CN108299420A

CN108299420A - Five cyclics alternatively adjusted under property estrogen receptor and its application

Info

Publication number: CN108299420A
Application number: CN201810021799.0A
Authority: CN
Inventors: 王勇; 赵立文; 张小猛; 刘奇; 徐岩; 雷时海; 王小伟; 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: 2018-07-20
Anticipated expiration: 2038-01-10
Also published as: TW201825489A; WO2018130123A1; CN108299420B

Abstract

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

Description

Pentacyclic compounds as selective estrogen receptor down-regulators and uses 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

the Estrogen Receptor (ER) is a ligand-activated transcriptional regulator protein that mediates induction of multiple biological effects through interaction with endogenous estrogens including 17 β -estradiol and estrone it has been found that ER has two isoforms, ER- α and ER- β, encoded by two different genes located in human chromosomes 6 and 14, respectively, ER- α is widely expressed in various tissues, and ER- β expression is restricted to only female reproductive systems and tissues such as brain, bone, both contain 6 domains and 4 functional regions, the N-terminal A/B functional region has a ligand-independent transcriptional activation domain AF-1 with constitutive activation activity (865) and transcriptional activation activity (865) and activates transcription of the target gene through interaction with basal transcription factors, co-activators and other transcription factors, and further has multiple phosphorylation sites, the C-Domain Binding Domain (DBD) can specifically bind to the target DNA and contains nuclear localization signals while the binding domain (DBD) plays a role in the central binding pocket and binding to the central binding domain of the target gene, and binding domain of the central binding domain of LBH 63H 5H, the central binding domain of the Receptor binding Domain (DBH) can bind to the target DNA binding domain of the Receptor binding domain of the ligand binding domain of LBH, the Receptor binding domain of LBH, the Receptor binding domain of the Receptor, the Receptor of the Receptor.

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,

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,

each R¹、R²Each independently selected from hydrogen, halogen, hydroxyAlkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxyl, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamino and cycloalkyl;

R³、R⁹each independently selected from the group consisting of hydrogen, alkanoyl, aminoacyl, alkylaminoacyl, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl;

R⁴、R⁵、R⁶、R⁷each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, and dialkylamido; or R⁴、R⁵Together with the carbon atom to which they are attached form a carbonyl, cycloalkyl; or R⁶、R⁷Together with the carbon atom to which they are attached form a carbonyl, cycloalkyl; 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;

x, Y, Z, W are each independently selected from N and C (R)¹⁰) Wherein R is¹⁰Selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylaminoalkyl, and cycloalkyl;

chemical bond(s)Each independently isOrAnd is

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

In some particular embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein: x, Y, Z, W are all C (R)¹⁰)。

In other specific embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein: x, Y, Z, W one is N and the other three are C (R)¹⁰)。

In other specific embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein: x, Y, Z, W two of them are N and the other two are C (R)¹⁰)。

In other specific embodiments, the compounds of the present invention are of formula I or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, wherein: x, Y, Z, W three of them are N and the other one is C (R)¹⁰)。

In some specific embodiments, the compound of formula I of the present invention is a compound of formula Ia below or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、X、R¹⁰M, n, o, chemical bondAs defined in formula I.

In other specific embodiments, the compounds of formula I of the present invention are of formula Ib, or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、Z、R¹⁰M, n, o, chemical bondAs defined in formula I.

In other specific embodiments, the compounds of formula I of the present invention are of formula Ic or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、Y、X、R¹⁰M, n, o, chemical bondAs defined in formula I.

In other specific embodiments, the compounds of formula I of the present invention are compounds of formula Id below or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、W、Z、R¹⁰M, n, o, chemical bondAs defined in formula I.

In other specific embodiments, the compounds of formula I of the present invention are of formula Ie or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof,

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、Y、Z、R¹⁰M, n, o, chemical bondAs defined in formula I.

In some preferred embodiments, the compounds of the present invention are of formula I, Ia, Ib, Ic, Id, or Ie or isomers, pharmaceutically acceptable salts, solvates, crystals, isosteres or prodrugs thereof, wherein:

each R¹、R²Each independently selected from hydrogen, 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, each R¹、R²Each independently selected from hydrogen, 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, each R¹、R²Each 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, and cyclohexyl.

R³、R⁹each independently selected from hydrogen and C_1-10Alkyl acyl, amino acyl, C_1-10Alkylaminoacyl radical, C_1-10Alkyl, halo C_1-10Alkyl, hydroxy C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, 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, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

further preferably, R³、R⁹Each independently selected from hydrogen and C_1-6Alkyl acyl, amino acyl, C_1-6Alkylaminoacyl radical, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, 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_1-6Alkylamino, di-C_1-6Alkylamino radical, C_3-10Cycloalkyl radical, C_3-10Heterocyclic group, C_6-18Aryl and C_5-18Heteroaryl substitution;

even more preferably, R³、R⁹Each independently selected from hydrogen, formyl, acetyl, propionyl, aminoacyl, methylaminoacyl, and ethylaminoacylAlkyl, propylaminoyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, 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, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-10Aryl and C_5-10Heteroaryl, said group being optionally substituted by one or more halogens, 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 radical, C_3-6Cycloalkyl radical, C_3-6Heterocyclic group, C_6-10Aryl and C_5-10Heteroaryl substituted.

R⁴、R⁵、R⁶、R⁷each independently selected from hydrogen, 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 and di-C_1-6An alkylamino group;

further preferably, R⁴、R⁵、R⁶、R⁷Each independently selected from hydrogen, 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 and di-C_1-3An alkylamino group;

even more preferably, R⁴、R⁵、R⁶、R⁷Each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, 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, ethylacrylamido, vinylacylamino, methylacyl, ethylacryl, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, and propylaminoacyl.

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.

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:

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,Carboxy, 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, amino, 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, propylaminoacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and boronic acid.

R¹⁰selected 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, R¹⁰Selected 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, R¹⁰Selected from the group consisting of hydrogen, 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, methylacylamino, methylacyl, ethylacylamino, vinylacyl, aminoacyl, methylaminoacyl, ethylaminoacyl, propylaminoacyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In some specific embodiments, a compound of formula I, Ia, Ib, Ic, Id, or Ie according to the present invention, or an isomer, pharmaceutically acceptable salt, solvate, crystal, isostere, or prodrug thereof, wherein each R is¹、R²、R⁸Each independently selected from fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluorineMethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, R³Is selected fromR⁴Is methyl, R⁵、R⁶、R⁷、R⁹Is H.

The present invention provides the following specific compounds:

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

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

1) reacting the compound shown in the formula 1 with trifluoromethanesulfonic anhydride to obtain a compound shown in the formula 2;

2) reacting the compound of formula 2 with the compound of formula 3 to obtain a compound of formula 4;

3) reacting the compound of formula 5 with the compound of formula 6 to obtain a compound of formula 7;

4) reacting the compound of formula 4 with the compound of formula 7 to obtain a compound of formula 8;

5) the compound of formula 8 is hydrolyzed to produce the compound of formula I.

Wherein the compound of formula 1, the compound of formula 3, the compound of formula 5 or the compound of formula 6 can be prepared by commercially available or conventional preparation methods known in the art, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹X, m, n and o have the meanings given in formula I; m is an alkyl group.

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 the use of a compound of formula I or its isomer, pharmaceutically acceptable salt, solvate, crystal, isostere or prodrug thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment and/or prevention of estrogen receptor-related diseases, wherein the estrogen receptor-related diseases or conditions include, but are not limited to, cancers associated with ER- α dysfunction (e.g., bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, etc.), leiomyoma (e.g., uterine leiomyoma, etc.), Central Nervous System (CNS) defects (e.g., alcoholism, migraine, etc.), cardiovascular system defects (e.g., aortic aneurysm, myocardial infarction susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, etc.), blood system defects (e.g., deep vein thrombosis, etc.), immune and inflammatory diseases (e.g., grave disease, arthritis, multiple sclerosis, liver cirrhosis, etc.), infections (e.g., hepatitis b type, chronic liver disease, etc.), metabolic defects (e.g., bone density, lower urinary tract, urinary.

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. For 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-、-CH(CH₃)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, dihydrobenzothiophenylPhenonyl, benzoxazolonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to aryl rings (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 recognized in the art for defining pharmaceutical analogs wherein one or more atoms (or groups of atoms) have been replaced with a replacement atom (or group of atoms) having similar steric and/or electronic characteristics as those atoms with which they are replaced, e.g., the isostere of carboxyl groups of the invention may be an aminoacyl group, specifically the isostere of-COOH of the invention may be-CH₂NH₂。

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" as used herein means that a therapeutically and/or prophylactically effective amount of a compound of the present invention is administered to a human or animal in need thereof to inhibit, slow down or reverse the growth, development or spread of an estrogen receptor-related disease in a subject, improve an estrogen receptor-related disease, or reduce the risk of an estrogen receptor-related disease, such as estrogen receptor-related diseases including estrogen receptor β -related diseases and estrogen receptor beta-related diseases, such as estrogen receptor dysfunction-related cancers (e.g., bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, etc.), smooth muscle tumors (e.g., uterine leiomyoma, etc.), Central Nervous System (CNS) defects (e.g., alcoholism, migraine, etc.), cardiovascular system defects (e.g., aortic aneurysm, aortic infarction, aortic valve, myocardial infarction, coronary sclerosis, hypertension, etc.), genital system defects (e.g., uterine fibroids, etc.), central nervous system defects (e.g., uterine fibroids, etc.), central nervous system defects (e.g., dementia, e.g., acute dementia, cardiovascular diseases (e.g., dementia, e.g., acute myelodysplasia, dementia with severe dementia, dementia with symptoms such as e.g., dementia with symptoms of hypomenorrhea, dementia, etc.), cardiovascular diseases (e.g., dementia, etc.), cardiovascular diseases, etc., osteoporosis, etc.), osteoporosis, etc., osteoporosis.

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 1: 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

Step a: synthesis of 2-fluoro-2-methylpropan-1-ol

Methyl 2-fluoro-2-methylpropionate (10g, 83.3mmol) was added to a 500mL three-necked flask, dissolved in 200mL anhydrous tetrahydrofuran, cooled to about-10 ℃ in a low temperature reactor, and slowly added in portions with lithium aluminum hydride (3.8g,100mmol) and the reaction was continued for 1h maintaining the temperature. After the reaction is finished, 3.8mL of water, 3.8mL of 15% NaOH solution and 7.6mL of water are sequentially added dropwise, the mixture is stirred for 15min and then filtered, a filter cake is washed by a small amount of tetrahydrofuran, and the filtrate is concentrated to dryness to obtain the title compound. ESI-Ms M/z 93.1[ M + H ]]⁺。

Step b: synthesis of 2-fluoro-2-methylpropyl trifluoromethanesulfonate

In a 250mL reaction flask, 2-fluoro-2-methylpropan-1-ol (2.9g, 31.5mmol) and 2, 6-lutidine (5.1mL, 44.1mmol) were added, dissolved in 30mL of dichloromethane, and then cooled to-10 ℃ with cooling. Trifluoromethanesulfonic anhydride (5.83mL, 34.7mmol) was dissolved in 20mL 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 (20 mL. times.2 times), a saturated aqueous sodium bicarbonate solution (20 mL. times.2 times) and a saturated aqueous sodium chloride solution (20 mL. times.2 times), dried over anhydrous sodium sulfate, and dichloromethane was removed under reduced pressure to give the title compound. ESI-Ms M/z 225.1[ M + H ]]⁺。

Step c: synthesis of (S) -2-amino-3- (1H-indol-3-yl) propan-1-ol

In a 100mL reaction flask, L-tryptophan methyl ester hydrochloride (2.0g,7.85mmol), methanol (1.5mL) were added followed by triethylamine (1.5mL), diethyl ether (50mL) and the system was stirred at-10 deg.C-0 deg.C for 1 h. After 1h, the white solid formed by the reaction was removed by filtration, the filtrate was collected and spin-dried to give a colorless oil, then 15mL of methanol was added thereto, sodium borohydride (356mg, 9.42mmol) was added thereto in portions under ice bath, and after 30min, the reaction was transferred to room temperature and stirred for several hours until the starting material disappeared. After the reaction is finished, adding water to quench the reaction, spin-drying methanol in the system, extracting with ethyl acetate, and combining ethyl acetateThe ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, concentrated and dried to give a white solid. Directly used for being charged into the next step. ESI-Ms M/z 191.2[ M + H ]]⁺。

Step d: synthesis of (S) -benzyl- (1-hydroxy-3- (1H-indol-3-yl) propan-2-yl) carbamate

(S) -2-amino-3- (1H-indol-3-yl) propan-1-ol (74g,389.5mmol) was placed in a 2L eggplant-shaped flask, 600mL of water and 600mL of acetone were added, stirring was performed at room temperature, sodium carbonate (70g,662.1mmol) was added, the temperature was reduced to 0 ℃, benzyl chloroformate (66g,389.5mmol) was added dropwise, stirring was performed at the same temperature for 30min, and the mixture was allowed to move to room temperature for reaction for 14H. The pH was adjusted to 2 with concentrated HCl, concentrated under reduced pressure to remove acetone, extracted with 500mL × 3 dichloromethane, the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, which was used directly in the next reaction without purification. ESI-Ms M/z 325.1[ M + H ]]⁺.

Step e: synthesis of (S) -2- (((benzyloxy) carbonyl) amino) -3- (1H-indol-3-yl) propyl-4-methylbenzenesulfonate

(S) -benzyl- (1-hydroxy-3- (1H-indol-3-yl) propan-2-yl) carbamate (110g,339.5mmol), triethylamine (95mL,679.0mmol) and 1L dichloromethane were mixed in a 2L eggplant-shaped flask, stirred until dissolved and cooled to-3 ℃. A solution of p-toluenesulfonyl chloride (71.2g,373.5mmol) in dichloromethane (100mL) was added dropwise to the reaction, stirred at the same temperature for 1h, and allowed to move to room temperature for further reaction for 20 h. The reaction mixture was washed with 500mL of 2 water, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give the title compound. ESI-Msm/z 479.1[ M + H ]]⁺.

Step f: synthesis of (R) -1- (1H-indol-3-yl) propan-2-amine

(S) -2- (((benzyloxy) carbonyl) amino) -3- (1H-indol-3-yl) propyl-4-methylbenzenesulfonate (110g,632.2mmol) was dissolved in 1.2L of ethanol, palladium hydroxide was added, stirring vigorously at room temperature for 2 days under a hydrogen atmosphere, filtration was carried out, the filtrate was concentrated to give a reddish brown oil, and the title compound was isolated by silica gel column chromatography. ESI-Ms M/z 175.1[ M + H ]]⁺.

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

And (3) adding the 2-fluoro-2-methylpropyl trifluoromethanesulfonate obtained in the step b (2g, 30mmol), (R) -1- (1H-indol-3-yl) propan-2-amine (4.3g, 25mmol) and diisopropylethylamine (8.7mL, 50mmol) into a 250mL reaction flask, dissolving with 50mL dioxane, reacting at 90 ℃ for 2H under the protection of argon, stopping the reaction, concentrating, and purifying by column chromatography to obtain the title compound. ESI-Ms M/z 249.1[ M + H ]]⁺.

Step h: 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 (diphenylphosphinopropane) nickel dichloride (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, dissolving with 50mL saturated sodium chlorideWashing, 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 i: synthesis of methyl 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-carboxylate

Reacting 3',5' -difluoro-4 '-formyl- [1,1' -biphenyl]Methyl-4-carboxylate (0.66g,2.4mmol), glacial acetic acid (1mL), toluene (20mL) and (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2-fluoro-2-methylpropan-1-amine (0.6g,2mmol) were mixed in a 50mL eggplant-shaped flask under argon, warmed to 80 ℃ and stirred overnight. The title compound was obtained by diluting with 100mL of ethyl acetate, washing with 50mL of saturated sodium bicarbonate and 50mL of saturated sodium chloride solution, drying, concentrating, and isolating by silica gel column chromatography. ESI-Ms M/z 507.1[ M + H ]]⁺.

Step j: 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

Methyl 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-carboxylate (0.5g,1mmol), 3mL methanol and 6mL tetrahydrofuran were mixed in a 50mL eggplant-shaped flask, stirred, cooled to 0 ℃, sodium hydroxide solution (2mL) was added dropwise, and reacted at room temperature for 2H. The pH was adjusted to 6 with 2M dilute hydrochloric acid, diluted with 50mL ethyl acetate, the organic layer was separated, washed with saturated sodium chloride solution, dried, concentrated, and isolated by silica gel column chromatography 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 2: 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) - [1,1' -biphenyl ] -4-carboxylic acid

The preparation process was similar to that of example 1 except that 4-bromo-2, 6-difluorobenzaldehyde, the starting material, was replaced with 4-bromo-2-chloro-6-fluorobenzaldehyde to give the title compound.¹H NMR(400MHz,DMSO-d₆)δ:13.02(s,1H),10.64(s,1H),8.01–7.97(d,2H),7.80–7.76(d,2H),7.42–7.39(d,3H),7.20–7.17(d,1H),7.02–6.93(m,2H),5.26(s,1H),3.48–3.45(d,1H),2.88–2.79(m,2H),2.58–2.53(m,1H),2.42–2.36(m,1H),1.23–1.01(m,9H).ESI-Msm/z:509.2[M+H]⁺.

Example 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) - [1,1' -biphenyl ] -4-carboxylic acid

The title compound was obtained in a similar manner to the preparation of example 1 except that 4-bromo-2, 6-difluorobenzaldehyde as the starting material was replaced with 4-bromo-2, 6-dichlorobenzaldehyde.¹H NMR(400MHz,DMSO-d₆)δ:13.00(s,1H),10.65(s,1H),8.00–7.98(d,2H),7.38–7.45(d,2H),7.30–7.35(d,3H),7.20–7.18(d,1H),7.02–6.93(m,2H),5.25(s,1H),3.48–3.45(d,1H),2.88–2.79(m,2H),2.58–2.53(m,1H),2.42–2.36(m,1H),1.22–1.01(m,9H).ESI-Msm/z:525.1[M+H]⁺.

Example 4: 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 ] -3-carboxylic acid

The preparation method was similar to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with (3- (methoxycarbonyl) phenyl) boronic acid to obtain 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 5: 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) -3,5 '-dimethoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation process was similar to that of example 1, 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 6: 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 '-methoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation was carried out in analogy to the preparation of example 1, except that the starting material 4-bromo-2, 6-difluorobenzaldehyde was replaced by 4-bromo-2-methoxy-6-fluorobenzaldehyde to give the title compound.¹H NMR(400MHz,DMSO-d₆)δ:13.02(s,1H),10.40(s,1H),7.95(s,1H),7.66–7.64(d,1H),7.36–7.34(m,3H),7.23(s,1H),7.15–7.12(m,1H),7.03(s,1H),6.95–6.90(m,2H),5.35(s,1H),3.90(s,3H),3.60–3.56(m,1H),3.07–2.86(m,2H),2.59–2.55(d,1H),2.50–2.40(m,1H),1.18–1.02(m,9H).ESI-Ms m/z:505.3[M+H]⁺.

Example 7: 2,3 '-difluoro-4' - ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) -5', 6-dimethoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation process was similar to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with (2-fluoro-6-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:13.00(s,1H),10.40(s,1H),7.67(d,1H),7.40–7.37(m,2H),7.25(s,1H),7.17–7.15(m,1H),7.06(s,1H),6.98–6.95(m,2H),5.36(s,1H),4.00(s,3H),3.96(s,3H),3.57–3.55(m,1H),3.11–2.89(m,2H),2.60–2.57(d,1H),2.52–2.43(m,1H),1.19–1.03(m,9H).ESI-Ms m/z:553.3[M+H]⁺.

Example 8: 2-chloro-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 '-methoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation process was similar to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with (2-chloro-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:13.01(s,1H),10.42(s,1H),7.69(d,1H),7.41–7.38(m,3H),7.27(s,1H),7.18–7.15(m,1H),7.08(s,1H),7.00–6.96(m,2H),5.35(s,1H),3.96(s,3H),3.57–3.55(m,1H),3.11–2.90(m,2H),2.60–2.57(d,1H),2.52–2.43(m,1H),1.19–1.03(m,9H).ESI-Ms m/z:539.1[M+H]⁺.

Example 9: 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) -2,5 '-dimethoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation is analogous to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid is usedThe title compound was prepared by changing to (2-methoxy-4- (methoxycarbonyl) phenyl) boronic acid and replacing the starting 4-bromo-2, 6-difluorobenzaldehyde with 4-bromo-2-methoxy-6-fluorobenzaldehyde.¹H NMR(400MHz,DMSO-d₆)δ:12.72(s,1H),10.42(s,1H),7.68(d,1H),7.41–7.37(m,3H),7.26(s,1H),7.19–7.16(m,1H),7.09(s,1H),7.01–6.95(m,2H),5.36(s,1H),4.00(s,3H),3.96(s,3H),3.57–3.55(m,1H),3.11–2.89(m,2H),2.60–2.57(d,1H),2.52–2.43(m,1H),1.19–1.03(m,9H).ESI-Ms m/z:535.3[M+H]⁺.

Example 10: 3',5' -difluoro-4 '- ((1R,3S) -2- (2-fluoro-2-methylpropyl) -3- (fluoromethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) -3-methoxy- [1,1' -biphenyl ] -4-carboxylic acid

Step a: synthesis of benzyl (S) - (1-fluoro-3- (1H-indol-3-yl) propan-2-yl) carbamate

(S) -2- (((benzyloxy) carbonyl) amino) -3- (1H-indol-3-yl) propyl-4-methylbenzenesulfonate (4.0g,8.36mmol) was dissolved in a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M,12mL) and the reaction was heated at 85 ℃ for 4 hours. After completion of the reaction, the reaction mixture was quenched with water (20mL), extracted with ethyl acetate (100mL) and separated, and the organic phase was washed with 20mL of a 2 saturated sodium chloride solution, collected, dried, concentrated, and the residue was chromatographed on a silica gel column to give the title compound. ESI-Ms M/z 327.1[ M + H ]]⁺.

Step b: synthesis of (S) -1-fluoro-3- (1H-indol-3-yl) propan-2-amine

The title compound was prepared in the same manner as in example 1, step f, starting from benzyl (S) - (1-fluoro-3- (1H-indol-3-yl) propan-2-yl) carbamate. ESI-Ms M/z 193.1[ M + H ]]⁺.

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

The title compound was prepared in the same manner as in example 1, step g, starting from (S) -1-fluoro-3- (1H-indol-3-yl) propan-2-amine. ESI-Ms M/z 267.1[ M + H ]]⁺.

Step d: synthesis of 3',5' -difluoro-4 '- ((1R,3S) -2- (2-fluoro-2-methylpropyl) -3- (fluoromethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) -3-methoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation process is analogous to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid is replaced by (3-methoxy-4- (methoxycarbonyl) phenyl) boronic acid and (R) -N- (1- (1H-indol-3-yl) propan-2-yl) -2-fluoro-2-methylpropan-1-amine is replaced by (S) -2-fluoro-N- (1-fluoro-3- (1H-indol-3-yl) propan-2-yl) -2-methylpropan-1-amine to give the title compound.¹H NMR(400MHz,DMSO-d₆)δ:12.72(s,1H),10.74(s,1H),7.67–7.65(d,1H),7.61–7.59(d,2H),7.53–7.51(d,1H),7.40–7.37(m,2H),7.21–6.19(d,1H),7.04–6.96(m,2H),5.09(s,1H),4.89–4.84(m,1H),4.77–4.72(m,1H),4.66–4.62(m,1H),3.92(s,3H),3.60–3.57(d,1H),2.85–2.73(m,2H),2.53–2.43(m,1H),1.18–1.10(m,6H).ESI-Ms m/z:541.2[M+H]⁺.

Example 11: synthesis of 3 '-fluoro-4' - ((1R,3S) -2- (2-fluoro-2-methylpropyl) -3- (fluoromethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) -3,5 '-dimethoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation was carried out in analogy to the preparation of example 10, except that the starting material 4-bromo-2, 6-difluorobenzaldehyde was replaced by 4-bromo-2-methoxy-6-fluorobenzaldehyde to give the title compound.¹H NMR(400MHz,DMSO-d₆)δ:12.75(s,1H),10.43(s,1H),7.67(d,1H),7.41–7.36(m,3H),7.26(s,1H),7.20–7.16(m,1H),7.10(s,1H),7.01–6.95(m,2H),5.35(s,1H),4.31(s,3H),4.25(d,2H),3.96(s,3H),3.58–3.55(m,1H),3.11–2.89(m,2H),2.60–2.57(d,1H),2.52–2.43(m,1H),1.19–1.03(m,6H).ESI-Ms m/z:553.5[M+H]⁺.

Example 12: 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) -3-methoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation process was similar to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with (3-methoxy-4- (methoxycarbonyl) phenyl) boronic acid to give the title compound.¹H NMR(400MHz,DMSO-d₆)δ:12.72(s,1H),10.45(s,1H),7.85–7.81(m,1H),7.53–7.50(m,3H),7.34–7.30(m,2H),7.19-7.17(m,1H),6.96–6.80(m,2H),5.26(s,1H),3.90(s,3H),3.56–3.49(m,1H),2.92–2.81(m,2H),2.60–2.44(m,2H),1.25–1.06(m,9H).ESI-Ms m/z:523.2[M+H]⁺.

Example 13: synthesis of 2,3',5' -trifluoro-4 '- ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indol-1-yl) -6-methoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation process was similar to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with (2-fluoro-6-methoxy-4- (methoxycarbonyl) phenyl) boronic acid to obtain the title compound.¹H NMR(400MHz,DMSO-d₆)δ:12.70(s,1H),10.88(s,1H),7.86–7.81(m,1H),7.68–7.62(m,2H),7.55–7.52(d,1H),7.32(s,1H),7.20-7.17(m,1H),6.95–6.81(m,2H),5.25(s,1H),3.79(s,3H),3.57–3.50(m,1H),2.96–2.91(m,2H),2.60–2.44(m,2H),1.27–1.05(m,9H).ESI-Ms m/z:541.2[M+H]⁺.

Example 14: synthesis of 2-chloro-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 method was similar to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with (2-chloro-4- (methoxycarbonyl) phenyl) boronic acid to prepare the title compound.¹H NMR(400MHz,DMSO-d₆)δ:13.10(s,1H),10.95(s,1H),7.99–7.91(m,2H),7.84–7.80(m,1H),7.56–7.30(m,3H),7.20-7.16(m,1H),7.04–6.96(d,2H),5.26(s,1H),3.59–3.54(m,1H),2.97–2.93(m,2H),2.64–2.45(m,2H),1.28–1.09(m,9H).ESI-Ms m/z:527.1[M+H]⁺.

Example 15: 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) -2-methoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation process was similar to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with (2-methoxy-4- (methoxycarbonyl) phenyl) boronic acid to give the title compound.¹H NMR(400MHz,DMSO-d₆)δ:12.75(s,1H),10.68(s,1H),8.00–7.96(d,1H),7.88–7.76(m,3H),7.53–7.50(d,1H),7.34–7.32(m,2H),7.00–6.91(d,2H),5.27(s,1H),3.79(s,3H),3.50–3.46(m,1H),2.88–2.75(m,2H),2.60–2.42(m,2H),1.27–1.05(m,9H).ESI-Ms m/z:523.2[M+H]⁺.

Example 16: 6- (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) nicotinic acid

The preparation method was similar to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with methyl 6- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) nicotinate to prepare the title compound.¹H NMR(400MHz,DMSO-d₆)δ:13.45(s,1H),10.76(s,1H),831(s,1H),8.10–8.05(d,1H),7.83–7.79(d,2H),7.48–7.41(d,2H),7.25–7.20(d,1H),7.05–6.97(m,2H),5.28(s,1H),3.50–3.47(d,1H),2.88–2.79(m,2H),2.60–2.55(m,1H),2.42–2.36(m,1H),1.22–1.01(m,9H).ESI-Ms m/z:494.1[M+H]⁺.

Example 17: 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) -3-methoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation process was similar to that of example 1 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, 6-dichlorobenzaldehyde to give the title compound.¹H NMR(400MHz,DMSO-d₆)δ:12.71(s,1H),10.38(s,1H),8.02-8.01(d,1H),7.75-7.74(d,1H),7.73-7.71(d,1H),7.42-7.41(d,2H),7.39-7.38(m,1H),7.18-7.16(d,1H),7.00-6.91(m,2H),5.64(s,1H),3.94(s,3H),3.76-3.73(m,1H),3.13-3.09(m,1H),3.03-2.95(m,1H),2.67-2.64(d,1H),2.34-2.23(m,1H),1.19-1.06(m,9H).ESI-Ms m/z:555.2[M+H]⁺.

Example 18: 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-carboxamide

100mg (197mmol) of the product 3',5' -difluoro-4 ' - ((1R,3R) -2- (2-fluoro-2-methylpropyl) -3-methyl-2, 3,4, 9-tetrahydro-1H-pyrido [3, 4-b) from example 1 step i]Indol-1-yl) - [1,1' -biphenyl]Methyl-4-carboxylate, 20mL ammonia in methanol was mixed in a 50mL eggplant-shaped flask, heated to 65 ℃ and stirred overnight. Concentration and purification by silica gel column chromatography gave the title compound.¹H NMR(400MHz,DMSO-d₆)δ:10.6(s,1H),8.06(s,1H),7.98–7.96(d,2H),7.87–7.85(d,2H),7.52–7.42(m,4H),7.21–7.19(d,1H),7.03–9.64(m,2H),5.28(s,1H),3.56–3.52(m,1H),2.94–2.89(m,2H),2.63–2.41(m,2H),1.26–1.07(m,9H).ESI-Ms m/z:492.1[M+H]⁺.

Example 19: 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) -3-methoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation process was similar to that of example 1, 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-chloro-6-fluorobenzaldehyde, to give the title compound.¹H NMR(400MHz,DMSO-d₆)δ:12.75(s,1H),10.49(s,1H),7.77(s,1H),7.65–7.60(m,2H),7.42–7.35(m,3H),7.19–7.17(d,1H),7.00–6.92(m,2H),5.38(s,1H),3.91(s,3H),3.70–3.66(m,1H),3.08–2.93(m,2H),2.64–2.60(d,1H),2.38–2.27(m,1H),1.16–1.05(m,9H).ESI-Ms m/z:539.1[M+H]⁺.

Example 20: 6- (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) nicotinic acid

The preparation process was similar to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with 5- (methoxycarbonyl) -2-pyridineboronic 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:13.40(s,1H),10.42(s,1H),9.12(s,1H),8.31–8.29(d,1H),8.18–8.16(d,1H),7.71(s,1H),7.43–7.38(m,1H),7.16–7.15(d,2H),6.97–6.93(m,2H),5.38(s,1H),3.97(s,3H),3.60–3.34(m,1H),2.97–2.84(m,2H),2.67–2.29(m,2H),1.16–1.05(m,9H).ESI-Ms m/z:506.2[M+H]⁺.

Example 21: 2-chloro-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) -6-methoxy- [1,1' -biphenyl ] -4-carboxylic acid

The preparation process was similar to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid was replaced with (3-methoxy-6-chloro-4- (methoxycarbonyl) phenyl) boronic acid to obtain the title compound.¹H NMR(400MHz,DMSO-d₆)δ:13.41(s,1H),10.77(s,1H),7.65–7.64(d,1H),7.56–7.55(d,1H),7.41–7.40(d,1H),7.24–7.22(d,1H),7.02–6.98(m,4H),5.3(s,1H),3.79(s,3H),3.52–3.51(m,1H),2.91–2.85(m,2H),2.62–2.61(d,1H),2.51–2.49(m,1H),1.25–1.08(m,9H).ESI-Ms m/z:557.2[M+H]⁺.

Example 22: 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) pyrimidine-5-carboxylic acid

The preparation process is analogous to that of example 1, except that the starting material (4- (methoxycarbonyl) phenyl) boronic acid is replaced with 5- (methoxycarbonyl) -2-pyrimidineboronic acid to give the title compound.¹H NMR(400MHz,DMSO-d₆)δ:13.50(s,1H),10.65(s,1H),9.32(s,1H),8.00-7.98(m,1H),7.44–7.18(m,4H),7.08–6.88(m,2H),5.30(s,1H),3.55(m,1H),2.96–2.91(m,2H),2.63–2.59(m,1H),2.41-2.37(m,1H),1.30–1.25(m,9H).ESI-Ms m/z:495.2[M+H]⁺.

Example 231- (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 Synthesis of methyl (S) -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 Synthesis of (S) -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 (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)]Synthesis of indoles

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) was dissolved in 10mL tetrahydrofuran and 5mL methanol, 7.5M sodium hydroxide solution (3.0mL, 22.5mmol) was added, the reaction was carried out at room temperature for 3h, the pH was adjusted to 6.5 with 2N hydrochloric acid, extraction was carried out with ethyl acetate, and the mixture was saturated with hydrochloric acidAnd sodium chloride, dried over anhydrous sodium sulfate, concentrated, and subjected to 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 241- (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 same as example 23, Steps c-dPreparation method except that the starting material (S) -3-fluoro-2-methylpropanol was replaced with 2, 2-difluoro-2-methylpropyl-1-ol to prepare the title compound. 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 was carried out in analogy to the preparation of example 23, 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 to give the title compound.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]⁺。

According to the synthesis of examples 1 to 24 of the present invention, the compounds of examples 25 to 43 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 a compound disclosed in WO 2014/191726(PCT/GB2014/051607) example 1 with 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 (AZD9496), 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 α (D8H8) Rabbit mAb, available from CST corporation;

Goat anti-Rabbit IgG(H+L)Secondary Antibody、Alexaconjugate, 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 Co, SichuanAnd (4) a driver.

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 assayedLuminescent 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

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 AZD 9496. When the half-life period of the compound is prolonged and the bioavailability is increased, the administration interval of the compound can be prolonged, the action time of the medicine is prolonged, the curative effect of the compound can be improved, the administration amount of the compound can be reduced, and therefore 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

MCF-7 breast cancer cells (purchased from Keyton) were cultured in MEM medium containing 10% fetal bovine serum, 100U/ml penicillin and 100. mu.g/ml streptomycin at 37 ℃ in a 5% CO2 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. Will be provided withTumor cells in logarithmic growth phase were used for in vivo tumor inoculation.

2. Sustained release tablet and cell inoculation

β -Estradiol sustained release tablets (Estradiol-17 β 60 days se1210.72mg, purchased from innovative research of America) were inoculated into the left back of each mouse 2-3 days before cell inoculation 1 week after inoculation, animals were urinated 3 times a week, and if necessary daily.

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 example 1, example 5 and example 24 of the present invention were significantly better at 0.6mg/kg than AZD9496 at the same dose, and far better at 2mg/kg than AZD 94966 mg/kg. Some of the compounds of the 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 an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof,

wherein,

each R¹、R²Each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitroCarboxy, cyano, amino, monoalkylamino, alkylacylamino, alkanoyl, aminoacyl, alkylaminoacyl, dialkylamido, and cycloalkyl groups;

chemical bond(s)Each independently isOrAnd is

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

2. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein X, Y, Z, W are all C (R)¹⁰)。

3. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein each R¹、R²Each independently selected from hydrogen, 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_3-10Cycloalkyl radical, R³、R⁹Each independently selected from hydrogen and C_1-10Alkyl acyl, amino acyl, C_1-10Alkylaminoacyl radical, C_1-10Alkyl, halo C_1-10Alkyl, hydroxy C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, 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, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

4. The compound according to any one of claims 1 to 3, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R⁴、R⁵、R⁶、R⁷Each independently selected from hydrogen, 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 and di-C_1-6An alkylamino group.

5. The compound according to any one of claims 1 to 3, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R⁴、R⁵Together with the carbon atom to which they are attached form a carbonyl group or C_3-10A cycloalkyl group; or R⁶、R⁷Together with the carbon atom to which they are attached form a carbonyl group or C_3-10A cycloalkyl group; or R⁴、R⁶Together with the carbon atom to which they are attached form C_3-10A cycloalkyl group.

6. The compound according to any one of claims 1 to 5, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein 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.

7. The compound of claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein R¹⁰Selected 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.

8. The compound according to claim 1, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein the compound is a compound selected from the group consisting of:

9. a pharmaceutical composition comprising a compound of any one of claims 1 to 8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 8, or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the treatment and/or prevention of an estrogen receptor related disorder.