3 times, PBS washing cells 2 times; acumen read the ratio of ER positive signal values to nuclear signal values. The results are shown in Table 2.

TABLE 2

"-" indicates not measured

As can be seen from the above experimental results, the compounds of the present invention have good inhibitory activity against ER level at a cell-based level.

Experimental example 2 evaluation of cell Activity of Compounds in vitro

1. Experimental Material

Test compounds: the compounds of the present invention and control compounds prepared in the above examples were each formulated in DMSO at 10mM, and then sequentially diluted 3-fold at 100.00nM, 33.33nM, 11.11nM, 3.70nM, 1.23nM, 0.41nM, 0.14nM, 0.045nM, 0.015 nM.

The breast cancer cell strain MCF-7 is purchased from Nanjing Kaiky Bio.

Reagent: MEM, FBS, Trypsin-EDTA, Penicillin-Streptomyces, available from GIBCO, USA;

luminescent Cell visual Assay Kit, available from Progema, USA; paclitaxel, available from Tai Chi pharmaceutical, Sichuan.

2. Experimental methods

2.1. Cell seeding

Culture expanded MCF-7 cells were trypsinized, resuspended in fresh medium and counted. The resuspended cells were adjusted to 2X 10⁴cells/mL and added to a 96 well cell culture plate at 100 μ L per well, two wells per concentration. At 37 ℃ with 5% CO₂Incubate for 24h under conditions.

2.2. Addition compound

The compound was diluted to 2 Xworking solution with DMSO, 100. mu.L was transferred to assay wells at 37 ℃ with 5% CO₂Incubate under conditions for 96 h.

2.3. Fluorescent readings

Add 50. mu.L to the wells to be assayed

Luminescent Cell Viability Assay buffer and gently shaken up. After 10 minutes, placing the sample on an Envison to read fluorescence readings, calculating the cell survival rate (cell survival (%)), and calculating the formula of (Com-Min)/(Max-Min), wherein Max is the reading of a solvent control group, Min is the reading of a cell-free control group, Com is the reading of a compound treatment group, and the data are processed by XLfit and fitted to obtain IC₅₀The results are shown in Table 3.

TABLE 3

"-" indicates not measured

As can be seen from the above experiments, the compound of the present invention shows good inhibitory activity against MCF-7 breast cancer cells.

Experimental example 3 evaluation of Compound pharmacokinetics in vivo

Test compounds: the compounds of the present invention and the control compounds prepared in the above examples were each formulated with vehicle to be 2mg/kg for oral administration and 1mg/kg for intravenous injection.

Balb/c mice, purchased from Experimental animals, Inc. of Wei Tony, Beijing.

After the mice are orally taken at 2mg/kg and statically injected at 1mg/kg for single administration, blood is collected from orbital venous plexus for 2min,5min,15min,30min,1h,2h,6h,10h and 24h respectively, after plasma is centrifugally collected, detection is carried out by using LC-MS/MS, the measured blood concentration at each time point is drawn into a drug concentration-time curve, and pharmacokinetic parameters are calculated. The results are shown in Table 4.

TABLE 4

Test compounds	T_1/2(h)	Cmax(ng/ml)	AUC(h*ng/ml)	F(％)
					AZD9496	1.1	703.7	1229.9	45.5
Example 1	1.3	647	1948.9	58.1
					Example 2	3.2	583.4	3232.8	62.6
Example 3	4.3	410.2	2413.5	86.6
					Example 4	3.7	793.4	4548.4	64.3
Example 5	5.7	493.7	4893.3	81.1
					Example 6	3.2	1457.7	8373.5	80.5
Example 7	4	255.1	2768.2	86
					Example 9	5.2	474.6	3115	115.5
Example 10	3.9	1102.7	4525.6	70.4
					Example 12	3.4	125.4	767.9	28.8
Example 13	6.9	1326.1	16451.4	88
					Example 14	2.7	1023.8	2895.8	62.4
Example 15	2.3	598.1	2441.3	39.9
					Example 16	-	-	-	-
Example 17	12.1	1277.7	16073.7	80.5
					Example 20	7.6	1210.7	13602.1	79.0
Example 22	6.4	1676.5	4991.7	77.5
					Example 23	6.4	403.5	2100.1	41.3

"-" indicates not measured

The above experimental results show that the half-life (T) of the compounds of the present invention_1/2) Peak concentration (Cmax), area under the curve (AUC) and bioavailability (F) were all significantly better than the control compound. When the half-life of the compound is prolonged and the bioavailability is increased, the compound canThe administration interval of the compound is prolonged, the action time of the medicine is prolonged, the curative effect of the compound can be improved, and the administration amount of the compound can be reduced, so that the medicine is more effective and safer. Therefore, the compound of the invention has more excellent in vivo antitumor activity, and the administration interval is longer.

Experimental example 4 evaluation of drug efficacy of Compound in vivo MCF-7 subcutaneous transplantation tumor model

1. Cell culture

The medium was incubated with MEM containing 10% fetal bovine serum, 100U/ml penicillin and 100. mu.g/ml streptomycin at 37 ℃ under 5% CO₂MCF-7 breast cancer cells (purchased from Ky medium) were cultured in an incubator. The initial concentration of the cell culture was 1X 10⁶And (4) one cell per mL, and bottling and passaging after the cells are full every 3 to 4 days. Tumor cells in logarithmic growth phase were used for in vivo tumor inoculation.

2. Sustained release tablet and cell inoculation

2-3 days before cell inoculation, a sustained release tablet of beta-Estradiol (Estradiol-17 beta 60 days SE1210.72mg, purchased from Innovative Research of America) was inoculated into the left back of each mouse. Animals were urinated 1 week after inoculation, 3 times a week, and daily if necessary.

Will contain 10X 10⁶PBS of the cells was mixed with 100. mu.L of Matrigel (final volume 200. mu.L) and inoculated to the right rear of the mice.

3. Tumor measurement and Experimental indices

Test compounds: the compounds of the invention and the control compounds prepared in the above examples. The compounds of the invention and the control compounds were administered once daily (QD) for three weeks (3W).

The experimental index is to investigate whether the tumor growth is inhibited, delayed or cured. Tumor diameters were measured three times a week with a vernier caliper. The formula for tumor volume is: v is 0.5a × b²And a and b represent the major and minor diameters of the tumor, respectively.

The antitumor effect of the test compound was evaluated by the relative tumor growth rate T/C (%) and the tumor inhibition rate (%). The calculation formula of the relative tumor proliferation rate T/C (%) is as follows: T/C%_RTV/C_RTV×100％(T_RTV: treatment group RTV; c_RTV: negative control group RTV). Calculating Relative Tumor Volume (RTV) according to the tumor measurement result, wherein the calculation formula is that RTV is V_t/V₀In which V is₀When administered in groups (i.e. d)₀) Measurement of the resulting tumor volume, V_tTumor volume at a certain measurement, T_RTVAnd C_RTVThe same day data was taken. The tumor inhibition rate (%) was (1-T/C) × 100%.

The results of the test compounds on evaluation of the antitumor drug efficacy of the model of human breast cancer cell line MCF-7 subcutaneous transplanted tumors are shown in Table 5, in which the T/C (%) corresponding to each example compound is the mean T/C (%) calculated based on the tumor volume on day 21 after administration in each dose group of animals of each example compound.

TABLE 5

The experimental result shows that the compound of the invention has obviously better tumor inhibition effect on breast cancer than that of the positive drug AZD 9496. The compounds of the present invention, for example, the compounds of example 3, example 10, example 13, example 17, example 20, were significantly better at 0.6mg/kg than AZD9496 at the same dose, and far better at 2mg/kg than AZD 94966 mg/kg. In addition, some of the compounds of the present invention produced an effect comparable to that of the positive drug AZD9496 at one-tenth of the dose (0.6mg/kg VS 6 mg/kg).

Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.

Claims

1. A compound shown in a general formula I or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

R¹is fluorine;

R²selected from fluorine and C_1-6An alkoxy group;

R³is halo C_1-6An alkyl group;

R⁴、R⁵are each independently selected from hydrogen and C_1-6An alkyl group;

R⁶、R⁷each independently is hydrogen;

each R⁸Each independently is hydrogen;

y is

Wherein R is¹¹Selected from hydroxy, amino, C_1-6Alkoxy and C_1-6An alkylamino group; ring A is selected from phenyl, pyrazolyl, azetidinyl, said phenyl, pyrazolyl, azetidinyl may be substituted by one or more C_1-6Alkyl radical, C_1-6Alkoxy, carboxyl, mono C_1-6Alkyl amino substitution;

chemical bond(s)

Each independently is

m is 1,2,3 or 4.

2. A compound or pharmaceutically acceptable salt thereof, wherein the compound is a compound selected from the group consisting of:

3. a pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. Use of a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for the treatment and/or prophylaxis of estrogen receptor related disorders.